EDITORIAL ADVISORY COMMITTEE

Albert J. Aguayo

Bernice Grafstein

Theodore Melnechuk

Dale Purves

Gordon M. Shepherd

Larry W. Swanson (Chairperson)

The History of Neuroscience in Autobiography

VOLUME 1

Edited by Larry R. Squire

SOCIETY FOR NEUROSCIENCE 1996

Washington, D.C.

Society for Neuroscience

1121 14th Street, NW., Suite 1010

Washington, D.C. 20005

© 1996 by the Society for Neuroscience.

All rights reserved.

Printed in the United States of America.

Library of Congress Catalog Card Number 96-70950

ISBN 0-916110-51-6

Contents

Denise Albe-Fessard

Julius Axelrod

Peter O. Bishop

Theodore H. Bullock

Irving T. Diamond

Robert Galambos

Viktor Hamburger

Sir Alan L. Hodgkin

David H. Hubel

Herbert H. Jasper

Sir Bernard Katz

Seymour S. Kety

Benjamin Libet

Louis Sokoloff

James M. Sprague

Curt von Euler

John Z. Young

Denise Albe-Fessard

BORN:

Paris, France

May 31, 1916

EDUCATION:

School of Physique et Chimie de Paris (Engineering, 1937)

Paris University, Doctor és Sciences, 1950

APPOINTMENTS:

Sorbonne, Université Pierre et Marie Curie (1957–1984)

HONORS AND AWARDS (SELECTED):

Chevalier de la légion d’honneur (1973)

Officier de l’ordre du mérite (1978)

International Association for the Study of Pain (First President, 1975)

Denise Albe-Fessard has carried out fundamental neurophysiological work on the organization of central nociceptive pathways. Her major contributions have centered on distinguishing between separate medial and lateral thalamic centers in nociception.

Denise Albe-Fessard

Childhood and Training, 1916–1939

I was born in Paris in 1916 during World War I (the Great War). Although I was quite young, I remember sheltering in a cellar at night when the zeppelins bombed Paris. In 1918 when Big Bertha began to fire on Paris, my parents sent my siblings and me to live in the south of France with my mother’s family. My parents, both from Languedoc, had lived in southern towns close to my father’s work after their wedding. An engineer for the railways, my father was mobilized and was involved in the construction of military lines that carried troops and munitions to the front. He was employed by the railway company of the Midi before the Great War and was responsible for the construction of tracks linking isolated mountain villages in the Pyrénées and then in the Cévennes.

My parents came from peasant families. My mother’s paternal grandparents were market gardeners in a village near Toulon. My father’s maternal forebears were farmers in the plain of Hérault. Of the other two greatgrandparents, one built stone houses in Nîmes and the other belonged to a family working a water mill on a coastal river, the Hérault. My great-grandfather operated the mill in Saint-Thibéri, but was deported to Algeria in 1848 with his two elder sons for giving food to republicans. My grandfather, another son, owned and operated the mill with his brother-in-law in the village of Bessan where my grandmother was born. Our family house still stands in Bessan, although the mill burned down after the birth of my father. The mill, constructed between the 13th and 15th centuries, is now almost totally in ruins, and only the dam is still in use.

These families of peasants and artisans wanted to provide a good education for their children, and so my father, Jacques Albe, and his two brothers became a teacher, a lawyer, and an engineer. To undertake the studies leading to these positions, they had to be boarders from the start of primary school in larger towns. They went home for only a month or two each year. My father began his studies in Béziers and finished them in Paris. On graduating from engineering school, he became an artillery officer at Nîmes, where he met my mother. They then settled in the Languedoc where their two families lived. Just before the Great War, my brothers were beginning their secondary studies and my father, who was then working in Béziers, decided to accept a position in Paris to keep them with him and spare them the hard life in boarding school that he had known. That is why I was born in Paris, the fourth and last child. I was lucky, for at that time it was more acceptable in Paris than in the provinces for girls to have the same education as boys. In middle class families at the end of the 19th century, when my mother was a child, it was exceptional for women to have a career other than mother of a family. It was frequently claimed that women were intellectually inferior.

When she arrived in Paris at about 30 years of age, my mother spoke French with the southern accent that my father had lost during his studies there, and she passed on to all four of her children the singsong speech that the French north of the Loire often associated with lack of culture. I had this southern accent until I was 11; while attending high school, I understood that it had to be lost, and I took on the “pointu” accent of the Parisians.

My mother hoped that her younger daughter might one day pursue the studies that she herself had dreamed of, and she insisted that I be placed in the free state school, not in private school like my older sister. At that time in France, education in state school was solid but nonreligious, which often led it to be condemned by “bourgeois” families. Such education was, however, one of the good achievements of the third republic. We learned arithmetic and French in state school as well as the basic facts, unattractive but solid, of history and geography. Of the people who received this primary education, the best ones most often continued their studies in secondary education, which led them to the normal schools and allowed them in turn to teach in primary school. Only a few pupils from the state school went on to secondary education in a high school, which was not free. At 10 years of age, the most gifted children from the primary school took examinations for scholarships offering free secondary education. In my class of about 35 pupils there were only two of us who sat for this competitive examination. The headmistress prepared us for the exam, and we both succeeded and went to different high schools.

My father asked that I be placed in a class where living languages were taught, not Latin and Greek. He knew that I was particularly gifted for what was then called arithmetic and geometry, but not for languages. Having learned the importance of living languages from personal experience, he thought that they would be more important than the dead languages for a scientific education. So I learned English, and Spanish a little later. Languages were taught in a bookish way that did not assist communication. I learned English mainly from reading Shakespeare, which was of no help on my first trip to England, nor for my first literature searches. I am grateful to my professor of Spanish, who made us read in the language after the first year.

At high school, the history of ancient civilizations, which encompassed our own country in its broader context, was imparted by excellent teachers who knew how to interest us in matters beyond the anecdotal and who also taught us to present a subject and to endeavor to place facts in a general context. I never lost the taste for history awakened by these teachers, whereas I understood only later, after traveling, the importance of geography. Two other subjects were the joy of all my secondary studies—mathematics and drawing. Algebra and geometry were well taught at the time, and learning them was the most satisfying activity for me until I was 18. Drawing was also a pleasure; my siblings and I had practiced drawing from life as our father had done. Like all girls at that time, I learned quite early to play the piano without obvious talent, and it was only later through my father’s influence that I learned to love classical music.

I had learned to read between ages five and six before entering primary school, and I think I must have been seven when I could read fluently. Henceforth I devoured all the books I could obtain. At first I was satisfied by the magazine called L’ouvrier, which my grandfather subscribed to and which published historical novels. This storybook history nurtured my childhood as it did for my elder brother, who shared my tastes and used to tell me about the history of Greece when he occasionally came to collect me after school when I was eight. My later reading, though always assiduous, was not so well organized, for my father had retained from his southern childhood certain ideas about authors that a young girl must not read. He hid the books of some of our best. I discovered them only when my mother gave them to me in secret, or when one of my friends lent them to me.

During my years of secondary education, I learned little about nature; natural science teaching was not very strong. When I first encountered philosophy in elementary mathematics class it replaced French lessons, which had always been a pleasant subject for me. The teacher in charge was certainly anticlerical. Having received a Catholic education, I did not agree with her way of seeing humanity, and our relations were bad. For a long time, I remained suspicious of everything concerning philosophy. However, I discovered soon after, thanks to a professor of logic in the Collège Chaptal, how interesting the history of scientific thought was.

Until the age of 11, I lived in the Paris apartment in the 17th arrondissement where I was born. Then my parents had a house built at Vanves, an inner suburb served by a convenient rail line. We went to live there, and I entered the Victor Duruy Lycée, which I left only after passing the baccalauréat in elementary mathematics. This move upset all my friendships, and I lost the affection of a boy I had known my whole childhood. He was good and intelligent, more literary than I. We met again in 1938, to be parted once more in 1940; he was among the first war dead, a young lieutenant killed during the French army’s advance along the Albert canal after the invasion of Belgium by the Germans.

My mother’s three younger brothers were also victims of the wars. One was killed in the Sahara, the second died of illness due to the Great War, leaving two daughters behind. The third, wounded several times, survived four years of trench warfare. My mother was particularly attached to him and he was to be my godfather, so my baptism was delayed six months as my uncle could not leave the battle raging at Verdun. My mother often told me about the piteous state of her brother when he came to spend his leave from the trenches, and of his despair when she accompanied him to the station in 1917 to rejoin the front. From these tales, I retained the conviction that the War of 1914 was the worst trial that men have had to undergo this century. All her life, my mother feared her sons might suffer the terrible conditions that her brothers had known.

After the death of my grandmother, the house at Nîmes, where we used to spend our holidays, was sold, so my parents had a holiday house built near the Atlantic Ocean in the Vendée. We often went to the village near Béziers where my father was born and where his older brother ran the family vineyard. He had no children and divided his property among his nephews and nieces, and I still own a part.

Once I obtained the baccalauréat in elementary mathematics at 17, I had to choose an area for higher studies. I was much influenced by my brothers, both good technicians. The younger, who was seven years my senior, had just finished a chemistry course at the school of physics and chemistry (PC). My brothers advised me not to study medicine because of the difficulties that women were facing at that time in the profession. So I decided to be an engineer like my father and one of my brothers. Several schools had recently begun to take women students, especially the PC directed by Paul Langevin. Entry was by special competition, and mathematics was important. I entered the Collège Chaptal and spent a year in a special preparatory class. The mathematics teacher, whose teaching was pleasure rather than work, was the best I ever knew. At the end of the year, I was accepted into the PC.

At that time studies in the school were spread over three years and were divided into three hours of lectures and five hours in the laboratory each day. At the PC I learned how to organize an experiment and write a report. I was less interested in the mathematics lectures, which were given by big names who did not meet their students; the half-year examinations were severe; one needed an average of 14 to 15 out of 20 to continue. After 18 months, we had to choose a specialty, and although I had intended to become a chemist, the analytical laboratory class cured me of it. On the other hand, I loved the physics courses, especially their practicals in electricity, and thus made a choice that influenced my whole career. In the last year I learned to build balanced amplifiers, studied the construction of generators, and saw the first complete cathode ray oscilloscope (CRO) arrive in the laboratory. I graduated as an engineer physicist in 1937.

It was difficult for women in physics to find work in industry. The leading firms did not employ them in their shops but offered them positions researching the literature. However, female chemists were better accepted in research centers, so I entered Rhône-Poulenc to work in chemistry. I found it so uninteresting that I left after a month. I wanted to prepare for a doctorate and took a job as technical assistant in the Centre National de la Recherche Scientifique (CNRS) with Daniel Auger, who had a small laboratory in the institute of physico-chemical biology. He was a plant electrophysiologist who worked on the seaweed Nitella, which has long filaments and is able to transmit action potentials like a nerve fiber but at a much slower speed. To study the slow electrical potentials of Nitella, measured in millivolts, a direct current amplifier was necessary. My job was to maintain the amplifier system, which introduced me to the problem I was to encounter from then on—the faithful recording of bioelectric phenomena. But first I had to have clear ideas about them, and I had none. Auger had worked for several years on the problem and did not understand my total ignorance of vital phenomena, whereas I had no idea what studies I needed to do to understand them. Even if I had an engineering degree, a university science degree was necessary to proceed to doctoral studies. I had intended to receive such a degree in physics. I slowly realized that there was also a degree in natural sciences allowing specialization in physiology. It was not until 1943 that I took that course. Meanwhile, I continued amplifying weak currents without understanding their origin. Auger certainly could have helped me, but he had fallen seriously ill. Only on seeing a demonstration of electroencephalography organized by Alfred Fessard at the “Palais de la Découverte” did I realize that weak potentials were also produced by the brain, with the same problems as in Nitella, albeit much briefer and more rapid than in excitable algae.

The usual galvanometers accurately followed slow events, but their inertia prevented them from recording the rapid phenomena of nerve and muscle in vertebrates. Happily, the events in Nitella were slow enough for ordinary galvanometers. Later, I discovered that electrophysiologists had been building galvanometers with progressively lighter moving elements for 50 years. The appearance of the CRO was the perfect solution, but it was not yet generally used. Even if tubes were available, it was usually necessary to build the time base and amplifier for biological recordings. Alfred Fessard had long collaborated with Daniel Auger and sometimes visited us; he had installed his own laboratory at the Collège de France in Henri Piéron’s department. Alfred Fessard was interested in the electroencephalogram (EEG), which is slow enough to be studied with a galvanometer. He also recorded action potentials of nerve and muscle, and from a grant of the Singer-Polignac foundation he had obtained a CRO, a French model in which the vacuum had to be re-established in the tube before each measurement. German tubes without this inconvenience had just appeared on the market, but it was still necessary to build the time base and amplifier.

At the Institute of Physico-Chemical Biology, the small laboratories were isolated and, despite the friendly welcome by Denise Lévy, the administrative secretary, and by Pierre Auger, the brother of my new chief, I had difficulty using the technical facilities. The university degree courses I was enrolled in were also disappointing for me. I was on my own, and the instruction was more theoretical than practical. All in all, these difficulties made me consider changing my profession. My mother died at that time, and life in a country that was just getting over social upsets, linked with the political conflicts of 1936, became more difficult under the threat of war with Germany.

During the War, 1939–1945

When war was declared in 1939, many laboratories were moved to the provinces, especially to the Bordeaux region, which at times had been the temporary capital during the Great War. I was sent as a CNRS technician to the laboratory of Professor Jean Mercier in the science faculty of Bordeaux, to join a team trying to improve the recognition by the human ear of the sounds made by different airplanes. I received a friendly welcome and, with another researcher, organized a laboratory at the air force base in Mérignac. I went there regularly and could see how ill prepared our air force was for the war. The equipment we needed was slow to arrive and I had plenty of free time, allowing me to pass certificates in physics taught by Professors Mercier and Alfred Kastler, and in theoretical mechanics taught by Professor Jean Trousset.

Daniel Auger became too ill to work. Alfred Fessard was mobilized and sent with Professor Piéron to a facility near Bordeaux for selecting aviators. The “funny” war was soon over; Parisians were trying to regroup in the Bordeaux region, and our laboratory at the science faculty even served for a while as headquarters for the war ministry, with General Charles de Gaulle briefly occupying the offices of the dean, Professor Mercier, who later directed the CNRS.

It was in a truck in the center of the recently bombed city of Bordeaux that I heard the announcement of Marshal Philippe Pétain requesting an armistice, and I wept bitterly with my companions. We thought we would be under the German heel for many years, with England alone unable to reverse the situation and Russia in a pact with Germany. The remaining French army had moved toward the Pyrénées. A departing Czech friend, Vladislav Kruta, left me his bicycle. The occupiers did not appear aggressive, and we did not know what to do or what to expect. We lived from day to day at the university, realizing it would be useful to leave but not knowing how. I often visited the family of my friend Denise Lévy, who became refugees in Arcachon, and learned from her niece about de Gaulle’s appeal to the nation. Few of us knew of it, and we could not see its significance, nor could we comprehend the opposition between two respected patriots. Those who had survived the Great War had extolled to us the human qualities of Pétain who had cared for soldiers’ lives more than other military leaders had, and it was hard for us to believe that he could so mistake the country’s interest as to make deals with the enemy. For us, any contradiction between the two men could be only in appearance.

At the science faculty we had been engaged in holding special baccalauréat classes and examinations. We had received three months’ salary in advance from the CNRS and our contract was terminated. We had to find new work, which was difficult under the circumstances. As my family had returned to Paris, I too had to go back. Fessard was demobilized, had started to set up a small electrophysiology laboratory at the Institut Marey in Paris, and suggested I ask for a position as a CNRS technical officer attached to the laboratory. So I returned to Paris in October 1940, after painful farewells to the friends left in Bordeaux. None of us imagined the restrictions we were to suffer. The house in Vanves where I lived with my father and sister had central heating, but we did not have enough coal to fuel it. The little coal we had allowed us to heat the smallest room, where the three of us lived. The bedrooms were icy. Moreover, we had no stocks of food, and food distribution was poorly organized. A black market network was in place, but the prices were too high for our salaries, and the assistance we later got from the country was not yet available. I have never been as cold and hungry as during that first winter of the occupation. After first trying to get us on their side, the occupying forces began to be aggressive, and I remember how the sudden application of an early curfew crammed the Métro cars with French people.

The laboratory at the Institut Marey was organized quite slowly. We had three rooms, and were very cold, with a stove in which we often had only old papers to burn. The equipment often broke down and it was impossible to find spare parts. So passed the next three years without leaving me much to remember but hunger and cold. However, I was able to finish my university physics degree, pass the examination in general chemistry in 1942, and enroll for the general physiology certificate, which I obtained in 1943. I married Alfred Fessard in 1942 and we lived in an apartment near the Institut Marey. We could heat only one room, often only in the evening during the severe war winters. My remaining memories of that period are above all linked to the search for food, with intellectual concerns taking second place, though I have noticed a significant memory loss for that epoch. We survived on stews of carrots and turnips, and the rare rabbit sent by a friend in the country. Thanks to my brothers and sister, to my sister-in-law whose husband was a prisoner of war, and to the family of my husband’s first wife, we managed to have some good days, the families closing ranks against adversity. For several months, I continued to see my Jewish friends whose lives were much harder than ours because they had to stay in hiding or try to reach the unoccupied zone. Denise Lévy’s family left slowly for the Massif Central. The Salomon family, whose daughter had stayed with me in Bordeaux, led a difficult life, and it was hard to assist them. A friend of my husband also went to the unoccupied zone, leaving us her radio set.

In the book shop near our apartment, a “collaborator” issued inflammatory talk every day, until one night a bomb put an end to his activities but nearly caused the arrest of innocent curious bystanders like me, who just had time to escape before a German patrol arrived. We lived near the Molitor swimming pool and used to hear the German soldiers go there in the morning singing their marching songs, which were characteristically fine, but beginning to annoy us a lot. I believe that this was the only contact most Parisians had with the occupiers over those months. I often saw French women move their children away when a German soldier, deprived of his family, would try to give them candy.

Our only relations with the Germans were at the laboratory, and in peculiar circumstances. One day a Cuban, who had worked part-time at the Institut Marey before the war, brought us a German civilian who offered to subsidize our research. We were able to get rid of him by showing our poverty in equipment and installations. We had another visit, this one in 1943: we saw a civilian standing at attention before the tomb of Etienne-Jules Marey, below the laboratory windows. It was a German who asked to speak to the directors, who were at the time my husband and Lucien Bull, an Englishman who had come to work with Marey about 1900 and who never left France. Bull had dual nationality but was a director at the École Pratique des Hautes Études, and hence a French official, which had spared him the trouble his nationality of origin could have given. However, he still had a slight English accent that was obvious to a good ear. The visitor told us he was in charge of a medical laboratory of the Kriegsmarine, and wanted to set up EEG examinations of submarine personnel. He was a Viennese psychophysicist named Robert Stigler (who had demonstrated the phenomenon of metacontrast) and, knowing that my husband had been one of the first to work on the EEG, he came seeking collaboration. To avoid his asking to use the laboratory, my husband told him of a demonstration of EEG techniques at the Palais de la Découverte and offered to show it to him. We all met by appointment at the Grand Palais, where Stigler arrived in a highranking marine officer’s uniform with some collaborators. He appraised the technique, was happy to see that metacontrast was also demonstrated at the Palais, and never insisted on returning to the laboratory to obtain our assistance. Even though he almost certainly understood Bull’s origins, the issue never came up. After the war, he came back to visit Bull at the laboratory. Stigler’s life had since been hard, his sons had been killed, and life was not easy in Vienna, and Lucien Bull received him as a friend.

With the Allied invasion imminent, my sister-in-law took my husband’s daughter, who lived with us, to her in-laws near Vercors, where we thought there would be more food and safety from the war. My husband, members of my family, and I stayed in Paris, where food supplies became even more scarce, electricity was cut off, and the Métro ran only a few hours a day. Luckily we still had bicycles to get about in Paris. I remember one day being on the only moving vehicle on the Champs Elysées. A German order came to hand over the bicycles, which was almost immediately countermanded by the prefecture. Barricades had been built at our door, the high school nearby was full of ferocious Tatars recruited by the Germans in Russia, and some men in a neighboring house were arrested one night and shot in the Bois de Boulogne. We shifted to Alexandre Monnier’s place at the Parc Moutsouris, which was less exposed to danger, returned to the rue Molitor by bicycle, then left again for avenue Mozart to stay with friends of my husband. There, near midnight, we heard the church bells sounding the arrival of the advance guard of the Leclerc column. The next day, trying to return home, we encountered the first jeep with two Americans followed by the Leclerc tanks, which unleashed the joy of the Parisians and the activity of snipers.

Although the liberation was far from solving the food problem, we were relieved of the great load of the occupation. We had no news of our family in Vercors. A few days later, we had the pleasure of receiving a telephone call at the laboratory (the Paris telephones had never stopped working) from Professor Bryan Matthews, whom my husband had worked with in Cambridge. He was on the Champs Elysées and was leaving the next day on a mission. To see us, he came all the way on foot, as the Métro was not yet working. This first contact with an Englishman is one of my greatest memories of the liberation. I remember him explaining the difference between V1 and V2 rockets, which the Germans were then using against England. A little later, we were also visited by some American colleagues, and I worked wonders to find something to offer them to eat. The Bastogne offensive terrified the Parisians, with bombing expected, and this time the Monniers came to our place as we had deeper cellars for shelter.

Professor Henri Laugier, whom I had heard a lot about, arrived from Algiers. He had led the CNRS before the war but the position was conferred on Frederic Joliot in 1944. Laugier wanted to resume his teaching at the Sorbonne and then be replaced by Alfred Fessard, but this proposal was opposed by Alexandre Monnier, already a professor at the faculty of science, who refused to have a competitor. These arguments helped to separate us forever from the Sorbonne group. We continued to keep the Institut Marey functioning modestly. The first years after the liberation were difficult, with laboratory supplies almost impossible to obtain.

From Electric Fish to Mammals, 1945–1955

In 1945 or 1946, Professor Edgar Adrian, with whom my husband had worked, invited us to Cambridge, where we stayed several days with Wilhelm Feldberg. We met the laboratory investigators William A.H. Rushton, Alan L. Hodgkin, and Andrew F. Huxley, but it now seems to me that Bryan Matthews was not yet demobilized from the forces. We attended a meeting of the Physiological Society at Oxford, where I met Eduardo Liddel and Charles Phillips, and lunched next to David Whitteridge who “for my own good” made me speak English, though I later realized he spoke perfect French, which he had learned from his French mother. His wife Gwenneth was a historian specializing in medieval French. These contacts gave rise to a long friendship. We had told the Whitteridges about the difficulties of our laboratory and left England with a bagful of parts from David Whitteridge. When we arrived at the Cambridge laboratory, we were questioned in a friendly way by Professor Sir Joseph Barcroft, who was still working, and he took us to see his sheep experiments. That trip leaves me with the memory of pleasant contacts somewhat spoiled by the mental confusion caused by the mixture of languages.

Back in France, my husband was next involved in organizing the selection of officers for the army, which brought us to know many British, French, and Allied psychologists and neurologists. To regain contact with American research, my husband left for the United States with Dr. Auguste Tournay, aboard a liberty ship, where they encountered Louis Bugnard, professor at the faculty of Toulouse, who became director of the institute for medical research (INSERM) and one of our best friends.

I was still at the CNRS, where a research grant had replaced my salary as technical officer, but I found it difficult to interface my training in physics with physiological research. A doctoral thesis seemed to demand a great deal of time, so I was pleased to accept a post as physics assistant in the one-year course of physics, chemistry, and biology (PCB) that medical students had to take. The post was suggested by my friend Georges Destriau, whom I had known in Bordeaux. I kept this position until 1950, and in this service made devoted friends who helped me when preparing my thesis took up a large part of my time.

The subject I then worked on did not inspire enthusiasm—it was whether the passage through spinal ganglia slowed down the messages in sensory fibers. The only merit of this research was that it required bipolar recordings of independent, closely neighboring electrical phenomena, and therefore the construction of balanced amplifiers. At this time we were visited by Professor Carlos Chagas of Rio de Janeiro, who had worked in Paris before the war. My husband had spent some time in Rio before the war, and Chagas suggested he return to work on a local electric fish, the Gymnote (Electrophorus electricus). In 1947, we set off in a ship of the Chargeurs Réunis line. In Rio we found other French people, Professor Henri Piéron and his wife Mathilde; Yves Legrand and his wife Françoise; Mme Gabrielle Mineur, who had been appointed cultural attaché at the embassy; André and Sabine Wurmser, who had spent part of the war in Brazil; Brazilian friends; the Chagas family; and members of the Ozorio de Almeida family, especially Miguel and his sister Branca. There was also Professor George Brown of University College of London, and several Brazilian researchers, such as Aristides Leão.

We wanted to understand how the Gymnote could develop such a high electromotive force; measurement showed that its principal electric organ produced short trains of brief impulses (2-3 msec) able to develop a potential of 300V out of water and over 100V when functioning in water. How the thousands of elementary electric plates, only tens of microns thick, arrayed in series in an organ nearly one meter long, managed to discharge almost simultaneously (one impulse of the organ lasting only a few milliseconds) was the topic of our first visit and part of the following visit. On our return to France, I pursued this study on another electric fish that produced sufficiently strong potentials, the Torpedo, on which my husband had already worked with Wilhelm Feldberg and David Nachmanson. These flat fish produce short impulse trains with a potential of 40V in open circuit, and they also have a mechanism for synchronizing the elementary electric plates. I devoted my summers to studying the function of these electric organs, when Torpedo could be caught in the Arcachon Basin, and when I had the chance to go to Brazil.

I returned to the Institute of Biophysics in Rio in 1950 with my husband, then alone for many summers between 1953 and 1958. These visits allowed me, with Hiss Martins Ferreira and Antonio Couceiro, to advance our knowledge of the electric organ. My first investigations on electric fish—Gymnote, Torpedo, Ray—allowed me to pass a science doctoral thesis in 1950. I later added microphysiologic studies to this first analysis, published mainly in Portuguese and French. The study of electric organs allowed me to apply my knowledge of electrical phenomena to a physiological problem and gave me the opportunity to better understand the function of the cells in the bulbar nuclei controlling electric organs. In Torpedo, the cell bodies of axons commanding the discharge are grouped in the electric lobe, whereas in the Gymnote and the Ray the cell bodies of the motor nerves for discharge are spread along the spinal cord. In all these fish, the firing of these cells is triggered by signals from bulbar nuclei are easily visible in histological sections, as demonstrated by Fessard and Antonio Couceiro in Gymnotes and by Fessard and Thomas Szabo in Torpedo. The cells of this bulbar center receive peripheral stimuli and send out trains of rhythmic commands for repetitive discharge of the electric organ. The cells in both the motor nuclei and the command center are large, so it was possible to study with microelectrodes the bulbar reflex arc; provoking the discharge, which we did.

After our first trip to Brazil, the Institut Marey laboratory expanded progressively into rooms that had been empty. Thanks to Mr. Georges Jamati, and to Professor Emile Terroine, the CNRS had established the Centre d’Études de Physiologie Nerveuse. The grants received added to those from the École Pratique des Hautes Études, where my husband was a laboratory director, and gave us the means to install new experimental rigs. We were joined by Pierre Buser, a young assistant at the École Normale Supérieure; Ladislas Tauc, a Czech investigator; Jacques Paillard; and Jean Scherrer, a neurologist who was returning from Chicago. Dr. Auguste Tournay, a neurologist who collaborated with my husband throughout the war, continued to come to the laboratory to study the electromyography of movement using himself as subject.

My husband was soon appointed to the Collège de France position vacated by Henri Piéron’s retirement, so the buildings of the Institut Marey were, by its reattachment to the Collège de France, progressively modernized because it was part of national building stock. My husband regularly attended meetings of the Physiological Society and urged me to try in electric fish the intracellular microelectrode technique that John C. Eccles and his colleagues had just used on spinal cord cells. I had the disinterested help of Tauc, who was already using microelectrodes for measuring the membrane potential of slime molds. He had perfected the technique for making microelectrodes and constructed the indispensable impedance-matching amplifier. Helped by his advice, I quickly learned to make glass electrodes using a Fontbrune microforge and built a vacuum-tube head-stage amplifier that we used for several years with electric fish and then with mammals. We spent the summer of 1952 at Arcachon doing intracellular recording in the electric lobe of Torpedo. We easily impaled the large cells of the lobe and observed intracellular phenomena like those already described by Eccles and colleagues in the cat spinal cord. This work was carried out with Buser, who had joined us in Arcachon. Microphysiologic recordings were later made in the bulbar command nucleus with Szabo, and at the electroplaque level in Rio in 1953 and 1954, where I was helped by the young researcher Carlos Eduardo Rocha-Miranda and a skillful technician, Raimundo Bernardes, who, using the microforge, made the best microelectrodes I have used.

Because intracellular microelectrode recordings had proved easy in fish, with Buser we tried to apply this technique to the large cells of the cat somatomotor cortex. But this procedure required respiratory and fixation procedures. Stereotaxic methods for placing electrodes in desired regions of the brain required a special apparatus perfected in the United States by Horace W. Magoun in Stephen W. Ranson’s laboratory. Jean Scherrer had learned the technique in Chicago, and he helped us with equipment that was built in France from plans brought back by Paul Dell. The first recordings in cells of the cat’s motor cortex showed us that a prolonged hyperpolarization followed the initial phase of excitation in response to messages from the periphery. For this work, we used chloralose anesthesia, most commonly employed by European physiologists.

Before World War II, my husband had been the first in France to practice EEG, so we had steady contact with those applying the technique clinically. The French EEG Society was founded, and Professor Frederic Bremer came to Paris for the occasion, as well as an English investigator, Grey Walter. At a later joint meeting with the English EEG Society, I met Henri Gastaut, then working with Grey Walter, whose work on EEG localization of cerebral tumors was well known, and many other French neurologists of the period. Meetings of the French EEG Society were organized in the old Charcot theater, a sort of narrow tunnel with an abrupt slope, now replaced by a modern structure, where we gave our first communications on cortical activities. The sessions of the EEG Society had a fruitful effect on the advancement of mammalian research in France. At that time, we were interested in problems of localizing epileptic foci and tumors, for which the noninvasive EEG technique was of great service at a time when modern imaging methods did not exist.

My first contacts with the Russian researchers Georgyi D. Smirnov and Vladimir S. Rusinov were made about 1954 at a conference organized by Henri Gastaut in Marseille. They had a great sense of humor and a good understanding of neurophysiology. We hit it off immediately and made plans for reciprocal visits, which political conditions did not always allow.

Invited by Belgian neurologists, my husband and I spent several weeks in Brussels, then in Antwerp, where we visited the clinic directed by Professor Ludo van Bogaert, and could admire the Bruegels.

To boost our activity, the CNRS organized a colloquium at the Institut Marey in 1949, gathering the big names in neurophysiology of the time, Alan L. Hodgkin and Rafael Lorente de Nó in particular. Their data on nerve fiber activity seemed to put them in opposition, whereas each held a part of the whole truth. Along with Stephen Kuffler, there was Frederic Bremer, who had managed to work right through the war, with his rapid grasp of problems and always a penetrating question. It was also a pleasure to meet Fernando de Castro, one of Santiago Ramón y Cajal’s last pupils, whose results with anastomosing sympathetic efferents and heterologous nerves were wrongly neglected in this period of difficulty for the non-Francoist Spanish. I saw him again in Madrid in 1966.

The neurology congress of 1951 in Paris gave us the opportunity to meet many well-known researchers such as Wilder Penfield and Warren McCulloch, but I remember above all the friendly attitude of John Fulton whose book was the neurophysiologists’ bible.

At the second CNRS colloquium at Gif in 1955, we presented our microphysiological results in electric fish and in cats. The latter were considered artifactual by some, but were supported by Professor Richard Jung of Freiburg, who like us had moved into microelectrode work. He had done work on the visual system, still not sufficiently recognized for its originality.

My memories of this time are mixed with the euphoria of obtaining new results on brain function and the difficulty of having to present them. Because my spoken English was far from fluent, I had to present my data in French, even to an Anglo-Saxon audience. My research was thus known only to a restricted circle, and most often it was only the French men who went abroad. My husband was punctilious in attributing my work when he presented it, but it is still true that the intellectual activity of women makes men suspicious, and they attribute it to a masculine influence—I did not escape this.

At that time my work was split into two annual periods. In winter I worked on cats and rabbits and started on frequency analysis of the EEG using English equipment bought by Dr. Herman Fischgold. Summers I usually spent in Rio on the microphysiology of the Gymnote, and during those visits I met several impressive personalities. Professor Bernardo Houssay, who used to go to Rio to forget for a few weeks his difficult conditions in Buenos Aires. He spoke fluent French with a trace of Pyrénées accent acquired from his grandmother. There was also Professor Celestino da Costa from Lisbon, several big names in European and American research, often among them Professors Edgar Adrian, Eleonor Zaimis, Wade Marshall, the charming Robert Oppenheimer, Corneille Heymans, Andre Cournand, and Robert Stampfli. My work on the electroplaque put me in competition with Harry Grundfest; and I met his wife, a painter, whose open mind I admired. I received great assistance from the French cultural attaché in Brazil, Mme Mineur, with whom I often stayed. Thanks to her, I was able to obtain grants permitting Carlos Eduardo Rocha-Miranda and Eduardo Oswaldo-Cruz to come to the Institut Marey for training, and Raimundo Bernardes was able to stay for several months with us. I also had the pleasure of meeting French visitors—Professor Paul Rivet, Professor Henri Laugier and his friend, who had a great aesthetic sense, and the Jean Vilar theater company.

One of my last studies on the Gymnote was on the action of curariform drugs on the electric organ. The work was initiated by Carlos Chagas, who was curious about all pharmacological developments and taught me much about different curares. With Antonio Couceiro, we also studied the distribution of cholinesterase in the electric organ. A meeting on curare was the finale of these investigations for me, but with my Brazilian pupils I soon began to do research on the cat and then the monkey. Conditions for working on mammals were not always good because of shortages of imported laboratory supplies, but the personal conditions were perfect with the understanding I enjoyed from Chagas, the institute director, and from all my laboratory friends, researchers, and technicians.

I was made a corresponding member of the Academy of Sciences of Brazil and received the Officer’s Cross of the Cruzeiro do Sul. I also enjoyed a family atmosphere in Brazil thanks to my friend Annah Chagas, her sister, and above all her four daughters who for several years took the place of the children I did not have. Through the Chagases I also met the great Brazilian painter Candido Portinari. His son came to study engineering in Paris, which brought us closer. During one of my Brazilian sojourns, in 1957, I went to a colloquium organized by the Mexican Raúl Hernández Peón in the southern Chilean city of Concepción, where he was teaching. He had worked in Magoun’s laboratory in Los Angeles and was full of original ideas. I thus was able to meet other Chilean brain researchers and visited Santiago and Valparaiso.

My repeated stays in Latin America ended only because the birth of my son made the trips difficult, and I returned to Rio only for short conference visits in 1966, 1970, and 1995. But I have maintained lasting contact with my Brazilian friends, who visit me in Paris. Annah and Carlos Chagas and my friend Aristides Leão never fail to come and discuss work with me. Antonio Couceiro and Hiss Martins Ferreira also made visits to Paris, and more recently two Chilean researchers made long stays in my laboratory.

After having recorded the activity of cerebral cortical neurons, I went on to look at cerebellar activities. To find out how best to activate the Purkinje cells, Thomas Szabo and I studied the spinal and bulbar pathways from the periphery to the cerebellum in the cat. These investigations were published only as short notes in French. Szabo left to train with Alfred Brodal and then devoted himself to studying, with my husband, signals emitted by electric fish for localization. This short excursion into cerebellar physiology had two advantages. It led me to study Brodal’s publications of admirable clarity. It also allowed me to meet Fernando Morin, an Italian working in the United States who came to visit me after an exchange of reprints. Thereafter he visited each year when passing through Paris.

From Cats to Primates, 1955–1968

The second phase of my research in mammals really began in 1955. I was trying to map in the chloralose-anesthetized cat the cortical region of potentials evoked by stimulating the anterior limb. With this anesthetic, multiple cortical recordings showed responses over relatively wide zones of the anterior cortex. In the course of rearranging my apparatus I accidentally stimulated the ipsilateral instead of the contralateral limb as normal. Ipsilateral stimuli evoked potentials with the same localization, but with longer latency. Responses of shorter latency were of course observed in the classical “primary” regions (SI and SII) as already described by Edgar Adrian, Clinton Woolsey, and Bard’s school. But we were seeing additional bilateral activities of latency, longer by several milliseconds. The same bilateral projections had been described a little earlier by Vahe Amassian. The signals producing these responses did not arrive by cortico-cortical pathways. The regions where these responses were seen were then called “associative,” and my existing notions of thalamic anatomy led me to seek their afferent relay in the dorsomedial nucleus. A systematic study showed that bilateral responses were not observed in this nucleus, but lower down in the region called centre médian (CM) in the cat brain atlas made by Herbert Jasper and Cosimo Ajmone-Marsan. Bilateral inflow also arrived in some other medial nuclei. By microphysiology we established that these convergent afferent responses could be recorded over the whole of a structure as well as in each of its cells. This work was done with Arlette Rougeul, a young postdoc who had just joined INSERM as a researcher. The work was published in French in the EEG Journal in 1958. The article, according to “Current Contents,” has been one of the most cited classics.

The results reported in the article were greeted in various ways and gave rise to interminable argument. An American team, led by Vernon Mountcastle, was at that time recording thalamic activities in barbiturateanesthetized animals but did not find the responses we called convergent, in either thalamus or cortex. Results similar to ours were, however, obtained by teams working in Seattle (Vahe Amassian, and several others), using chloralose. This difference in effect of different anesthetics deserved to be investigated, not to be dismissed in one or the other condition as erroneous. An anesthetic substance cannot create a pathway, but can only modify its use. Another criticism came from William Mehler, who challenged our nomenclature. For him the CM was present only in primates, and the zones where we found convergent activity in the cat corresponded to another thalamic nucleus, centralis lateralis. In any event, under certain anesthetic conditions, the part of the region later referred to as the medial thalamus receives, as does the ventral posterior thalamic nucleus, signals derived from the periphery. But the cells of the region are activated from less restricted peripheral regions than those of the lateral thalamus and are not spatially organized as a function of the peripheral region that emits the signals.

The region where convergent signals are received is close to the medial part of the ventral posterior nucleus. The anatomist Jerzy Rose thought we might by error have poorly defined the nuclear boundaries. His pupil Lawrence Kruger visited me, assured himself it was not so, participated in recordings, and left convinced. I found friendly understanding also from Clinton Woolsey and some of his pupils. David Bowsher at Liverpool had, like W. Mehler in the United States, studied the course of the spinothalamic tract in primates (then considered the only conductor of thermal and painful signals) and came to work with me over several periods, when together we studied this medial spinothalamic projection in monkeys. This work was possible because an anatomic laboratory had been organized at the Institut Marey. Thanks to Mme Suzanne Laplante, a CNRS technician who was attached quite early to the Centre d’Études de Physiologie Nerveuse, this laboratory was well equipped and active. Classical staining methods for verifying electrode positions were used, and other techniques using degeneration and transport of markers were developed that allowed us to correlate macroscopic anatomy with electro-physiological research. In this we were influenced by the ideas of Carl Vogt, for whom the techniques of recording and of anatomy had to be used in parallel. My husband, Pierre Buser, and I visited Cecile and Oscar Vogt early in the 1950s in the laboratory installed for them in Neustadt, which held only a fraction of the anatomical material they had once assembled in Berlin. Oscar Vogt explained some of his ideas on neurological diseases and recounted his relations with the socialists at the turn of the century. I was impressed by the intelligence and vast culture of the Vogts, who continued to work despite their age and the difficulties they had known during the Hitler period. The German researchers I later knew best, Richard Jung and Rudolf Hassler, were their pupils, whereas Jerzy Rose, Lorente de Nó, and Jerzy Olszewski had worked in their laboratory. Later I was to know their daughter Marthe Vogt, who had begun her career in Berlin. She showed me her mother’s thesis, which at the start of the century had used a modification of the Flechsig method to describe the primary sensory projection zones on the cat cortex, the same regions that were rediscovered much later by electrophysiology.

Several events in the years 1956 to 1958 changed my way of life and reduced the time I could allot to research. In 1956, the French physiological society, in which Professors Robert Courrier, Henri Hermann, Georges Morin, and Daniel Cordier played an important role, asked Pierre Buser and me to present a report on central nervous system (CNS) activities. Buser chose to deal with associative activities, so I undertook the primary projection of somatic, visual, and auditory afferents. In so doing, I drew up an extensive bibliography and received unpublished articles from numerous authors. Thus I made contact with Professor Yasuji Katzuki in Tokyo, with Archie Tunturi, and with Vernon Mountcastle who had just published important articles with Jerzy Rose on the microelectrode study of primary somatic thalamic relay activities. I presented the report in Geneva. My text had been checked by my friend Valentine Bonnet, who was working with Bremer but had come to Paris to learn about microelectrodes. The oral presentation was prepared with my friend Serge Tsoulatse, a Georgian who was working part time in the laboratory. Bonnet correctly advised me to remove the section I had devoted to the projection of pain afferents, as she judged it to be incomplete.

This first contact with this difficult pain problem left its mark on me, and it later became one of the main lines of my research. When working on the CM of the cat, Lawrence Kruger and I had observed a double response, the second with a latency attributable to the arrival of C fiber input. This finding fitted with the spinothalamic projections observed by the anatomists at the medial thalamic level. But the second response coincided with the end of a prolonged inhibition that followed excitatory responses of this nucleus in chloralose-anesthetized animals. As the first interpretation was probably not sustainable, we investigated the types of fiber delivering somatic messages to the CM. Alberto Mallart, a trainee from Barcelona, showed in my laboratory that large-diameter fibers conducted somatic inputs to the CM. If the medial thalamus was involved in the reception of pain signals, its role had to be complex and warranted further study. Mallart also drew my attention to the importance of collaterals from the posterior columns, described by Ramón y Cajal, in the function of the spinothalamic pathways.

Since presenting my thesis in 1950, I had been appointed assistant director of the laboratory directed by my husband at the École Pratique des Hautes Études, thanks to Henri Piéron who at that time was president of the natural science section of the school. I had therefore given up my teaching in first year medicine at the Institute of Physico-Chemical Biology and devoted myself entirely to research, with some administrative duties imposed by the laboratory of nervous physiology, which was expanding. I had asked to be listed as having aptitude for advanced teaching but had not achieved this until 1955. Professor Pierre Grasset, who had important influence in biology and psychophysiology teaching, suggested that I apply for the second position of lecturer in psychophysiology that had just been created at the Sorbonne. Professor Laugier strongly supported my candidacy. I was appointed maître de conferences in 1957 after visiting most of the professors then teaching at the Sorbonne. I remember some interesting visits, particularly with mathematicians; and the visit when I met the professor of biochemistry, Claude Fromageot, who proposed a collaboration—soon interrupted by his untimely death—for which I began to prepare an atlas of the rat thalamus.

Once appointed, I had to prepare my lectures, and I had never taught physiology. I gave my first lecture in the physiology theater of the old Sorbonne. I was petrified with fear and hence no doubt uninteresting to the audience. With time, I overcame the stress of teaching in large theaters with large audiences. In the first semester, Professor André Soulairac, coordinator of psychophysiology teaching, let me teach the basics of neurophysiology, my specialty. But in the second semester he asked me to deal with animal behavior from the viewpoint developed by two American authors who had worked on invertebrate behavior and whose book was unobtainable. I had absolute need of it, as I had never before studied these questions. My friend Therésé Kleindienst, then at the Bibliothèque Nationale, was most efficient, and I soon had a copy of the book. Although to justify my appointment I strove to approach problems of behavioral research, the animal psychologists did not admit me to their company for a long time. So I do not regret the efforts I put in that gave me a fuller knowledge of animal research. Anyway, the leadership of the CNRS was soon to appoint me to membership on the psychophysiology commission, and there I met the psychoanalysts Daniel Lagache and Juliette Boutonnier, as well as specialists in human and animal behavior with whom I established good relations.

Nicole, my husband’s daughter from his first marriage, lived with us, and we got on well. In 1952, after passing her university exam (agrégation) in natural sciences, she worked in a laboratory dealing with paleobotany. She married Louis Grambast, a researcher in this specialty, and they had a daughter in 1956. In 1957 I lost my father, and in 1959 I brought into the world my son Jean, who greatly resembles my father. I had long wanted a child, and the risk of women over 40 producing Down’s syndrome children was only known publicly a few weeks before Jean’s birth. Yves Galifret, a pupil of Piéron’s, who was then at the Institut Marey, helped out with my teaching. When I wrote my report for the association of physiologists, I had appraised the work of Mountcastle, and at my request my husband had invited him to give a lecture at the Collège de France. Mountcastle came to Paris to do this in April 1959, but unfortunately he arrived while I was still in the hospital with Jean. He came to visit me, but the environment was not conducive to discussing the discrepancies between my thalamic recordings and his. Because we got off to a bad start, contacts between us were never amicable.

After my recovery, I arranged things so that Jean’s presence did not reduce my research activities too much. Trips abroad were abandoned for some years and were replaced by frequent sojourns to a house we had bought in 1959, to take Jean out of the polluted air of Paris. The property was an old run-down farm from before the revolution, which we gradually made habitable room by room, thanks to a prize from the French Academy of Sciences and to the aid of a technician working part-time at the lnstitut Marey, who helped me in his free time. Jean found in this village of Seine et Marne those country roots that far-off Languedoc could no longer provide.

During my times in Brazil, I had met Eleonor Zaimis, professor of pharmacology at the Royal Free Hospital medical school in London. I often visited her in London. She organized lectures for me and introduced me to Charles Downman who taught in the same school, often had me rejoin Marthe Vogt, who was then working at Cambridge, and introduced me to Robert Lim who was studying the transmission of pain signals. Eleonor left London to return to Greece, but when I visited her in Athens in 1982 she was nearly blind and died soon after.

In 1958 a Belgian researcher, Jean Massion, came to work with me. He was a pupil of Professor Jean Cole of Louvain, whom we met regularly at the French physiological society. Cole had trained three pupils in research—Jan Gybels, who was doing further training with Herbert Jasper in Canada; Michel Meulders, who was with Giuseppe Moruzzi; and Massion. So Massion could have his own research topic, we began a microelectrode investigation of the red nucleus, which in the cat gives rise to the rubrospinal pathways, partly duplicating the pyramidal tracts. In particular, we looked at relations of the red nucleus with the cerebellum through which a pathway significantly inhibits some rubral cells. Massion under-took further study of this nucleus, and he was able to pass his thesis of agrégation and to obtain a CNRS post when he chose to settle in France. Until then, I had collaborated mainly with Brazilians, and later with Lawrence Kruger. Michel Dussardier, who had done interesting work on rumination at the Institut Marey, and later in the INRA (Institut national de la recherche agronomique) station at Jouy en Josas, chose me as director of the thesis he had to lodge quickly in order to apply for the position of professor of physiology of Marseille. It was the first thesis I had supervised since I was appointed professor, and it was the start of Dussardier’s career there, where he established an important school investigating visceral systems. It was also the start of a long friendship; his frequent critiques have always been useful. At that stage, I had never had lasting direct collaboration with German trainees, but I remember well the ones who visited Buser, and those who visited the laboratory—Jung and some of his pupils, particularly Otto Creutzfeld, and researchers I met on visits to Freiburg. At that time French and German people felt united and European. My relations with Rudolf Hassler, after a poor start at the Brussels physiology congress, became amicable. At Brussels, too, I first met Professor Hans Schaefer of Heidelberg, whose book on electrophysiology and work on neuromuscular transmission I knew. Around 1965, he invited me to Heidelberg where, among other researchers, I met Robert Schmidt, who had returned from training with John C. Eccles. Again at Brussels, around 1955, I met the two Czechs Jan Bureš and Olga Burešovà who were using spreading depression described by my friend Aristides Leão, and who asked me to send him their publications.

Contacts with Soviet researchers initiated at the Marseille congress organized by Gastaut were followed by an invitation to Moscow for those then working on the brain. So to Moscow went Fessard, Henri Gastaut, Herbert Jasper, Horace Magoun, Clinton Woolsey, Hsiang-Tung Chang, Mary Brazier, Raúl Hernandez Peón, Robert Naquet, and many others. Our friends Georgyi D. Smirnov and Vladimir S. Rusinov were present, as well as Ezrad A. Astratyan and Piotr K. Anokhin, whom we were later to see often in Paris. I was invited to the congress, but I could not go because I was awaiting the birth of my son. After that meeting, the International Brain Research Organization (IBRO) was created, with my husband actively involved in its development. The general secretary of IBRO was then in Paris, whose presence allowed us to receive visits from many foreign researchers attending meetings of the organization. Thus I established contacts with Alfred Brodal, then with Professors Henrich Waelsch and Klaus Una, who served terms as general secretary, and later with Herbert Jasper, when I became a friend of his wife, Margaret. When Mary Brazier agreed at a difficult time to become the IBRO secretary, I had just been elected a member of the general assembly. Mary asked me to take over the grants program common to UNESCO and IBRO, which I did until her departure. I resigned because of feeling, at a later meeting, that my work was not appreciated by some of the French. I have been sorry to see changes in the IBRO institution, the only one that allowed scientific relations between the East and West during the era of the Iron Curtain. During that period I received many Russian, Czech, Hungarian, and Romanian trainees, usually for brief stays. Thus I met Endre Grastyan and Niklos Rethelyi, who I later saw again in Hungary. I also remember a telephone call from Georgyi Smirnov to congratulate me on Jean’s birth. Our relations with the Russian scientists remained friendly even when government politics hardened.

A few months after Jean’s birth, the International Physiology Congress was held in Buenos Aires, but I had to stay in Paris. One day I had a call from Professor Jerzy Konorski in Warsaw. He was going to Buenos Aires and had to get a visa in Paris, and asked for my help. I went to fetch him from the airport, and he soon managed to leave for Argentina. We made excellent contact, both speaking in what Konorski referred to as continental English. Afterward he sent me his pupil Elizabeth Jankovska, who left to work with Anders Lundberg in Sweden. Konorski also invited me to spend two weeks in Warsaw, where I first met Mircea Steriade from Romania. I returned to Warsaw for a symposium just before Konorski died. He saw difficult political times ahead and told me that visits to Poland were going to be impossible. At the same meeting I saw Professor Adrian for the last time, as well as Donald Lindsley and several scientists from Leningrad.

In 1962 Professor Cyril A. Keele of London organized a symposium on pain in humans and animals; Bowsher and I were invited, and we grouped our contributions together. There I first met Ainsley Iggo, Ingve Zotterman, and M.J. McComas. My results in the cortex and the CM were also presented at a Pisa symposium organized by Giuseppe Moruzzi in honor of Frederic Bremer, with Horace Magoun, Mary Brazier, Ragnar Granit, and Cosmo Ajmone-Marsan present. The Magoun school had already found in the brainstem of the awake animal responses similar to those I had observed in the thalamus, and these responses were suppressed by certain anesthetics. On this occasion, I first had the courage to make a presentation in English. My friend Suzanne Tyc-Dumont urged me and helped me to do it, and ever since I have given my results in English in Anglophone countries and during visits to Germany, Japan, and Russia. But even after improving my English thanks to American collaborators, I have always had some difficulty of expression in that language, above all in replying quickly to questions. It is always difficult to be subtle in a foreign language, and the necessary simplicity of my oral expression has often led me to be accused of aggressiveness. I think that those who have so misjudged me ought to have had to present their own work in a language not their own—they would have understood me better.

I frequently visited Czechoslovakia, invited first by Jan Bureš. On the eve of my departure for Prague in 1962, President Kennedy gave his speech on the Cuban missile crisis, and I wondered whether I should cancel my trip. Massion, who was taking me to the airport, remarked that an atomic bomb would not have different effects on Paris versus Prague, so I went. In Prague I could not learn how events were developing, as foreign broadcasts were jammed, and it was reminiscent of Paris during the occupation. I asked at the hotel for permission to telephone Paris, on the pretext that my little boy was ill. My husband, not realizing the sort of atmosphere in Prague, replied that the child had never been ill, and asked if I was having problems there; terrified, I hung up. The next day I visited Bureš’ laboratory in the Academy of Sciences for which comfortable premises would later be built. Then they had only a single large room where experiments were organized in different corners, manifesting the qualities of the experimenters.

I next visited our friend in Brno, Professor Vladislav Kruta, who had come to France in the 1930s to work in Louis Lapicque’s laboratory before the second world war, where he met my husband. He had married a French woman and returned to Czechoslovakia as professor in the faculty of medicine. At the time of the German occupation of his country, the Krutas were in France, where his wife and children spent the whole war with her family. In 1940, Kruta himself left Bordeaux for England. He was with the Allied armies through the war and returned to France just after the Normandy landing. He had brought all sorts of little things he rightly thought we would be lacking, and I have never forgotten the distribution of all those presents. He then returned to Czechoslovakia. He would have left when the Communist regime was installed but thought it important that free minds should not abandon the place, and he stayed in Brno. He was still a professor in this faculty on my first visit, but he was soon sidelined from teaching and the laboratory, and then forced to retire. Curiously, it was then that he was able to come to France easily. It seems that the Communist government was happy when a retiree did not return so they need not pay a pension any longer. We found ourselves sympathetic from his first visit, and even though I could not return to see him in Brno on later visits, Kruta always arranged to go to Prague for a couple of days to see me during my frequent visits to the researchers in the academy laboratory—the Bureš’, Pavel Hnik, Ladislav Viclický, and others.

My first time in Brno it was cold, the Krutas could heat only their kitchen, food supplies were scarce, and we still had no information about Russo-American relations. As I was about to leave, the détente occurred. I then went to the Plzen physiological laboratory where I met Yamila Hassmanova and Richard Rokyta, who both later worked with me at the Institut Marey. On my return to Prague, I saw Kruta again and during a stroll with Bureš we saw the demolition of a large statue of Stalin. I returned to Paris with good memories and an assortment of Czech marionettes to earn my son’s pardon for my absence.

The first American to come to work in the Institut Marey was Robert Livingston in about 1950. In 1958, Lawrence Kruger stopped over in Paris on his way to spend a year in London in the anatomical laboratory of W.E. Le Gros Clark. Kruger paid us many visits from England thereafter, in the course of which we began to write two articles. He returned to Los Angeles shortly after Jean’s birth. There he advised a young postdoctoral researcher, Richard Wendt, to go and work for a few months in Paris. This was a happy event for me. I greatly admired Dick, as we called him. He was a skillful researcher already experienced in single-cell studies, with a balanced, pleasant character, and we had a period of productive collaboration. He did some work on the amygdala, then on the orbital cortex, and he was the first to use the method of local cooling by butane expansion using the deep probe just put into use by Max Dondey for my friend, the neurosurgeon Jacques Le Beau. That technique was later neglected and abandoned in France; the required improvements aroused disputes about priority. These localized cooling probes were used in the Institut Marey by Robert Naquet and Monique Denavit in the mesencephalic reticular formation of “chronic” cats. Naquet was at the time director of a laboratory in Marseille, but he came to Paris regularly to work at Marey.

In the 1950s, brain activities were, in the majority, recorded in anesthetized animals. Barbiturates or chloralose were the most frequently used anesthetics, however, these substances were not only modifying the animal awakeness but also the cells’ activities. To avoid this last effect, recording without anesthesia was a necessity. Different solutions were found by different working teams. One solution was to implant, in aseptic conditions, recording and stimulating electrodes in anesthetised animals and to wait for the disappearance of the anesthetic effect during a few days before recording. The animals were prepared in such a way that they were free to move and did not feel pain from fixation techniques. The electrodes were said to be chronically implanted. Such animals were rapidly called “chronic” animals. They were used to study the behavioral effects of blockade that were produced by the cooling of localized brain structure.

The Institut Marey progressively lost some of its older researchers. Jean Scherrer, after passing the physiology agrégation, rejoined the Salpêtrière, where he organized several conferences between neurologists and physiologists. Pierre Buser had been appointed maître de conferences about 1955 in the physiology department of the Sorbonne, and in 1960 he set up his laboratory on the new premises at the former Halle aux Vins on the quai St. Bernard. Our collaboration had ended several years earlier, and he was working on the motor cortex of cats with Michel Imbert. I was teaching the psychophysiology certificate, which was an option for the degree in physiology, and many science students who wanted to get a doctorate chose it. So I had an audience of psychologists and scientists, and the examinations included an oral exam through which it was possible to get to know the candidates better. In this way, I oriented various psychology students toward physiology—Jean Delacour and Michel Imbert, as well as science students—Monique Denavit, Elizabeth Trouche, Jacques Glowinski, and many others, not all of whom stayed in research.

When I met Glowinski, he had just finished his studies in pharmacy. After a brilliant oral exam, I suggested that he go into neurochemistry, which was just beginning to develop, and I thought of finding him a training post at the Pasteur Institute. That attempt met with some difficulties, so I looked for ways to place him in an American laboratory. He was accepted by Julius Axelrod, who was starting to shine in neurochemistry. Because the available position had to be filled quickly, I saw our friend Louis Bugnard, who in a few weeks obtained a grant for Glowinski to leave for the National Institutes of Health (NIH). Before going, he learned rat stereotaxy at the Institut Marey. I had steered Glowinski toward neurochemistry in agreement with Professor Guillaume Valette, dean of pharmacy, who was going to find him a permanent post on his return. Unfortunately, after his long stay at NIH, the situation had changed in the faculty of pharmacy, and Glowinski rejoined us, setting up a laboratory on the premises my husband had prudently reserved for him in the Collège de France. Rhône-Poulenc and INSERM contributed generously to his set-up.

The Institut Marey had several departments; mine was on the top floor. Its equipment and personnel were of different origins—CNRS, Collège de France, university, and grants over several years from the United States Air Force and NIH. Professor David McK. Rioch of the American naval laboratory had visited our laboratory and offered aid, but he had to withdraw it as the Navy could not be in competition with the Air Force. I always remember his friendly attitude and visited him my first time in the United States when Nauta and William Mehler were working in his laboratory.

In 1962 or 1963, while Dick Wendt was working on amygdaloid responses, I learned that a Russian trainee, Mme Olga Merkulova, a pupil of Vladimir N. Chernigovsky, was arriving earlier than expected at the Institut Marey. Only Dick’s research related to Chernigovsky’s on visceral projections. Dick was kindness personified, so I asked him to collaborate with Merkulova. At that time of cold war, a Russo-American team was not necessarily viable, and for a while there were a few snags, but progressively our Russian and American colleagues developed a sound friendship. One day Merkulova, who had a son in Russia, told me that Dick Wendt was like another son to her, and she wished he could work with her one day in Leningrad. She went back after six months, and I have not seen her since. Although we exchanged letters, I never had the courage to tell her that Dick Wendt died in sad circumstances soon after his return to the United States. He had stayed several years with me, then obtained a post at the Massachusetts Institute of Technology (MIT) in the department of Walter Rosenblith, but Dick was ill and could not bear the pressure of his illness. Before leaving Paris, he promised me he would return from his “training course” in the United States. In turn, he entrusted me with another investigator, John Liebeskind, who played an important role in my research. I received a letter in almost perfect French from Liebeskind, a young American postdoc, asking to come and work in France for a limited time. I replied in excellent English, offering a place for the following years. When Liebeskind arrived, he spoke no French, and my English was still poor. His letter had been written by Dick, mine by George Krauthamer, an American who had just arrived in Paris and who was perfectly bilingual.

Krauthamer was married to a black American, Eleanor, who had trained in sociology. She came to work in the laboratory with Mme Laplante and quickly learned the anatomical techniques. George Krauthamer was a skillful researcher who had spent several years in France as a schoolboy before emigrating with his parents to the United States. He served in the American army and later worked with Hans Teuber and was familiar with behavioral methods. With us he soon assimilated the techniques of neurophysiology. We had intended to work with Krauthamer on the behavioral role of the projections to the caudate nucleus demonstrated with the Brazilians. After some fruitless tests, we noticed that stimulus trains to the caudate nucleus suppressed all activities arriving in the medial thalamus and associative cortex, without affecting primary responses. This became George Krauthamer’s personal topic, which he pursued with several collaborators; American, Japanese, and French. He remained at the Institut Marey for several years on NIH contracts and returned to the United States in 1966 after a period as a part-time assistant secretary of IBRO.

With John Liebeskind I returned to recording unitary activity in the somatomotor cortex, the problem that had initiated my research on mammals. This time we recorded in monkeys, in which cortical mapping had been started with my Brazilian friends. We placed microelectrodes in the pre-Rolandic cortical region where Clinton Woolsey and Hsiang-Tung Chang, as well as Karl H. Pribram and Lawrence Kruger, had demonstrated evoked potentials on stimulating dorsal roots or motor nerves. Microelectrode recording showed that cells there were activated by movement but also by muscle stimulation. Those experiments were always long, and I recall once leaving the laboratory toward midnight, exhausted, after we had begun to record from a pyramidal cell that responded tonically to movement, and to flexion or extension of the hind limb with prolonged excitation or inhibition. At about 7 a.m. John came looking for me; the cell was still active. Frank Echlin, a New York neurosurgeon who had formerly worked with my husband, participated in these experiments during visits of several weeks; his wife came also, and we are friends to this day.

Professor Adrian was to retire, and his pupils organized a symposium. I was invited at Bryan Matthews’ initiative, and I presented our first results on the representation of muscle afferents in the motor cortex. There I again encountered many English friends and American acquaintances. I dined for the first time in the hall of Kings College. Women had not been admitted to these dinners before, and a female student of Adrian and I found ourselves in evening gowns at the foot of a table full of men, in an icy hall. On my previous visit, Lady E. Adrian had looked after me while my husband was invited to the high table. Only 10 years later, at a meeting organized by the psychophysiologists, were the rules moderated, and I dined at the high table.

Dr. William D. Neff, who had heard me present an overview of our work at an American meeting, asked me to summarize it for the neurobiology review he edited. For the first time, I wrote the text in English; it was corrected by American and English friends visiting the laboratory.

The responses we had obtained in cat and monkey with chloralose anesthesia had always been received with reservations, the more so because the responses to muscle input we found in the motor cortex of monkeys had not been observed in the cat by Mountcastle’s team, who thought such signals only reached the cerebellum. The actions of different anesthetics then had to be explained. With Pierre Aléonard we decided to look for responses in the unanesthetized animal. Aléonard was the technician who had helped me in many of the experiments I have described. He had fashioned a sealed chamber maintaining liquid over the cortex during microelectrode recording and had made bipolar recording electrodes inspired by those of Magoun.

To avoid using anesthesia during recording, in a preliminary stage we placed bipolar concentric recording electrodes in anesthetized cats and fixed them at the upper limit of the structures to be recorded, with indwelling stimulation electrodes on a cutaneous nerve of each anterior paw. The assembly led to a connector fixed to the skull. Operated in aseptic conditions, the animals supported these implants well; they remained friendly and allowed recording of responses to moderate stimulation without need for restraint. The recording electrodes had a central part that could be lowered by fractions of a millimeter, with the main part fixed. We thus observed bilateral responses to stimulation of cutaneous nerves—similar to the responses described with chloralose—several days after the animals had eliminated all trace of anesthetic.

To our astonishment, these responses were not consistently present, appearing only when the animal took no notice of what we were doing, and disappearing when it looked at us. These observations, made with Aléonard and Mallart, showed us that responses in the medial thalamus were of large amplitude only when the animal was drowsy or in slow-wave sleep and were absent or of feeble amplitude in the awake animal or one in paradoxical sleep. Thenceforth most of my recordings were done in “chronic” cats and monkeys, and we practically gave up using chloralose anesthesia. The responses of the medial thalamus were almost completely forgotten for a time, but recent research on thalamic activity in chronic pain has recalled that this part of the thalamus certainly plays a role in pain sensation.

This work was done in the department I directed at the Institut Marey, and it was matched by the department directed by Ladislas Tauc, dealing essentially with more elementary phenomena. Attached to Tauc’s department was a pupil of Buser, who had not followed him to the university and who worked with the former Argentine researcher Hersch Gerschenfeld, who with his wife had obtained CNRS positions. Mme Dora Gerschenfeld had left for the university with Buser, along with Michel Imbert and Gesira Battini. At that time several new workers, French and foreign, joined us—Philippe Richard of INRA and Henri Korn, a neurologist who worked for a while with Dick Wendt then did related research with Pierre Auffray from INRA. I also had Jim O’Brien and Angharad Hews-Pimpaneau, who was English but was married to a Frenchman; Ilan Spector from Israel; Yamila Hassmanova, a Czech; and later Yeheskel Ben-Ari, another Israeli. I had long wanted to average evoked potentials from “chronic” animals but the methods were not easily available. The apparatus built by George D. Dawson in London used capacitive memory. In Paris, Scherrer at the Salpêtrière was the first to have an averager, thanks to his pupils’ technical prowess.

Computer systems were developing, and Walter Rosenblith at MIT had equipment that was relatively easy to use. Assisted by the research department of the American Air Force, we set up a collaboration. We implanted cats in Paris and shipped them to Boston, where evoked potentials could be studied during the sleep-waking cycle. This procedure allowed us to quantify the amplitude variations over relatively stable states of vigilance, monitored by simultaneous records of cortical and muscular activity. These experiments were performed around 1963 with Jean Massion, who accompanied me to Boston. They were pursued further, always with Rosenblith’s assistance, by one of my researchers, Gisèle Guilbaud, who thus began a doctoral thesis which she completed in Paris with the averager we finally obtained. While in Boston, I gave a seminar in my imperfect English on the responses observed in the medial thalamus. I was surprised to see in the audience an English friend, the psychologist Richard Oldfield, who was visiting a neighboring laboratory. I always spoke to him in French, which he used perfectly, and I was ashamed to reveal my poor English. I then decided to improve my vocabulary by reading the simple English books recommended by my “English teacher,” John Liebeskind, who spoke excellent French.

From 1961 on, much of my time was devoted to a new theme, recording thalamic activity in humans. The neurosurgeon Jacques Le Beau had for some years paid friendly visits to my laboratory. One day he invited me to a lecture by a colleague, Gerard Guiot, who had for several years been trying to alleviate Parkinsonian rigidity and, above all, tremor, by localized brain lesions. After trying pallidal lesions, he began making them in a thalamic region anterior and superior to the ventral posterior (VP) nucleus. The lesion site was close to the internal capsule, which he was careful not to damage. To localize his electrode, he was using the threshold stimulus through the electrode to provoke a motor response—the farther away from the capsule the higher the threshold—but this evaluation lacked precision. During the discussion, I suggested that the coordinates could be corrected by seeking the thalamic zone showing evoked potentials, thus demarcating the VP just next to the zone to be lesioned. Michel Jouvet and Raúl Hernandez Peón had already recorded responses in the human VP. The next day Guiot, neurosurgeon at the Hôpital Foch in Suresnes, near the Institut Marey, came to the laboratory to persuade me to set up the technique at Foch. I hesitated in view of the difficulties to be met in working on humans, but Pierre Aléonard, who had an enterprising spirit, insisted that I accept.

We quickly organized exploration of the human brain with deep electrodes. Luckily, by grounding the patient’s chair, we were able to eliminate artifacts due to mains interference. Aléonard made bipolar concentric electrodes that were similar to those used in animals and large enough to reach the anterior thalamus from the occipital cortex. These recording electrodes passed easily through the tubes for admitting the coagulation electrodes. With little spare recording equipment, we had to take amplifiers, cameras, and stimulators to the hospital for each intervention. The parasagittal trajectories used by Guiot went from the posterior cortex through the pulvinar before reaching the VP. Cellular structures were easily distinguished by their spiking activity from fiber regions, which were practically silent with our electrodes. As in animals, natural stimulation of the periphery gave us evoked potentials in VP and thus allowed us to verify the lateral and anterior positions required for the coagulation electrode. We used this technique for several years and with its success were able to obtain the funds to buy recording equipment for the hospital.

That was the last study I did with Aléonard’s assistance. He was intelligent and technically proficient but, having been orphaned when young, he had been unable to pursue his studies and suffered from it. He did not see that technique was not everything; it had to be complemented by knowledge of the literature. I offered to lighten his duties so he could pass the examinations that would allow him to do independent research, but he refused and attached himself to Jean-Marie Besson’s team. He died rather early from a heart attack, leaving behind young children and a seriously ill wife.

These first recordings in humans were done with a team including a radiologist, Etienne Herzog, who was easy to work with. The team also included Geneviéve Arfel, an electroencephalographer; Guy Vourc’h, an anesthetist; and Serge Brion, a neuroanatomist. We quickly became friends. Many foreign trainees were present in Guiot’s department. A Canadian, Jules Hardy, was there when recording began, and he went to Spain with Guiot to present the findings to an international congress. I thus had the occasion to work with trainees from Spain and Latin America, whom I remember with pleasure. We often had visits from neurosurgeons or neurologists during the operations, so I met specialists I would not have known otherwise. I think particularly of a Barcelona neurologist, of Spanish neurosurgeons S. Obrador and G. Dierssen, Antonio Subirana, Antony M. Halliday and Valentine Logue, John Bates from London, Claude Bertrand from Montréal, F. John Guillingham from Edinburgh, and Rudolf Hassler, Wilhelm Umbach, Hirotaro Narabayashi, and Albrecht Struppler, who would become firm friends. Young French neurosurgeons also did their internships at Foch, among them was Patrick Derome, with whom I worked longest.

Using somewhat finer electrodes, we were then able to observe bursts from thalamic neuron units at the tremor frequency. Some were nothing but evoked activities, but others seemed to precede the tremor. Herbert Jasper, IBRO secretary, back in Montréal also began recording with Gilles Bertrand, but using fine tungsten electrodes, as I learned during my visit to the French University of Montréal and the English language Institute of Neurology, with Guiot in 1963 or 1964. I had prepared two complementary lectures, one for the University of Montréal and one for the Neurological Institute. Alas, the Anglophones did not attend the first, and only a few Francophones the second.

We also presented our results on rhythmic thalamic activity at the New York congress of 1966, organized by Melvin D. Yahr and Dominick Purpura, where I again encountered Pierre Cordeau. This French Canadian had received part of his education in English, and he helped to link the two communities. With Jan Gybels he had observed activity preceding trembling in the cortex of a macaque with tremor from an operation done by Louis Poirier of Quebec. Like me, Cordeau was an engineer who had converted to physiology, and we understood each other. We maintained our friendship until his premature death. He had sent me his pupil, Yves Lamarre, who worked on the rhythmic activities in monkeys and who later completed his training with Ragnar Granit and then Vernon Mountcastle.

Our work on humans had some repercussions, and in 1964 the Foreign Affairs ministry sent Guiot and me to present our results in Japan; I also spoke globally of my neurophysiological work, Guiot of his neurosurgical results. Our visit was organized by Yasuji Katsuki, the dean of medicine in Tokyo who specialized in audition, and by Hirotaro Narabayashi, one of the first neurosurgeons to make thalamic lesions in Parkinsonians.

My trip began with a short stay in Los Angeles to visit the Brain Research Institute set up by Horace Magoun, where Lawrence Kruger and Madge and Arnold Scheibel worked. I had met the Scheibels in Paris when they worked with Moruzzi. Susumu Hagiwara was there also. He was a colleague of Katsuki and was the first Japanese to contact me after World War II. Like me, Hagiwara had worked on an electric fish, the narcine, and we had exchanged letters and publications. He had visited France after my husband’s trip to Japan in 1961, as had Katzuki and his wife. We met with Guiot in San Francisco, and our results were presented in the neurosurgery department, where I met Benjamin Libet and his wife, who have remained friends of ours. Mme Guiot joined us, and we left for Japan. We went to Tokyo, Osaka, Nagoya, and Kyoto, then back to Tokyo. We often saw the anatomist Hajime Mannen, who spoke perfect French after working in Paris; Toshihiko Tokizane; T. Tomita, who was making superb ultrafine microelectrodes; and many others. Narabayashi took us for a weekend to Hakone, accompanied by his assistant, Chihiro Ohye.

We decided that Ohye would come to our laboratory and the hospital for a few months. This was made possible by a grant provided by my old friend Dr. Pinchas Borenstein. Ohye completed this tour with Louis Poirier in Canada. Ohye often came to work at the Institut Marey with me, Massion, or Jean Féger. He is one of my oldest collaborators and one of the most faithful. For his part, Narabayashi was always an attentive friend, as were Katzuki and his wife, and Hagiwara. In this sense, my visit to Japan was a great success, and it must be said that my Japanese friends were ahead of their time, for without them I would not, as a woman involved in research, have been well accepted there.

On our return to Paris in 1964, we obtained support from the CNRS for a technician to follow up the patients operated on at Foch. Foreign teams began to use our technique. I would have liked computer methods to determine in which structures the abnormal activities of Parkinsonians originated. But the number of operations diminished with the appearance of drugs that reduced the dopamine deficit of the corpus striatum in Parkinson’s disease. Professor Bugnard, director of INSERM, had set up a unit at Foch to allow us to promote research on Parkinson’s disease, as well as on other CNS diseases. We had foreseen a program on pain, with the neurosurgeon Dr. Jacques Rougerie. I also pursued some investigations with Dondey and Le Beau on the use of cooling probes in neurosurgery, but the great initial enthusiasm for collaboration between scientist and neurosurgeon was over, and each side resumed the course of its own work.

Grey Walter invited me to present the results obtained in Parkinsonians at the EEG congress of 1965 in Vienna. There I met Russian researchers who were dealing with similar problems—Mme Natalia Bechtereva and Mme Svetlana Raeva. The latter obtained a grant for six months to work with me in Paris. With sound training in electrophysiology, she made in Moscow the sort of recordings we were terminating in Paris. She, Ohye, and Narabayashi were for years almost the only ones to perform lesions on VIM (the anterior part of the VP thalamic nucleus) and to continue research on the human thalamus. About 1985, there was a renewal in the study of thalamic structures in humans, thanks to Ronald Tasker.

For several years, I divided my time between the Hôpital Foch and the Institut Marey. My research in animal physiology had been reduced, but thanks to Liebeskind, Lamarre, Krauthamer, and Massion, work continued with the monkey motor cortex, the caudate nucleus, and the red nucleus. Then, with new researchers, we studied the facial motor cortex, the claustrum, and the role of the amygdala in learning.

I met Professor Wade Marshall, director of the neurophysiology laboratory of NIH in Bethesda, while he was working in Brazil with Leão on spreading depression. After Jean’s birth, we met again at the congress in Montpellier, where Wendt presented his work on the amygdala. I visited him in Bethesda and we decided Wade would go to Paris with his wife Louise for a six month sabbatical. Wade Marshall was one of the earlier investigators of the cortex using the CRO. He was at that time looking at the effects of respiratory gas composition on cortical activities, reflected in variations of cortical direct current. We continued this work together in Paris, using an apparatus—a capnograph—to measure expired CO₂ levels in animals. The methods were already available for humans, Vourc’h had told me of them, and a colleague of his lent us the equipment needed for the investigations. This work led to the systematic use of the capnograph in animal physiology, and it was carried on further during visits to NIH. One of the recent arrivals at the Institut Marey, Jean-Marie Besson, joined in, and we worked with Wade’s collaborator, Dr. C.D. Woody. So my sojourns to the United States began with Wade’s laboratory, and I have kept lasting contact with Louise, who now lives in Los Angeles. Approaching retirement, Wade endured the effects of loss of power, his publications were attacked more freely and sharply. He suffered from such bitterness and died not long after retiring.

In 1964 to 1965, we were visited by a Russian professor, Arpashev I. Karamian, for several weeks, and despite the absence of a common language and difficulties with scientific discussion through an interpreter, we got on well. I met him again later in Moscow.

The American Air Force had developed a chimpanzee breeding-station at the Holloman Air Base in New Mexico. It was tempting to study in a related brain the activities of the thalamic structure we knew so well in Parkinsonian humans. So in 1967 a research program was organized with the Air Force team, and I went to Holloman for two months, accompanied by Patrick Derome from Guiot’s team, whose thesis was on recordings in the somesthetic thalamus of Parkinsonians. Derome stayed a month and established the stereotaxy for chimpanzees, based on what had been done in humans. He implanted sterile cortical perforated plates, allowing us to work on the somatomotor cortex of the unanesthetized chimpanzee. John Liebeskind, now in Los Angeles, joined us at Holloman, with two technicians from the Institut Marey. I took Jean with me, hoping that at eight-years-old the experience would help his study of English later. Colonel Clyde Kratochvil, who was in charge of the laboratory, was most welcoming. The physiologist Jack Rhodes and others there worked with us. The research facilities were guaranteed by a contract with the Air Force. Our technicians got on well with their American colleagues. We installed a laboratory for glass microelectrode recording, and with Liebeskind we examined in the cortex how motor effects of stimulation were linked to afferent signals received by cells recorded in the same sites, depending on the cortical zone. My husband came for several days, then left for Paris with Jean. I returned to Paris a little later after a detour to Montréal for a symposium on Parkinsonism. I had the unpleasant experience the day before my presentation of finding that all my slides had been left at Holloman, and I had to give my talk with chalk and blackboard. I returned to Holloman again for several weeks to try to finish some chronic experiments with Liebeskind, knowing that further visits would be needed for these experiments to bear fruit. But this was at the end of 1967, and after the chaos in Paris in May 1968 it was not possible to get the necessary funds and favorable conditions to work at Holloman. Finally the chimpanzee station, created mainly for sending a primate into space, was disbanded.

On returning to Paris, I learned that Jean Massion had agreed to join the Institute of Psychophysiology at Marseille directed by Jacques Paillard, a former researcher at the Institut Marey who had specialized, with my husband and Dr. Tournay, in the electromyography of human movement. Svetlana Raeva arrived from Russia, and with her I studied relations between the substantia nigra (SN) and caudate nucleus in cat and rat. This work had been started with Marthe Vogt, who wanted to look at dopamine liberation in the striatum after nigral stimulation. Marthe had spent two weeks in Paris to establish the stereotaxic bases for stimulating the SN. The nigro-caudate pathway demonstrated by a Swedish team using fluorescence methods was thus studied by electrophysiology, together with a caudatonigral pathway. Our preliminary publication followed on the heels of a paper by Tomas L. Frigyesi and Dominick Purpura, which showed similar results. The SN-caudate nucleus relations remained a topic of interest for some of my researchers for a long time.

An Australian university researcher, John McKenzie, arrived from Melbourne in 1968 with his family for a sabbatical year in France, and with Paul Feltz he studied the effects of repetitive nigral stimulation on the caudate nucleus. McKenzie often returned to Paris and later worked with Jean Féger. The visits of others were not so happy. A Brazilian who had worked in Russia asked to spend a year in my laboratory while awaiting authorization to return to his country. He arrived while Raeva was here and pretended to work with her, but he certainly engaged in other activities and disappeared in May 1968 after being seen in many political demonstrations. An American, Rosalie Futnick, who had strongly insisted on coming here, also disappeared after some political demonstrations.

The Institut Marey laboratory had become too big and was overpopulated. Difficulties arose between researchers, mainly because of rivalries. The people working with Tauc on molluscan neurons were devoted to the elementary cellular phenomena of synaptic excitation and inhibition. They found their space and funds insufficient. They also believed that an understanding of the nervous system could be gained only by their approach, and their remarks stole all enthusiasm from those investigating the CNS of vertebrates, some of whom abandoned their former research program for more elementary problems. And the French trainees arriving from the diploma of higher studies (DEA) who I was teaching were not always up to standard.

In 1967, I made my first visit to Russia. I was invited, together with Pierre Buser, W.H. Nauta, and Marthe Vogt, to a symposium organized at the Moscow Brain Institute by Semjon A. Sarkisov, successor to my friend Smirnov, who died young. Arpashev I. Karamian was also at the symposium, accompanied by his pupil, Nicolas P. Vesselkin, who spoke perfect French. I met other workers, Vladimir Skribilsky and Leonid L. Voronin, who despite material difficulties had developed intracellular brain microelectrode recording. I also met several female professors or researchers and got on particularly well with them. I again met up with Svetlana Raeva and her husband, an enthusiastic and obliging Georgian. I have ever since maintained good relations with the brain institute and its director Oleg Adrianov, an anatomist who replaced Sarkisov until he died recently. Adrianov often came to see us in Paris, and I returned to Moscow in 1980 at his invitation.

The CNRS had decided to move the Centre d’Études de Physiologie Nerveuse to Gif sur Yvette; the site was selected, and plans were drawn up. Separate departments were envisaged, and everyone wanted theirs to be the most important. My husband was still to be director of the center, but he was two years from retirement and many saw themselves as potential director.

Animal Models of Parkinsonian and Pain Syndromes, 1968–1984

I was still teaching in psychophysiology, but I had enough independence and my colleagues quickly had me promoted to a full personal chair. I continued to group the courses into one day per week, but the neurophysiology teaching in which I was also involved took another morning. I was elected president of the commission for animal biology of the faculty of science, which often occupied one day per week. And for several years, I was an expert for the army department that funded physiological research, an obligation I remember with pleasure. All these duties reduced my time at the Institut Marey, and we did not really recognize the growing disquiet. The first difficulties arose in the faculty of sciences where students were more and more numerous. To satisfy their demands, our dean obtained a significant number of lecturing positions that had to be filled quickly, although good candidates were rare. The students grew more discontented and, although we had received the means to improve their conditions of study, it could not be done fast enough to satisfy them. For awhile the unrest was confined to the Sorbonne and the laboratory was fairly calm.

In May 1968, I had been invited for some months by Brodal to give a lecture in Oslo, and I went. The cancellation of an Air France flight landed me a day late in Norway, but I was welcomed and was happy to meet researchers who had previously been only names to me, including F. Walberg, E. Rinvik, and Per Andersen. I left for Paris after watching a sunset over Oslo fjord with Brodal and his wife. When it was announced on the plane that we were landing in Brussels, my first reaction was that I had caught the wrong flight; I had once made such a mistake in the United States and found myself in Houston instead of Boston. But this time it was nothing of the kind—the Paris airports were closed by a general strike. Driving back to Paris by an indirect route to avoid customs, I found the city totally disorganized. I was able to get to my apartment but understood how serious things were only upon going to the laboratory.

A general assembly was meeting that included researchers, technicians, and cleaning staff, presided over by a young researcher. I heard criticism of the bosses who were opposed to the employees, researchers, students, and technicians. I started to say that in our profession of research we were all employees of the state and this opposition did not exist, but the president called me to order and told me to speak only when I was recognized. Thunderstruck, I left, and only on exceptional occasions returned to that type of general assembly. However, I had to attend similar sessions at the faculty of sciences, where agitators wearing Mao jackets came to announce student deaths. There was not one student death in 1968, but there was much destruction of material. I also encountered material problems because the centers for postal cheques, which looked after our salaries, were on strike. Luckily a grocer friend gave us credit, and the faculty paid us an advance. We were, however, able to go on May 20 with Jean-François Dormont, a pupil of Massion’s, to the symposium on Parkinson’s disease in Edinburgh.

When I got back to Paris, the children were not going to school and the laboratory was unbearable. I had enough petrol left to go to our house in Touquin and try to live out this difficult time in a calmer country environment. I had not foreseen that problems would arise in domestic life also. The daughter of my son’s baby-sitter used to live with us during vacation, but at 15 years of age she was in complete revolt. When calm returned, I refused to have her at my place, so her mother, who had looked after Jean from birth, left us, obliging me to find a new solution. De Gaulle eventually put an end to the disorder created by the absence of government, and we were able to return to Paris. However, many of the things we were attached to were destroyed and the return to work was difficult.

At the Institut Marey, the agitators did not forgive me for not bowing to their arguments and for refusing the system they tried to establish. Some of my students, impressed by the agitators’ speeches, had been led on, others kept quiet out of fear and pretended not to know me. To finish with these absurdities, the “laboratory collective” conducted a sort of trial of my husband because he intended to accept in his group one researcher who was not liked by another. My husband, who had not properly realized what was happening, was greatly affected by this episode. A friend suggested I leave for Canada. I simply decided to separate myself from the Centre d’Etudes I had helped to create, but which was now in the hands of sectarians, who in any case were soon to abandon the laboratory whose atmosphere they had destroyed. When order returned to the Paris region, the baccalauréat examinations had to be held, but only orals could be organized. Usually, tertiary teachers had little input into this exam, but this time they were called on to organize the boards of examiners. When summer holidays arrived, all the general assemblies dispersed to go camping. I went to Brittany with Jean, but it was hard to forget the weeks we had just lived through. People in the provinces had no idea of the stresses we had borne; it merely seemed to them that Parisians had aged.

The absurdities of 1968 greatly upset the work of French researchers, who had taken many pains after World War II to catch up with other countries, and never fully recovered from this trial. The organization of the new universities from elements of the old was made out of political considerations, without regard for the needs of students, teachers, or research.

For my part, I had decided to join the INSERM laboratory created by Bugnard for Guiot and me. Guiot was in accord, as was Mme Arfel. However, the premises had to be reorganized to install experimental laboratories. The plans for the change were well advanced, but when it came to fixing dates, Guiot told me he no longer agreed to my joining his laboratory. My husband advised me to stay at the Institut Marey, which would be evacuated by the CNRS personnel but would remain the property of the Collège de France. So I reorganized a smaller laboratory, with sadly reduced funds.

For several years an Algerian student, Mohamed Abdelmoumene, had been with me. I had met him when I went to Algiers after the independence war to visit Annette Roger, whom I knew well in Gastaut’s department. Abdelmoumène had arrived at the Institut Marey when his government was changing direction. He was cultured, worked and wrote well, and obtained a CNRS post. I advised him to study the inhibitory effects of higher centers on spinal levels. Abdelmoumène chose to look at such inhibition using dorsal root potentials, and for this he collaborated with Jean-Marie Besson. Later, on my advice, they and their collaborators studied these controls with microelectrodes. Then Abdelmoumène passed the physiology agrégation in the faculty of medicine and was appointed professor of physiology in Algiers, choosing Algerian nationality. Besson stayed with me at the Institut Marey, forming a team with Gisèle Guilbaud, who had just passed her thesis on evoked potentials in “chronic” animals. Besson had himself changed his research theme. After working with Wade Marshall, Woody, and me, he passed his thesis on problems associated with the action of different respiratory gases, and then worked with Abdelmoumène on the control of spinal afferent signals.

Besson’s wife, Marie-Josèphe, had obtained her secondary agrègation, and after a year teaching in the country had taken the post of assistant in my department at the faculty of sciences. She was trained as a biochemist, and I thought she would do better at research in the laboratory that Glowinski was developing at the Collège de France. She did her doctoral thesis there and continued her research while she served as senior tutor in psychophysiology at the faculty. Shortly before my retirement she became a professor in the same faculty. We maintained good relations, and she took over some of my former students.

At the faculty, a unit for teaching and research (UER) had been created, grouping researchers in physiology and embryology. The first director was a biophysicist, but the major power was in the hands of Professors Alexandre Monnier, Andrè Thomas, Andrè Soulairac, and Louis Gallien, with whom I never got on too well. My position was thus precarious. I was astonished several years later (about 1972) to be called on to direct the UER of physiology. I accepted and was reappointed to these duties until my retirement in 1985. During that time I had the pleasure of seeing my friends Alfred Brodal and, a little later, Stephen Kuffler and Susumu Hagiwara, receive an honorary doctorate from our university.

With the return of calm, we could work. I was first visited by Ian Donaldson, a neurophysiologist who was working on humans at Edinburgh with the neurosurgeon Guillingham. Donaldson and I continued the study of monkeys begun with Liebeskind on the chimpanzee cortex. Donaldson’s wife, Patricia, studied histological techniques with Mme Laplante. The Donaldsons returned to work in England, first at Oxford with Whitteridge and then in Edinburgh. We are still in contact. About the same time I received an honorary doctorate from the free University of Brussels, presented by Professor Pierre Rijlant.

During this period Ainsley Iggo, who was editing the volume on somatic sensation in the series published by Springer with Richard Jung as general editor, asked me to write an article on nonspecific projections. I associated Besson with it, and he helped with the bibliography on the spinal relays.

My friend Guy Vourc’h who came to see me, although Guiot had excluded me from the Foch laboratory, entrusted me with his assistant, Alexandre Levante, who worked in the laboratory as well as in Vourc’h’s department at Foch. Levante stayed with me for many years.

We worked with the antidromic technique for determining direct connections, with the Czech visitor Rokyta. We looked in the medial thalamus of the cat and monkey for cells projecting to the cortex. Some of the work was done with a Russian visitor, Karine Vetchinkina, who spoke French fluently, as her father had been in the Normandy-Niemen division during World War II. I believe he ran it and, being a widower, raised his little girl himself, among French aviators. Her knowledge of French made her choose to teach at the Patrice Lumumba University, which trained cadets for service in Africa. She had not lost her Francophilia, and we stayed great friends until her recent death. She was in Paris during the period after the Prague Spring, so the discussions with Rokyta were vehement, but of good will. Levante, of Russian origin, spoke the language too, and the atmosphere was pleasant and relaxed.

Through a trip to Sweden at Zotterman’s invitation about 1972 I was convinced that I should investigate electrophysiologically the location of the cells of origin of the spinothalamic pathway. Besson’s group did not want to undertake the task, so I decided to do it with Levante. It was an interesting experience. First of all, in many cats we failed to find cells projecting directly to VP thalamus. This type of cell was, however, found in significant numbers in the first two monkeys tried, and we verified that these cells were activated by nociceptive afferents. To do these experiments, we corrected the stereotaxic coordinates by the method used in humans—radiography of the ventricles with a contrast medium.

I presented the results at a symposium on pain organized in 1973 by John Bonica in Seattle. I had already presented them in France and in Moruzzi’s laboratory in Pisa, and in the laboratory of my friend Edward Perl at Chapel Hill on the way to Seattle. A pupil of William D. Willis, who was working on the same problem in the monkey, though unknown to me, was at the lecture and quickly published their results. At that symposium I met two Italian researchers, Paolo Procacci and Carlo Pagni, with whom I was to maintain a long relationship; and once again, Patrick D. Wall, Jörgen Liebeskind, and several Americans. The creation of the International Association for the Study of Pain (IASP) was initiated at that symposium. On the return trip, I stopped in Toronto to see Ronald Tasker, whom I knew mainly by correspondence. Back in Paris, I undertook with Gunnar Grant and Jörgen Boivie of Stockholm a study of spinothalamic cells by retrograde marking with horseradish peroxidase.

Around that time I wrote a chapter on somatic sensations in Kayser’s Physiology (Flammarion) in collaboration with Suzanne Tyc-Dumont with whom I had maintained amicable relations since her stay at the Institut Marey in the 1960s. I also received the Cross of Chevalier of the Légion d’Honneur, conferred by Professor Courrier, life secretary of the French Academy of Sciences, who always gave me solid support. With the support of our vice-dean, Robert Courrier nominated me for the prize of the city of Paris. This prize allowed me to buy a plot in Brittany, where I had a small house built in the village where Vourc’h was born, where I had spent some weeks each year with my son.

Blaine Nashold came to Paris on sabbatical, and we studied the problem of pain after loss of afferents in humans. We tried to develop a rat model of events after deafferentation. We began the work with a technician from the École Pratique des Hautes Études, Marie-Christine Lombard, who had already received a diploma and could now do a third cycle thesis. Dentists came to the faculty as pupils in 1975 after a change in their course. Knowing this I gave a lecture on facial sensation, which I had not dealt with previously. With two dental students, Alain Woda and Jean Azerad, we studied the location in the spinal trigeminal nucleus of cells connected to VP thalamus.

My husband had been retired from the Collège de France for several years, succeeded by our friend Yves Laporte, who was thus responsible for the Institut Marey. The general secretary of the Collège de France at the time was not pleased to see funds leaving to maintain a laboratory dependent on the university, and he defended us poorly against territorial claims by the tennis club at the Roland Garros Stadium next door. The Institut Marey was condemned, and we had to find another site for my research laboratory. I obtained premises at the faculty quai St. Bernard, where I was teaching, which had been made available by the death of our colleague, Gallien.

Besson’s group at the Institut Marey had progressively separated from my team. Their methods differed from mine, and I was not keen on remaining responsible for their work. In any case I did not have the space for them at the university and was happy when the Hôpital Foch offered them the laboratory that Guiot had not been able to get going. Besson soon exchanged these premises for a laboratory located at Saint Anne hospital.

Thanks to Professor Pierre Dejours and also to Robert Naquet, Paul Dell, and others, on leaving the CNRS Centre d’Études I was able to obtain funding for an associated research team, which was renewed until my retirement. This allowed me to retain Mme Laplante, and my laboratory thus kept up histology of good quality. During this period I also received useful support from the Assistance for Medical Research. Jean Féger, who worked with me at Marey, came to the university with me. He later set up his own laboratory in another Parisian university. Paul Feltz worked with us for some time, then took a position as professor at Strasbourg. During those years, I was appointed several times to the consultative committee on universities, which chose candidates for professorial positions. I also returned to Moscow at Adrianov’s invitation, meeting up again with Skribilsky, Voronin, Raeva, and Vetchinkina. I also went to Leningrad to meet Alexandre S. Batuev and visited Platon G. Kostyuk’s laboratory in Kiev.

Toward 1976, with Professor Courrier’s accord, I presented myself as a candidate for the French Academy of Sciences. Professor Maurice Fontaine was a fine referee for me, but I was not the only one to have friends. My opposing candidate was Professor Jacques Benoit, a friend of Courrier. Benoit received more votes than I, but I was not bitter. However, some had said I took credit for work I had not done. I was not given the opportunity to establish the truth, and I never again presented myself as a candidate.

About that time I made contact with Hsiang-Tung Chang, a professor in Shanghai. I knew his work well but had never met him. I received several letters from him and sent documents he asked for. I had the pleasure of his visit around 1978, and he came to dinner with several of his colleagues after a lecture I had organized for him at the university. We worked on related topics and understood one another well. Through him I was invited to Shanghai, but at the time a surgical intervention prevented me from leaving Paris. A second invitation came at the unhappy time of my husband’s terminal illness, so I was never able to go to China.

My husband died at 80 years of age. He had suffered from having to leave his office at the Institut Marey, and he never got used to the offices installed for him at the university and the Collège de France. He devoted his last years to assembling and distributing to the museum the remaining vestiges of Etienne-Jules Marey’s work that we kept after the Institut Marey was destroyed. Thanks to my husband those materials are now mainly in the Museum of Beaune, Marey’s native city.

In 1980, I went at Iggo’s invitation to a conference in Berlin on pain and society. There I met Hans W. Kosterlitz, Peter Nathan, Fernando Cervero, Huda Akil, and others. In my last active years, I had some brilliant pupils—Jean-Michel Deniau and Gilles Chevalier continued work on the SN; Pierre Cesaro, a neurologist, worked with me on the relations between corpus striatum and medial thalamus in rats; Jean-Claude Willer, a pupil of Andre Hugelin, did experiments I was involved with on sensory fibers in humans (Peter Nathan came to Paris for his thesis); and finally, my old friend Ed Perl often came to work in my laboratory and give lectures, with visits from his wife and two daughters. A Mexican, Miguel Condès-Lara, a Hindu, Saraj Keisar, and an Australian scholarship-holder, Pamela Sanderson, worked with me on the remote effects of spreading depression propagating at cortical or striatal levels. In 1982, Karen Berkley invited me to speak in Los Angeles at a symposium of the neuroscience congress, on central projection of pain signals in humans.

I received the French Order of Merit, proposed by the president of our university whose efforts to put the university’s work in order have been estimable. Thanks to the International Union of Physiological Sciences, I was able to go to the congresses in New Delhi, Budapest, Sydney, and Vancouver. In 1983, I went to a symposium on the basal ganglia organized near Melbourne by McKenzie, where the International Basal Ganglia Society (IBAGS) was created. This society has met several times in different countries, and I was the président d’honneur for the fourth triennial meeting held on the Giens peninsula near Hyères in 1992.

Robert Naquet, Jean Scherrer, Pierre Dejours, and Yves Laporte have remained devoted friends. Another friend, Daniel Bargeton, who took great pains to defend me at the time of my academy candidature, unfortunately died soon after. I have always maintained good relations with my foreign collaborators. Tauc, Glowinski, Massion, Denavit, and Trouche have never neglected me. My friend Professor C. Lucking nominated me as an honorary member of the German EEG Society and invited me to Freiburg for the ceremony. There I once more met Richard Jung, whom Lucking succeeded, and my old friend Creutzfeld. I have received the medal of the city of Grenoble, and more recently of the City of Paris, the Spiegel and Wycis silver medal. Narabayashi, with the aid of JeanBaptiste Thiebaut and a Swedish friend, Christian Soop, organized a congress at Evian on microelectrode recording in humans, where I was the guest of honor.

Back to Work with Neurosurgeons, 1984–1996

Soon after my retirement, Ronald Tasker invited me to come to his department in Toronto for a few months in 1985 as an exchange professor. Together we revived the recordings permitting demarcation of thalamic structures in humans. Our collaboration has been most pleasant, each respecting the other’s work. I have enjoyed the efficient help of Jonathan Dostrovsky and the fine team we formed with a Japanese trainee, Katsumi Yamashiro, and an American of Polish-Mexican origin, Jacob Chodakiewitz. This work was continued by a stay with the neurosurgeon Ronald Young in Los Angeles, where I again encountered Chodakiewitz and met the efficient Patricia Rinaldi, who was easy to work with, and a German neurosurgeon, Wolker Tronnier.

I was invited back to Japan in 1984 by Ohye and Narabayashi, and was welcomed by many friends—Yasuji Katsuki, Yotaka Oomura, Hiroshi Mannen, Toshikatsu Yokota, Katsumi Sasaki, Masao Ito, several neurosurgeons, and others, as well as Professor C. Brooks and his pupil Kiyomi Koisumi. I found that the material situation had greatly improved for scientists, but the situation of Japanese women in research still seemed to be difficult.

On returning to Moscow in 1990 at Raeva’s invitation, I met Chihiro Ohye once again. Raeva’s work is excellent, and I have been happy to help her publish in the EEG Journal. Vladimir Skribilsky, who I had encountered only in Eastern Europe, was at last able to visit Paris. We went to Chartres, which this admirer of old churches had long wanted to see.

When I had to leave my university laboratory in 1985, I was able to set up a research post in Professor Alain Rérat’s INRA laboratory with some equipment American friends had given and some the CNRS had loaned. Bernadette Felix was there finishing a thesis on the goose brain. Pamela Sanderson came with me to Jouy en Josas, with one of my last students, Olivier Rampin, and a trainee from Gabon, Roger Mavoungou. Mavoungou had worked several years at the university and done his thesis while at Jouy en Josas on the activities produced in the pars reticulata of the SN by destruction of the pars compacta, a study still in progress.

The period surrounding my retirement should be called the Italian period, for I spent many months in Bologna and then Chieti. My contact with Italian research began late, though I had known Moruzzi and his pupils. I did not know P. Procacci well until 1976, when he organized the first IASP congress in Florence. We prepared the program with Carlo Pagni, and John Bonica was not entirely satisfied with it. Nevertheless, Bonica asked me, and I was astonished at this, to be the first president of the society. I did my best to fulfill that task, which I was to pass on to Bonica at the following congress in Montreal. In 1982, I attended a symposium on thalamo-cortical relations, organized by Giorgio Macchi in Milan.

Previously I had been visited by Professor Antonio Urbano, a Sicilian working on the claustrum. He invited me to Sicily, where I met his deputy, Salvatore Sapienza, who came to work with me at the university for several years. Sapienza was careful and competent, and I happily received one of his pupils, Rosario Giuffrida. At Sapienza’s suggestion, I was invited to give a lecture on pain to the Italian Physiological Society. The professor of pharmacology at Bologna, Carmela Rapisarda, was interested in my report describing the use of spreading depression and invited me to initiate a study with this technique and to give some lectures on pain. In this way, I spent several months after my retirement in the Institute of Physiology of Bologna directed by Professor Pierluigi Parmeggiani. With Rosario Giuffrida and Georgio Aicardi we used spreading depression to study the control of the red nucleus by localized cortical regions. Unfortunately, the reviewers for the American journal to which we sent an article for publication had no idea of spreading depression, and the article was rejected. It was subsequently published by the Archives Italiennes, thanks to Ottavio Pompeiano. We should have put up a fight, but Mme Rapisarda was ill and our collaboration ended.

At a symposium on headache organized by Leonardo Vecchiet and Federigo Sicuteri, I met Marie-Adele Giamberardino. She later came to work with me at Jouy en Josas and established a technique to model the pain of renal colic. Our collaboration has continued. I returned several times to Vecchiet’s department in Chieti, where with Marie-Adele we set up a laboratory, the first results of which were presented at an international symposium. There I met Professor Renato Galetti, who had a deep understanding of referred pain and whose influence on the Italian school is doubtless underrated. From his pupils, I discovered an interest in research on visceral and referred pain.

During this Italian period, I gave several lectures on pain, which impelled me to write a didactic book, which is now published.

In 1989, I was nominated to the French committee for evaluating universities, on the recommendation of my colleague, Alfred Jost, then permanent secretary of the French Academy of Sciences. I just finished this mandate of four years, which involved visiting universities and drawing up reports. This activity allowed me to meet and evaluate colleagues in other disciplines and to assess the progress accomplished by provincial universities.

At INRA we established stereotaxic methods with radiological intracerebral reference points for the pig, which were to serve as the main model for nutritional research. An atlas of the pig brain was constructed and awaits publication. Our technique is in use by the Japanese.

I was invited to meetings to mark the retirement of my foreign friends Janos Szentagothai, Albrecht Struppler, and Ainsley Iggo. I celebrated the honorary doctorate of my friend Manfred Zimmerman in Siena. In 1989, Otto Creutzfeld and I were invited by the chair of physiology to visit the East Berlin university, where my former Chilean pupil, Guy Santibanez, was teaching. My Montréal friends invited me in 1987 to give the J. Barbeau Lecture. In 1995, my friend Richard Keynes and I were invited to go to Brazil for the 50th anniversary of the research institute.

The INRA laboratory where I used to work disappeared, after a change of direction. With no place to continue my research, I thought I would stop laboratory work completely. But with pleasure I joined the laboratory originally created by my friend Borenstein at the Villejuif Hospital, where he ended his career and where I am now working with his former pupil, Mme Françoise Gekiere and with Guy Allègre, who was my technician 30 years ago at the Institut Marey.

I will soon be 80, and with this autobiography I have reviewed the work accomplished in 50 years of research. I have realized that collaboration is easier and more lasting when done with foreigners, no doubt because power struggles are avoided. I have also realized that fashions in science are a dangerous impediment to progress, and it is well to resist yielding to them.

In ending, I want to thank all who have helped me in my research, and to excuse myself if space limitations have not allowed me to mention them all. I also want to thank warmly Dr. McKenzie, who has written the English version of this text, and Miss C.A. Stewart, who kindly prepared the manuscript.

Selected Publications

Caractéres et organisation de la décharge des poissons électriques. Arch Sci Physiol 1950;4:299–334, 4:413–434, 1951;5:45–73, 197–206, 1951;6:105–124.

(with Buser P) Activités intracellulaires recueillies dans le cortex sigmoïde du chat: participation des neurones pyramidaux au potentiel évoqué somesthésique. J Physiol Paris 1955;47:67–69.

(with Buser P) Analyse microphysiologique des mécanismes de commande de la décharge chez la Torpille. In: CNRS, ed. Microphysiologie des éléments éxcitables. Paris: CNRS. 1955;305–324.

Activités de projection et d’association du néocortex cérébral des mammifères: les projections primaires. J Physiol Paris 1957;49:521–588.

(with Rougeul A) Activités d’origine somesthésique enregistrées sur le cortex du chat anesthésié au chloralose. Rôle du centre médian du thalamus. Electroencephalogr Clin Neurophysiol 1958;10:131–152.

(with Oswaldo-Cruz E, Rocha-Miranda CE) Activités évoquées dans le noyau caudé du chat en réponse à différents types d’afferences: I, étude macrophysiologique. Electroencephalogr Clin Neurophysiol 1960;12:405–420.

II Etude microphysiologique. Electroencephalogr Clin Neurophysiol 1960; 12:649–661.

(with Wendt R) Sensory responses of the amygdala with special references to somatic afferent pathways. Physiologie de l’Hippocampe. CNRS, 1962; 172–200.

(with Kruger L) Duality of unit discharges from cat centrum medianum in response to natural and electrical stimuli. J Neurophysiol 1962;25:1–20.

(with Fessard A) Thalamic integrations and their consequences at the telencephalic level. Specific and nonspecific mechanisms of sensory motor integration, Vol I. Brain mechanism. Prog Brain Res 1963;1:115–143.

(with Massion J) Dualité des voies sensorielles afférentes contrôlant l’activité du Noyau Rouge. Electroencephalogr Clin Neurophysiol 1963;15:436–454.

(with Arfel G, Guiot G) Activités caractéristiques de quelques structures cérébrales chez l’homme. Ann Chir 1963;17:1185–1214.

(with Bowsher D) Responses of monkey thalamus to somatic stimuli under chloralose anesthesia. Electroencephalogr Clin Neurophysiol 1965;19:1–15.

(with Krauthamer G) Inhibition of nonspecific sensory activities following striopallidal and capsular stimulation. J Neurophysiol 1965;28:100–124.

(with Liebeskind J) Origine des messages somatosensitifs activant les cellules du cortex moteur chez le singe. Exp Brain Res 1966;1:127–146.

(with Korn H, Wendt R) Somatic projections to the orbital cortex of the cat. Electroencephalogr Clin Neurophysiol 1966;21:209–226.

(with Guiot G, Lamarre Y, Arfel G) Activation of thalamocortical projections related to tremorogenic processus. In: Purpura D, Yahr MD, eds. The thalamus. New York: Columbia University Press, 1966;237–253.

Organisation of somatic central projections. In: Neff WD, ed. Contribution to sensory physiology. New York: Academic Press. 1967;2:101–167.

(with Feltz P, Krauthamer G) Neurons of the medial diencephalon. I: somatosensory responses and caudate inhibition. J Neurophysiol 1967;30:55–80.

(with Tyc-Dumont S) Fonction somato-sensible. In: Kayser C., ed. Traite de physiologie. Paris: Flammarion, 1969;437–519.

(with Feltz P) A study of an ascending nigrocaudate pathway. Electroencephalogr Clin Neurophysiol 1972;33:179–193.

Electrophysiological methods for the identification of thalamic nuclei. Z Neural 1973;205:15–28.

Physio-pathologie du Parkinson. In: Merck Sharp & Dohme, eds. Le point sur la maladie de Parkinson. Brussels: Merck Sharp & Dohme, 1973;1–30.

(with Besson JM) Convergent thalamic and cortical projections. The non-specific system. In: Iggo A, ed. Handbook of sensory physiology, Vol. II. Somatosensory system. Berlin: Springer-Verlag, 1973;490–560.

(with Levante A, Lamour Y) Origin of spinothalamic and spinoreticular pathways in cats and monkeys. Adv Neurol 1974;4:157–166.

(with Levante A, Lamour J) Origin of spinothalamic tract in monkeys. Brain Res 1974;65:503–509.

Cortex moteur, centre réflexe (in Russian). In: Batuev, AS ed. Organisation sensorielle du mouvement. Leningrad: Edition Naouka, 1975;13–24.

(with Willer JC, Boureau F) Role of large diameter cutaneous afferents in transmission of nociceptive messages: electrophysiological study in man. Brain Res 1978;152:358–364.

(with Lombard M-C, Nashold BS) Deafferentation hypersensitivity in the rat after dorsal rhyzotomy. A possible animal model for chronic pain. Pain 1979;6:163–174.

(with Lombard M-C) Animal models for chronic pain. In: Kosterlitz HW, Terenius L, eds. Pain and society. Dahlem Konferenzen. Weinheim, Germany: Verlag Chemie, 1980:299–310.

(with Azerad J, Woda A) Physiological properties of neurons in different parts of the cat trigeminal sensory complex. Brain Res 1982;246:7–21.

(with Willer J-C) Further studies on the role of afferent input from relatively large diameter fibers in transmission of nociceptive messages in human. Brain Res 1983;278:318–321.

(with Condés-Lara M, Sanderson P) The focal tonic cortical control of intralaminar nuclei may involve a cortical loop. Acta Morphol Hung 1983;3:9–26.

(with Sanderson P) Utilisation de la dépression envahissante de Leão pour l’étude des relations entre structures centrales. Ann Acad Brazil Cien C 1984;56:371–383.

(with Berkley KJ, Kruger L, Ralston HJ, Willis WD) Diencephalic mechanism of pain. Brain Res Brain Res Rev 1985;9:217–296.

(with Tasker R, Yamashiro K, Chodakiewitz J, Dostrovsky J) Comparison in man of short latency averaged evoked potentials recorded in thalamic and scalp hand zone of representation. Electroencephalogr Clin Neurophysiol 1986;65:405–415.

Interactions entre recherches fondamentale et clinique. Deux exemples tirés d’une expérience personnelle. Can J Neurol Sci 1988;15:324–332.

(with Vecchiet L, Giamberardino MA, Dragani L) Pain from renal/ureteral calculosis: evaluation of sensory thresholds in the lumbar area. Pain 1989; 36:289–295.

(with Giamberardino MA, Rampin O) Comparison between different animal models of chronic pain. In: Lipton S, et al., eds. Advances in pain research and therapy. New York: Raven Press, 1990;11–27.

(with Sanderson P, Mavoungou R) The influence of striatum on the substantia nigra: a study using the spreading depression technique. Brain Res Bull 1990;24:213–219.

(with Rinaldi P, Young R) Possible role of cortical and sub-cortical structures in the pathology of referred visceral pain and hyperalgesia. In: Vecchiet L, et al., eds. Pain research and clinical management. New trends in referred pain and hyperalgesia, Vol. 7. Amsterdam: Elsevier, 1993;73–81.

La douleur. In: Masson, ed.: Mécanismes et bases de ses traitements. Paris: 1996;201.

Julius Axelrod

BORN:

New York, New York

May 30, 1912

EDUCATION:

College of the City of New York, B.S., 1933

New York University, M.A., 1941

George Washington University, Ph.D., 1955

APPOINTMENTS:

Goldwater Memorial Hospital, Third New York University Research Division (1946)

National Heart Institute (1949)

National Institute of Mental Health; Chief, Section on Pharmacology (1955)

National Institute of Mental Health Guest Researcher (1984)

Scientist Emeritus of the National Institutes of Health (1996)

HONORS AND AWARDS (SELECTED):

Nobel Prize for Physiology or Medicine (1970)

American Academy of Arts and Sciences (1971)

National Academy of Sciences USA (1971)

Foreign Member of the Royal Society of London (1979)

Leibniz Medal, Academy of Sciences, East Germany (1984)

Mahoney Award “Decade of the Brain” (1991)

Ralph W. Gerard Prize, Society for Neuroscience (1992)

Julius Axelrod has carried out extensive, fundamental research on a wide range of topics, including biochemical mechanisms of drug and hormone actions and metabolism; enzymology; pineal gland membranes; and transduction mechanisms. He is most well known for his Nobel Prize-winning elucidation of the storage, release, and inactivation of catecholamine neurotransmitters and the effect of psychoactive drugs.

Julius Axelrod

Beginnings*

Successful scientists are generally recognized at a young age. They go to the best schools on scholarships, receive their postdoctoral training fellowships at prestigious laboratories, and publish early. None of this happened to me.

My parents emigrated at the beginning of this century from Polish Galicia. They met and married in America, and eventually settled in the Lower East Side of New York, then a Jewish ghetto. My father, Isadore, was a basketmaker who sold flower baskets to merchants and grocers. I was born in 1912 in a tenement on East Houston Street in Manhattan.

I attended PS22, a school built before the Civil War. Another student at that school before my time was I.I. Rabi, who later became a worldrenowned physicist. After PS22 I attended Seward Park High School. I really wanted to go to Stuyvesant, a high school for bright students, but my grades were not good enough. Seward Park High School had many famous graduates, mostly entertainers: Zero Mostel, Walter Matthau, and Tony Curtis. My real education was obtained at the Hamilton Fish Park Library, a block from my home. I was a voracious reader and read through several books a week, from Upton Sinclair, H.L. Mencken, and Tolstoy to pulp novels such as the Frank Merriwell and Nick Carter series.

After graduating from Seward Park High School, I attended New York University in the hope that it would give me a better chance to get into medical school. After a year my money ran out, and I transferred to the tuition-free City College of New York in 1930. City College was a proletarian Harvard, which subsequently graduated seven Nobel Laureates. I majored in biology and chemistry, but my best grades were in history, philosophy, and literature. Because I had to work after school, I did most of my studying during the subway trip to and from uptown City College. Studying in a crowded, noisy New York subway gave me considerable powers of concentration. When I graduated from City College, I applied to several medical schools but was not accepted by any.

In 1933, the year I graduated from college, the country was in the depths of a depression. More than 20 percent of the working population was unemployed, and there were few jobs available for City College graduates. I had heard about a laboratory position that was available at the Harriman Research Laboratory at New York University, and although the position paid $25 a month, I was happy to work in a laboratory. I assisted Dr. K.G. Falk, a biochemist, in his research on enzymes in malignant tumors. I also purified salts for the preparation of buffer solutions and determined their pH. The instrument used to measure pH at that time was a complex apparatus; the glass electrode occupied almost half a room. In 1935 the laboratory ran out of funds and I was fortunate to get a position as a chemist in the Laboratory of Industrial Hygiene. This laboratory was a nonprofit organization and was set up by New York City’s Department of Health to test vitamin supplements added to foods. I worked in the Laboratory of Industrial Hygiene from 1935 to 1946.

My duties there were to modify published methods for measuring vitamins A, B, B₂, C, and D so that they could be assayed in various food products that city inspectors randomly collected. Vitamins had just been introduced at that time, and the New York City Department of Health wanted to establish that accurate amounts of vitamins were added to milk and other food products. The methods used for measuring vitamins then were chemical, biological, and microbiological. It required some ingenuity to modify the methods described in the literature to assays of food products. This experience in modifying methods was slightly more than routine, but it proved to be useful in my later research. The laboratory subscribed to the Journal of Biological Chemistry, which I read with great interest. Reading this journal made it possible to keep up with advances in enzymology, nutrition, and methodology. During the time I was in the Laboratory of Industrial Hygiene, I received an M.S. degree in chemistry at New York University in 1942 by taking courses at night. My thesis was on the ester-hydrolyzing enzymes in tumor tissues. Because of the loss of one eye in a laboratory accident, I was deferred from the draft during World War II. In 1938 I married Sally Taub, a graduate of Hunter College, who later became an elementary school teacher. We had two sons, Paul and Alfred, born in 1946 and 1949.

First Experience in Research: Goldwater Memorial Hospital

I expected that I would remain in the Laboratory of Industrial Hygiene for the rest of my working life. It was not a bad job, the work was moderately interesting, and the salary was adequate. One day early in 1946 the Institute for the Study of Analgesic and Sedative Drugs approached the president of the Laboratory of Industrial Hygiene with a problem. The president of the laboratory at that time was George B. Wallace, a distinguished pharmacologist who had just retired as chairman of the department of pharmacology at New York University. Many analgesic preparations contained nonaspirin analgesics, such as acetanilide or phenacetin. Some people who became habituated to these preparations developed methemoglobinemia. The Institute for the Study of Analgesic and Sedative Drugs offered a small grant to the Laboratory of Industrial Hygiene to find out why acetanilide and phenacetin taken in large amounts produced methemoglobinemia. Dr. Wallace asked me if I would like to work on this problem. I had little experience in this kind of research, and he suggested that I consult Dr. Bernard “Steve” Brodie. Dr. Brodie was a former member of the department of pharmacology at New York University and was doing research at Goldwater Memorial Hospital, a New York University division.

I met with Brodie in February 1946 to discuss the problem of analgesics. It was a fateful meeting for me. Brodie and I talked for several hours about what kind of experiments could be done to find out how acetanilide might produce methemoglobinemia. Talking to Brodie about research was one of my most stimulating experiences. He invited me to spend some time in his laboratory to work on this problem.

One of a number of possible products of acetanilide that would cause the toxic effects was aniline. It had previously been shown that aniline could produce methemoglobinemia. Thus, one approach was to find out whether acetanilide could be deacetylated to form aniline in the body. With the help and guidance of Steve Brodie, I developed a method for measuring aniline in nanogram amounts in urine and plasma. After the administration of acetanilide to human subjects, aniline was found to be present in urine and plasma. A direct relationship between the level of aniline in blood and the amount of methemoglobin present was soon observed (Brodie and Axelrod, 1948). This was my first taste of real research, and I loved it.

Very little acetanilide was found in the urine, suggesting extensive metabolism in the body. As acetanilide was almost completely transformed in the body, we looked for other metabolic products. Methods to detect possible metabolites, p-aminophenol and N-acetyl-p-aminophenol, were developed that were specific and sensitive enough to be used in the plasma and urine. Within a few weeks, we identified the major metabolite as hydroxylated acetanilide N-acetyl-p-aminophenol and its conjugates. This metabolite was also found to be as potent as acetanilide in analgesic activity. By taking serial plasma samples, acetanilide was shown to be rapidly transformed to N-acetyl-p-aminophenol (Brodie and Axelrod, 1948). After the administration of N-acetyl-p-aminophenol, negligible amounts of methemoglobin were produced. As a result of these studies, Brodie and I stated in our paper (Brodie and Axelrod, 1948), “the results are compatible with the assumption that acetanilide exerts its action mainly through N-acetyl-p-aminophenol [now known as acetaminophen]. The latter compound administered orally was not attended by the formation of methemoglobinemia. It is possible therefore, that it might have distinct advantage over acetanilide as an analgesic.” This was my first paper, and I was determined to continue doing research.

Soon after Brodie and I examined the physiological disposition and metabolism of acetanilide, we turned our attention to a related analgesic drug, phenacetin (acetophenetidin). I spent some time developing sensitive and specific methods for the identification of phenacetin and its possible metabolite, p-phenetidine. Brodie and I soon found that in humans, the major metabolic product was also N-acetyl-p-aminophenol arising from the deethylation of the parent compound (Brodie and Axelrod, 1949). A minor metabolite was p-phenetidine, which we found was responsible for the methemoglobinemia formed after the administration of large amounts of phenacetin to dogs. After the administration of phenacetin to human subjects, N-acetyl-p-aminophenol was rapidly formed. The speed and the amount with which N-acetyl-p-aminophenol was formed in the body suggested that the analgesic activity resided in its deethylated metabolite.

The laboratories at Goldwater Memorial Hospital where I began my research career were set up during World War II to test newly synthesized antimalarial drugs for their clinical effectiveness. Early in the war, the Japanese had cut off most of the world’s supply of the antimalarial quinine. James Shannon, then a renal physiologist at New York University, was put in charge of this program. Shannon had the remarkable capacity to pick the bright young people to carry out research on the antimalarial project. Members of the team that worked at Goldwater in addition to Steve Brodie were Sid Udenfriend, Robert Berliner, Bob Bowman, Tom Kennedy, and Gordon Zubrod. The atmosphere at Goldwater was highly stimulating, and an outpouring of important new findings resulted. It was in this atmosphere that, in a period of a few years, I became a researcher.

After completion of the studies on acetanilide and phenacetin, Brodie invited me to stay on at Goldwater to study the fate of other analgesic drugs. We received a small grant from the Institute for the Study of Analgesic and Sedative Drugs, and the Laboratory of Industrial Hygiene paid my salary. Another drug we investigated was the analgesic antipyrine. A sensitive method for the detection of this drug was developed, which has since been used by other investigators as a marker to determine the activity of drug-metabolizing enzymes in vivo. We identified 4-hydroxyantipyrine and its sulfate conjugate as metabolites of antipyrine. We also observed that antipyrine distributed in the same manner as body water. Because of this property, antipyrine has been used for the measurement of body water. Another analgesic we studied was aminopyrine. Many of the drugs whose fate Brodie and I studied were later used by many investigators as substrates for the microsomal drugmetabolizing enzymes: aminopyrine for N-demethylation, phenacetin for O-dealkylation, and aniline for hydroxylation. Together with Jack Cooper, we developed a method for measuring the anticoagulant dicoumerol in plasma. In a study on the disposition of dicoumerol in humans, an exceedingly wide difference in the plasma levels of this drug was found, suggesting genetic differences in drug metabolism.

Move to the National Heart Institute

Because I did not have a doctorate degree, I realized that I would have little chance for advancement in any hospital attached to an academic institution. I had neither the inclination nor the money to spend several years getting a Ph.D., so I decided to join the National Heart Institute as a research chemist. In 1949, Shannon was chosen as the director of the newly organized National Heart Institute in Bethesda, and he offered me a position. Also coming to the National Institutes of Health (NIH) at that time were many members of the Goldwater staff—Brodie, Sidney Udenfriend, Robert Berliner, Thomas Kennedy, and Robert Bowman.

At the National Heart Institute from 1950 to 1952, I collaborated with Brodie and his staff on the metabolism of analgesics and adrenergic blocking agents and the actions of ascorbic acid on drug metabolism. After a while, I became dissatisfied with working with a large team and was allowed to work independently. The first problem I chose was an examination of the physiological disposition of caffeine in humans. Very little was known about the physiological disposition and metabolism of this widely used compound. A method for measuring caffeine in biological material was developed, and the plasma half-life and distribution were determined (Axelrod and Reichenthal, 1953). Because of my work on analgesics and caffeine, I was delighted to be elected without a doctorate as a member of the American Society of Pharmacology and Experimental Therapeutics in 1953. K.K. Chen and Steve Brodie were my sponsors.

At that time, I became intrigued with the sympathomimetic amines. In 1910, George Barger and Henry Dale reported that numerous B-phenylethanolamine derivatives simulated the effects of sympathetic nerve stimulation with varying degrees of intensity and precision. They coined the term sympathomimetic amines. Sympathomimetic amines such as amphetamine, mescaline, and ephedrine also produced unusual behavioral effects. In 1952 very little information concerning the metabolism and physiological disposition of these amines was known. Because of my experience in drug metabolism, I decided to undertake a study on the fate of ephedrine and amphetamine. In retrospect, this was an important decision.

The first amine that I studied was ephedrine. Ephedrine, the active principle of Ma Huang, an herb used by ancient Chinese physicians, was introduced to modern medicine by Chen and Schmidt in 1930. I soon found that ephedrine was transformed in animals by two pathways (demethylation and hydroxylation) to yield metabolic products that had pressor activity. Various animal species showed considerable differences in the relative importance of these two metabolic routes. The next sympathomimetic amines I examined were amphetamine and methylamphetamine. These compounds were shown to be metabolized by a variety of metabolic pathways including hydroxylation, demethylation, deamination, and conjugation. Marked species variations in the transformation of these drugs were also observed.

The Discovery of the Microsomal Drug Metabolizing Enzymes

When amphetamine was given to rabbits, it disappeared without a trace. This puzzled me, so I decided to look for enzymes that metabolized this drug. I had no experience in enzymology, but there were many outstanding enzymologists in Building 3 on the NIH campus where my laboratory was located. Gordon Tomkins, who occupied the lab bench next to mine, offered me good advice. Gordon had the capacity of demystifying enzymology and told me that all I needed to start in vitro experiments was a method of measuring amphetamine, an animal liver, and a razor blade. I did my first in vitro experiment with rabbit liver in January 1953. When rabbit liver slices were incubated in Krebs-Ringer buffer solutions with amphetamine, the drug was almost completely metabolized. On homogenization of the rabbit liver, amphetamine was not metabolized unless cofactors such as DPN (NAD), TPN (NADP), and ATP were added. I then decided to examine which subcellular fraction was responsible for transforming amphetamine. Hogeboom and Schneider had just described a reproducible method for separating the various subcellular fractions by homogenizing tissue in isotonic sucrose and subjecting the homogenate to differential centrifugation. After separation of nuclei, mitochondria, microsomes, and the cytosol, none of these fractions were able to metabolize amphetamine, even in the presence of added cofactors. However, when the microsomes and cytosol were combined, amphetamine rapidly disappeared on the addition of DPN, TPN, and ATP. At that time Bert La Du, a colleague at the NIH, observed that the demethylation of aminopyrine in a dialyzed rat liver whole homogenate required TPN. In a subsequent experiment I found that amphetamine was metabolized in a dialyzed preparation of microsomes and cytosol in the presence of TPN, but not DPN or ATP. However, when microsomes and cytosol were separately incubated, little or no drug was metabolized, despite the addition of TPN. I realized then that I was dealing with a unique enzymatic reaction.

Before I went further, I decided to identify the metabolic products of amphetamine produced when the combined microsomes and cytosolic fraction were incubated with TPN. One of the possible metabolic pathways might be deamination, leading to the formation of phenylacetone. After incubation of amphetamine with the above preparations, phenylacetone and ammonia were identified. These results indicated that amphetamine was deaminated by an oxidative enzyme requiring TPN either in the microsomes or cytosol to form phenylacetone and ammonia. Because of its properties and the structure of its substrate, it was apparent that this enzyme differed from another deaminating enzyme, monoamine oxidase.

Where was the enzyme located, in the microsomes or the soluble supernatant fraction? An approach that I used to locate the enzyme was to heat each fraction for a few minutes at 55°C, a temperature that would destroy heat-sensitive enzymes. When the cytosol was heated to 55°C and then added to unheated microsomes and TPN, amphetamine was deaminated. When the microsomes were heated and added to the cytosolic fraction together with TPN, amphetamine was not metabolized. This was a crucial experiment, which demonstrated that a heat-labile enzyme that deaminated amphetamines was localized in the microsomes and that the cytosol provided factors involving TPN necessary for this reaction.

Bernard Horecker, then working in Building 3, prepared several substrates for the TPN-requiring dehydrogenase for his classic work on the pentose phosphate pathway. He generously supplied me with these substrates, which I could test on my preparation. I found that the addition of glucose-6-phosphate, isocitric acid, or phosphogluconic acid, together with TPN, to unwashed microsomes transformed amphetamine. A reaction common to these substrates is the generation of TPNH, suggesting that the enzymes in the cytosol fraction were reducing TPN. Incubating microsomes with a TPNH-generating system using glucose-6-phosphate and glucose-6-phosphate dehydrogenase resulted in the deamination of amphetamine. On incubation of chemically synthesized TPNH, microsomes, and oxygen, amphetamine was deaminated. At about the same time, I also found that ephedrine was demethylated to norephedrine and formaldehyde by enzymes present in rabbit microsomes that required TPNH and oxygen. By the end of June 1953, I felt confident that I had described a new enzyme that was localized in the microsomes, required TPNH and oxygen, and could deaminate and demethylate drugs. I reported these findings at the 1953 fall meeting of the American Society of Pharmacology and Experimental Therapeutics (Axelrod, 1954).

After the description of the TPNH-requiring microsomal enzymes that deaminated amphetamine and demethylated ephedrine, several members of the Laboratory of Chemical Pharmacology at the NIH described similar enzyme systems that could metabolize other drugs by a variety of pathways: N-demethylation of aminopyrine (La Du, Gaudette, Trousof, and Brodie), oxidation of barbiturates (Cooper and Brodie), and the hydroxylation of aniline (Mitoma and Udenfriend) as reviewed in the Annual Review of Biochemistry (Brodie et al., 1958). In a study of the N-demethylation of narcotic drugs that I made soon after, it became apparent that there were multiple microsomal enzymes that required TPNH and O₂ (Axelrod, 1956a). Research on the microsomal enzymes (now called cytochrome-P450 mono-oxygenases) has expanded enormously and has had a profound influence on biomedical science, ranging from studies of metabolism of normally occurring compounds to carcinogenesis. In retrospect, the discovery of the microsomal enzymes is among the best work I did.

Brodie and I were struck by the findings of investigators at Smith Kline & French that SKF525A, a compound with little pharmacological action of its own, prolonged the duration of action of a wide variety of drugs. We conjectured that the compound might exert its effects by inhibiting the metabolism of drugs. The effects of SKF525A on the metabolism of ephedrine in dogs and on the metabolism and duration of action of hexabarbital in the plasma and the sleeping time in rats and dogs was examined. We found that SKF525A slowed the metabolism of ephedrine in dogs. It prolonged the presence of hexabarbital in the plasma and sleeping time in rats and dogs. Thus, the ability of SKF525A to prolong the action of drugs could be explained by its ability to slow their metabolism. As soon as the microsomal enzymes were described, it was observed that SKF525A inhibited this class of enzymes. Subsequently, SKF525A was widely used as an inhibitor of the microsomal enzymes.

The effect of the microsomal enzymes on the duration of drug actions was examined with the collaboration of Gertrude Quinn, a graduate student at George Washington University, and Steve Brodie. Because sleeping time of hexabarbital was easy to measure, we chose that drug to make this study. Jack Cooper and Brodie had found that hexabarbital was metabolized by microsomal enzymes in the liver. The sleeping time of a given dose of hexabarbital was compared with its plasma half-life and with the activity of a liver enzyme preparation using the barbiturate as a substrate in a number of mammalian species. There were considerable differences in the plasma half-life, sleeping time, and enzyme activity among the various species (Quinn et al., 1958). A high correlation was observed between the plasma half-life and sleeping time of the barbiturate. There was also an inverse relationship between the duration of action of hexabarbital and its ability to be metabolized by the microsomal enzymes.

In 1956, I reported that narcotic drugs such as morphine, meperidine, and methadone were N-demethylated by the liver, requiring TPNH and O₂ (Axelrod, 1956a). Differences in the rate of N-demethylation of various narcotic drugs in several species made it apparent that more than one enzyme was involved in their demethylation. There was also a marked sex difference in N-demethylation of narcotic drugs by rat liver microsomal enzymes. Microsomes obtained from male rats were found to N-demethylate narcotic drugs much faster than those from female rats. When testosterone was administered to oophorectomized female rats, the activity of the demethylating enzyme was markedly increased. Estradiol given to male rats decreased the enzyme activity. Subsequent work by many investigators found similar sex differences in microsomal enzyme activity for many metabolic pathways.

While working on the metabolism of narcotic drugs, I observed that repeated administration of narcotic drugs not only produced tolerance to these drugs, but also markedly reduced the ability to N-demethylate them enzymatically (Axelrod, 1956b). There was also a correlation between the rate of demethylation of opiate substrates and their cross-tolerance to morphine. Opiate antagonists not only blocked the development of tolerance, but also prevented the reduction of enzyme activity. On the basis of these observations, a mechanism for tolerance to narcotic drugs was proposed. In a paper reporting these experiments (Axelrod, 1956b) the following statement was made: “The changes in enzyme activity in morphine-treated rats suggests a mechanism for the development of tolerance to narcotic drugs. If one assumes that enzymes which N-demethylate narcotic drugs and the receptors for these drugs are closely related, then the continuous interaction of narcotic drugs with the demethylating enzymes inactivates the enzymes. Likewise, the continuous interaction of narcotic drugs with their receptors may inactivate the receptors. Thus, a decreased response to narcotic drugs may develop as a result of unavailability of receptor sites.” This hypothesis stimulated considerable critical reaction, mostly negative.

Although I had just described the physiological disposition of caffeine, demonstrated the variety of metabolic pathways of amphetamine and ephedrine, and independently described the microsomal enzymes and their role in drug metabolism, it was difficult for me to obtain a promotion to a higher rank at the National Heart Institute because I had no doctorate. I decided to get a Ph.D. degree at George Washington University, because few courses were required if a candidate already had an M.S. degree. However, it would be necessary to take demanding comprehensive examinations in several subjects. Paul K. Smith, then chairman of pharmacology, accepted me as a graduate student in his department. He allowed me to submit my work on the metabolism of sympathomimetic amines and the microsomal enzymes for my dissertation. I took a year off to attend courses at George Washington University, and I found going back to school pleasant and challenging. A few of the medical students did better than I did on the pharmacology examinations. On one occasion a question was asked on a multiple-choice examination on antipyrine, a compound on which I published several papers, and I gave the wrong answer. After a year’s study, I passed a tough comprehensive examination, and my thesis, “The Fate of Phenylisopropylamines,” was accepted. In 1955, at the age of 42 years, I received my Ph.D.

Setting Up A Laboratory at the National Institute of Mental Health

While studying for my Ph.D., I was invited by Edward Evarts to set up a Section of Pharmacology in his Laboratory of Clinical Sciences at the National Institute of Mental Health (NIMH). To get started in my new position at the NIMH I took a few afternoons off my classes at George Washington University to do laboratory work. I thought that a study of the metabolism and distribution of LSD would be an appropriate problem for my new laboratory at the NIMH. LSD was then used as an experimental drug by psychiatrists to study abnormal behavior. Bob Bowman at the NIH was in the process of building a spectrofluorometer. He was kind enough to let me use his experimental model, which allowed me to develop a very sensitive fluorometric assay for LSD. This made it possible to measure the nanogram amounts found in brain and other tissues. This instrument later became the well-known Aminco Bowman spectrofluorometer. The availability of this instrument made it possible for many laboratories to devise sensitive methods for the measurement of endogenous epinephrine, norepinephrine, dopamine, and serotonin in brain and other tissues. These newly developed methods for biogenic amines were crucial in the subsequent rapid expansion in neurotransmitter research.

Just before I left the Heart Institute, I read a report in the literature that uridine diphosphate glucuronic acid (UDPGA) was a necessary cofactor for the formation of phenolic glucuronide in a cell-free preparation of livers. Jack Strominger, a biochemist then at the NIH, and I discussed the possible mechanism for the enzymatic synthesis of UDPGA. We suspected that it would arise from the oxidation of uridine diphosphate glucose (UDPG) by either TPN or DPN. We obtained a sample of UDPG from Herman Kalckar and did a preliminary experiment in which I measured the disappearance of morphine in guinea pig liver. When morphine was incubated with guinea pig liver microsomes and the soluble fraction with DPN and UDPG, morphine was metabolized; TPN had no effect. When either DPN or UDPG, soluble fraction, or liver was omitted, the disappearance of morphine was negligible. After a period of incubation during which the mixture was heated in 1N HCl, the morphine that disappeared was recovered. These experiments suggested that morphine was enzymatically conjugated in the presence of UDPG and DPN, presumably by the formation of UDPGA followed by morphine glucuronide formation. I had little time to continue this problem because I was in the process of getting my Ph.D. Strominger and co-workers then went on to purify an enzyme UDPG dehydrogenase that formed UDPGA from UDPG and DPN.

After completion of my Ph.D., I returned to the glucuronide problem in my new laboratory at the NIMH. As expected from my preliminary experiment with morphine, I found that morphine and other narcotic drugs formed glucuronide conjugates by an enzyme present in liver microsomes that required UDPGA. Working together, Joe Inscoe, a graduate student at George Washington University, and I showed that glucuronide formation could be induced by benzpyrene and 3-methylcholanthrene.

The work on glucuronide conjugation led to a study on the role of glucuronic acid conjugation on bilirubin metabolism. Rudi Schmid, then at the NIH, made the interesting observation that bilirubin was transformed to a glucuronide. Schmid and I then went on to describe the enzymatic formation of bilirubin glucuronide by enzymes in the liver requiring UDPGA. This conjugating enzyme served as a mechanism for inactivating bilirubin. This finding led to an interesting clinical observation concerning a defect in glucuronide formation. In congenital jaundice there is a marked elevation of free bilirubin in the blood. This fact suggested to us that something might be wrong with glucuronide formation in this disease. The availability of a mutant strain of rats (Gunn rats) that exhibited congenital jaundice made it possible to examine whether the glucuronide-forming enzyme was defective. We then went on to demonstrate that these rats showed a marked defect in the ability to synthesize glucuronides from UDPGA (Axelrod et al., 1957). Glucuronide formation was also examined in humans with congenital jaundice by measuring the rate and magnitude of plasma acetaminophen glucuronide after the administration of the acetaminophen. A defect in glucuronide formation in this disease was demonstrated.

Catecholamine Research

When I joined the NIMH, I knew very little about neuroscience. My impression of neuroscience then was that it was concerned mainly with electrophysiology, brain anatomy, and behavior. To me these subjects were somewhat strange and esoteric and concerned with complicated electronic equipment. I believed that an investigator had to be a gifted experimentalist and theorist to do research in the neurosciences. Ed Evarts, my lab chief, assured me that I could work on whatever problem I thought would be likely to yield new information. The philosophy of Seymour Kety, then head of the Intramural Programs of the NIMH, was to allow investigators working in the laboratories of the NIMH to do their research on whatever was potentially productive and important. Kety believed that without sufficient basic knowledge about the life processes, doing targeted research on mental illness would be a waste of time and money.

Instead of working on a neurobiological problem, I thought it would be best to work on one that I knew something about, and that might be appropriate to the mission of the NIMH. I began to experiment on the metabolism and physiological disposition of LSD and the enzymes involved in the metabolism of narcotic drugs. I also worked on the enzymatic synthesis of glucuronides described above.

Although the NIMH administrators were supportive of the type of research I was doing, I still felt guilty that I was not working on some aspect of the nervous system or mental illness. Dr. Kety, in a seminar to our laboratory, gave a fascinating account of the findings of two Canadian psychiatrists. They reported that adrenochrome produced schizophreniclike hallucinations when it was ingested. Because of these behavioral effects, they proposed that schizophrenia could be caused by an abnormal metabolism of epinephrine to adrenochrome. I was intrigued by this proposal. In searching the literature, I was surprised to find that little was known about the metabolism of epinephrine at that time, in 1957. In view of the provocative hypothesis about the abnormal metabolism of epinephrine in schizophrenia, I decided to work on the metabolism of epinephrine. Epinephrine was then believed to be metabolized and inactivated by deamination by monoamine oxidase. However, with the introduction of monoamine oxidase inhibitors by Albert Zeller and co-workers, it was observed that, after the inhibition of monoamine oxidase in vivo, the physiological actions of administered epinephrine were still rapidly ended. This finding indicated that enzymes other than monoamine oxidase metabolized epinephrine. A possible route of metabolism of epinephrine might be via oxidation. I spent several months looking at oxidative enzymes for epinephrine without any success.

An abstract in the March 1957 Federation Proceedings gave me an important clue regarding a possible pathway for the metabolism of epinephrine. In this abstract, Armstrong and McMillan (1957) reported that patients with norepinephrine-forming tumors (pheochromocytomas) excreted large amounts of an O-methylated product, 3-methoxy-4-hydroxymandelic acid (VMA). This finding suggested that this metabolite could be formed by the O-methylation and deamination of epinephrine or norepinephrine. The O-methylation of catecholamines was an intriguing possibility that could be experimentally tested. A potential methyl donor could be S-adenosylmethionine. That afternoon I incubated epinephrine with a homogenate of rat liver, ATP, and methionine. I did not have S-adenosylmethionine available, but Cantoni (1953) had shown that an enzyme in the liver could convert ATP and methionine to adenosylmethionine. I found that epinephrine was rapidly metabolized in the presence of ATP, methionine and liver homogenate. When either ATP or methionine was omitted or the homogenate was heated, there was a negligible disappearance of epinephrine. This experiment suggested that epinephrine was O-methylated in the presence of a methyl donor, presumably S-adenosylmethionine. In a subsequent experiment, I obtained S-adenosylmethionine and observed that incubating liver homogenate with the methyl donor resulted in the metabolism of epinephrine. The most likely site of methylation would be on the meta hydroxyl group of epinephrine to form 3-O-methylepinephrine. I prevailed on my colleague Bernhard Witkop, an organic chemist, to synthesize the O-methyl metabolite of epinephrine. A few days later Sheroh Senoh, a visiting scientist in Witkop’s laboratory, synthesized meta-Omethylepinephrine. After incubating liver and S-adenosylmethionine, the metabolite formed from epinephrine was identified as meta-O-methylepinephrine, which we named metanephrine, indicating the existence of an Omethylating enzyme. The O-methylating enzyme was purified and found to O-methylate catechols, including norepinephrine, dopamine, L-DOPA, and synthetic catechols, but not monophenols (Axelrod, 1971). In view of the substrate specificity, the enzyme was named catechol-O-methyltransferase (COMT). The enzyme was found to be widely distributed in tissues, including the brain.

Injecting catecholamines into animals resulted in the excretion of the respective O-methylated metabolites. We soon identified normally occurring O-methylated metabolites such as normetanephrine, metanephrine, 3-methoxy tyramine, and 3-methoxy-4-hydroxyphenylglycol (MHPG) in liver and brain. As a result of the discovery of the O-methylated metabolites, the pathways of catecholamine metabolism were clarified (Axelrod, 1971). Catecholamines were metabolized by O-methylation, deamination, glycol formation, oxidation, and conjugation. As a result of these findings, I then considered myself a neurochemist. This work also gave me a longlasting interest in methylation reactions that I describe later. The metabolites of catecholamines, particularly MHPG, have been used as a marker in many studies in biological psychiatry.

A major problem in neurobiology research is the mechanism by which neurotransmitters are inactivated. At the time I described the metabolic pathway for catecholamines in 1957, it was believed that the actions of neurotransmitters were terminated by enzymatic transformation. Acetylcholine was already known to be rapidly inactivated by acetylcholinesterase. However, when the principal enzymes for the metabolism of catecholamines, catechol-O-methyltransferase and monoamine oxidase, were almost completely inhibited in vivo, the physiological actions of injected epinephrine were rapidly ended. These experiments indicated that there were other mechanisms for the rapid inactivation of catecholamines.

The answer to the question of the inactivation of catecholamines came in an unexpected way. When the metabolism of catecholamines was described, Seymour Kety and co-workers set out to examine whether or not there was an abnormal metabolism of epinephrine in schizophrenic patients. To carry out this study, Kety asked the New England Nuclear Corporation to prepare tritium-labeled epinephrine and norepinephrine of high specific activity. The first batch of ³H-epinephrine that arrived in late 1957 was labeled on the 7 position, which we found to be stable. Kety was kind enough to give me some of the ³H-epinephrine for my studies. I thought it would be a good idea to examine the tissue distribution and half-life of ³H-epinephrine in animals.

About that time, Hans Weil-Malherbe spent three months in my laboratory as a visiting scientist, and together we developed methods of measuring ³H-epinephrine and its metabolites in tissues and plasma. To our surprise, when ³H-epinephrine was injected into cats, it persisted unchanged in the heart, spleen, and the salivary and adrenal glands long after its physiological effects were ended. This phenomenon puzzled us. We also found that ³H-epinephrine did not cross the blood-brain barrier. Just about this time Gordon Whitby, a graduate student from Cambridge University, came to our laboratory to do his Ph.D. thesis. I suggested that he use methods for assaying ³H-norepinephrine similar to those we used for ³H-epinephrine to study its tissue distribution. As in the case of ³H-epinephrine, ³H-norepinephrine persisted in organs rich in sympathetic nerves (heart, spleen, salivary gland). These studies gave us a clue regarding the inactivation of catecholamine neurotransmitters: uptake and retention in sympathetic nerves.

The crucial experiment that established that catecholamines were selectively taken up in sympathetic neurons was suggested by George Hertting from the University of Vienna, who joined my laboratory as a visiting scientist. In the next experiment, the superior cervical ganglia of cats were taken out of one side, resulting in a unilateral degeneration of sympathetic nerves in the salivary gland and eye muscles. On the injection of ³H-norepinephrine, radioactive catecholamine accumulated on the innervated side, but very little appeared on the denervated side (Hertting et al., 1961). This simple experiment clearly showed that sympathetic nerves take up and store norepinephrine. In another series of experiments, Hertting and I found that injected ³H-norepinephrine taken up by sympathetic nerves was released when these nerves were stimulated (Hertting and Axelrod, 1961). As a result of these experiments, we proposed that norepinephrine is rapidly inactivated by reuptake into sympathetic nerves. Other slower mechanisms for the inactivation of catecholamines proposed were removal by the bloodstream, metabolism by O-methylation, and/or deamination by liver and kidney.

In 1961, the first postdoctoral fellow, Lincoln Potter, joined my laboratory via the NIH Research Associates Program. The NIH Research Associates Program and the Pharmacology Research Associates Program provided an opportunity for recent Ph.D. and M.D. graduates to spend two or three years in Bethesda doing full-time research. Because of the number of applicants for this program, the investigators in the Intramural Program at the NIH would get the best and brightest postdoctoral fellows. During the past 25 years more than 60 postdoctoral fellows joined my laboratory to do full-time research. With one or two exceptions, most of the postdocs who worked in my laboratory went on to productive careers in research.

When Linc Potter joined my laboratory, we directed our attention to the sites of the intraneural storage of norepinephrine. We suspected that ³H-norepinephrine, already shown to be taken up by sympathetic neurons, would label intracellular storage sites. ³H-norepinephrine was injected into rats, and their hearts were homogenized in isotonic sucrose. The various cellular fractions were then separated in a continuous sucrose gradient. There was a sharp peak of radioactive norepinephrine in a fraction that coincided with endogenous catecholamines and dopamine-Bhydroxylase, the enzyme that converts dopamine to norepinephrine. The norepinephrine-containing particles exerted a pressor response only when they were lysed. In another experiment, ³H-norepinephrine was injected, and the pineal gland, an organ rich in sympathetic nerve terminals, was subjected to radioautography and electron microscopy. Photographic grains of ³H-norepinephrine were highly localized over dense core-granulated vesicles of about 500 angstroms (Axelrod, 1971). All these experiments indicated that norepinephrine in sympathetic nerves was stored in small, dense core vesicles.

Subsequent studies with another postdoc, Dick Weinshilboum, showed that on stimulation of the hypogastric nerve of the vas deferens, both norepinephrine and dopamine-ß-hydroxylase were discharged from the nerve terminals. This finding suggested that norepinephrine and dopamine-ß-hydroxylase were colocalized in the catecholamine storage vesicles of sympathetic nerves and were then discharged together by exocytosis (Weinshilboum et al., 1971). These findings led us to the postulation that the released dopamine-B-hydroxylase would appear in the blood, which was soon confirmed. Later, our laboratory and others found abnormally low levels of plasma dopamine-ß-hydroxylase in familial dysautonomia and Down’s syndrome, and high levels in patients with torsion dystonia, neuroblastoma, and certain forms of hypertension.

As soon as it was found that catecholamines could be taken up and inactivated by reuptake into sympathetic nerve terminals, my co-workers and I turned our attention to the effect of adrenergic drugs on this process. We designed relatively simple experiments for this study, injecting the drug into rats and then measuring the uptake of injected ³H-norepinephrine in tissues. Cocaine was the first drug we examined. It had been postulated that cocaine causes supersensitivity to norepinephrine by interfering with its inactivation. After pretreatment of cats with cocaine, there was a marked reduction of ³H-norepinephrine in tissues that were innervated by sympathetic nerves after the injection of the radioactive catecholamine (Whitby et al., 1960). This experiment indicated that cocaine blocked the reuptake of norepinephrine in nerves and thus allowed large amounts of catecholamine to remain at the synaptic cleft and act on the postsynaptic receptors for longer periods of time. Using a similar approach, we observed that antidepressant drugs amphetamine and other sympathomimetic amines also blocked the uptake of norepinephrine (Axelrod, 1971). In another type of experiment, using an isolated perfused beating rat heart whose nerves had previously been labeled with ³H-norepinephrine, we found that the physiological action of sympathomimetic amines, such as tyramine, was mediated by releasing the norepinephrine from sympathetic nerves (Axelrod et al., 1962). After repeated treatment of the isolated heart with tyramine, the heart rate and amplitude of contraction were gradually reduced, presumably by the depletion of the releasable stores of the neurotransmitters. After replenishing the isolated heart with exogenous norepinephrine, the heart rate and amplitude of contraction of the isolated heart were restored. Amphetamine also released norepinephrine, and it was later shown by others that the physiological effects of the amine were due to the release of dopamine.

Most of my early work in catecholamines was done in the peripheral sympathetic nervous system. Hans Weil-Malherbe and I had found that catecholamines did not cross the blood-brain barrier. This finding made it impossible to study the metabolism, storage, and release of norepinephrine in the brain by peripheral administration of ³H-norepinephrine. It was Jacques Glowinski, a visiting scientist from France, who circumvented this problem. He devised a technique to introduce ³H-norepinephrine directly into the brain by injection into the lateral ventricle. Subsequent experiments showed that ³H-norepinephrine was mixed with the endogenous catecholamines in the brain. As in the peripheral nervous system, the ³H-norepinephrine was found to be metabolized by O-methylation and deamination. In a series of experiments we established that ³H-norepinephrine could serve as a useful tool in studying the activity of brain adrenergic nerves (Axelrod, 1971).

After labeling adrenergic neurons in the brain (Glowinski and Axelrod, 1964), we examined the effect of psychoactive drugs on brain biogenic amines. We found that only the clinically effective antidepressant drugs block the reuptake of 3H-norepinephrine in adrenergic nerve terminals. This finding, together with the observation that monoamine oxidase inhibitors have antidepressant actions and that reserpine, a depleter of biogenic amines, sometimes causes depression, led to the formulation of the catecholamine hypothesis of depression (Schildkraut, 1965). We also found that amphetamines block the reuptake as well as the release of 3Hnorepinephrine in the brain. Other investigators later showed the paranoid psychosis caused by excessive ingestion of amphetamines is due to the release of the catecholamine dopamine. One of the reasons that Les Iversen came to my lab as a postdoctoral fellow was to learn about the brain and its chemistry. Iversen and Glowinski worked extensively together in my laboratory on the effects of drugs on the adrenergic system in different areas of the brain. To conduct this study they devised a method of dissection of various parts of the brain that has become a classic procedure.

For several years our laboratory was concerned with the adaptive mechanism of the sympathoadrenal axis. One such mechanism, the induction of the catecholamine’s biosynthetic enzyme, tyrosine hydroxylase, was observed in an unexpected manner, as often happens in research. Hans Thoenen, then working in Basel, asked to spend a sabbatical year in my laboratory. He and Tranzer had observed that injected 6-hydroxydopamine selectively destroys catecholamine-containing nerve terminals (Thoenen and Tranzer, 1968). I invited Thoenen to join my laboratory and bring 6-hydroxydopamine. The first experiment that Thoenen tried was to examine the effects of the destruction of peripheral sympathetic nerves on tyrosine hydroxylase. As expected, after the injection of 6-hydroxydopamine, tyrosine hydroxylase almost completely disappeared from sympathetically innervated nerves. A surprising observation was a marked elevation of tyrosine hydroxylase in the adrenal medulla. 6-Hydroxydopamine was known to cause persistent firing of nerves. We suspected that tyrosine hydroxylase was elevated in the adrenal medulla by continuous firing of the splanchnic nerve innervating the adrenals. This supposition was confirmed when other drugs that caused prolonged nerve firing, such as reserpine and a2-adrenergic blocking agents, also increased tyrosine hydroxylase (Thoenen et al., 1969). Subsequent experiments showed that increased nerve firing induced the synthesis of new tyrosine hydroxylase molecules in nerve cell bodies and the adrenal medulla in a transsynaptic manner. Similar results were obtained with another catecholamine biosynthetic enzyme, dopamine-ß-hydroxylase.

Another regulatory mechanism for catecholamine synthesis was found by asking the right questions rather than by serendipity. The ratio of epinephrine to norepinephrine in the adrenal medulla was known to be dependent on how much of the medulla was enveloped by the adrenal cortex. In species in which the cortex is separated from the medulla, norepinephrine is the predominant catecholamine. In species in which the medulla is surrounded by the adrenal cortex, the methylated catecholamine, epinephrine, is by far the major amine. Dick Wurtman, a research associate in my laboratory, suggested an elegant experiment to determine the role of the adrenal cortex in regulating the synthesis of epinephrine. He removed the rat pituitary, a procedure that depleted glucocorticoid in the adrenal cortex, and then measured the effect on the levels of the epinephrine-forming enzyme, phenylethanolamine-N-methyltransferase (PNMT), in the medulla. I had just characterized PNMT and found that it was highly localized in the adrenal medulla. The ablation of the pituitary caused a profound decrease in PNMT in the medulla after several days (Wurtman and Axelrod, 1966). The administration of adrenocorticotropic hormone (ACTH), a peptide that increases the formation of glucocorticoids in the adrenal cortex, or the injection of the synthetic glucocorticoid, dexamethasone, increased PNMT in hypophysectomized rats almost to normal values.

Methyltransferase Research

After the description of catechol-O-methyltransferase (COMT), I became very much involved with methyltransferase enzymes (Axelrod, 1981). I spent most of my time at the lab bench working on methylating enzymes for many years. Soon after describing COMT, I turned my attention to the enzymatic N-methylation of histamine. A major pathway for histamine metabolism occurs via N-methylation. This finding prompted a search for a potential histamine-methylating enzyme. As is the case with other methyltransferases, I suspected that the most likely methyl donor would be S-adenosylmethionine. To make the identity of the histamine methylating enzyme possible, Donald Brown, a postdoc in the lab of a colleague, and I synthesized [¹⁴C-methyl]-S-adenosylmethionine enzymatically from rabbit liver with ¹⁴C-methylmethionine and ATP. Because of its ability to label the O or N groups of potential substrates by the transfer of ³H-methylmethionine, the availability of ¹⁴C-S-adenosylmethionine led to the discovery of a number of methyltransferase enzymes. Histamine N-methyltransferase was soon found and purified and its properties described. The enzyme is highly localized in the brain, and it also has an absolute specificity for histamine. Other methyltransferases soon discovered using [¹⁴C-methyl]-S-adenosylmethionine were PNMT, hydroxyindole O-methyltransferase, the melatonin-forming enzyme, a protein carboxymethyltransferase enzyme, and a nonspecific N-methyltransferase. This latter enzyme was found to convert tryptamine, a compound normally present in the brain, to N-N-dimethyltryptamine, a psychotomimetic agent.

These methyltransferase enzymes, together with [3H-methyl]-Sadenosylmethionine of high specific activity were used in developing very sensitive methods for the measurement of trace biogenic amines. We were able to detect, localize, and measure octopamine, tryptamine, phenylethylamine, phenylethanolamine, and tyramine in the brain and other tissues. The methyltransferases and [3H-methyl]-S-adenosylmethionine also made it possible to measure norepinephrine, dopamine, histamine, and serotonin in 130 separate brain nuclei. Because of the sensitivity of the enzymatic micromethods, my colleagues and I were able to show the coexistence of several neurotransmitters in single identified neurons of Aplysia (Brownstein et al., 1974). Later, Thomas Hokfelt et al. (1980), using immunohistofluorescent techniques, demonstrated the coexistence of neurotransmitters in many nerve tracts.

The Pineal Gland

I was struck by an article from Aaron Lerner’s laboratory, published in 1958, that described the isolation of 5-methoxy-N-acetyltryptamine (melatonin) from the bovine pineal gland, a compound that had powerful actions in blanching the skin of tadpoles (Lerner et al., 1958). This compound attracted my attention for two reasons: it had a methoxy group and a serotonin nucleus. The methoxy group of melatonin had a special attraction for me. Also, at that time, serotonin was believed to be involved in psychoses because of its structural resemblance to LSD. I thought it would be fun to spend some time working on the pineal gland, an organ that was a mystery to me. The best way to start was to concentrate my efforts on aspects of the problem that I was familiar with, such as O-methylation.

Herbert Weissbach expressed an interest in collaborating with me to work out the biosynthetic pathway for melatonin. Weissbach had already made important contributions on the metabolism of serotonin. The availability of S-adenosyl-1-methionine with a radioactive methyl group provided an opportunity to examine whether the pineal gland could form labeled melatonin from potential precursor compounds. When we incubated bovine pineal extracts with N-acetylserotonin and [¹⁴C-methyl]-S-adenosyl-lmethionine, a radioactive product that we soon identified as melatonin was found (Axelrod and Weissbach, 1961). Weissbach and I then purified the melatonin-forming enzyme, which we named hydroxyindole-O-methyltransferase (HIOMT), from the bovine pineal gland. We also found another enzyme that converted serotonin to N-acetylserotonin in the rat pineal gland. From these observations, we proposed that the synthesis of melatonin in the pineal proceeds as follows: tryptophan → 5-hydroxytryptophan → serotonin → N-acetylserotonin → melatonin (Axelrod, 1974). Irwin Kopin, Weissbach, and I also found that melatonin was metabolized mainly by a microsomal enzyme via 6-hydroxylation. In a study of the tissue distribution of HIOMT we observed that the enzyme was highly localized in the pineal. This finding convinced me that the pineal was a biochemically active organ containing an unusual enzyme and product and was worth further study.

During 1960 to 1962 I spent little time doing pineal research. Most of my efforts were directed toward the biochemistry of catecholamines and the effect of psychoactive drugs. In 1962, when Wurtman joined my laboratory, I thought that he should devote most of his time to catecholamine research. As a medical student Wurtman had already made an important finding that bovine pineal extracts blocked gonadal growth in rats induced by light. Although pineal research was not a fashionable subject for research then, Wurtman and I were caught up by the romance of this organ, so we decided to spend our spare time working on the pineal. We thought that a good place to start was the isolation of the gonad-inhibitory factor of the pineal. Neither of us wanted to go through a tiresome isolation and bioassay procedure, and we decided to take a chance and examine the effects of melatonin. We found that melatonin reduced ovarian weight and decreased the incidence of estrus in the rat (Wurtman and Axelrod, 1965).

Wurtman and I turned our attention to the effects of light on the biochemistry of the pineal. We found that keeping rats in the dark for a period of time increased HIOMT activity, compared to those kept in continuous light. This experiment gave Wurtman and me a biochemical marker to study how light transmits its message to an internal organ. Ariens Kappers had found that the pineal is innervated by sympathetic nerves arising from the superior cervical ganglia. This finding suggested an experiment to determine the effects of light on the pineal by removing the superior cervical ganglia and examining the effects of light and dark on the HIOMT. When the superior cervical ganglia were removed, the effects of light on HIOMT were abolished. This experiment told us that the effects of light on melatonin synthesis were mediated via sympathetic nerves arising from the superior cervical ganglia.

In 1964, Sol Snyder joined my laboratory as a postdoc, and he too was fascinated by pineal research. Quay had just made an important observation that the levels of serotonin, a precursor of melatonin, in the pineal are high during the day and low at night. Snyder and I developed a very sensitive assay for measuring serotonin in a single pineal. This gave us the opportunity to study how the serotonin rhythm, which can serve as a marker for the melatonin rhythm, is regulated by light in a tiny organ such as the pineal. We found that in normal rats in continuous darkness, or in blinded rats, the daily serotonin rhythm in the pineal persisted (Snyder et al., 1965). This finding indicated that the indoleamine rhythms in the pineal were controlled by an internal clock. Keeping rats in constant light abolished the circadian serotonin rhythm, showing that light somehow stopped the biological clock. These experiments were the first demonstration that the rhythms of indoleamines in the pineal were endogenous and that they were synchronized by environmental light stimuli. We found that the circadian serotonin rhythm was abolished after ganglionectomy and also after decentralization of the superior cervical ganglion, indicating that the circadian clock for the serotonin and presumably the melatonin rhythm resided somewhere in the brain. Wurtman and I published an article in Scientific American in which we suggested that the pineal serves as a neuroendocrine transducer, converting light signals to hormone synthesis via the brain and noradrenergic nerves (Wurtman and Axelrod, 1965).

Harvey Shein, a psychiatrist at McLean Hospital, Wurtman, who was then at the Massachusetts Institute of Technology (MIT), and I decided to see whether the rat pineal in organ culture metabolized tryptophan to melatonin, and it did. This finding provided an opportunity to examine whether the neurotransmitter of the sympathetic nerve, norepinephrine, could affect the synthesis of melatonin in pineal organ culture. The addition of norepinephrine to rat pineals in organ culture increased the synthesis of melatonin from tryptophan. Shein and Wurtman then showed that noradrenaline specifically stimulated the ß-adrenergic receptor.

For two years after 1970 I did little work on the pineal until Takeo Deguchi, a biochemist from Kyoto, joined my laboratory. Because interest in receptors was beginning to grow at that time, we decided that the pineal gland would be a good model to study the regulation of the ß-adrenergic receptor. The activity of the ß-adrenergic receptor could be determined by measuring changes in serotonin N-acetyltransferase (NAT). David Klein previously showed that pineal serotonin NAT had a marked circadian rhythm that was controlled by a ß-adrenergic receptor (Klein and Weller, 1970). Deguchi and I devised a rapid assay for NAT and soon confirmed Klein’s findings. We then found that the nighttime rise in NAT was abolished by ß-adrenergic blocking agents, reserpine, decentralization, ganglionectomy, and agents that inhibit protein synthesis (Axelrod, 1974). This finding told us that noradrenaline released from sympathetic nerves innervating the pineal gland stimulated the B-adrenergic receptor, which then activated the cellular machinery for the synthesis of NAT. Blocking the ß-adrenergic receptor with propranolol at night or exposing rats to light also caused a rapid fall in NAT. These results indicated that unless the ß-adrenergic receptor is stimulated by norepinephrine at a relatively high frequency, NAT rapidly decays. We thought that the rapid synthesis and decrease in NAT would provide a useful model to study the molecular events in receptor-linked synthesis of a specific protein (NAT) leading to the formation of a hormone (melatonin).

The regulation of supersensitivity and subsensitivity of receptors is an important biological problem. The rapidly changing pineal NAT provided a productive approach to study the mechanism of super- and subsensitivity of the ß-adrenergic receptor (Axelrod, 1974). Procedures that depleted the neuronal input of noradrenaline in the rat pineal (denervation, constant light, or reserpine) caused a superinduction of NAT when rat pineals were cultured and treated with the ß-adrenergic agonist, 1-isoproterenol. When pineal ß-adrenergic receptors were repeatedly stimulated by injections of 1-isoproterenol into rats, the cultured pineals became almost unresponsive to the ß-adrenergic agonist. In collaboration, my postdoctoral fellows Jorge Romero and Martin Zatz and I showed that the regulation of NAT and subsequent melatonin synthesis consists of a complex series of steps involving B-adrenergic receptors, cyclic AMP, cyclic GMP, protein kinases, specific activation of mRNA for NAT, and synthesis of NAT. Decreased nerve activity induced by light caused an increase in receptor number and adenylate cyclase and kinase activity. This cascade of events then explained why a small change in release of noradrenaline from nerves causes a large change in pineal NAT. With the onset of darkness, there is an increase in sympathetic nerve activity that acts on the supersensitive receptor, cyclase, kinase, etc. This, we believed, considerably amplifies the signal (norepinephrine) to cause the large nighttime rise in NAT formation. Klein later showed that norepinephrine acting on an al-adrenergic receptor further amplified the NAT levels.

Later, most of the research in my laboratory was concerned with how neurotransmitters transmit their specific messages. Fusao Hirata, a visiting scientist in my laboratory, and I observed that the occupation of certain receptors stimulated the methylation of phospholipids. On the basis of these findings we proposed a mechanism for the transduction of biological signals (Hirata and Axelrod, 1980). This proposal generated considerable controversy, and the role of phospholipid methylation in signal transduction still remains to be resolved. With the collaboration of several postdoctoral fellows, we reported on the interaction of stress hormones (catecholamines, ACTH, and glucocorticoids) and the multireceptor release of ACTH (Axelrod and Reisine, 1984).

Recent Research

In 1984, I retired from government service at the age of 72. I had no intention to stop doing research. Fortunately I was invited to join the Laboratory of Cell Biology at the NIMH as a visiting scientist by my former postdoc, Mike Brownstein. Mike generously gave me laboratory space, a small office, and funds to continue my research.

About the time I retired, an explosive growth occurred in our knowledge concerning neurotransmitter receptors and how they transduce their specific messages into the cell. It was observed that ligands bind to receptors and activate GTP binding proteins (G proteins). G proteins are heterotrimers composed of α, β, and γ subunits. On activation, the G protein dissociates into α and βγ subunits (Birnbaumer, 1990). The α subunit then stimulates effector systems to generate second messengers. My interest in phospholipase A₂ as an effector enzyme and arachidonic acid as a second messenger stemmed from a previous observation that the chemotactic peptide f-met-leu-phe liberated arachidonic acid from neutrophils (Hirata et al., 1979). A direct association between the amount of arachidonic acid released by f-met-leu-phe and the extent of chemotaxis was found.

Using a thyroid cell line, FRTLS, we (Burch et al., 1986) found that noradrenaline via an α₁-adrenergic receptor stimulated the release of arachidonic acid and the two second messengers of phospholipase C, inositol triphosphate and diacylglycerol. This finding provided an opportunity to examine whether arachidonic acid arises from phospholipase A₂ or phospholipase C. The belief at that time was that arachidonic acid is released by diacylglycerol generated from phospholipase C. In a series of experiments using inhibitors of α₁-noradrenergic agonists, phospholipase C activators and inhibitors of G proteins, we demonstrated that the noradrenaline via an α₁-adrenergic receptor can release arachidonic acid by the activation of phospholipase A₂ and that this phospholipase is linked to G proteins. The characterization of the G protein associated with phospholipase A₂ remains to be determined. Subsequently, my postdocs and I have found that several neurotransmitter receptors such as bradykinin; muscarinic m₁, m₃ and m₅ receptors; and the cytokine interleukin-1 activate phospholipase’ A₂ and release arachidonic acid as a second messenger via G proteins (Axelrod, 1990). We and others have shown that stimulation of a single receptor can activate G proteins linked to many effectors such as adenylate cyclase, phospholipases A₂ and C, and ion channels.

The most direct evidence showing that phospholipase A₂ can activate G proteins was found by examining the effect of light on isolated rod outer segments of the bovine retina. The G protein present in rod outer segments is transducin. Like all G proteins, transducin is a heterotrimer consisting of αβγ subunits. In 1986, Carole Jelsema and I found that the βγ dimer of transducin can activate phospholipase A₂ in the rod outer segments. These observations contradicted the dogma at that time that only the α subunit can activate effector systems. The βγ dimer also serves to reassociate with the α subunit to terminate the actions of the receptor ligand (Birnbaumer, 1990). We submitted our findings to Nature and after many months of review our manuscript was rejected. Our findings on the effect of the βγ dimer were subsequently published in the Proceedings of the National Academy of Sciences (Jelsema and Axelrod, 1987). Subsequently, many papers were published showing that the βγ dimers can activate many effectors (Clapham and Neer, 1993) such as phospholipase C, receptor kinase, yeast mating factor, adenylate cyclase, and ion channels.

Because of my long-standing interest in psychoactive drugs, my coworkers and I have been involved for the past few years in an investigation of cannabinoids. The hemp plant Cannabis sativa, the source of marijuana and hashish, has been used for thousands of years for its medicinal and euphoric effects. The psychoactive principle of marijuana was isolated and identified as delta-9-tetrahydrocannabinol (THC). About 35 years ago my colleagues and I reported on the physiological disposition and metabolism of ¹⁴C-THC in humans (Lemberger et al., 1970). We found that ¹⁴CTHC and its metabolites were excreted for more than eight days. THC was then shown to be stored in body fat (Kreuz and Axelrod, 1973).

My interest in cannabinoids was recently revived by the identification and cloning of the cannabinoid receptor in the brain by my colleagues in the Laboratory of Cell Biology (Matsuda et al., 1990). This receptor was found to be a member of the G protein superfamily that spans the plasma membrane seven times. The cannabinoid receptor is functionally coupled to the inhibition of adenylate cyclase and N-type calcium channels (Felder et al., 1993). The presence of a cannabinoid receptor in the brain indicated the existence of a natural ligand for this receptor. The endogenous ligand for the cannabinoid receptor was isolated from the brain, identified as arachi-donylethanolamide and named anandamide (Devane et al., 1992), derived from ananda, the Sanskrit word for bliss. Anandamide was found to bind to the transfected human cannabinoid receptor with high affinity and to inhibit adenylate cyclase and N-type calcium channels (Felder et al., 1993). When injected into rodents, anandamide induces hypomotility and hypothermia (Crawley et al., 1993).

The enzyme that synthesizes anandamide was found in brain membranes (Devane and Axelrod, 1994). This enzyme, anandamide synthase, acts by conjugating arachidonic acid and other fatty acids with ethanolamine. Arachidonic acid was found to be the best substrate for this enzyme.

Anandamide synthase activity was found to be highest in the hippocampus followed by thalamus, cortex, and striatum, and lowest in the cerebellum, pons, and medulla. The ability of brain tissues to synthesize anandamide enzymatically, and the presence of specific receptors for this compound suggest the presence of anandamide-containing (anandaergic) neurons. Experiments with cultured brain cells demonstrated a receptor-evoked synthesis and release of anandamide from neurons, suggesting that anandamide is a novel neurotransmitter.

Little is known about the physiological role of anandamide and its pharmacological effects at high doses. Recent experiments using hippocampal slices showed that anandamide can inhibit long-term potentiation, a form of memory. Anandamide also blocks long-term transformation of GABAergic synaptic inhibition to synaptic excitation (Collin et al., 1995). Research on anandamide has a promising future. It has the potential to become a member of a new class of neurotransmitters (fatty acid amides) and I hope to be occupied with research on this compound for some time.

Afterword

F. Scott Fitzgerald once stated that there are no second acts in American lives. After a mediocre first act, my second act was a smash. So far the third act has not been so bad. I often reflect on why I succeeded in research. For someone with my educational, social, and economic background it would be unlikely that I would have made it. In today’s climate of intense competition for positions and funds it would have been almost impossible for a late bloomer like myself to get started. I soon learned that it did not require a great brain to do original research. One must be highly motivated, exercise good judgment, have intelligence, imagination, determination, and a little luck. One of the most important qualities in doing research, I found, was to ask the right questions at the right time. I learned that it takes the same effort to work on an important problem as on a pedestrian or trivial one. When opportunities came I made the right choices.

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Peter O. Bishop

BORN:

Tamworth, New South Wales, Australia

June 14, 1917

EDUCATION:

University of Sydney, M.B., B.S., 1940

University of Sydney, D.Sc., 1967

APPOINTMENTS:

Royal Prince Alfred Hospital, Sydney (1941)

University of Sydney (1946)

Australian National University, Canberra (1967)

Professor Emeritus, Australian National University (1983)

HONORS AND AWARDS (SELECTED):

Fellow, Australian Academy of Science (1967)

Fellow, Royal Society of London (1977)

Officer of the Order of Australia (1986)

Australia Prize (Jointly, 1993)

Peter Bishop is best known for his pioneering neurophysiological work on the cat optic nerve, lateral geniculate body, and striate cortex, where he characterized neurons involved in stereopsis. In addition, he developed some of the first mathematical models of the eye itself, which were essential in guiding the neurophysiological work.

Peter O. Bishop

Family History¹

My forebears, both paternal and maternal, lived in southern England. For a time immediately after World War II, I also lived in England and was able to get in touch with my Bishop relatives and, off and on over the years since then, I have kept up the association. My grandfather, Herbert Orlebar Bishop, was born at Barnstaple in Devon. The name Orlebar, originally Orlingberga, is of Norman origin. I am descended from Richard Orlebar (1736–1803) of Hinwich in Bedfordshire. The Orlebar name came into the Bishop family when Richard Orlebar’s granddaughter married into the family in 1812.

In 1870 at the age of 19 my grandfather migrated to Australia, where he was employed as a “line repairer” in the Department of Post and Telegraph in Queensland. Even at that time, Queensland was sparsely populated. Free European settlers had arrived only in the 1840s, and Queensland was the last of the Australian states to become a separate colony. Herbert subsequently became officer-in-charge of various post offices in remote settlements and later in country towns. He remained with the department for the remainder of his working life.

Herbert married Amy Cowan in 1876; my father, Ernest, born in 1877, was the eldest of their six children. With Herbert posted to the settlements of Cunnamulla and Port Douglas, both remote from Brisbane, my father had little, if any, formal education in his early years. At about age 12, he was sent from Port Douglas to the state school at Yeppoon near Rockhampton, 640 miles to the south. At age 14, he was a state scholar and became a boarder at the grammar school in Toowoomba. After leaving school, my father served as an “apprentice,” training as a surveyor for entry into the New South Wales Department of Lands. He spent his early years in the department camping in the field, mostly in fairly wild country carrying out surveys for roads and settlements in the northeastern parts of New South Wales. He remained with the department, finally becoming district surveyor for the land district of Armidale from 1924 until his retirement in 1941.

My maternal great-grandfather, George Vidal, was born in 1815 in Spanish Town, Jamaica, of English parents. For his schooling, he was sent to Eton in England, and subsequently to Trinity College, Cambridge. He graduated with a B.A. in 1839. He was determined to become an Anglo-Catholic missionary and, with that in mind, migrated to Australia in 1840. Soon after his arrival in Sydney, he was ordained into the Church of England. He made a brief visit to England in 1845, where he married Jane Creak before returning to Sydney. My grandfather, Henry Vidal, was the eighth of my great-grandparents’ 10 children. Henry was a public servant in the New South Wales Harbours and Rivers Department. My mother, Mildred, was the fourth of nine children.

I was born at Tamworth, New South Wales, in 1917, the second of my parents’ five children. I was seven years old when my father became the district surveyor in Armidale, a town some 360 miles north of Sydney. The family moved to Armidale, and I attended the state primary and high schools there. At age 14, I became a boarder at Barker College, Hornsby, on the outskirts of Sydney. The Depression was then at its height and the school was small, with only 78 pupils. I enjoyed mathematics and physics the most and my original intention was to study engineering at the university. I was not particularly attracted to medicine. As a result of my mother’s influence, however, I finally decided to enter the medical school at Sydney University.

Medical School and Hospital, 1935–1942

In the 1930s, the medical school was dominated largely by clinicians in private medical practice, and relatively little research was done. Biochemistry became a separate department only in 1938, and pharmacology in 1949. Lectures in the various disciplines were of an introductory nature, hardly suited to form the basis for a career in research. However, I have never regretted my decision to enter medical school, although I always wished I could have had a better grounding in mathematics.

During the medical course, I was attracted to anatomy, particularly neuroanatomy. In the third year, I dissected a brain. I will never forget the fascination of actually holding a human brain in my hands and realizing that it once belonged to a person like myself with the same sorts of thoughts and feelings as I had. This experience had a tremendous impact on me, and from then on I never questioned that I would try to make a career in brain research.

In the 1920s and 1930s, most of the exciting brain research was done by anatomists rather than physiologists, at least it seemed so to me. I read all I could of the works by people like Arthur Keith, Grafton Elliot Smith, W.E. Le Gros Clark, and F. Wood Jones. As a result of my third year neuroanatomical dissections and my general reading, I wrote an article, “The Nature of Consciousness,” that was published in the Sydney University medical journal. This article brought me to the attention of the professor of anatomy, A.N. Burkitt, and to A.A. Abbie. Dr. Abbie, senior lecturer in anatomy, subsequently published a reply to my article in the medical journal. His paper, also titled “The Nature of Consciousness,” was largely a refutation of the ideas I had put forward, but his criticism was kindly. I became friendly with him and, through him, with Burkitt. Abbie subsequently became professor of anatomy in Adelaide, and I saw little of him after my undergraduate days. However, I kept up my friendship with the members of the department of anatomy in Sydney until Burkitt’s retirement from the chair in 1955.

When England declared war on Germany in September 1939, many of the resident medical officers in the hospitals immediately joined the armed services. Consequently, the medical course was shortened and my class graduated early, in 1940. In the final year, although we had yet to graduate, we worked in hospitals in place of those who had gone to war. I was in residence in the Royal Prince Alfred Hospital, where I spent a great deal of my final year in the operating theaters giving open ether anesthesia.

By that time, my interest in neurology was fairly well known and, after graduation, I was offered the position of resident medical officer in charge of neurosurgery, a position that would ordinarily have been taken by a senior resident. In neurosurgery I was under Professor (Sir Harold) Dew and Gilbert Phillips, both of whom were to have an important influence on my career. Dew was one of the pioneers of neurosurgery in Australia, and Phillips was a rising star in the field. In 1941, I was made neurological registrar responsible for both neurosurgery and psychiatry.

Another major event took place at this time that was to have a profound effect on my life. I met Hilare Louise Holmes, a member of the nursing staff in the neurosurgical operating theater. We were married in February 1942, just after I was called up for service in the navy.

World War II, 1942–1946

As a surgeon lieutenant, I served at sea in the Atlantic, Indian, and Pacific Oceans, first on the cruiser Adelaide and then on the destroyer Quiberon. Toward the end of the war, I was stationed at Madang on the north coast of New Guinea. Although the war with Japan ended in August 1945, I was unable to return to Sydney until early 1946. While I was in Madang, I applied for, and was awarded, a fellowship of the Postgraduate Committee in Medicine of the University of Sydney. As a result of my association with Gilbert Phillips, an arrangement was made for me to go to Oxford to work under Sir Hugh Cairns. During the war, Phillips had joined Cairn’s neurosurgical unit in the course of the North African Campaign, so he was well known to Sir Hugh.

By the time Hilare and I sailed for England in July 1946, we had two small children, one about two and one-half years and the other just over a year old. Our ship, the Stirling Castle, was still under troopship conditions, with many service personnel returning to England from duty in the Far East. Men and women had separate accommodations. I shared a 14-berth cabin, but fortunately my wife had a separate cabin for herself and the children. We sailed nonstop from Fremantle, in Western Australia, to Southampton, England. With Oxford full of returning servicemen and women, we were unable to find suitable accommodation in the city, and we finally leased an old cottage in Wiltshire on top of the Downs not far from the picturesque village of Ham. On the National Grid, the ordnance survey for England and Wales, the cottage was appropriately called Bishop’s Barn! I trained in London during the week and traveled down to Wiltshire at the weekend. Later the family moved to London.

Oxford and London, 1946–1950

In my application to the postgraduate committee at Sydney University, I proposed to study the neuropsychiatric defects in persons who had suffered relatively localized cerebral gunshot wounds. By the time I arrived in Oxford, my original plans had become rather hazy. Cairns certainly had the impression that I had come to train as a neurosurgeon. His idea was that I should spend some time training in clinical neurology at the National Hospital at Queen Square in London before going back to Oxford to resume my neurosurgical career. With this in mind, he arranged for me to be clinical clerk to Sir Charles Symonds. I found the clinical work and intellectual environment of Queen Square tremendously stimulating. In addition to Symonds, people like F.M.R. Walshe and Macdonald Critchley were there, and Gordon Holmes, although retired, was still coming in regularly. At that time, I was still thinking in terms of a clinical career. However, one day I happened into a laboratory in the basement of the hospital, where I met George Dawson working away with electronic equipment. I asked if I could come in and watch the experiment.

Dawson was one of the first people in Britain to build and use electroencephalograph (EEG) amplifiers in a clinical setting and, when I first met him, he was making EEG recordings from patients with myoclonic epilepsy. He was also trying to find out whether it was possible to record potentials from the scalp of normal subjects after electrical stimulation of the ulnar nerve at the wrist or elbow. I soon became the normal subject, with stimulating electrodes at my wrist and elbow. Dawson is universally recognized as the pioneer of averaging techniques in the recording of biological potentials. However, the potentials he recorded from my scalp were particularly marked, barely needing the photographic averaging by the superimposition of the cathode-ray traces. So, when Dawson (1947) published the first records of evoked potentials to be obtained from a normal subject, the records he used for the illustrations came from my scalp. This experience made me realize that I was better suited to laboratory than clinical research and, about the middle of 1947, I gave up any idea of going back to Oxford to pursue a neurosurgical career.

University College of London, 1947–1950

With my stipend paid from Australia, I approached Professor E.A. Carmichael, director of the research unit at the National Hospital, about the possibility of getting a research appointment at the hospital. Perhaps not surprisingly, he showed little enthusiasm when I told him I was 30 years old and had never done any research. However, he did arrange for me to see C. Lovatt Evans, professor of physiology at University College of London. Lovatt Evans was soon to retire, so he in turn referred me to J.Z. Young, “that young man from Oxford” who just the year before had been appointed to the chair of anatomy at the college. Young took me on immediately and gave me a big empty room on the top floor of the anatomy building in a section that seemed to form part of A.V. Hill’s Biophysics Research Unit.

Bernard (later Sir Bernard) Katz had a laboratory just across the corridor from my room. I remember going to see him when I first arrived. He was excited about a little response from a stimulated medullated nerve that he had just observed for the first time, now called the local response that precedes and initiates the nerve action potential. He pointed out to me the little wiggle on the cathode-ray tube trace, but I could neither see nor understand what he was so excited about; with fast single sweeps of a short persistence cathode-ray tube trace, one has to be trained to see such things.

Professor Young suggested that I investigate the claim that changes in the EEG record had been obtained in rabbits as a result of some learning procedures. So I had a research project, an empty room, no research training, and no knowledge of electronics. I was grateful to Professor Young for the generous, but general, support he gave me while I was at University College, but I was never given a research supervisor, so I worked entirely on my own.

It seemed to me that a direct-coupled amplifier was needed to record both resting potentials and the low-frequency EEG waves. Knowing no electronics, I enrolled in a course at the Northampton Polytechnic and attended classes two or three nights a week for two years. Unfortunately, the course dealt with amplifiers, pulse generators, and related equipment only in the second year. I could not wait for this background theoretical knowledge because I had to start building equipment I needed for the research project. Fortunately I had the occasional, but nevertheless considerable, help from E.J. Harris, a member of the biophysics research unit. In building the equipment, I gained a reasonably good grounding in electronics and the ability to use the tools and equipment in the mechanical workshop. The first seven papers I published all concerned electronics, some of which I wrote in collaboration with Harris.

Beginning Vision Research

Meanwhile, as a result of all the reading I had been doing, I decided not to go on with the original research project. Instead, by using the rather primitive DC amplifier I had assembled, I attempted to determine whether resting potentials were associated with the highly stratified cell layers in the optic tectum of the frog. I quickly realized that the large potentials I recorded had little to do with neural activity but were due mainly to polarization potentials associated with the steel microelectrodes I was using and to the injury potentials caused by tissue damage. However, my recording from the optic tectum in the frog was the beginning of my lifelong association with the visual system.

As work on the frog might seem rather remote to the practical concerns of a hospital in Sydney, I decided to work on the mammalian visual system. My acquaintance with the tectal visual system in the frog prompted me to consider investigating the visual system in the cat. The leading investigators in the field at that time were George Bishop and James O’Leary at Washington University, St. Louis. I read their papers and decided to begin by attempting to repeat their main observations.

Work in neurophysiology at that time centered largely on problems relating to nerve conduction and neuromuscular and synaptic transmission. Little work was done on systems neurophysiology. This situation was true particularly at Washington University where Bishop was associated with J. Erlanger and H.S. Gasser in work for which the latter two received the Nobel Prize in 1944. Erlanger and Gasser used electrical stimulation to produce a compound action potential in a frog’s sciatic nerve. They established the classification of the various types of fibers to be found in a peripheral nerve, designated A, B, and C in descending order of conduction velocity and, in the case of myelinated nerve, also in descending order of fiber diameter. It was, therefore, not surprising that Bishop and O’Leary were using electrical stimulation of the optic nerve in the cat to study the different groups of fibers in the nerve and tract based on their conduction velocities and were attempting to interpret the field potentials associated with synaptic transmission in the lateral geniculate nucleus and cerebral cortex. As I had already decided to work on the visual system in the cat, it was also not surprising that I came to work on the same problems and use much the same general techniques as those of Bishop and O’Leary.

Use of the cat as the experimental animal required the development of a range of new equipment, most of which was not commercially available at the time. This additional equipment included an electronic stimulator, a suitable slow time base for the oscilloscope, and a camera for recording the cathode-ray tube trace. In addition, I had to design and build a stereotaxic cat head holder and a micromanipulator for directing the recording microelectrode into the lateral geniculate nucleus. Fortunately, the recording of the nerve action potentials did not require a DC amplifier. However, the development of such an amplifier had become an obsession with me, and I continued to work on the DC amplifier design throughout much of my stay at University College. The final design was published in the American journal, Review of Scientific Instruments. Despite the effort needed to develop all this equipment, I managed to make a study of the field potentials associated with synaptic transmission in the lateral geniculate nucleus after electrical stimulation of the optic nerve. The paper was published in the Proceedings of the Royal Society.

In my last year in England, I became a fellow of the (Australian) National Health and Medical Research Council (NH&MRC). Before that I had been a fellow of the Sydney University Postgraduate Committee in Medicine. The postgraduate committee was extraordinarily supportive over the first three years of my stay in England, always agreeing to my various changes in plan, although the changes were made mostly without reference to the committee in Sydney. I doubt that today such a committee would so readily agree to similar changes in plan when the work was such a radical departure from a career in neurosurgery. Before I returned to Sydney early in 1950, the NH&MRC gave me a grant of £1,000 to buy equipment that enabled me to build up a considerable stock of electronic components that were to stand me in good stead after my return.

Return to Australia, May 1950

One of my main sponsors while I was in England was Professor Dew, professor of surgery at Sydney University. When I returned to Sydney, I joined the department of surgery there. Dew gave me four large rooms that were bare except for tables and chairs so I had, once again, to build all the equipment I needed except for some items that I had brought back from England.

Just the year before, in 1949, the faculty of medicine had introduced a new degree, the Bachelor of Science (Medical) or B.Sc.(Med.). The new degree allowed selected students, after completing the third or fourth year of the medical course, to spend an extra year working on a research project either with, or supervised by, a senior member of one of the departments. I immediately saw the importance of this innovation, and I determined to give it every support. I called my largely empty rooms in the department of surgery the “Brain Research Unit.” Although I was not then a member of the Faculty of Medicine, the faculty approved my application to have students for the new degree work under my supervision. In 1950, my first year back in Sydney, I had four B.Sc.(Med.) students, one of whom, Richard Gye, subsequently became a neurosurgeon and dean of the faculty. As I had only been back for a few months, I had to devise experiments that could be carried out with what little equipment was available. Every year thereafter, until I left Sydney University in 1967, I always had one or more students working with me, not just under my supervision. Without their help, I could not have managed the large administrative load I had when I became head of the department in 1955.

For some years after I came back to Sydney, I continued to use the technique of electrical stimulation of the optic nerve to study the properties of the fiber groups in the nerve and to investigate the field potentials associated with synaptic transmission in the lateral geniculate nucleus. In 1951, my second year back, Jim Lance and Brian Turner, both recent medical graduates, came to work with me as research fellows. Lance later founded the first academic department of neurology in Australia and became the foundation professor of neurology at the University of New South Wales. That year I also had four B.Sc.(Med.) students, David Jeremy, Bill Levick, Jim McLeod, and Annette Walshe, and we accomplished a fair amount of research.

The nerve fibers in the central nervous system had been assumed to have the same general properties as those in the periphery. The optic nerve preparation provided a unique opportunity for determining the properties of a central tract, as developmentally and structurally, the optic nerve must be considered a central tract. We (Bishop et al., 1953) showed that all the fibers in the optic nerve of the cat had the same properties as the group A fibers in the periphery. In a similar study of the pyramidal tract, David Jeremy, Jim Lance, and I showed that all the myelinated fibers in that tract probably also belonged to the A group. Subsequently, Lance made a series of independent studies on the pyramidal tract. By recording field potentials, Jim McLeod and I studied the two main groups of fibers in the optic nerve, as well as the properties of their synaptic potentials in the lateral geniculate nucleus. McLeod was later to become a full professor of medicine in the University of Sydney, as well as Bushell Professor of Neurology.

That same year, Bill Levick and I studied saltatory conduction in the single isolated fiber from the tibial nerve of the cane toad. Levick carried out all the single fiber dissections and became proficient at isolating single nerve fibers up to 15 mm in length. Some years later, after he completed the medical course and carried out his hospital residency, Levick came back to work with me as a research fellow and, as will be detailed later, he made a singular contribution to my research.

In 1951, I was appointed to my first tenured position as a senior lecturer in the department of physiology. Professor F.S. Cotton, the professor of physiology, treated me generously. He allowed me to retain my laboratories in the department of surgery, and the few formal teaching commitments I had did not interrupt my research activities to any great extent. However, Cotton retired at the end of 1954, and I was appointed to succeed him as professor and head of the department.

University in Crisis

Beginning in 1955, my life was to undergo a radical change. In the early 1950s, Sydney was the only university in New South Wales and, consequently, it had the only medical school. The department of physiology, and the university in general, were in poor shape because of years of financial neglect and the large influx of students in the years immediately after World War II. I had had a sound training in neuroanatomy and neurophysiology, but I knew relatively little about the other bodily systems. The department at that time was responsible for 14 different courses in physiology, including those in the faculties of dentistry, medicine, science, and veterinary science. In addition to these standard undergraduate courses, the department had a separate series of lectures for each of the postgraduate medical diplomas, such as those for gynecology and obstetrics and dermatology; it also had courses for the various allied medical personnel, including occupational therapy, physiotherapy, speech therapy, and so on.

Apart from me, there were only four full-time members on the academic staff of the department, two of whom resigned during my first year. That left only a senior lecturer (William Lawrence) and a teaching fellow (Arthur Everitt). Lawrence had had considerable experience with the physiology practical classes and, while he organized these classes, I took the responsibility for organizing the various courses of lectures. It was possible to maintain reasonable academic standards only by having a large number of part-time lecturers, most of whom were fairly recent medical graduates in the early stages of developing a practice. Inevitably, I had to do a great deal of the lecturing myself, mostly on systems other than the nervous system. With such a heavy administrative and teaching load, I was able to devote much less time to my research activities. Even so, I still was able to supervise B.Sc.(Med.) students but at a much reduced level of involvement.

In 1956, I induced Paul Korner and William (Liam) Burke to accept appointments to senior lectureships, and subsequently both became full professors. In the following years, many more staff appointments eased my load considerably. But the overall teaching load increased even faster than the staff increased. In my first year as head of the department, the medical course had little more than 200 second-year students. In every year from then on nearly 100 more were added; by 1961 there were 620 students in the second year. Numbers increased in the other faculties as well, but less dramatically than in medicine. Nevertheless, we finally had a total of about 1,500 students taking physiology in the various faculties and courses.

From the start, I pressed for the introduction of a quota system to limit student numbers, particularly in the faculty of medicine, but for some years the university offered little support. Two main events finally led to the introduction of a quota system in the faculty of medicine, the first such quota in the university. The Federal Government set up a Committee of Inquiry into Tertiary Education in Australia. Among the farreaching recommendations of the committee was one relating to the problem of student numbers. In particular, the committee recommended the establishment of a second medical school in New South Wales. Then, in 1963, after the second medical school at Kensington in Sydney was established, it finally was possible for Sydney University to have a limit of 300 entrants to its medical school. Since then, the quota has been set at 240. The above account provides a background against which to set my research activities during my early years as head of the department.

Research Activities, 1955–1967

Aside from the above diversion we can now return to the account of my research activities. In 1954, Ross Davis, then a medical student, and I used electrical stimulation of the optic nerve and field potential recordings to study the recovery of responsiveness and other aspects of synaptic transmission in the lateral geniculate nucleus. Then, in 1958, after medical graduation and a year in a hospital as an intern, Davis returned to work with me as a research fellow. In the mid-1950s, we had made many attempts to obtain intracellular records but, using the techniques available to us at that time, the recordings we achieved were always too brief to be of practical use. Unlike the large motoneurons in the spinal cord, the relatively small geniculate cells could not withstand the injury caused by the insertion of the microelectrode. Nevertheless, we were able to make good extracellular records from single units even over quite long recording times.

While still using electrical stimulation of the optic nerve, but now recording from single units extracellularly, we again studied the synaptic events in the lateral geniculate nucleus (Bishop et al., 1962). In a series of three papers, Burke, Davis, and I provided a detailed description of the various waveforms of the responses of single optic tract and radiation axons and of the responses from geniculate cell bodies when they are activated either orthodromically via the optic tract or antidromically via the optic radiation. The responses from the cell bodies could be fractionated into three components, namely the slow S-potential, considered to be the extracellularly recorded excitatory postsynaptic potential (EPSP) evoked by the retinal afferents; the A-potential, apparently derived from the initial segment of the geniculate cell body-axon region; and the B-potential, believed to represent the invasion of the soma-dendritic membrane. Many geniculate synapses have a high safety factor. At times, a single retinal afferent axon can be found that leads to a single all-or-none S-potential which could, in turn, occasionally be sufficient to discharge the cell. These papers are still relevant today, and they are regularly cited in the literature. Subsequently, the concept of a transfer ratio (proportion of afferent S-potentials that generate geniculate action potentials) has been used as a way to study the efficacy of signal transmission through the lateral geniculate nucleus.

In 1958, I was invited to attend a symposium in Paris in honor of Henri Piéron. The trip gave me the opportunity to visit vision laboratories, in Denmark, Sweden, the United Kingdom, and the United States. While in Baltimore, Maryland, I visited Steve Kuffler in the Wilmer Institute at The Johns Hopkins University, and I had the opportunity to watch an experiment by David Hubel and Torsten Wiesel. At that time they were at the start of their career together and were recording from single units in the cat cerebral cortex. They were using the multibeam ophthalmoscope that S.A. Talbot and S.W. Kuffler had designed and built some years before in 1952. At that earlier time, the instrument represented an important technical advance because small flashing lights could be focused on the retina under direct viewing with the eye intact and, except for the introduction of the microelectrode, its optics preserved. Watching their experiments had a profound effect on me and, when I returned to Sydney, Hubel and Wiesel soon appreciated the marked constraints that the multibeam ophthalmoscope imposed. Instead, for stimuli, they turned to the use of small targets moved by hand over the surface of a tangent screen placed in front of the cat. On my return to Sydney, I immediately set to work to design and build a cat multibeam ophthalmoscope. The instrument was finally assembled, but it was used only for the one set of experiments that Tetsuro Ogawa, Levick, and I did. By that time, we had recognized the same experimental constraints that Hubel and Wiesel had appreciated a year or so before.

The department of surgery was located in a building some distance from the department of physiology, and by the late 1950s I had completed the move from one building to the other, giving me two new fully equipped laboratories and associated facilities. The experience with the multibeam ophthalmoscope had been a powerful influence in directing my research toward the use of more natural stimuli and intact visual optics, and the new laboratories, fitted with tangent screens, had already been designed with this new approach in mind. Furthermore we had, by then, gained considerable experience in the use of extracellular single unit recording in the lateral geniculate nucleus and later in the visual cortex.

In retrospect, 1959 can be seen as a watershed year in the history of visual neurophysiology, as most of our knowledge of the visual system dates from that time. That was the year Hubel and Wiesel (1959) published their first report on the receptive fields of simple cells in the visual cortex. They found the stimulus features important for striate neurons to be straight lines, bars, and edges, having an orientation and, usually, a direction of movement that were characteristic and critical for the discharge of the cell. In the same year, Lettvin et al. (1959) published a paper with the title “What the frog’s eye tells the frog’s brain.” The title of the paper and the speculations it contained undoubtedly caught the imagination of the time. The authors proposed to present the frog with as wide a range of visible stimuli as they could, including things it would be disposed to eat, things from which it would flee, sundry geometrical figures, stationary and moving about, and so on.

In many ways, the years 1959 to 1967 were the most exciting and fruitful of my career. Liam Burke had worked with me for some time before that, and now I had a further succession of able collaborators, each of whom was to bring to bear their own experience and expertise. In addition to Ross Davis and Bill Levick, there were George Vakkur, the Sydney medical graduate; Tetsuro Ogawa and Tosaku Nikara from Japan; Bob Rodieck from the Massachusetts Institute of Technology (MIT) in Cambridge, Massachusetts; and Wlod Kozak from Warsaw, via the Eccles’ laboratories in Canberra. In addition to their collaboration with me, many of these researchers also had other independent projects.

Visual Optics and Neuro-ophthalmology

There was a further factor that drove the direction of my research toward a consideration of visual optics and neuro-ophthalmology. We had begun a study to determine the projection of the visual field onto the lateral geniculate nucleus. It became clear to us that, for this project, we would need a detailed knowledge of the cat’s optics. A thorough search of the literature failed to reveal a sufficiently detailed account of the visual optics of the cat or, indeed, of any other animal. So we (Vakkur and Bishop, 1963) began the preparation of a cat schematic eye. Whereas our main concern with the schematic eye was the practical need to provide a quantitative framework for neurophysiologic studies, the project appears to have been the first example where the information derived from a schematic eye was used in an explicitly comparative manner to shed light on the possible adaptive significance of ocular structures (Martin, 1983). Thus, in effect, we pioneered the new field of comparative neuro-ophthalmology.

A schematic eye is a self-consistent mathematical model of the optical system of the average eye. We arrived at a final schematic eye model by two independent methods. Vakkur, Kozak, and I made an initial examination of the eye as a whole that provided a measure of the posterior nodal distance and the out-of-focus distance. Then, assuming the refractive index of the vitreous humor, the values as measured above fixed the positions of the posterior three cardinal points (principal, nodal, and focal) of the optical system with respect to the receptor layer of the retina. Established in this way, the cardinal points do not require information about the cornea and lens. The second method, independent of the first, is the reverse of the above procedure (Vakkur and Bishop, 1963). The development of the cornea-lens optical system fixes the position of the cardinal points with respect to the plane of the anterior corneal surface. Then, by measuring the overall length of the eyeball and estimating the combined thickness of the sclera and choroid, these cardinal points can also be referred to the receoptor layer of the retina as was done by the first method. The two sets of data showed a remarkable level of agreement.

Although the paraxial lens equation (Gauss) used to develop the schematic eye treats only rays close to the optic axis, the observations and measurements that we made were far more extensive and useful than those provided by the paraxial system. The additional information included a complete metrological treatment of the globe and its components, together with their average values, the positions and sizes of the entrance and exit pupils, and the extent of the monocular and binocular visual fields. For our later studies, particularly in relation to binocular vision, it was important to establish the accuracy with which the center of the area centralis and the visual axis could be determined, as well as the relationship of the visual axis with respect to both the positions of the optic disk and the blind spot. A further important experimental consideration concerns the positions the eyes assume when the anesthetized animal is completely paralyzed—the so-called position of paralysis. Our schematic eye studies are now regularly cited in the literature, and the data they contain continue to be used widely.

The study that Kozak, Levick, Vakkur, and I did on the projection of the visual field onto the lateral geniculate nucleus was the first attempt to establish in any animal the details of the projection by electrophysiologic methods. Of the possible systems of coordinates for defining directions in the visual field, we finally decided on a particular system of spherical coordinates. Using single unit recording, the visual direction of the center of a receptive field of a neuron was expressed in terms of two angles, azimuth and elevation, of the coordinate system, the polar axis of which passed through the nodal point of the eye at right angles to the fixation plane. This coordinate system is now universally used to specify the visual field locations of the receptive fields of cells in the central nervous system. An important concept to arise from this study was the projection line. This concept refers to a column of cells, the receptive fields of which all have a common visual direction in the visual field so that each column can be regarded as representing a particular direction. In the cat lateral geniculate nucleus, a projection line is approximately confined to a parasagittal plane and passes downward and backward through all the separate cellular layers of the nucleus.

Binocular Vision and Stereopsis

In 1964, Jack Pettigrew, then a B.Sc.(Med.) student, came to work with Tetsuro Nikara and me on the problem of binocular interaction on single cells in the cat’s striate cortex. As will be described later, this study led to the discovery that most of the striate cells were stimulus-disparity-selective. The experimental techniques and observations that were made over the previous few years provided the essential ingredients that led to this discovery. By then, Levick had been able to modify a commercial RIDL 256-Channel Analyzer for the computation of poststimulus time histograms, which were later to prove essential for our quantitative assessment of the level of binocular facilitation. The binocular project also involved further essential innovations (Bishop and Pettigrew, 1986). The development of a more effective intravenously administered drug mixture, as well as other associated techniques, made it possible to reduce the residual eye movements in the paralyzed cat preparation to an acceptably low level. Further, the use of a specially adapted Risley counter-rotating prism assembly enabled the positions of the two receptive fields of a striate cell to be moved in small steps over the surface of the tangent screen.

In early November 1965, I attended the Caltech symposium on “Information Processing in Sight Sensory Systems,” where I met Horace Barlow. Just before the symposium, Pettigrew had, as part of his thesis for the B.Sc.(Med.) degree, included our work on the disparity-selectivity of striate cells, and I took the thesis with me to the meeting. When I showed it to Barlow, he found that the work was similar to the project he had planned for Colin Blakemore’s Ph.D. thesis. Soon afterwards, Barlow invited Pettigrew to visit Berkeley and spend some time in mid-1966 working with Blakemore and himself. By then, I had begun working with another B.Sc.(Med.) student, Doug Joshua, along the same general lines. With the continuing collaboration between the two departments in Sydney and Berkeley, progress was rapid. We already knew that each of the two receptive fields of a cortical cell has the same highly specific stimulus requirements, and Barlow made an important contribution by suggesting that the cortical cells could be acting as feature detectors with a high probability of responding to a particular feature in the two retinal images that corresponded to one and the same object feature in the external world.

At this stage it will be helpful to give a brief account of our work on binocular depth discrimination, or stereopsis, an activity for which the two eyes are essential. Because the two eyes are horizontally separated in the head, each eye sees a given object feature from slightly different vantage points, leading to a small horizontal difference in the relative positions of their images on the retinas of the two eyes. The images of the fixation point, by occupying the same relative positions on the two retinas, are by that token exactly corresponding. The plane through the fixation point that is orthogonal to the visual axis constitutes a reference surface for expressing the relative positions of image points on the two retinas. Of the image points that are noncorresponding, some are closer to the reference plane than their companion image in the other eye. The various object points therefore have a range of different retinal image locations or. disparities and so are detected by the nervous system as representing varying intervals in depth to one or the other side of the reference plane. The neural theory of binocular depth discrimination requires that binocular cells in the striate cortex have at least two properties. First, because of the differing directions or positions of its two receptive fields, each binocular neuron should respond selectively to the position disparity that corresponds to the particular depth interval at which the two receptive fields are in spatial register. In addition, each cell should be capable of a fine discrimination of that stimulus disparity within its narrow responsive range and should be either inhibited or ineffective outside this range. Second, a population of such cells should show a range of different receptive field position disparities, so that a range of different horizontal stimulus disparities can be detected. It therefore was natural that we should give particular attention to these properties.

The neural theory of binocular depth discrimination as outlined above is now widely accepted. The theory is based on the concept that the two receptive fields of a binocular cell are to be regarded as feature detectors and as such must have an identical structure and spatial organization. It is, however, still undecided just how object features are represented in the brain, and it is possible that they are actually represented in terms of their spatial Fourier components. On this basis, DeAngelis et al. (1995) proposed that horizontal disparities are encoded by binocular cells not in terms of the position disparities of their left and right receptive fields but rather in terms of the differences in the shapes (or phases) of their receptive fields.

By early 1967, the Berkeley group had been able to complete its analysis of the disparity data and to present them for publication later that year (Barlow et al., 1967). At that time, I was working with two other B.Sc.(Med.) students, Warren Kinston and Matthew Vadas, on a somewhat unrelated problem concerned with the nuclei medial to the lateral geniculate nucleus. Then a further complicating event arose. In January 1967, I was invited to accept the chair of physiology in the John Curtin School of Medical Research in succession to Sir John Eccles who had, the previous year, resigned to go to the United States. However, I was not able to make the move to Canberra until June. We had a problem, therefore, in getting our disparity data published. By working with B.Sc.(Med.) students, much of the final analysis of the data and the task of writing the paper for publication were my responsibility. Hence our papers on binocular interaction were not published until 1968, and one even later (Pettigrew et al., 1968; Joshua and Bishop, 1970).

The Australian National University, 1967–1984

I was sad to leave Sydney University and to sever my association with B.Sc.(Med.) students.² I always felt that, with the means available, the university had treated me generously.

Within the Australian National University, the John Curtin School is one of the schools that forms the Institute of Advanced Studies. The institute is a center for research and postgraduate training without involvement in undergraduate teaching. The emphasis on research, coupled with the departmental structure that existed in the John Curtin School at the time of my appointment, provided the head of a department with the ability to redirect the department’s research effort. An essential element of the redirection process was the school’s policy of keeping the number of tenured members of the academic staff to 50 percent or less. The intention always was that about half of the research personnel in the institute would be visitors coming from elsewhere in Australia or from abroad and staying for three to five years. On this basis, the necessary research fellowships were provided and, subject to the departmental budget, the head of the department made the recommendations for the award of fellowships. As a result, the systems neurophysiology of vision became the dominant interest of the department.

The Ph.D. degree was first introduced in Australia about 1949, and the Australian National University originally was established in Canberra to provide the necessary graduate research training. However, at the time, most graduates from Australian universities preferred to continue their training either at their home university or abroad. As a result of that preference, coupled with the specialized nature of the work we were doing in what was then a fairly new field, the visitors we attracted tended to be mostly postdoctoral scientists from abroad.

In the late 1940s, when the Australian National University was founded, Canberra was a small and isolated community. As a result, the John Curtin School had to be largely self-sufficient, having readily available its own full range of workshop facilities, including fitting and turning, instrument making, joinery, and so on. When I arrived in Canberra, these workshop facilities were still largely intact. In addition, the head technical officer of the department, Lionel Davies, who had remained after Eccles’ departure for the United States, had considerable expertise as an instrument maker. Furthermore, Robert Tupper, who had come with me from the department in Sydney, now was responsible for the development and maintenance of the electronic equipment. I had, therefore, an unparalleled opportunity to design and construct laboratories suitable for the systems neurophysiology of vision that we were now contemplating. Before too long, three of what were eventually seven fully equipped research laboratories were ready for occupation.

Early in 1968, G.H. Henry joined me in Canberra after spending the previous year working abroad as a Churchill fellow. In collaboration with various colleagues, Henry and I worked together for the next seven years. Our colleagues included J.C. Coombs, I. Darian-Smith, and K.J. Sanderson, all from Australia, and C.J. Smith (New York), A.W. Goodwin (South Africa), and B. Dreher (Poland). Toward the end of 1967, Bill Levick came to the department from the University of California, Berkeley, and soon afterwards Brian Cleland joined him from Northwestern University, Chicago. With separate laboratory facilities, Levick and Cleland were able to work independently of Henry and me. As additional laboratories were fitted out, two relatively long-term appointments were made, first Jon Stone and somewhat later, Austin Hughes. Again, with separate laboratory facilities, they were each able to work independently although mostly in collaboration with colleagues from abroad.

First Experiments in Canberra

The first experiment we did in Canberra (Henry et al., 1969) was to study the binocular interaction on those simple cells in the striate cortex that were considered to be exclusively monocular. Up to that time, binocular influences of an inhibitory nature had been largely neglected, particularly in relation to cells considered exclusively monocular. This neglect was not surprising because inhibition can be observed only in the presence of some form of excitatory activity.

Simple neurons usually have a low or absent maintained discharge. However, such a discharge can be produced by controlled stimulation of the dominant eye using the activated-discharge technique. To do this, the dominant eye was stimulated by small amplitude oscillations of an optimally oriented light bar moving continuously to and fro in the optimal direction over the excitatory region of the receptive field. At the same time as this background discharge was produced, the suspected position of the nondominant eye receptive field was tested by a stimulus considered to be optimal for the dominant eye. Though approximately optimal in each case, the conditioning and testing stimuli were driven at different and asynchronous frequencies by separate and independent function generators. As the spikes were collected in phase with the testing stimulus while those due to the activated discharge were collected randomly, the analyzer bins were filled relatively uniformly when the nondominant eye was occluded. We found that, despite being ostensibly monocular, all the cells showed clear binocular effects. A predominantly inhibitory receptive field for the nondominant eye could usually be found in the contralateral hemifield at a position approximately corresponding to the receptive field for the dominant eye.

The above technique revealed the receptive field for the nondominant eye to be mainly suppressive. However, a small region of subliminal excitation was commonly found within the subliminal receptive field. This excitatory region was located in the contralateral hemifield in close correspondence to the excitatory region in the receptive field of the dominant eye, and it had approximately the same relatively small size as the latter region. Particularly striking was the steep transition from strong inhibition at one position to a peak of facilitation at another all in the space of a few minutes of arc. The peak of binocular facilitation provided by the nondominant eye, together with the surrounding inhibition, is clearly important for the discrimination of retinal image position disparities.

The experiments described above were important also because they provided a test for two further methods of examining the nature of binocular interaction. One was the prism displacement procedure that we had already used in Sydney, in which the two receptive fields were stimulated as the receptive field of one eye was moved stepwise into and out of exact correspondence by prisms placed in front of the dominant eye. The other or phase shift method is, in effect, the equivalent to the prism displacement procedure. However, this time the prisms are used to separate the two receptive fields widely on the rear projection screen so they can be stimulated, separately but optimally in each case, by light bars moving over their respective receptive fields. With the two stimulus sweeps at first in synchrony, advancing or retarding the stimulus sweep for one eye is then equivalent to the prism displacement procedure. Considerable precision is possible with this second method because the start of the stimulus sweep can be controlled in small steps. All three methods gave identical results, each demonstrating the same excitatory and inhibitory effects on the part of the nondominant eye. The activated-discharge technique is a relatively fast procedure and has the important advantage that it produces a continuous profile of the response across the receptive field.

According to the general belief at the time of these experiments, there is little, if any, binocular interaction in the lateral geniculate nucleus. This premise gave us an early opportunity to test for binocular interaction in the nucleus using the activated-discharge technique (Sanderson et al., 1971). Contrary to general belief, we found that the great majority of the cells in all the laminae were, in fact, binocularly activated and that, of these cells, the great majority of the receptive fields for the nondominant eye was purely inhibitory. Of the few nondominant cells that had receptive fields that were excitatory, the effect was so weak that, with only one or two exceptions, it could not be appreciated by hand plotting. The location of the nondominant eye receptive field was always in approximate correspondence with the receptive field for the dominant eye.

Most of the experiments that Henry and I did over the ensuing years were concerned with the receptive field properties of the various types of cell in the striate cortex, although we gave special attention to the property of selectivity in relation to orientation and the direction of movement. One early observation that Henry, Dreher, and I made concerned the hypercomplex property of end-inhibition. End-inhibition refers to the observation that the excitatory response from a cell can be reduced if the length of the stimulating bar is extended beyond some optimal value. It was a property thought only to be found in cells at a relatively high level in a simple, complex, and hypercomplex hierarchical sequence. Our finding was that the property was not a later acquisition by complex cells but a general property of all the various cell types in the striate cortex. Some time later, Orban, Kato, and I made a particularly detailed study of the inhibitory properties of the end-zone region.

After United States President Lyndon Johnson visited Australia in 1966, the respective governments set up the United States-Australia bilateral agreement for scientific and technical cooperation. By that time, the publications on vision from the John Curtin School had attracted fairly wide general interest, particularly in the United States, and Peter Gouras wrote to me from the National Eye Institute in Bethesda, Md., about the possibility of organizing a symposium on vision under the terms of this agreement. He suggested that the meeting be held in Canberra. I responded enthusiastically to his proposal, with the result that the National Eye Institute and the John Curtin School jointly organized a week-long symposium. It was held in Canberra February 7-11, 1972, with Gouras responsible for arrangements in the United States and me in Australia. Among the leading visual scientists invited to attend, some 22 came from the United States. The major emphasis was on the neurophysiology of visual mechanisms using single unit recording at the various levels of the visual pathway. The proceedings of the symposium, including selected parts of the discussions that followed each presentation, were published in two dedicated issues for May and June 1972 of the journal Investigative Ophthalmology (now Investigative Ophthalmology and Visual Science) just three months after the meeting.

Binocular Interactions in Relation to Stereoscopic Vision

Among the studies we did in Canberra, I will comment on only a few that seem in hindsight to be of general interest, particularly the role of binocular interactions in relation to stereoscopic vision.

In 1975, Henry spent a sabbatical year at the University of Washington, Seattle, working with Ray and Jenny Lund who were subsequently to make a year-long return visit to work with Henry in Canberra. On his return from Seattle, Henry began working independently of me with his own laboratory facilities. From 1976 onward, all my collaborators except Stjepan Marčelja came from abroad, but a complete list must include those I have already mentioned.³

In recent years, two different approaches have developed toward an understanding of the operation of the visual cortex. The usual approach, my own included, has largely concerned the role of simple cells as feature detectors, with attention on the spatial organization of their receptive fields, and with lines and edges regarded as the elementary features extracted by the cells. The alternative approach is based on the application of spatial frequency (Fourier) methods and, by concentrating attention on the sensitivity to sinusoidal gratings of varying spatial frequencies, this approach has tended to neglect the discrimination of spatial position. Not until Janusz Kulikowski came to work with me, did I give serious consideration to the application of spatial frequency methods.

Gabor’s analysis (1946) of auditory communication applies equally well to the communication of visual signals, and Marčelja (1980) was the first to appreciate the relevance of Gabor’s ideas to the coding of visual signals in the nervous system. With respect to auditory communication, Gabor pointed out that if one wishes to encode a communication signal compactly into a succession of elementary signals or samples spaced in time, one has to accept a compromise between the “spread” of each of the samples, both in the time domain and in the frequency domain. The nature of this compromise can be appreciated by considering the note of a tuning fork. To be sure of the frequency of the note, one has to listen to many cycles of the vibration; but the longer one takes to make a decision about the frequency of the vibration, the more indeterminate becomes the precise time at which one can say the note occurred. Similarly, precision regarding the time of occurrence of the note can be achieved only at the expense of the lack of precision regarding the frequency of the note.

Spatial frequency considerations along the lines of a Gabor representation provide an explanation for the shape and organization of the receptive fields of simple cells in the striate cortex in that they contain a varying number of narrow elongated subregions arranged in a side-by-side fashion with subregions that respond at light ON alternating with those that respond at light OFF. Furthermore, a response to high spatial frequencies is needed to discriminate thin lines and sharp edges, and the same compromise exists between the discrimination of these features and their precise location in space. Whereas a detailed exposition of the concepts would be out of place here, a brief outline of certain aspects is needed to place our observations in context.

At the outset, it was clear that our rear-projection methods had to be replaced by stimuli generated on the face of an oscilloscope so we could obtain stimuli that were either lighter or darker than the background, but each equal in contrast. For this series of experiments, only monocular stimulation was used, and our observations were largely confined to the responses of simple cells in the striate cortex. As a basis for the application of Fourier analysis, we carried out the following experimental procedures on a series of simple cells (Kulikowski and Bishop, 1981). As the application of Fourier methods requires that spatial summation over the receptive field be linear, we first confirmed earlier reports concerning the essential linearity of simple cells. Next, we recorded each cell’s spatial response profile (receptive field) to narrow stationary and moving bars that were both brighter and darker than the background and we examined the relationship between these responses and those to moving light and dark edges. Then, using the same series of cells, we recorded their responses to stationary and drifting sinusoidal gratings. Finally, on the assumption that simple cells operate linearly, we compared the spatial response profiles recorded experimentally with those predicted by inverse Fourier transformation of the spatial frequency tuning curves. Conversely, the spatial frequency tuning curves recorded experimentally were compared with those predicted from the response profiles to stationary and moving stimuli.

Theoretical considerations indicate that, for any given spatial frequency tuning curve (bandwidth) and optimal spatial frequency, the inverse Fourier transform should predict the spatial response profile (receptive field) modeled as a Gaussian function, as well as the spatial period of the subregions within the Gaussian envelope (number and dimensions of the subregions). The spatial period (combined width of two subregions) is inversely proportional to the optimal spatial frequency. In general, it can be said that the narrower the bandwidth, the greater the number of subregions needed to achieve the required selectivity; and the higher the optimal spatial frequency the narrower the width of the individual subregions in the receptive field.

Our experimental observations indicate that the overall width of the response profiles obtained from a series of simple cells as well as the number and widths of the individual response peaks in the profiles are all in reasonably good agreement with those to be expected on the basis of Fourier transforms of their respective spatial frequency tuning curves and optimal spatial frequency. The simple cell with the narrowest bandwidth that we have observed (0.94 octave) has an optimal spatial frequency of 2.0 cycles/degree. To achieve such a relatively high degree of spatial frequency selectivity on the basis of a Gabor representation, this cell would require a receptive field profile with an overall width of about 1.2 degrees having 5 response peaks with amplitudes all above the 10 percent level and having a width of about 0.25 degrees for each peak. These values agree reasonably well with those for the profile that we obtained experimentally from this cell in response to moving light and dark bars.

The cell with the highest optimal spatial frequency that we have observed (2.3 cycles/degree) should be adequate to account for the cut-off spatial frequency of 9 cycles/degree determined experimentally for the cat. The same reasonably good level of agreement is found for cells at the other end of the scale, namely those with the broadest spatial frequency tuning curves and the lowest optimal spatial frequencies. However, the Gabor representation suggests that the most common receptive field types are those with three or four subregions, whereas we found that receptive fields with two subregions are much more common than those with three or four. It is possible that the high threshold for discharge in simple cells conceals subregions with a relatively low sensitivity.

Some years later, we again considered the role of simple cells as feature detectors in a local stereoscopic mechanism (Maske et al., 1984). To assign a depth value to a particular feature, the two receptive fields of a binocularly activated cell must respond to one and the same object feature. This can be done only if the organizations of the two receptive fields are identical, or nearly so. In our experiments, we selected a series of simple cells that had monocular responses from each eye of sufficient amplitude to be able to examine each of their receptive field organizations in quantitative detail. By that time, we had developed a rear-projection system that was able to provide stimuli that were both lighter and darker than the background. Using Risley counter-rotating prism assemblies, the two receptive fields were widely separated on the projection screen so that the receptive field for one eye could be stimulated independently of the receptive field for the other eye.

The two receptive fields of a given cell were remarkably similar with respect to a range of different attributes. The number and spatial sequence of the subregions in response to the movement of light and dark bars were always the same, as were the interpeak separations. The direction selectivity for any given cell was nearly always the same, independent of stimulus contrast. Estimates of the horizontal and vertical position disparities of the response peaks provided a particularly stringent test for the degree of similarity. Some significant differences, however, exist between the two receptive fields, namely, with respect to the overall ocular dominance and position disparity, preferred stimulus orientation and, rarely in Area 17, direction selectivity. Except for ocular dominance—the functional role of which remains a mystery—the remaining attribute differences have key roles in binocular vision.

As a disparity-encoding process for a given cell, the main feature used to determine the phase difference between the receptive fields for the two eyes is the overall shapes of the response peaks to light and dark bars (DeAngelis et al., 1995). Our rear projection methods made it difficult to achieve an exact balance between the contrasts of the light and dark bars, so there would have been some distortion in the overall shapes of the response peaks to the two kinds of bar. Hence, from our observations, we would have been unable to arrive at any conclusion regarding the role of phase differences in a disparity-encoding scheme. However, it should be noted that, even on a monocular basis, there can be different phase-sensitive responses to different stimuli with a 90 degree phase difference between the response to a bar and response to an edge (Kulikowski and Bishop, 1981).

In a paper on the ability of striate cells to discriminate orientation and position disparities (Nelson et al., 1977), we concluded that the binocular response is very sensitive to position disparity but relatively insensitive to fairly large orientation disparity changes. A quantitative analysis showed that simple striate cells are probably able to discriminate position disparities known from behavioral testing to be near the limit for the cat. When the two receptive fields of a simple cell are in spatial register (zero position disparity) the amplitude of the binocularly facilitated response to an optimal stimulus can be as much as two or three times the sum of the two separate monocular responses to the same stimulus. However, this binocular response can be considerably reduced by a position disparity as small as a 10-minute arc.

Retirement and General Activities

By the end of 1982, I reached the statutory retiring age of 65, and I had to give up my laboratory in the John Curtin School. For two years after my retirement, at the invitation of Richard Mark, I worked as a visiting fellow in the Australian National Univeristy’s Research School of Biological Sciences and was able to get most of the backlog of our research material ready for publication. During this period, my wife and I spent some time in Dunedin, New Zealand. There, at the invitation of John Parr, I worked in the department of ophthalmology of the Otago Medical School. Then, for most of 1985 and 1986, my wife and I lived in Europe, where we had the pleasure of visiting colleagues who had worked with me in Canberra. I was able to take part in the work that Guy Orban and his colleagues were doing in his laboratory in the medical school of Katholieke Universiteit, Leuven, Belgium. Then my wife and I moved to Zurich. There, in the department of neurology of the University Hospital Zurich, Esther Peterhans was doing experiments on the awake performing monkey. My involvement in these experiments enabled me to gain a much better appreciation of the considerable possibilities offered by experiments of this kind. Finally, my wife and I spent most of 1986 with Fergus Campbell in Cambridge, England, where I was the overseas visiting fellow at St. John’s College. We much enjoyed living in an attached cottage in the grounds of the College and walking daily to town across the Bridge of Sighs.

In much earlier times, before my retirement, my wife and I had lived abroad for extended periods. In addition to the years in England immediately after the war, we spent 1963 in Cambridge, Massachusetts, where I worked in Pat Wall’s biology department at MIT. The experiment I did with Arthur Taub at MIT was the first and only occasion that I deserted the visual system to work on the spinal cord. At the invitation of the Japan Society for the Promotion of Science, my wife and I twice visited Japan. In 1974, as a guest of Kitsuya Iwama, I joined the work in progress in the department of neurophysiology of the Osaka University Medical School. Then, some years later in 1982, at the invitation of Motohiko Murakami, my wife and I lived in Shinjuku in Tokyo to be handy to the department of physiology of the Keio University School of Medicine.

On our return from England at the end of 1986, we moved from Canberra to live at Avoca Beach, a small coastal resort halfway between Sydney and Newcastle. Soon after the move to Avoca, Jonathan Stone, now Challis Professor of Anatomy at Sydney University, kindly invited me to accept a research associateship in the department, and since then I have made regular visits to the university, mainly to work in the library.

I have become interested in the role of vertical disparities in the binocular process, particularly in relation to the size and depth constancies. Our earlier experiments in Sydney had shown that the receptive field position disparities are distributed as much in the vertical as in the horizontal direction and that many cortical cells are specifically sensitive to vertical retinal image disparities. Soon after these observations were first reported, they were subjected to criticism on the grounds that only horizontal retinal image disparities contribute to stereoscopic depth perception.

Recently, I have published papers making a strong case for the essential role that vertical disparities play in relation to both the size and depth constancies (Bishop, 1994). These papers have led me to conclude that random-dot stereograms, being confined to one plane and so without any real depth intervals, cannot serve as a model for the perception of depth in relation to real three-dimensional objects. These observations are of the nature of thought experiments, as I have had to rely to a large extent on the experimental results of others. Many of my conclusions are counter to long-held beliefs, so it is not surprising that journal referees should subject them to searching criticism. This is as it should be, although the long delays occasioned by the refereeing process can be rather frustrating.

Apart from my university activities, I have served on the main national and international committees concerned with research in the physiological sciences. From 1959 to 1966, I was a member of the Research Advisory Committee of the Australian NH&MRC. This committee is responsible for making recommendations regarding all government research grants in the area of the health sciences. Much later, from 1972 to 1976, I also served on the Australian Research Grants Committee (now the Australian Research Council), which recommends government research grants in areas other than medicine. In the international sphere, from 1968 to 1977, I was a member of the Council of the International Union of Physiological Sciences, and later I also was a member of the Governing Council of the International Brain Research Organization (IBRO). In 1960, I was one of the founders of the Australian Physiological and Pharmacological Society, organized its first scientific meeting, and served as its first treasurer. In 1967, I became a fellow of the Australian Academy of Science and, 10 years later, a fellow of the Royal Society of London. The Australian Honours List for 1986 made me an Officer of the Order of Australia, and the Commonwealth Government jointly awarded Horace Barlow, Vernon Mountcastle, and me the 1993 Australia Prize. I was pleased to be made an Honorary Doctor of Medicine by my old university as well as an Honorary Life Member of its faculty of medicine.

Though I have had a fortunate life, my one great sadness is that, with my exacting work schedule, I saw so little of my wife, Hilare, and my family. We have three children. Our elder daughter, Phillippa, married a cardiac surgeon, Douglas Baird, and they have four children, now all grown up. Our second daughter, Clare, is a senior member of the staff of the Department of Immigration in Canberra. Over a period of 15 years, she served abroad in posts as diverse as Hanoi and New York. Our son, Roderick, graduated in medicine at Sydney University and is a specialist in Emergency Medicine. He is married to Margaret Wallen, a pediatric occupational therapist, and they have one daughter.

Only by providing me with a stable home life and taking full responsibility for its management did my wife enable me to lead the kind of life that my work demanded. More than that, she also made the department very much a family affair, meeting overseas visitors and their families on their arrival and being generally concerned for their welfare, particularly during the process of settling into a new environment. We welcomed visitors to the department in our home, and once or twice during the year, but always at Christmas time, my wife entertained the whole department at our home. The many visitors to the department remember Hilare with warm affection.

Selected Publications

Bishop PO, Burke W, Davis R. The interpretation of the extracellular response of single lateral geniculate cells. J Physiol (Lond) 1962;162:451–472.

Bishop PO, Jeremy D, Lance JW. The optic nerve. Properties of a central tract. J Physiol (Lond) 1953;121:415–432.

Bishop PO, Pettigrew JD. Neural mechanisms of binocular vision. Vision Res 1986;26:1587–1600.

Bishop PO. Size constancy, depth constancy and vertical disparities: A further quantitative interpretation. Biol Cybern 1994;71:37–47.

Henry GH, Bishop PO, Coombs JS. Inhibitory and sub-liminal excitatory receptive fields of simple units in cat striate cortex. Vision Res 1969;9:1289–1296.

Joshua DE, Bishop PO. Binocular single vision and depth discrimination. Receptive field disparities for central and peripheral vision and binocular interaction on peripheral single units in cat striate cortex. Exp Brain Res 1970;10:389–416.

Kulikowski JJ, Bishop PO. Linear analysis of the responses of simple cells in the cat visual cortex. Exp Brain Res 1981;44:386–400.

Maske R, Yamane S, Bishop PO. Binocular simple cells for local stereopsis: Comparison of receptive field organizations for the two eyes. Vision Res 1984;24:1921–1929.

Nelson JI, Kato H, Bishop PO. The discrimination of orientation and position disparities by binocularly-activated neurons in cat striate cortex. J Neurophysiol 1977;40:260–284.

Pettigrew JD, Nikara T, Bishop PO. Binocular interaction on single units in cat striate cortex: Simultaneous stimulation by single moving slit with receptive fields in correspondance. Exp Brain Res 1968;6:391–410.

Sanderson KJ, Bishop PO, Darian-Smith I. The properties of the binocular receptive fields of lateral geniculate neurons. Exp Brain Res 1971;13:178–207.

Vakkur GJ, Bishop PO. The schematic eye in the cat. Vision Res 1963;3:357–381.

Other Publications Cited

Barlow HB, Blakemore C, Pettigrew JD. The neural mechanisms of binocular depth discrimination. J Physiol (Lond) 1967;193:327–342.

Dawson GD. Cerebral responses to electrical stimulation of peripheral nerve in man. J Neurol Neurosurg Psychiat 1947;10:137–140.

DeAngelis GC, Ohzawa I, Freeman RD. Neuronal mechanisms underlying stereopsis: How do simple cells in the visual cortex encode binocular disparity? Perception 1995;24:3–31.

Gabor D. Theory of communication. J IEE (Lond) 1946;93:429–457.

Hubel DH, Wiesel TN. Receptive fields of single neurones in the cat’s striate cortex. J Physiol (Lond) 1959;148:574–591.

Lettvin JY, Maturana HR, McCulloch WS, Pitts WH. What the frog’s eye tells the frog’s brain. Proc IRE 1959;47:1940–1951.

Marčelja S. Mathematical description of the response of simple cortical cells. J Opt Soc Am 1980;70:1297–1300.

Martin GR. Schematic eye models in vertebrates. In: Ottoson D, ed. Progress in sensory physiology, Vol. 4. Berlin: Springer-Verlag, 1983;43–81.

¹I thank W. Burke and W.R. Levick for checking my draft against their recollections.

²Alphabetically, they were: D.S. Bell, R. Davis, W.A. Evans, G.B. Field, D.C. Glenn, C.S. Grace, J.G. Grudzinskas, R.S. Gye, B.L. Hennessy, D. Jeremy, D.E. Joshua, B.R. Kelly, W.J. Kinston, J.G. McLeod, W.R. Levick, J.D. Pettigrew, J. Scougall, J.R. Smith, J. Stone, M.A. Vadas, and A.M. Walshe.

³Alphabetically, they were: R.M. Camarda (Italy), A. Harvey (England), H. Kato (Japan), J.J. Kulikowski (England), R. Maske (South Africa), J.I. Nelson (USA), G. Orban (Belgium), E. Peterhans (Switzerland), and S. Yamane (Japan).

Theodore H. Bullock

BORN:

Nanking, China

May 16, 1915

EDUCATION:

University of California, Berkeley, A.B., 1936

University of California, Berkeley, Ph.D. (Zoology, 1940)

APPOINTMENTS:

Yale University School of Medicine (1942)

University of Missouri School of Medicine (1944)

University of California, Los Angeles (1946)

University of California, San Diego (1966)

Professor of Neurosciences Emeritus, University of California, San Diego (1982)

HONORS AND AWARDS (SELECTED):

American Academy of Arts and Sciences (1961)

National Academy of Sciences USA (1963)

Karl Spencer Lashley Prize, American Philosophical Society (1968)

Ralph W. Gerard Prize, Society for Neuroscience (1984)

Ted Bullock has had exceptionally diverse research interests, from invertebrate neurophysiology to human electroencephalography. His interest in nonspiking electrical events led to the discovery of electroreception in fish, and his two volume treatise with Adrian Horridge, Structure and Function in the Nervous Systems of Invertebrates, is the most comprehensive, authorative review of the topic ever written.

Theodore H. Bullock

They tell me I was born on a sunny Sunday in May in Nanking, China, in 1915. I was the second of four children of Presbyterian missionary parents, Amasa Archibald Bullock and Ruth Beckwith. Before my parents met, my father had answered a call for Western teachers, published by the empress. He subsequently spent a year in Ch’eng-tu, in western Szechwan, teaching chemistry, his major subject at the University of California, Berkeley. In China, he fell in love with the people, their eagerness to listen, and their respect for learning. Finding a niche that suited him, he returned to the United States to take a master’s degree in education at The University of Chicago and then to do advanced work in psychology at Columbia. His Berkeley roommate’s sister was at Hartford Theological Seminary preparing to be a missionary, and father and she had corresponded but not met before he went to visit. In four days he secured her assent to return with him and spend a life in China. They left for China in 1909, honeymooning on the way for six months in Europe and India. Father joined the faculty of the University of Nanking to start its normal school and, among other activities, its program in agriculture. The still extant guest book of our home shows the signatures of Sun Yatsen, then president of China, and several members of his cabinet.

Most of my childhood memories center on a later home in the compound of the Central China Teacher’s College in a village outside Wuchang. (In 1980 I had the thrill of finding that house, now a preschool, and the campus, now a normal school, well inside the metropolis of Wuhan.) Our home and schooling, while immersed in the native environment and with Chinese playmates, were as American as possible, to minimize problems when the children returned to the States. We returned in 1928, when I was 13, on my fifth transPacific crossing. A myriad of happy images and memories of the years in China are still vivid. Are they filtered by time? Do they account for leanings and bents—such as feeling like a citizen of the world first, of the United States second?

My parents were Victorian in social mores, conservatives economically, but liberal religiously and politically. My father certainly encouraged curiosity and a spirit of inquiry (misprinted in one book dedication to him as “the spirit of iniquity”); mother just wanted us to do anything well. My older cousin Mary Beckwith was a spinster and a serious amateur conchologist. Over Christmas of 1926 she had us at her house in La Jolla, California (where, 40 years later, I returned to stay) and got me started in shell collecting. Back in central China I collected freshwater and terrestrial shells in kitchen middens and on ivy-covered walls. To identify my prizes I took them to the museum in the British Concession in Shanghai, when we sought refuge there for some months while Chiang Kai-shek drove up from the south through Wuchang. In Berkeley, while attending Garfield Junior High School in 1928, I recall pedaling downtown on my bicycle and buying cowries (Cypraea spp.) from an eccentric dealer on Shattuck Avenue to add to my collection.

Two phases of high school years in Los Angeles and Pasadena were especially influential. Pasadena High School and Junior College was a combined school of high standard, and several biology teachers encouraged student research projects as well as participation in instruction. I learned a wide range of histological microtechniques and became particularly familiar with the Cajal and Del Rio Hortega methods for silver and gold impregnation of neurons, astrocytes, oligodendroglia, and microglia in normal rat brain and after needle wounds. Slides of these stains are still in my collection along with many later ones and some historic gifts from classical microscopists. The first tangible evidence that I might have some ability was a prize given by my teachers, a stimulating 1908 book on comparative histology by Dahlgren and Kepner. Pomona College had a marine station at Laguna Beach and admitted even a high school student to the summer session. Over four summers I took marine biology and other courses as well as student research. One project that gave positive feedback was methylene blue staining of the nerve plexus in the pharyngeal wall of amphioxus. Crustacean muscle nerves stained easily; sea anemone and starfish nerve cells or fibers never stained.

The hardest nugget of this writing project has been to find the words to answer the question, why am I doing science; what was the basic motivation? It would be much easier to pass over this tricky bit of self analysis, letting the record speak. Something makes me try, anyway, at the risk of being misunderstood. The fact is that when I first began to think about vocations, I wanted to belong to something with a large and nonmaterial purpose. I thought a lot about the church, the foreign service, or a world organization. I remember the inspiration of a youth congress on comparative religions of the world and the respect for others that it inculcated. A second requirement arose later, as I became aware of what people do in various jobs. I found I wanted something where the demand is to be creative, with the limitation between my ears, rather than what has been planned by others or comes to the door or fits within guidelines. I envied composers, architects, and city planners. Although occupations involving service to people had a certain pull, the greater tug had been those that offered more scope for discovery. It wasn’t that I always wanted to work with animals. But a decisive influence, suggesting research and teaching in zoology, must have come from the happenstance of a generous relative, cousin Martha Beckwith, sister of Mary, who made possible the summer course just mentioned, in the same year that my biology teachers were encouraging me in independent projects. This plan dawned, withstood tests, and turned out to fit the bill; it has been everything I could wish for in challenges, satisfactions, human contacts, and the possibility—ever present though faint—that something one does may be significant.

With an associate in arts (A.A.) degree from Pasadena Junior College, in 1934 I went to the University of California at Berkeley for my junior and senior years, majoring in zoology. On the side I worked on a large termite research project under the protozoologist C.A. Kofoid, making slides of the rich fauna of protozoans in the termite gut. One of Kofoid’s pet ideas was the “neuromotorium” he had described in advanced ciliates, a silver-stained spot supposed to coordinate the rapidly switching ciliary beating of different clusters of cilia, according to the microsurgical experiments of C.V. Taylor on Euplotes. When Wally, a favorite elephant of the children of San Francisco, had the misfortune to step backwards and kill his keeper, he was duly condemned and executed with postmortem rites performed by the chief of pathology at the university, who handed out bits of the elephant’s tissue to ranks of scientists waiting with bottles of fixatives. Kofoid sent me with a preheated Thermos bottle of hot Schaudinn’s solution to get fresh material from the caecum, where giant heterotrich ciliates live, sporting spiral membranelles and, presumably, the best of all neuromotoriums. When I returned to the lab and found I had preserved this valuable material in hot water, having neglected to replace it with Schaudinn’s, I expected the earth to open and swallow me up. Luckily, Kofoid left for a collecting trip to the antiquarian bookstores of Europe and months later could see my error in its true perspective—or this chapter would never have been written.

It was a long breath hold, in 1936, applying for a teaching assistantship in competition with many others from across the country. Luckily I landed one and within a year Martha Runquist and I were married on the $500 per year salary. In the third year I was elevated to chief teaching assistant and stepped up to $550 per year, so we both bought new shoes. Among many others, some of the teachers and courses I remember were S.F. Light on invertebrates, R.M. Eakin on general zoology, J.A. Long on embryology, Richard Goldschmidt on cytology, S.C. Brooks on general physiology, J.M.D. Olmsted on mammalian physiology, H.M. Evans on the history of biology, Joseph Grinnell on vertebrates, Stanley Freeborn on insect morphology and insect physiology, and John Gullberg on microscopy. Among my near contemporaries I can mention only a few: Aubrey Gorbman, Fred and Avery Test, Olga Hartman, Bill and Mollie Balamuth, Bob Fernald, Morgan Harris, Frank Pitelka, Norman Kemp, John Mohr, and Mimi Stokes James. I did my thesis with S.F. Light on the anatomy and physiology of the nervous system of a group of invertebrates, the enteropneusts, in the days when the dissertation was an unpublishable tome; it was four years before my last chapter was published. Ever since, I have pressured my students to submit the thesis in the form of chapters ready for submission, if not already sent, to a prestigious journal.

This is a story about ideas: thinking of them, re-examining them, formulating them for teaching to beginners or to postdocs, selecting them for investing research time—all within a defined domain of natural science. Sustained thought, reiterated questions, the rigorous boundaries of logic and evidence, the ever-present demand for controls and explicit effort to disprove, a tremendous dependence on the subjective component, on imagery and imagination—these converged on a limited number and range of particular issues. Still, there have been multiple themes. Besides transient phases, I have chosen to arrange these reminiscences around the warp and woof of a few main threads and leitmotifs of the scientific interests I indulged in over many years. Some are explicit sections; others are not treated separately. Some biases will be obvious and may rear their heads more than once. A penchant for the relatively neglected issue, technic, or animal group and avoidance of the popular one can be discerned. I am certainly not the one to interpret this—is it fear of competition or love of prospecting? Of course, I rationalized it as the latter and perpetrated a preachment, one Friday night at the Marine Biological Laboratory (MBL) in Woods Hole, Massachusetts, on the need for prospectors in the face of the gold rush of popular, reductionist cell biology. I have also preached on the need for more comparison of taxa, particularly the phyla and classes representing major grades of complexity of brains, and the need for descriptive exploration of the phenomenology they manifest—natural history, in the best sense. In a recent, invited piece I have already recounted many of my memories about controversies and quiet revolutions in brain science at the middle (“mesoscopic”) levels of integration that lie between ionic channels and psychological phenomena (Bullock, 1995).

Family and Off-Campus Life

My choice of families was fortunate on both sides. I have said my parents were supportive; they understood and appreciated teaching and encouraged my bent for scientific research. My two brothers were both in commercial research laboratories, my sister was a nurse, and they each brought choice in-laws into the circle. The sizable Runquist clan on Martha’s side was salt of the earth and made me feel accepted, although my occupation, beyond teaching, was hard to explain. Martha and our two wonderful children made our home easy to come back to and hard to leave so often; their unquestioning patience was an undeserved miracle. The pleasures of bedtime reading, singing around the piano, camping, school open house, and going to visit one or another grandma and grandpa meant a lot more to me than the share of my time they got. I enjoyed puttering in the garden, terracing the slope, fixing things at the level of drip irrigation systems, and raccoon-proofing the garbage pail. As a superb cook and thoughtful hostess, Martha made legends I still hear about from friends around the world with her buffet dinners and Christmas parties for graduate students and visiting firemen. The community Methodist church was an important part of life, Martha being a professional staff member while I got as far as committees on social concerns and the Amnesty International chapter. Although our churches have been what is conventionally called liberal theologically, it is a mercy that I have not had to explain my own beliefs; I’m sure some of our dear friends would be shocked at the level of scientific humanism. I’ll come back to home and family again, but here begin to overview my research interests.

An Anatomical Leitmotif

Although I cannot claim substantial, original contribution, an interest and respect for structure reappears over the years and had a strong influence on my thinking. At first—that is, in high school—my anatomical interest was in making specialized technics work for silver and gold staining of neurons, astrocytes, microglia, and oligodendroglia. These methods had been published by the then still living Spanish anatomist, Santiago Ramón y Cajal, who shared with the Italian Camillo Golgi, the first Nobel Prize in anatomy. By about 1930 I was a student in Pasadena, fascinated with the more challenging histological stains. When I succeeded with these, the idea took hold of seeing for myself the reported changes in microglia with time and distance from a needle stab wound in the cortex of a rat. When this also succeeded I screwed up my courage and took the interurban train to the giant Los Angeles County Hospital to visit the neuropathologist, Cyrus Courville, whose name I had encountered in the literature, to consult him about both glial stains and the Marchi method for tracing connections of myelinated tracts. I still have the 65-year-old slides I made showing corticospinal fibers decussating in the rat medulla and fewer but scattered fibers in the pigeon spinal cord after lesions in the cerebrum on one side. What made an impression on me as a junior college kid about that visit was listening to the great pathologist dictating his observations to his secretary in perfectly formed sentences while doing his brain slicing of the postmortem specimens of that week. In 1951, he again did me and others a service by publishing the English translation of Cajal’s Precepts and Counsels on Scientific Investigation, Stimulants of the Spirit, with advice on how a scientist should choose a wife and a project.

Most of my anatomical forays have been done with collaborators. I looked, sketchily, at the giant fibers of many polychaete annelids, including some of their synapses. Wade Fox joined me to describe the remarkable sensory nerve endings of the infrared receptors in the facial pit of pit vipers, and was aided by lucky silver impregnations. Elizabeth Batham and I examined electron microscopically the infoldings in the larger axons of the sea slug, Aplysia. I encouraged my student, Ellis Berkowitz, to collaborate with electron microscopists and apply their tool to verifying the absence of true, tightly wrapped myelin sheaths in the spinal cord of lampreys (Schultz et al., 1956). Before saying too confidently that these sheaths are not to be found in agnathans, perhaps invented in some corner of the brain or trigeminal roots, I persuaded Jean Moore to join with Douglas Fields and look again, at many levels and at the much better brain of hagfish. They found the absence complete, implying an invention of true myelin in ancestors of modern elasmobranchs, who have abundant, well developed myelin sheaths. The principal evidence of my appreciation of anatomy, however, is in the studies of many students and postdocs who took my advice and supplemented their physiological contributions with proper anatomical controls. Some went on to do major morphological work on their own or with my laboratory neighbor, Glenn Northcutt. This appreciation of anatomy also led to chapters in my books and had a profound influence on my speculations, for example, about the evolution of complexity and of the number of kinds of nerve cells.

A Thread of Research on Nerve Nets

Having chosen for my Ph.D. thesis a G.H. Parker-type study of an obscure group of worms, significant mainly for being the lowliest creatures to have been listed at one time among the chordates (our own phylum), it was not a great surprise but rather welcome news to discover that these worms have a nerve net. Nerve nets are well developed in jellyfish and their cnidarian relatives but elsewhere, from flatworm skin to mammalian gut, are generally absent, not properly demonstrated, or conduct only locally. Nerve nets are the simplest form of nervous organization and may coexist with a centralized nervous system, but this is unusual.

Nerve net is a well defined term, established in the last century, for a certain form of nervous organization to be distinguished from a peripheral plexus or tangle of nerve fibers. The main criterion of a nerve net is diffuse conduction, that is, spread of excitation from any stimulated locus to any other place, even after incomplete cuts anywhere, as though the conduction system is netlike and lacks essential pathways like nerve, which are bundles of parallel fibers. Nerve nets are quite different from a popular object of study today, called neural nets (better spoken of as neuroid nets), which are principally models in computers. The term neural net is also sometimes applied to local assemblies of cells in gray matter with unknown connectivity.

My interest in nerve nets focused on how we can account for a diverse repertoire of behavior in cnidarians (jellyfish, anemones, corals, and others) with the known properties and anatomy of the nervous system—an interest we call today neuroethology. This was a direct extension of the work of Carl Pantin (1935) who believed that he could more nearly account for the known variety of movements of sea anemones, local and general, spontaneous and responsive, than could be done for any other animals by the variety of dynamic properties of junctions. Jellyfish have quite another lifestyle and my first aim, at Woods Hole in 1940 and in Pensacola, Florida, during the first few weeks after the Japanese attack on Pearl Harbor, was to compare jellyfish with Pantin’s story on sea anemones. This project worked out well and the next step, a bizarre one for me, was determined by a conversation with David Nachmansohn, then also a visiting investigator at Yale. He believed the acetylcholine mechanism, with its specific enzymes, was important for both conduction and transmission, intracellularly in both axon and synapse, rather than only extracellularly at synapses. I agreed to provide material for chemical analysis from various invertebrates and spent hours picking out the caprellid amphipods from, seemingly, bushels of the colonial hydroid, Tubularia, to purge the cnidarian of advanced arthropod molecules. Cnidarian and other taxa proved to have the cholinergic machinery, and I became a party to a vigorous debate in the literature about the role of acetylcholine in conduction. The debate simmered for decades after I left it to return to integrative and organizational questions. I have not heard that the case is closed yet! Nerve nets continue to fascinate me and receive intermittent attention at long intervals.

The next major advance was in Robert Josephson’s thesis (1961). He not only did novel experimental physiology in a new group, the colonial hydroids, but with the help of computer and modeling experts designed a digital model based on the most realistic anatomy and physiology. The model was used to extend the efforts of Adrian Horridge (1957) to account for the diverse forms of spread of excitation in coral colonies within the known parameters of cnidarian nets. Up to the present, this has not been accomplished, but we have not given up because even these simple and randomly distributed variables offer a large range of permutations to test (probabilities of synaptic connection and of requirement for facilitation). This was dramatically shown in a Ph.D. thesis under Michael Passano at the University of Wisconsin by David Smith (Smith and Bullock, 1990). Smith found a critical combination of parameters in a model that can, in a computer, spread excitation not around corners but only in straight lines, as I had found in 1965 in the skin of sea urchins and declared to be inexplicable with familiar nerve net organization! In the meantime, the Josephson, Reiss, and Worthy model had been improved and used in a satisfyingly affirmative test of the question whether such randomly constructed nets can show preferred (most effective) temporal patterns of stimulation (Fehmi and Bullock, 1967). At this writing I am hopeful about a newly programmed model that might permit more thorough tests of the range of responses of cnidarian-like nets. The capabilities of primitive nets and of the variables we know about are still not appreciated, especially when one adds degrees and distributions of spontaneous patterns and of superposed modulation by a second net. I am confident that true nerve nets and realistic models of them still have much to teach us.

Postdoctoral Years at Yale and the MBL at Woods Hole

When I finished the Ph.D. requirements in 1940, a postdoctoral year of further training and pure research was uncommon. The traditional goal for the relatively privileged was a period in Germany, England, or Scandinavia but these opportunities were closed; Europe was already at war. I was extremely fortunate to be awarded a Sterling Fellowship in zoology at Yale. Before reporting to J.S. Nicholas in New Haven, my mentor in the Osborn Zoological Laboratory, I spent the summer at the MBL at Woods Hole on Cape Cod. The next summer, Martha and I went again to the MBL without knowing where we might be in September but, luckily, a Rockefeller Fellowship in neurophysiology under H.S. Burr at Yale came through just in time.

Four years at Yale and summers at Woods Hole were formative and influential. Besides meeting a wide cross section of people in zoology, physiology, anatomy, and related fields, the opportunities to learn new techniques, especially electrophysiological ones, and to apply them to simple invertebrate preparations were golden. I became imprinted on comparative physiology and on the importance of combining anatomy and physiology, on the value of simple systems, and on the diversity of integrative mechanisms in the nervous system. At brown bag lunches, teas, or seminars, I came to know Alexander Petrunkevitch, Ross Harrison, Evelyn Hutchinson, Dan Merriman, and Grace Pickford, among others in zoology and H.S. Burr, Ralph Meader, Warren McCulloch, Harold Green, John Fulton, Leon Stone, and others in the medical school.

Other lifelong influences, already strong at Berkeley and enhanced in New Haven, included an appreciation for the history of science. In 1943 Yale gave a prize to the medical student with the best list of errors found in Vesalius’ epochal De Humani Corporis Fabrica, on its 400th anniversary. I developed a deep respect for the reservoir of information in the older literature, which at that time meant pre-1925 and especially late 19th century, when the profusion of scientific journals was hardly 50 years old. Confession being good for the soul, I must underline how handicapped I have always been by failing to gain a level of working proficiency in German and French, although we had to pass exams for a so-called reading knowledge in both, and I had to read and distill thousands of papers in the normal course of business. Later I have felt bad not knowing Spanish—all the worse because the smattering that sticks is so useful and so much fun, as was the smattering of Portuguese, Italian, and Serbo-Croatian I picked up on working visits to Amazonia, Naples, and Yugoslavia.

After a few summers at Woods Hole I was invited to join the teaching staff of the historic course in invertebrate zoology at the MBL (1944–1946). Later I was invited to take charge of the course (1955–1957), selecting 55 students from a long list of applicants, plus nine staff members, assigning the phyla, choosing the destinations of the boat trips for field work and the captains who timed each of the teams’ turns on a succession of stations. The organization of this complex course went smoothly, but that was about as close to administration as I ever got. Although not inclined to buy a cottage in Woods Hole, we returned many times over the years and it is heartwarming to see our grown children eager to visit the haunts of their early years and show them to our grandsons. I was particularly honored to be asked to return in 1991 as Alexander Forbes Lecturer for the second time, after 28 years.

Early in 1942, just settling in to the Rockefeller Fellowship, I was recruited into a war research project on mustard gas prophylactics and antidotes and, by the summer, into teaching gross and neuroanatomy under the wartime pressures of accelerated production of medics. I had a rather obese cadaver all to myself from which to learn gross anatomy a few weeks ahead of the students, in a small, top-floor room during the hot months.

A Thread of Research on Slow Potentials

No doubt this recurrent motif originated from the major research concern for direct current (DC) fields of my second postdoctoral sponsor, Harold S. Burr of the Yale anatomy department. I was never much excited by the steady potentials seen between virtually any two points on the surface of the body, whether plant, hydroid, or human. I did find it intriguing that a salamander egg became electrically quite busy with fluctuating potentials after several cleavages. The hypothesis of Gesell (1940) seemed both plausible and heuristic: that DC fields can influence the level of excitability and of spontaneous firing of neurons, whether the field is extrinsic or, as he proposed, also intrinsic—a standing potential difference between the dendrites and the axon. In any event, I developed a permanent interest in the intercellular effects of DC and slowly changing fields.

Such effects appealed to me, for one reason, because they pointed to the possibility that besides individual impulses and synapses, other means of communicating are possible between cells or from the synchronized population to the individual cell. The notion of field effects on neighboring cells is still current, exciting, and unproved, although a strong case can be made from direct evidence under artificial conditions and indirect evidence under normal conditions. I first attempted to test the notion by polarizing the semi-isolated cardiac ganglion of Limulus, a thread-like concentration of cells on top of the heart that drives the neurogenic rhythm. Lifting the ganglion off the heart allows a weak electric current to modulate the rate of heartbeat command discharges. I found that both polarities caused acceleration, and I had to fall back on the explanation that the large number of ganglion cells are oriented in various directions and those excited by the current win out over those that are slowed down.

We needed a smaller ganglion. Fortunately, Alexandrowicz (1932) had described the cardiac ganglion of crayfish and lobsters as having only nine cells. Of these, four turned out to be pacemakers and oriented predominantly the same way. This preparation speeded up the heart rate in one direction of polarization and slowed it down in the other. But it was some years before we knew this because my first attempts to prepare the lobster heart so that it maintained a normal beat failed. Only after Donald Maynard joined the laboratory to do a thesis on this ganglion and brought his skill to bear did this and other experiments succeed, opening a new window on integrative properties of neurons, to be discussed below under that rubric.

Still later, with Carlo Terzuolo, we pushed the sensitivity of nerve cells to DC a notch higher by using the tonic stretch receptor of the crayfish abdomen. Extracellular fields of only 50 μV across the cell sufficed to accelerate or decelerate, according to the polarity. This preparation permitted intracellular penetration, but it was not surprising that we could see no change in the membrane potential during an imposed change in firing rate—for two reasons. One is that, in our uniform field configuration, all the current entering the cell on the anodal side of its electrical equator must leave it on the cathodal side, hyperpolarizing one region and depolarizing the other. These regions might be out in the processes, whereas the soma where we penetrate might be close to the equator. A second reason is that the membrane potential of this pacemaker cell is constantly in flux by millivolts, and a few microvolts will be difficult to see, even by averaging. Electroreceptors, as we learned shortly, can be up to several orders of magnitude more sensitive still, but not to DC. They are tuned to a best frequency which in some species or organs is a fraction of a Hertz, in others up to 5,000 Hz.

Low frequency electrical connections between cells, quite unlike electrical synapses tuned to millisecond presynaptic impulses, were found in the lobster cardiac ganglion (Watanabe and Bullock, 1960). As mentioned elsewhere (see Neural Integration Thread), the ganglia electrotonically spread slow potentials directly from one cell to another, not through the extracellular compartment. This nonconventional form of communication might occur quite widely without having been detected. Because of that possibility I consider this discovery to be particularly important. It represents one member of a family of forms of communication between cells unlike the orthodox synaptic form; the family includes electrical and chemical field effects of shorter and longer range, even perhaps physical effects, such as pushing or dehydrating, which are playing roles of unknown proportion in the recesses of the brain.

In view of this highly speculative bet (a more accurate term than theory or hypothesis, which have become so fashionable as to be overused in the competition for attention and grants), this may be as good a place as any for the following remark. I believe the pervasiveness of the subjective element in the process of doing science is often overlooked but can hardly be exaggerated. It works both ways—that means it often works against us. Many times I have felt like reminding discussants that what seems patently obvious to them in formulations, priorities, and weighing of evidence seems patently different to some other, also presumably informed individuals. Beyond the ordinary undervaluation of areas we do not appreciate is an unfortunately common undervaluation of other scientists in our own area. Without elaboration, I simply refer, with regret, to the many cases I have known of ad hominem antipathy based on no scientific argument but real or imagined behavior. Less ignobly but more widespread and insidious: how much more real and hence weighty is the evidence we have seen for ourselves than the other fellow’s evidence, which we have only read. Less common is the overconfidence of self-recognized authorities, particularly in the hard sciences—which can spice up a colloquium amusingly. One has led a sheltered life who has not heard some exchange like this, in the question period after a seminar by a famous visitor:

“Unfortunately, your algorithm is inapplicable under those conditions, on basic physical principles.”

“Thank you, I meant to make it clear that we and our physical-mathematical consultants have shown that it is indeed applicable.”

“It happens that I am knowledgeable in this field and the laws of physics and simple math definitively exclude it.”

“Very sorry, you must be overlooking Spandau’s recent reanalysis.”

“On the contrary, I…. ”

But, of course, subjectivity is not to be avoided—it is the root of the new idea and the basis of the motivation to follow through. These facets need no comment from me.

What I am told would be interesting to some readers is my own, highly subjective view of the goals of neuroscience, the strategies, fads, and discouragements of its researchers and the outlook for different approaches. One hears “What is it going to take? Do we have to work out every synaptic coupling strength, every channel time constant in each cell, and all the subcellular parameters before we can test the adequacy of our understanding with a realistic model? What constitutes understanding? How are we going to formulate a general theory of the brain?” My reaction is that I am excited about the opportunities in unraveling how brains work, despite the serious obstacles to general models and theories, because I see our knowledge as so preliminary that further revolutions are the only certainty—at least as drastic as those we have already experienced. I expect these revolutions to occur independently in each field—chemistry, anatomy, physiology—and each level—molecular, cellular, small assembly, and multilayered system—as they have in my lifetime (Bullock, 1995). The goals and opportunities I see as most heuristic, at this stage in our science, are not great simplifications, like the neuron doctrine, or great interdisciplinary cooperations, like anatomy and behavior in the brain imaging of active areas during cognitive tasks—significant and satisfying as these advances are. The most heuristic opportunities are rather discoveries of new entities, relations, dependencies, and proportions– natural history or phenomenology of the organized assemblage of neural tissue. All my experience leads me to expect that major novelties will turn up, as they have year in and year out, each opening new windows and multiplying the degrees of freedom. To reiterate a small part of a long list of such findings within not so many decades, witness graded synaptic potentials, lateral inhibition, presynaptic inhibition, gap junctions, nonsynaptic electrotonic connections, corollary discharge, multiplicity of modulators, multiplicity of channels, kindling, face-selective cells, and plasticity of cortical maps. These are permanent advances; models and theories can be helpful in recognizing the next measurement to be made but are almost certain to have a transient vintage. For many purposes I have found that analogies stimulate ideas for new measurements—like the crowd at the stadium as an analogy of assemblies of nerve cells. To the complaint that I am only adding intricacy and minutiae to an already impossibly complex task, I can only answer, that’s the way it is and it can only get more so. Who can say what is unimportant? Within the vast area of our inadequate information base, an especially conspicuous dimension is ignorance of the relative importance of the known variables. I feel keenly that at least the generalists and the theorists, the modelers and the synthesizers should remind themselves often that our enormous knowledge of nervous systems is still extremely primitive. Hence my optimism and sense of adventure—there is greater opportunity than anywhere else I can imagine for solid new discovery, from elementary fact to broad principle, from subcellular to cognitive level, from simple to complex grades of evolution, from early to mature and aged stages, and from normal to pathologic states. We are not suffering from lack of a general theory but lack of simple facts—mostly due to technical difficulties.

I present these remarks early to avoid their being anticlimactic near the end! They may seem abstract or worse here, without the bases that many later sections provide. I will return to some more specific comments on strategy in some of those sections.

Neural Integration Thread

An interest in the multitude of ways that output as a function of input can be varied, within and among neurons, has particularly appealed to me, perhaps because it gives the feeling that one is finding out something intimate and solid about how the brain works, especially how it evaluates and compares. My first summer in Woods Hole, in 1940, when I chose to extend the crude experiments of my thesis on the enteropneust nerve net to jellyfish, I used the methods Pantin (1935) had introduced with sea anemones—basically just single, controlled shocks and isotonic recording of the strength of response. His discovery of junctional facilitation impressed me with its simple elegance and power to explain widely diverse behavior by differing time constants of build-up and decay. An integrative property of this name was known to Sherrington and others at the reflex and higher levels but not at the synaptic level, probably because it did not happen at the healthy neuromuscular junction of frogs and cats. Wiersma and Van Harreveld (1938) found facilitation highly developed and differentiated among different crustacean neuromuscular junctions. I found (Bullock, 1943) that this simple dependence on the amplitude of the last contraction and the interval to the next one can account for about 85 percent of the fluctuation in strength of jellyfish swimming beats, leaving 15 percent to free will!

At this time the local potential, discovered by Bernard Katz and Alan Hodgkin (references in Bullock, 1995) in crab nerve—a subthreshold, graded, nonlinear response within a few millimeters of the stimulus—was under debate. It seemed to me a good candidate for a postsynaptic explanation of the inferred state of facilitation. What caught my attention, especially in 1946 after watching the labile subthreshold responses of the single giant synapse in the squid (before the first intracellular junctional potentials of Paul Fatt and Bernard Katz), was the multiplicity of apparently independent variables that must converge to determine output as a function of input. Accommodation can be small or large; afterpotentials can be in either direction, each small or large; cells can be more or less iterative, more or less regular; some are sensitive to temporal pattern at a given mean frequency of arriving impulses, others not; some are spontaneous and others not; firing rate can be a steep or a shallow function of depolarization; excitability can vary independently of responsivity. All this was before the discovery of the host of synaptic variables that continues today to grow with each year’s journals. Summarizing our understanding, I listed 48 variables like the seven just given, in a textbook (Bullock et al., 1977). There are workers who recoil from this enumeration as hopeless complexity or who become engrossed with the ultimate explanation of one or another property in terms of ion channels and third messengers. My choice has been the approach of the naturalist anxious to know all the phenomena nature presents and their occurrence and dependencies, before dismissing any as trivial. This choice led to studies of similarities of axons and synapses in some of these integrative properties, sense organs as models of synapses, fatigue and subnormal responses as models, quasi-artificial synapses, the distinction between excitability and responsivity, and specializations in certain axons that are tolerant of stretch while maintaining conduction velocity with decreased diameter.

An intracellular phase began in 1955 with the indispensable skills of Susumu Hagiwara. We worked first on the squid giant synapse I had exploited extracellularly, then on the lobster cardiac ganglion, a miniature model of a brain, with only nine cells. These nine cells include pacemakers showing spontaneity and pattern, and follower cells that filter, integrate, and amplify their input. These preparations underline anew the permutations of integrative variables.

As in other phases, post- and predoctoral co-workers were vital and immensely rewarding friends—in this case, besides Hagiwara, there were Carlo Terzuolo, Takuzo Otani, and Akira Watanabe. Akira brought a new dimension, not only to us but to neurobiology, when he discovered the direct electrical connections between neurons in the lobster cardiac ganglion. Subsequently, we showed these connections can usefully spread slow and sustained subthreshold potentials between cells, electrotonically, but cannot propagate or transmit impulses (see also A Thread of Research on Slow Potentials, above). My contribution was to suggest the experiment to show that these connections can provide a nonspiking feedback from follower onto pacemaker cells, whereas no synaptic feedback has been found in this preparation. This and other new integrative variables led me to formulate the locus concept, expounded in a review in Science (Bullock, 1959). This concept underlines the idea that the subthreshold activity in a neuron is local and distinct in its various parts, such as the one or more pacemaker regions, terminals of separate axon branches, and discrete afferent dendritic regions. Each part is a site of integration and possible lability and plasticity. I began to add the evolutionary dimension in 1958. In 1961, stimulated by our first recordings from electrosensory afferents in electric fish, I began to think of the variety of forms of signaling between cells as coding principles, both in the domain of nerve impulse trains and in the nonspiking mode.

It should not be surprising that the brain, the most complex system known (apart from systems of brains), has many degrees of freedom. Just because a McCulloch-Pitts model (McCulloch and Pitts, 1943) or another one made of limited kinds of units and variables is believed, in principle, to be able to do anything, it does not follow that the brain works that way. Fishing for new principles of operation in real brains is surely one of the most rewarding routes to new discovery about what evolution has accomplished in the nervous systems of animals. Modeling subsystems or operations of the brain is today the fashionable thing—and I cheer and support those willing to join the hunt, with whatever weapons. Modelers underline that they have to select the variables that seem important and simplify or standardize the many others known to exist, on the assumption that the latter are not important. I cannot help pleading, over and over, that we have no proper basis for selecting and should keep open other variables from the long list known. Especially important, we should undertake more descriptive exploration for new phenomena in wet brains. I am sure we have yet to uncover major surprises. “Classical” synapses, for example, may not be the overwhelmingly important form of interaction between cells that we confidently assume.

My own involvement in neural integration moved up from single synapses and intracellular views of single integrating cells to simple interactions like the results of repetitive trains of inhibitory (J.S. Schulman) or excitatory (J.P. Segundo) impulses on a pacemaker. The elementary case was the tonic stretch receptor of crayfish, where anomalous acceleration from inhibitory input manifests phase locking and provides one of the best examples of a biological value of “noisy” irregularity, better called useful jitter.

The reports of Wiersma and Waterman, beginning in the mid-1950s, of units in the optic lobe of lobsters and crayfish that respond selectively to natural stimuli with a combination of visual features, began a whole new chapter in sensory processing and brain operations that has interested me much more than my meager contributions to it would suggest. From personal observation of the experiments of Jerry Lettvin and his colleagues on similar units in the frog optic tectum in 1957, I became convinced of their reality and their importance for brain physiology, although these two propositions had a long uphill road to general acceptance and still have not found a real place in the prevalent models of sensory recognition.

My own experience was interesting. Aspiring to contribute to what I perceived as an exciting new field, in 1959 I proposed to my visiting investigator from Germany, an established expert in central visual units, that we try to find the units that Lettvin and company had reported in the frog tectum, in order—if we could confirm their reality—to add quantitative detail. These units respond well only to small objects or contours, preferably darker than the background and sharp edged (focused), moving within a 5° excitatory receptive field, in the absence of too much movement in the surrounding inhibitory receptive field. He demurred, saying it was a flash in the pan and would soon be found to fit into the scheme of ON-center, OFF-surround units known from the cat retina. Perhaps out of respect for his host, he offered to allow his wife, Ulla Grüsser-Cornehls to waste time on this wild goose chase if she wished. But this adept and dedicated worker could not find such units! I telephoned Jerry and he promptly flew to California, showed us how, and found the units within minutes in the first preparation. After that, Ulla (Grüsser-Cornehls et al., 1963) had no difficulty and published papers for more than 25 years on these complex recognition units, actually retinal ganglion cells or their tectal endings. These units and counterparts in higher, cerebral levels, such as the face-selective units and others in the primate temporal lobe, and song-specific units in cerebral nuclei in finches remain in need of both reductionist analysis and assessment of their normal role and adequacy to explain behavioral recognition. Clearly small sets of nearly equivalent complex recognition units that need not fire in particular spatiotemporal patterns do exist. No one proposes that this solution accounts for all or most recognition, but ideas are needed for uncovering what classes of stimuli they do operate upon.

I find neglected and hence attractive the compound activity of organized groups of cells and their complex electrical signs. New levels of integrative mechanisms require exploration—synchronization, quadratic phase coupling of nonharmonic frequencies, population thresholds, and the like. Obviously I subscribe to the tactical rule that we cannot wait for an adequate understanding at simpler integrative levels before plunging into investigation of more complex levels (see EEG and EP/ERP Compound Field Potential Thread).

I have argued that the standard concept of the brain as a system of circuits has long been inadequate, except as a first approximation. Adding up to something far different from any accepted meaning of “circuit” are a number of whole categories of features of neural systems, especially the more advanced levels of them. The known variety of geometric configurations of axonal ramifications and dendritic arbors, making the functional contacts not a 1-μm electron microscopic specialization, but a defined spatial array of them, is one category. Field effects, electrical and chemical, of various degrees of diffuseness or intimacy form another category. The variety of transmitters and modulators and their specific distribution within as well as among cells is a third category. The great variety of integrative properties characteristic for each locus, plus extensions of them like the kind of nonsynaptic, slow electrotonic communication described above, may be considered a heterogeneous fourth category. Some of the integrative properties overlap with Pasko Rakic’s “local circuits,” for example, nonspiking neurons. These are well known in invertebrates and in the retina and are highly likely in vertebrate brains. Even more likely is the transmission of graded influence between spikes.

I reject the criticism that this catalogue of variables is an appeal to a hopeless complexity; it is a call for more effort to assess what is really going on, more descriptive natural history, before assuming that familiar circuitry with impulses and classical synapses is the main and adequate principle. Consider the retina. Better known than many other systems, it is still full of such noncircuit dynamics as induced rhythms, traveling waves, and temporally precise expectation waves (omitted stimulus potentials, OSPs, see EEG and EP/ERP Compound Field Potential Thread).

Giant Systems Phase

In the 1930s and for decades thereafter, the giant fibers of earthworms, crayfish, squid, and many teleosts were nothing more than an extreme specialization for some advantage, like an elephant’s trunk or tusks. We focused on giant fibers as accessible cellular units, hoping their membrane and synaptic properties were not too specialized to teach us general physiology. Each had had its dramatic history of discovery and debate as to whether it was vascular, supportive, or neural. My own interest was not so much in the cellular and membrane mechanisms as in the organization of the afferent and efferent system and the integration at giant synapses. That interest began with the 5-μm fibers, giants relative to all others, in the wormlike hemichordates.

Earthworms were more interesting, having two complementary chains of syncytial units with septal synapses and afferent connections only from the front end to the median chain and from the tail end to the lateral chains, plus efferent connections to anchoring bristles that cause a pulling in of the head end when the median system is excited or of the tail end when the lateral system is excited. The system was unique, too, in that the single impulses in a true physiological unit could be recorded in the intact, behaving animal. I spent some time in the early 1940s developing a circular race track carved in paraffin and covered with a glass plate, in which an earthworm could crawl while we electrically stimulated and recorded from several places, permitting quantitative measures such as conduction times to be followed day after day in the same unit, during acclimation or other treatments. The arrangement worked well, but I failed to make any publishable discoveries! The earthworm’s marine relatives, polychaete annelids, were interesting for other reasons, mainly because of the extreme diversity, among families, in the development of giant fibers and of the nervous system as a whole. The diversity made them the most valuable group for arriving at a plausible view of the biological meaning and behavioral correlates of giant systems, with confirmation from work with crustaceans, cephalopods, teleosts, and others, including odd groups like phoronids and lungfish.

The function of Mauthner’s fibers in fish had been debated for many years. I well remember the day a paper came out in Nature, reporting that African lungfish have unusually large Mauthner’s axons. I sent out to the tropical fish store for a specimen, and Don Wilson found that he could record impulses in a single axon firing to a gentle tap from the surface of the intact animal, independent of escape movements. It appeared that giant fiber systems are not so much escape mechanisms as startle response devices and that saving time by fast conduction is not as important as synchronizing a widespread musculature.

University of Missouri at Columbia, 1944–1946; UCLA, 1946–1966

With two postdoctoral years, I qualified for the title of instructor at Yale in my third year. I felt lucky to be offered an assistant professorship at the University of Missouri Medical School in 1944, to teach first-year gross anatomy and second-year advanced topographic and applied anatomy to the medical students, and anatomy cum physiology to prenursing students. At that time a two-year medical school, Missouri required a relatively heavy teaching schedule, but I enjoyed it and in addition was able to do some research.

Good fortune intervened again when I landed a job in 1946 at UCLA in my own field of zoology. I enjoyed teaching the introductory course, Zoology 1A, as well as advanced invertebrate biology, with student projects in physiology and experimental ecology. As a university, UCLA was young and malleable then, so that some of the committee work was interesting and actually brought about innovation—academic senate bodies, the new medical school, the life sciences building and its sea water system, the Brain Research Institute (BRI), and later the Molecular Biology Institute, departmental planning and recruitment, and the local chapter of the American Association of University Professors, of which I was president from 1955 to 1956.

I learned three things in these UCLA years. (1) A complex organization such as a university, having evolved procedures and rules for every situation, is in constant need of individuals who will propose new precedents. (2) Everybody agrees that inadequate communication is a root cause of much of the world’s grief, but few apply that insight to their own situation. (3) Always send carbon copies to everybody you can think of. The same and a few other diplomatic lessons helped out in dealings with the American Physiological Society, the American Society of Zoologists (of which I was president for a term and a half in 1964 to 1965), the Neuroscience Research Program (in which I served as chairman of an advisory committee to the director at a crucial period) and its work sessions and intensive study programs, the National Academy of Sciences (NAS) (where I served as chairman of the Section of Zoology during the time of its dissolution and served in the same capacity in the newly created Section of Neurobiology), some divisional and program committees of the National Science Foundation (NSF), and study sections and two councils of the National Institutes of Health. In those days there was relatively better communication on some matters; for example as a recent and raw recruit, I had to stand in front of the NAS membership and speak for the election of a fairly controversial nominee, as was then done for every nominee.

Although my own research was focused on comparative neurophysiology at the level of the synapse or a simple circuit of neurons, I supervised Ph.D. theses and postdoctoral projects in physiological ecology, mainly in temperature acclimation, until the field became too large for me to follow in addition to the expanding literature in neurobiology—about 1963. This interest led to serving on several committees, including the Environmental Biology Panel of NSF, under George Sprugel, Ladd Prosser, and Dwight Billings, and participating in some expeditions, such as the second resurvey of Bikini and Eniwetak atolls, right after the first hydrogen bomb test in 1948.

To equip and protect my first graduate student, Robert Lindberg, who studied the field biology of the California spiny lobster, I had to provide not only face masks, hoses, and a portable air compressor light enough to launch in a skiff through the surf, and later, a self-contained underwater breathing apparatus, but also the first rules in the University of California for the safety of divers.

During those years our daughter Chris and son Stephen were growing up in Pacific Palisades. Martha drove millions of sorties jitneying them to countless activities, the vector sum of which eventually led to satisfying careers for all. The line between home and science was often fuzzy, as when bags of rattlesnakes hung in the garage. During car-pooling with two additional families, the long-suffering kids were a captive audience for many a long-winded answer to what they thought was a simple question; so they grew up patient and tolerant.

Courses and Teaching: Graduate Students and Postdocs

If the threads of research were the warp of the fabric, the woof was teaching, which enriched and invigorated me from 1936 to the present, with only sabbatical interludes. Perhaps a better metaphor would be an emulsion, with teaching the continuous phase and research the discontinuous phase. Much of the pleasure and challenge—not often commented on—is the daily range from dealing with beginners in structured settings (college courses) to graduate students doing theses, postdoctoral learners acquiring self-confidence and independence, and senior visiting investigators from East, West, North, and South. In the latter category I count well over 100,* and I have supervised 34 doctoral students. They have been particularly close friends, bearing and forbearing for five years or more, on average. Many and diverse have been the graduate student weddings Martha and I attended. I feel fortunate that most of my students went through the system before the current fashion for qualifying exams that hardly go beyond a defense of the proposed thesis—a concession to specialization that reduces the incentive to breadth in our future teachers and scientists.

I began teaching as an occasional invited expositor and tutor at Pasadena Junior College for my teacher, M.W. de Laubenfels, while I was a college freshman. At Berkeley the zoology department took seriously the inculcation of high standards of preparation by TAs for every laboratory exercise and oral quiz, and conducted training sessions of two or more hours weekly. I either took or conducted these sessions every term from 1936 to 1939. In contrast, the medical students in anatomy courses at Yale were “treated as adults” and left largely on their own, with a cadaver, books, a partner, and easy access to instructors but no required examinations for two years. I enjoyed both systems and, at UCLA, both the large elementary classes and small advanced classes. In the large, lower-division zoology classes I had full responsibility for the schedule, labs, field trips, and TA training. In the advanced classes I experimented with project-oriented lab courses, inspired by the MBL experience, and still have a great file of project reports in invertebrate comparative and ecological physiology, which have been a gold mine for thesis proposals.

Even the core medical school courses and still more the elective courses at the University of California, San Diego (UCSD) gave scope for experiment. I recall arranging with Sir John Eccles, then in Buffalo, New York, to stand by for a call. I then answered the expected student question after my lecture on the cerebellum, “Let’s ask Eccles what he thinks.” I dialed him and the class talked directly to him over a speakerphone. I was one of the few lecturers who used the autoscoring machine—with a set of buttons at each student’s place—to ask a few questions at the start of the hour and another few at the end; this worked well with carefully prepared questions. With graduate students and postdocs, phases of experimentation have been rampant—tutorials and written propositions, journal clubs, a “Peripatetic Seminar in First Principles,” and a cooperative “Neurological Study Unit,” often planned with Bob Livingston, plus neuro-campouts, tide pool trips, and Friday afternoon conferences on everything.

My course in scientific communication has run for 28 years and was a direct outgrowth of courses in scientific writing I attended in Berkeley in the 1930s, given by Joseph Grinnell, and in Los Angeles in the 1950s, given by Victor Hall. I broadened the scope to making the transition from student to professional, including use of the library, history of scientific communication, the roles of scientific societies, verbal and poster contributions at meetings, the preparation of illustrations, grantsmanship, letter writing, informal communication, ethics, the academic marketplace, and communication between scientists and the public. For some years Theodore Melnechuk was my coinstructor and brought a broad and unique experience in many areas. More recently, Glenn Northcutt has joined me; in addition we have an invited expert at nearly every meeting. Many are the opportunities to advise, admonish, and inculcate, giving examples from experience. One troublesome topic has gradually become more difficult—who should be coauthors, and how should this be determined? It is not much help to pronounce, realistically, that practices differ among laboratories and to advise open and early discussion. The upward spiral of numbers of coauthors cannot long continue, but what counterforces will emerge to resist the inflationary pressures for coauthorship, which go beyond any reasonable attribution of real authorship or ability to defend the propositions?

Science is an acutely historic process because one always wants to know what’s been done and what’s not been done. The privilege and good fortune of being able to do science, to profess research, to think hard and long about what needs to be done, and then do it, write about it, and lecture about it is so vividly real that one almost feels guilty of self-indulgence, enjoying life more than one deserves. It is hard, however, to accept the fact that one’s work, far from definitively correcting the mistakes or inadequacies of the past and adding valuable new understanding, will become the flotsam and jetsam of the moment, soon to be passé and in a shorter and shorter span, forgotten –within 25 years, not even cited. I know. I have both experiences every day.

Add to that the enormous and nearly ever-present pleasure of dealing with other people—co-workers, students, and seniors—on a plane of the most satisfying level, mutually appreciating creativity, daily and hourly seeing improvements or advances, seldom distracted by personality clashes, rivalries, or profits and losses. “Exciting” would be the most overused word if we used it for each occasion that deserved it—dozens of times per week in a normal period of lab work, journal reading, phone calls, e-mail with colleagues around the world, and coffee breaks with co-workers. All the synonyms in the thesaurus apply now and then, some only once a week, like electrifying or delighting, others maybe once a day, like intriguing or fascinating. One might even call it a sensory-enriched environment such as keeps old rats’ dendritic spines turgid.

Physiological Ecology Thread

This phase of activity, lasting through most of the UCLA period, was an alternative area for graduate theses and postdoctoral projects; I was deeply interested in comparative physiology of ecological import and particularly, temperature acclimation (Rao and Bullock, 1954; Bullock, 1955, 1958a), but confined myself to synthetic papers. Some of the issues and ideas are mentioned in A Technical and Mathematical Leitmotif. My first graduate student (R.G. Lindberg) chose a field study of the southern California spiny lobster and others studied osmotic (W.J. Gross) and hemocyanin (J.R. Redmond) problems. Most, however, carved out aspects of adaptation to habitat temperature (J.L. Roberts, P.A. Dehnel, E. Segal, P.E. Pickens). Postdocs K.P. Rao and O. Kinne measured responses to salinity and temperature in a number of taxa. H. Barnes concentrated on cirripedes and their feeding, metabolism, respiration, and behavior in relation to salinity, ions, general ecology, and distribution.

The interest in ecological physiology was a natural result of my upbringing in invertebrate zoology, which always included living material and, whenever possible, field work, and of my later focus on physiology, which came largely from teaching experimental invertebrate biology at the MBL and comparative physiology at UCLA. The story of a boost from field and aquarium studies of an unexpected behavior in limpets is recounted in the section Behavioral Thread. A number of expeditions to do neuroethology on the coral reef, at the Japanese seashore, in the Amazon, in the Gulf of California, and elsewhere whetted my appetite for more contact with the field. Service on a number of national committees dealing with ecology meant acquaintance with many leading ecologists of a generation now largely gone. The impossibility of keeping reasonably informed in this field, as well as in neurobiology, compelled my retreat from active engagement in it by the mid-1960s but did not quench an amateur interest, which has been continuously stimulated since then by having ecological lab neighbors of a yeasty ilk at the Scripps Institution of Oceanography (SIO).

Expeditions and Field Work

The MBL at Woods Hole taught me that even moderately complex electrophysiology could be done by packing up everything, down to the last screwdriver, setting up in a day or two, even in damp rooms on simple benches, if only the jellyfish, worms, squid, or rays are available. Visiting marine stations or making our own temporary laboratory in a shed on the shore, my students and I learned how to ask Brazilian collectors in Portuguese for unusual electric fish, how to catch baby sharks on the mid-Pacific reef with a Polynesian throw net, how to look for a school of squid in Monterey Bay at night by the faint glow of the luminescence they stir up from the microplankton, and how to repair Ampex instrumentation recorders on deck under the tropical moon. The unexpected became the norm as we worked—for a few weeks every hundred or more weeks—at Pacific Grove, Plymouth, Naples, Friday Harbor, and similar civilized stations, and at Bikini atoll, Barro Colorado Island in Panama, a tiny zoo in Belem, Brazil, a public aquarium on the Izu peninsula in Japan, a billfisherman’s cottage near La Paz on the Sea of Cortez, and a former sea captain’s house in Kotor, Yugoslavia. Among my co-workers, the lesson came harder to some—always be flexible and ready to adapt, but be sure to get reportable answers to significant questions in a short time. My own experience has been only about two dozen such expeditions but I surveyed systematically the experiences of several hundred scientists who worked, in the first few years of the SIO Research Vessel (R/V) Alpha Helix, on short-term physiological and biochemical, anatomical, and behavioral operations in remote locations, most of them without previous experience of this kind. The findings were surprisingly favorable in terms of published output but underlined the requirement for imaginative improvisation.

A Technical and Mathematical Leitmotif

Any claim under this motif seems out of place from one with such limited training in the basic disciplines of hard science. I have always felt these weaknesses keenly and occasionally made a commitment to devote the time to rectifying one or another, but failed to follow through. I have neglected not only mathematics but chemistry and molecular biology, the hallmarks of today’s neuroscience. Surprisingly, I have found that practical biophysics and some applications of mathematics are approachable with little more than concept and intuition, plus guardian angels in human form who protected me from the more egregious errors. One such expert was the electronics engineer who drew me a circuit for a pulse-generator-stimulator in 1941 when no such item was on the market; I learned some basic electronics building that circuit, discovering only at the end that we had both forgotten to include an on-off switch.

Electrophysiology took an early postdoctoral grip on my fancy, thanks to kind hosts at Yale, where I divided my time in 1940 to 1941 between the laboratories of J.S. Nicholas, embryologist in the zoology department, and H.S. Burr, electrophysiologist in the anatomy department. I was introduced to electroencephalographic (EEG) recording and evoked potentials (EPs) by watching Warren McCulloch, Clyde Marshall, and Les Nims conduct strychnine spike neuronography in monkeys. This is a method for finding direct cortico-cortical and cortico-subcortical connections, and was introduced by the team leader, Dusser de Barenne. After a 72-hour experiment, the team was pleased to accept my offer to clean up, which gave me the opportunity to learn the knobs and dials, record spikes and brain waves from monkeys, and pick up some of the black magic and pitfalls of electrode preparation and placement.

I never got over the wonder and excitement of seeing a green streak on the cathode ray oscilloscope (CRO) that betokens a real, living response, hence a connection and a congeries of dynamic properties between the site of stimulation and the recording electrode—subject to a myriad of artifacts and misinterpretations that suggest, in their turn, control experiments and more fun. The opportunity is infinite for devising procedures, and one must be as interested in results as in improvements to avoid the common syndrome of instrumentation fixation. When four-gun cathode ray tubes became available, before good, high frequency electronic switching, we rigged a standard, single-gun CRO for such a tube and enjoyed four-channel recording, the start of a permanent passion for simultaneous observation at many places. The first and last paper for which I was paid ($25, as I remember) described how to calibrate camera shutters with a CRO.

Frustration stimulated the cathode ray direct-recording caper, which had to do with the difficulty of choosing between two means of recording. The CRO had to be photographed, with consequent delay for developing before seeing results. The moving mirror oscillograph, from which recording paper came out developed, could not follow frequencies high enough to record nerve impulses faithfully. I journeyed to DuMont headquarters in New Jersey and was encouraged to try my idea of collecting the cathode ray beam at the screen, on one of a row of wires and delivering it, after amplifying the current, to one of a row of pins fixed over a strip of moving Teledeltos (electrically marked) paper. DuMont gave me an empty glass cathode ray tube, the glass blower at Yale sealed into the screen the row of platinum wires, DuMont installed the cathode ray gun and sealed the evacuated tube—and I failed to confine the collected current to one or two wires! Another idea was based on a new kind of cathode ray tube with a high-frequency spinning beam (hundreds of kHz) and a circle of collector wires, announced by a small spin-off company of DuMont. I visited them and proposed to gate the cathode ray current at the same frequency as the rotating beam to record a DC signal on one wire and to frequency-modulate the rotation for AC signals, the collector wires feeding a row of pins marking a moving strip as before. This plan for a direct-recording high frequency oscillograph sounded good to the company, who said they would try it, but I never heard of it again.

When I invented a way of continuously displaying spike intervals-vstime (by condenser charging—long before digital computers) and told H.K. Hartline that we called it our PIP, for pulse interval plotter, he said they had something of the kind, hitherto unnamed—and christened it, on the spot, his time interval totaler.

Besides devices and procedures, something has made me get involved in relatively neglected quantitative natural history, from extremely simple projects to those well over my head but intuitively promising. One example is the comparison of temperature effect (“Q₁₀”) at different temperatures and after acclimation. Another is the comparison of extent of temperature acclimation possible among different physiological processes in species from different habitats and latitudes. I came to the view that animals are not just a collection of molecules and structures but as much a bundle of rates that have to be in harmony—one cannot for long have more egestion than ingestion. Different rate functions often acclimate to different degrees, some more than others. The reason, so I proposed, that all animals don’t live everywhere, by acclimation, is that in poor acclimators, the rates get out of harmony. These examples come from projects in my ecological physiology period (see Physiological Ecology Thread).

In the area of sensory physiology, I became intrigued with the comparison of sensory receptors, pacemakers, and neurons generally, with respect to their regularity and distribution of interspike intervals as a function of the mean frequency of discharge. Although a strong tendency is widespread for regularity to increase as mean frequency rises, relatively as well as absolutely, cells are not all alike. A wide variety exists, from clocklike cells to jittery and extremely sputtery ones, compared at a common mean rate—and I still have no idea why. Two extremes are the highly regular pacemakers in the brain of certain species of weakly electric fish that command electric organ discharges (EODs) with a standard deviation of intervals 0.01 percent of the mean (100 times smaller than classical “clock” cells) and the highly irregular infrared receptors of rattlesnakes that maintain a spontaneous background with interval variation several times the mean. I believe we still have a poor empirical knowledge of the distribution of these properties among species, parts of the brain, stages of development, and extrinsic influences—as with most others of the dozens of “personality” properties. Further natural history is needed at least as much as models based on inadequately informed simplification.

The last example of this urge to quantify, even to the point of getting in over my head, involves the closer description of the structure of activity in brain waves, as I explain later.

Sensory Physiology Thread

Herpetologists R.B. Cowles and K.S. Norris (subsequently known in cetaceology) pointed out to me in 1951 the facial pit of pit vipers and the conclusion of the latest papers that it might be a sense organ detecting a slight warming of the air by warm-blooded prey. On a lucky guess that nearby trigeminal nerve branches supply the pit, we anesthetized a rattlesnake and found heavy traffic of spontaneous activity in the steady state, without intentional stimulation. Simple tests showed that purely radiant heat suffices to enhance and radiant cold to suppress this activity, independent of the intervening air temperature. As a sense organ, it was fascinating for several reasons. One is that the spontaneous discharge of each afferent unit is extremely irregular, leading us to speculate that perhaps several subthreshold oscillations of different frequencies arise in separate sensory terminals and add, like local potentials, in a nonlinear fashion to cross threshold irregularly. Regularity becomes both absolutely and relatively greater as stimulation drives up the mean discharge rate. A second aspect of general interest is the problem of explaining the high sensitivity. The possibility of a wavelength-specific photochemistry could be virtually excluded and instead a high sensitivity to temperature change of the nerve terminals could be directly shown—extending to a few millidegrees centigrade, providing it happens rapidly. This may not be much different from the sensitivity to temperature change in the sensory terminals of our face but the pit viper sensory membrane requires a millionfold less caloric flux to raise the nerve ending temperature that much—because the sensory membrane is small and barely 15 μm thick, with an air space behind it. The nerve endings are directly under the 2 to 3 μm-thick epidermis. The physiology and light microscope anatomy occupied several years and got me hooked on sensory physiology as a window onto neural processes.

A 1952 visit by Yasuji Katsuki, the prominent auditory physiologist, led to the second sensory sally—into the lobster statocyst, then called an otocyst. Because hearing is uncommon among aquatic invertebrates and stimulation with acoustic signals has tricky artifacts, I was wary of doing experiments myself. With Katsuki’s expertise and the able assistance of a student, Melvin Cohen, we soon decided this organ was not really acoustic, and Mel went on to do a thesis on the variety of things it really does.

Yasuji also told us his idea, based on the properties of lateral line receptors in fish, that some sense organs have dual channels. One set of receptors has thin afferent axons, low thresholds, low slopes of the intensity/response function, more tonic responses, and larger receptive fields. The other set of receptors has thicker fibers, higher thresholds, better intensity discrimination, more rapid adaptation, and smaller fields. In a literature survey, I found evidence of a similar dichotomy in nine cases, ranging from earthworm giant fibers to mammalian lung mechanoreceptors—not justifying a rule, but a common example of parallel channels for distinct aspects of information processing.

Electroreceptors were unknown but called for by the ingenious experiments of Lissmann and Machin on a weakly electric African fish in 1958. We guessed the afferent fibers might be in the lateral line nerve and soon found a place where the right branch is just below the skin in common knife fishes from Amazonia. With my skillful colleagues, Susumu Hagiwara, Kiyoshi Kusano, and Koroku Negishi, we readily isolated single fibers, and two important discoveries emerged. First, the afferent nerve fibers respond not only to feeble electrical gradients, they respond to naturally occurring electrical events of biological significance to the species, namely the EODs of the same fish, as distorted by either conducting or dielectric objects, such as other fish or stones, and the EODs of other conspecifics. Hence, the receptors can be called electroreceptors. Second, some of the afferent fibers in species with sustained, regular, ca. 300 Hz EODs follow those EODs one to one and encode useful information, not by any change in maintained impulse discharge rate but by a maintained shift in phase (precise to a fraction of a degree) relative to the EOD and other afferent fibers. Other fibers encode by a change in their probability of following; that is, they miss some cycles of the EOD and fire on other cycles, within 20° or so. This was the clearest evidence that besides the classical frequency-of-impulses code there are other nerve impulse codes. We spent some time defining several of the codes and reviewed the subject with the late Donald Perkel (Perkel and Bullock, 1968).

In addition to these first two surprises, others cropped up. One was the sharp tuning of these EOD-sensitive receptors to the particular EOD frequency of each individual fish and the ringing oscillation of the receptor at that frequency, when stimulated with a brief square pulse. Another was a whole class of electroreceptors that is stimulated not by EODs but by slower fluctuations, below ca. 30 Hz, largely because of ventilatory and locomotor movements of skin and gill generators of sustained leakage currents in the same or other fish. This finding opened up the possibility, subsequently confirmed in many families of siluriforms, and in sturgeons, polypteriforms, lungfish, and others, that many nonelectric fishes and even lampreys can have electroreception as a distinct, specialized sensory modality—as Kalmijn had shown for nonelectric rays and sharks, and later workers showed for a number of urodele amphibians.

Some evolutionary surprises are mentioned later in the section EEG and EP/ERP Compound Field Potential Thread. I always thought of electroreception as interesting, not only as a unique modality some taxa have and we do not, but also as a source of general principles. Because such sense organs have evolved not once but several times (see Evolutionary and Comparative Thread), could there be central neurons sensitive to microvolt or fractional microvolt fields within the brain itself? Even if the sensitivity is only to tens or hundreds of microvolts, this possibility would mean the larger brain waves and EPs and many of the little-studied ultraslow potentials could normally influence firing probabilities or cause transmitter release without impulses. A long list of features known only or particularly well in electroreceptors is given in an edited volume on electroreception (Bullock and Heiligenberg, 1986). These features include ultrastructural changes with activity, tight junctions far from the equator that make asymmetrical voltage drops across apical and basal membranes, resonance of receptors and its plasticity, and the meaning of efferent innervation of receptors. Similarly for central features, the list includes computed maps (one of the first, crude computed maps was that of Eric Knudsen in the catfish electrosensory midbrain, before he went on to show the elegant acoustic one in the owl; Peter Hartline’s rattlesnake infrared map in the tectum was another), parallel pathways for submodalities, several ways for dealing with unwanted reafference, central filtering, best frequencies for amplitude modulation, descending control of adaptation rate in medullary nuclei, and several other principles that may apply to other modalities.

The auditory modality is considered to be part of the octavo-lateralis system in aquatic vertebrates and may actually involve electroreception! Hal Davis and others have suggested that the cochlear microphonic is a step in the transduction of sound. I had a hobby for years of asking cochleologists how big the cochlear microphonic is right at the hair cell. Answers scattered widely, and I had to remind myself that science does not normally work like a parliament or a bookie joint in arriving at decisions.

I got further into auditory research through diplomatic channels. My old friend Yasuji Katsuki and I had just co-organized a satisfying symposium in Tokyo, supported by the U.S.-Japan Bi-National Science Program, and we realized that a study of the unique performance of dolphins in echolocation would be an appropriate follow-up, hands-on research collaboration between our countries. My associates Nobuo Suga and Allan Grinnell were experienced auditory physiologists. Katsuki put together a team from his side, both national agencies approved, and we had two short seasons of joint experiments. We learned that two parallel auditory systems are beautifully clear and already separate at the midbrain level, one for processing social communicating sounds and the other for echo-locating sounds; we believe that similar parallel subsystems exist in other animals but are somewhat more difficult to distinguish. In the echo-locating system, frequency modulation direction and span are effective in governing amplitude of response even within a 20-μsec, average 50-kHz ultrasonic click, and the rise time of amplitude modulation is discriminated even down to 20 μsec or less. Sounds—at least the clicks—enter the head principally through the mandible rather than the external auditory meatus. Far-field auditory brainstem responses (ABRs) are particularly robust and astonishingly similar to those of the rat and other mammals, including the precise latency of each wave.

We wondered whether anything like the ABR—which is so consistent in all mammals tested, including manatees (expeditions to Brazil and Florida), that one can speak of homologous waves—could be found in birds, reptiles, amphibians, teleosts, and elasmobranchs. Jeff Corwin, Jeff Schweitzer, and I surveyed species of these groups (Corwin et al., 1982) and found something quite similar, despite the great differences in the sense organ. The ABR can be averaged from an impressive distance, unlike anything known in other modalities, has several fast waves and then slower waves, but neither can be individually homologized outside the mammals. Corwin brought an intimate knowledge of elasmobranchs and together we showed that at least some families of sharks can hear rather faint sounds from some distance away in the air—or at least the brain responds at the midbrain level (Bullock and Corwin, 1979). This study was facilitated by a period on the coral reef at Eniwetak atoll in the Marshall Islands, where we could catch baby Black Tip Reef sharks, by running them down on the shallow reef, and then suspend them with rubber bands in a small tank after placing fine wire electrodes in chosen parts of the brain. Jeff Corwin succeeded in the microsurgery to show which macula of the labyrinth is mainly responsible for acoustic reception and discovered an unprecedented range in the size of this macula between families of elasmobranchs. He also found continuous addition of sensory hair cells throughout life, more and more sense cells converging onto the fixed number of afferent nerve fibers. In the meantime other co-workers and I had studied single units or EPs to acoustic events in several taxa—insects (Suga), teleosts (Piddington, Echteler), reptiles (Campbell, Suga, Hartline), doves (Biederman-Thorson), bats (Suga, Grinnell), manatees (McClune), pinnipeds (Ridgway, Suga), and sloths.

The still poorly understood sensory system of the lateral line of many aquatic vertebrates was a logical target, which my colleagues and I took up in the mid-1980s with Horst Bleckmann. My hope was to discern the combinations of stimulus parameters the brain is interested in discriminating, which in turn might explain the marked peripheral specializations among species by finding the parameter combinations with the greatest dynamic range of response, especially in higher central evoked and unit responses. We compared species with ordinary and quite specialized lateral lines but did not hit on the “Open Sesame” that I expected. Later, Horst and his students found central units that prefer movement, and I still bet on units that discriminate texture of turbulence and distance of disturbance. Preliminary findings of W. Plassmann that there are best frequencies of amplitude modulation and that they change with carrier frequency also intrigued me. A pleasant surprise was the prediction and confirmation by Ulli Budelmann and Horst Bleckmann that a lateral line analog exists in the head “lines” of the cuttlefish, Sepia. Glenn Northcutt and I expected to find some sensory functions by recording from the tiny nervus terminalis in the shark, Squalus, but instead we found it has tonically active efferent impulses, subject to suppression by somatosensory stimulation of the face.

Sensory functions of the cerebellum in rays, catfish, gymnotiform electric fish, and rats have forced themselves on our attention in several studies with R.A. Bombardieri and A.S. Feng, L. Crispino, S.-L. Tong, L. Lee, E. Fiebig, and J. New. To mention just a few points, we are curious about the meaning of segregation of cerebellar cortical areas responsive to visual, tactile, electroreceptive, vestibular, and lateral line input in fishes; the apparently unsystematic body maps; the enormous differences in size and foliation of the cerebellum among families of rays and among families of sharks, as well as among teleosts; the prominent responses in the cerebellum to stimuli applied to certain parts of the cerebral pallium; and the specific enhancement or suppression of sensory EPs in the tectum or pallium by properly timed stimuli to the cerebellum.

EEG and EP/ERP Compound Field Potential Thread

In a preliminary survey of several phyla in 1945, stimulated by the early work of C.L. Prosser, I noted that the ongoing activity of the higher ganglia of all the invertebrates examined—insects, Limulus, crayfish, slugs, and earthworms—was alike in being dominated by single unit spikes, with weak and inconspicuous slow waves. However, such activity of all the vertebrates examined—fish, frogs, rats, and monkeys—resembled human brain waves in being dominated by slow waves with rare or inconspicuous unit spikes. This double-sided puzzle (why are spikes so readily recorded in invertebrates but demand special technics in the vertebrates, and why are slow waves the opposite?) is important at two levels: what is the biophysical explanation, and what can be the behavioral or organizational meaning, whether consequence or cause?

The puzzles remain unsolved, although a few possible insights may be relevant. After looking at compound field potentials in many species, places, and conditions, I am betting (call them working hypotheses) that the slow-potential side of the puzzle has a basis in subthreshold synchronization and consequences in cognitive style, and that the spike side of the puzzle has bases partly in tissue impedance, partly in cell size, and possibly in the extent of glial membranes. Each of these variables cries out for quantitative natural history.

The similarity of the EEG among vertebrates, from fish to mammal, at least in the shape of the power spectrum, is even more intriguing because the structure of the cerebrum, especially its mantle, is so different and the functions and organizational dynamics are probably equally different. My hypothesis is that differences in electrophysiological dynamics exist, although they are overlooked in the preoccupation of the literature with the voltage-vs-time plot and the Fourier spectra. Hence my expert colleagues and I have been searching for new or unfamiliar descriptors of more cooperative properties on finer scales that might reveal a difference among taxa, or among brain states, stages, or parts. I believe that these compound field potentials are information-rich in ways we have not learned how to assess.

We began with coherence (a frequency-specific measure of cooperativity between two simultaneous time series), especially its distribution and spatial fine structure, in the millimeter domain. Later we examined the temporal fluctuations in the fraction-of-a-second domain. Recently we took the first extensive look at the bicoherence on similar scales; this measures a nonlinear higher moment, the quadratic phase coupling between frequency components. Again we find very local differentiation and short-term shifts. Both approaches show that essential dynamics of the EEG are not fundamentally global or large in scale but extremely local and never steady for more than a second or two but fluctuating in a way suggestive of complex, local processes, mainly nonrhythmic. The structure of activity and its origins are apparently quite different from the generally accepted view, which is based chiefly on scalp recordings and analysis that assumes sinusoidal oscillators and independence of frequencies. These conclusions have not yet resonated with many authorities and have the status of fringiform perpetrations.

This last statement summarizes the status of these ideas among cognoscenti who appreciate compound, slow waves. But a large segment of those investigating central processing do not find such waves worth discussing, let alone recording, and confine their data to the spike firing of units. A regrettable degree of mutual disparagement between those who favor the single-unit spike approach and those who favor the compound slow-potential approach has held back progress. Having done a good deal of each, it is my position that we need both windows, that they are not redundant but reveal distinct fractions of the whole—and together far less than the whole.

I am still in the stage of groping for descriptors that might measure other cooperative properties of the complex vector sum of large numbers of generators and slow as well as fast processes that we believe constitute the EEG as well as the EPs and the event-related potentials (ERPs). My bet, that the time series we record is information-rich, includes the large, seemingly stochastic component. This component should not be called noise (antisignal, in dictionaries), and neither should a large or substantial amount of noise be assumed to be present in every nerve cell; we know better.

The raw record and its decomposition into linear spectra of power, coherence, and phase at each frequency are quite inadequate as descriptors and in my opinion have misled many workers into accepting that the vertebrate EEG is basically a mixture of rhythms from more or less independent oscillators. Even with the limited view of these linear methods, we found abundant evidence, over more than two octaves, that the frequency components isolated artificially by the Fourier transform are not independent but tend to covary in space and time as though the generators are not oscillatory but wide-band events—in the general case. Of course, it is well known that under special conditions one or two, rarely three rhythms, can stand out sufficiently from the wide-band background (for example, alpha, theta, and gamma rhythms and their subspecies) to justify the inference of oscillators. These conditions account for only part of the time, leaving most of the lifetime of most mammals, and especially the nonmammalian majority of vertebrates, without evidence of rhythms.

Nevertheless, while recognizing that the prevailing state, without evidence of rhythms, includes alert, attending, and cognitively active times, I am fascinated by the special conditions that induce rhythms of a wide variety, from those of jellyfish, sensory receptors, and denervated muscles to those in higher brain levels after onset and offset of certain stimuli, those accompanying apparent expectation and presumed cognitive processing, such as “binding.” We are in a very early stage of understanding their mechanisms and their functional meanings.

The phenomenology of brain activity is still little known with respect to the second-by-second time course and the millimeter-by-millimeter spatial distribution of activity, particularly signs of interactions, synchronization, cross-correlation, or other forms of cooperativity. It is rare to find such detailed studies as Walter Freeman’s, with many closely spaced recording electrodes, analyzed with fraction-of-a-second temporal resolution. We badly need a lucky guess whether the most insightful measure will be coherence and its derivatives, partial and multiple coherence, or the nonlinear higher moments of quadratic phase coupling in the bispectrum and bicoherence, or estimates of mutual information or entropy, or dynamical forms of dimensionality and attractors—or something else! The issue of scale has a serious effect. Coherence between pairs of loci falls off to insignificance in millimeters, on the average, both subdurally and with gross electrodes in the depths of the temporal lobe in rats and rabbits (hardly twice as far in humans) but often spreads much less when recorded with microelectrodes intracortically. Recorded on the scalp, it sometimes spreads much farther. It’s a jungle in there—a fascinating community of diverse species and interrelations—and, according to my intuition, the greatest reservoir of new principles yet to be discovered.

The Eps—a term I use in an old-fashioned sense for the relatively more exogenous, lower-level responses, time-locked to sensory stimuli with little or no cognitive dependency—were a major aim of several projects cited in the section, Sensory Physiology Thread. They come into play when a sensory event stirs up either new activity or “reordered” (phase shifted) ongoing activity, or both. Commonly, the EP is a complex sequence of responses; a simple event such as a flash of light or an acoustic click triggers a succession of faster and slower central processes, and often induces a number of cycles of an oscillation at a characteristic frequency (Bullock, 1992). EPs are useful for proving sensitivity to a stimulus, showing specialization compared to other taxa, tracing pathways, showing alteration in the dynamical properties at successive stages of processing, and interactions with other modalities.

Sharing many of the puzzles of the EEG are the ERPs, a term I reserve for relatively more endogenous, higher-level responses, time-locked to events that in humans would have a large cognitive component. Bob Galambos and his students had been pulling discoveries out of the hat for years before it finally sank in to me that we knew nothing of the evolution in nonmammals concerning the kinds of “cognitive waves” they were studying in humans, time-locked to a thought (“There’s one!” “What’s that?”). We began with fish and the paradigm of the omitted stimulus in a regular train of stimuli. It quickly developed that rays and grunion (teleosts) and also turtles show large, clear, and complex sequences of waves to missing stimuli; we call them omitted stimulus potentials, or OSPs. A few repetitions of a simple stimulus in a certain range of interstimulus intervals may reveal a decline in the EP and, if the train stops or a single stimulus is omitted, a relatively large rebound complex, with fast, slow, and oscillatory phases—the OSP. The diminished EP may be viewed as a suppression of the OSP that would have arisen if the stimulus were not there; the OSP is a postinhibitory release. Its nearly constant latency after the due-time of the missing stimulus reflects a kind of expectation of something exactly on schedule. We found an OSP already in the retina for flashes, and in the first brainstem nucleus for some other modalities—telling us that it need not be a higher cognitive process but an early and relatively simple consequence of the simultaneous excitation and inhibition from each stimulus, with asymmetrical time constants of buildup and decay. The higher brain levels may add further meaning and dependence on the form of attention involved. We believe it may be relevant to investigators of human scalp waves under subtle cognitive regimes that there may be major precognitive processing that determines some of the dynamics. Because we do not know where gnosis comes in, these waves and the regimes invented for research on humans, to the extent that they can be adapted for other species, might be a powerful tool for uncovering hints about the evolution of cognition. My strong bias to much of the literature on the origin of consciousness and intelligence is that, as a zoologist, I expect them to come in degrees—not along a single, smooth incline but with saltations and qualitatively different varieties and components. Most importantly, I like to underline that they are not too slippery or vague to investigate and that a major agenda of great interest and challenge to ingenuity is still ahead (Bullock, 1986b).

Evolutionary and Comparative Thread

These considerations lead me to an even wider proposition, a deep-seated belief that, for basically complex questions such as the operations of the brain, comparing taxa can contribute a unique perspective. A long list of examples is already known (Bullock, 1984a), and I am sure even more fundamental quiet revolutions are coming. A conclusion I defended in an essay in Trends in Neuroscience (1986a) is that differences found between taxa are as important as commonalities, in understanding how brains work and how life should be understood.

Nature has provided two great gifts: life and then diversity of living things, jellyfish and humans, worms and crocodiles. I don’t undervalue the investigation of commonalities but can’t avoid the conclusion that diversity has been relatively neglected, especially as concerns the brain.

My penchant for comparison and fascination with differences between taxa (as well as between individuals, life stages, and states, though these three never found much time in the agenda) surely dates from the beginnings of my biological exposure to diversity—sea shells, invertebrate phyla, coelenterates, and polychaetes. My teaching, besides Zoology 1A, was largely comparative—physiology, invertebrate biology, and neurology. Whereas a lovely literature on “comparative” neurobiology brings out a long list of intriguing stories, it does not automatically lead to comparative principles. Most of it is general physiology on favorable species. Some is the study of adaptations to certain environments or lifestyles—lateral radiation or microevolution.

An explicit interest in macroevolution and in differences between taxa at the level of classes and phyla, whether or not they can be explained as adaptive, dates from graduate student days when I was much impressed by the arguments of Richard Goldschmidt and thought that they were not getting the acceptance they deserved. But it did not appear in my own writings until the historic pair of symposia mounted by G.G. Simpson and Ann Roe on evolution and behavior in 1955 and 1958 (Bullock, 1958b).

Another long period elapsed before my colleagues and I did something further, namely examine many taxa, put together a list of species—mostly fish—that have or that lack a specialized peripheral and central electrosensory system, and then propose a phylogeny for this trait (Bullock et al., 1983). Probably less read than this—or another study, with Jean Moore and Doug Fields on the evolution of myelin—was an editorial of potentially broad significance in the newsletter of the International Brain Research Organization on “The application of scientific evidence to the issues of the use of animals in research: the evolutionary dimension in the problem of animal awareness” (Bullock, 1984b).

Elsewhere (see sections A Technical and Mathematical Leitmotif, and EEG and EP/ERP Compound Field Potential Thread), I have told the story of my early and long drawn-out interest in the evolution of that sign of activity in organized nervous tissue, the compound field potentials such as “brain waves,” and evoked and ERPs—an interest that is still far from satisfied because some basic answers elude us, largely from inadequate study of nonmammalian and invertebrate groups with modern methods.

Most recently, I have been beating the drum for more explicit study of the differences between brains of different classes and phyla that are obviously distinct in the level of complexity of the brain (Bullock, 1993b). Complexity is defined as the number of kinds of parts, processes, interactions, and behavioral consequences in repertoire and discriminations. First we have to distinguish between “lateral” radiations as adaptive changes within approximately the same general grade of complexity and “vertical” changes in grade, which may or may not be obviously adaptive. Then we can focus attention on the latter. Low-power microscopic anatomy indicates conspicuously more complex histological differentiation in some orders of polychaete worms than others, and the same for some arthropods, for some molluscs, and for “higher” compared to “lower” vertebrates. Yet it is astonishing how meager our information is about the detailed basis of complexity, particularly in physiological processes and interactions but also in behavioral abilities, knowledge, discriminations, and shades of response. Because evolution is a central feature of the biological world and nothing else approaches the span of complexity that the nervous system has evolved, I conclude that we have neglected a major facet of the biological world, presumably in our preoccupation with commonalities and adaptions within a grade of organization.

Behavioral Thread

I could not teach a course in animal behavior without a lot of preparation. It took me a long time to understand what some authors meant by “ethology,” although I was privileged to be a member of the historic 1954 symposium convened by Bill Verplanck, when several European ethologists made their first full-fledged explanation this side of the Atlantic, in the basement of Harvard’s Memorial Hall. My guess is that I was invited, not because of a known competence in animal behavior, but because of the appearance of a single paper in 1953, quite out of my usual turf, on predator recognition by gastropods-an ability then almost unknown in invertebrates, except for scallops and a few other species. That study had started in 1947 when I was teaching field invertebrate zoology for the University of California, Berkeley at the Hopkins Marine Station, under Ralph Smith and Frank Pitelka. On the last day, students gave reports and Eugene Haderlie, studying the movements of limpets, described low tide species that fled from contact with a few tube feet of a starfish arm. That was something new, but he did not elect to continue and collect convincing evidence, so I did, over several years, and the 1953 paper resulted.

Intact, behaving animals were a common denominator of my papers—jellyfish, earthworms, sloths, sharks, cuttlefish, and others. Some studies used restrained subjects or “preparations” with stimuli and experimental questions relevant to the natural conditions. Where and how does patterned discharge arise (Bullock, 1961a)? Can recognition of complex, natural combinations of stimulus features (for example, small, dark, sharp-edged, moving contours within a 5° visual field) occur early in the visual pathway, as claimed by Lettvin, Maturana, and co-workers (Grüsser-Cornehls et al., 1963)? What do electric fish do to minimize the jamming effect of neighbors discharging at nearly the same rate (Scheich et al., 1973)?

Some of the behaviorally slanted questions precipitated reviewish essays, for example on animal minds, on startle responses, on suggestions for an agenda on comparative cognition (Bullock, 1986b), and on the comparative neurobiology of expectation (Bullock et al., 1993b; see also EEG and EP/ERP Compound Field Potential Thread).

The three-toed sloth is a special case. Watching this species and handling it in the American tropics, the notion was irresistible that such an elementary feature of its whole behavior and habit of life as slowness ought to be amenable to physiological study. At least we should be able to exclude one of two alternatives in the lovable and tractable three-toed genus, which is much slower than the more familiar two-toed form. Is it (1) capable of quick movements, like a lazy cat, if induced or motivated properly, or (2) is there a lowerlevel bottleneck, perhaps in the muscles, preventing quick movements, even if the brain commands them? Per Enger and I were able to answer this, virtually excluding the first and definitely confirming the second alternative (Enger and Bullock, 1965). Subsequent work convinced me that the brain is not issuing commands that the muscles cannot execute. The sloth brain is slow in conduction, in transmission, in EPs, in rhythms such as nystagmus, and in other measures—but I am sure the major specialization for slowness still eludes us. A leading clinical neurologist, James Toole, wondered if this animal is a model of a clinical condition called myotonia and came to our lab to do a long series of tests. That was one of the most satisfying collaborations I have had with clinicians. Toole was able to exclude his hypothesis as well as some others such as hypothyroidism. My hunch is that the specialization is diffuse and multiple—perhaps a combination, for example, of neurons that cannot accelerate their firing rate rapidly, plus perhaps some transmitter or modulator equilibrium in limbic centers way over to one side of the mammalian norm (Bullock, 1983). This is clearly an unfinished agenda item—still interesting, heuristic, and potentially basic.

Unfinished Projects

The story just cited is not my only unfinished project, and my history would be distorted if it lacked reference to the many worthy but overambitious, dumb but fun, and half-baked projects that never saw the light of day or the lamp of publication.

The one with the greatest longevity is a taxonomic monograph of the eastern Pacific enteropneusts, a task I inherited in 1939 from W.E. Ritter, founder of SIO. His manuscript of ca. 1898 on a passel of new species from southern California to the Aleutian Islands—the specimens and slides of which had dried up and faded beyond recognition—plus another gaggle of new species that turned up during and after my thesis work, together would add a substantial percentage to the known world list. A Byzantine series of twists and turns has so far failed to allow the combined manuscript to be completed, illustrated, and published, although in its ups and downs it has been within 5 percent of completion. Fortunately, there is still hope, even though two of the coauthors are deceased.

Less dramatic were various aborted studies such as those on the physiology of bryozoan and nemertean nerve nets, and on oscillatory, visual, induced rhythms in the brains of 17-year cicadas, like those reported by Jahn and Crescitelli (1938) in grasshoppers and moths. I allow myself the embarrassment of touching on these few examples from a much larger set lest an inexperienced reader get a false impression of efficiency or catch per unit effort!

Unfinished, too, are various projects under the rubric of hobbies. A fair number of bonsai are still taking final shape on our patio. A small number of free-form sculptures in clay, wood, and stone are always vulnerable to another reshaping. Both of these responsive metiers have given a degree of personal satisfaction while challenging the imagination and creative juices.

From the vantage point of experience, I ought to have some advice for young scientists from my mistakes—and I have. By all means, keep a day book of some sort—not necessarily a full diary but one with entries that record when you did something of interest and whom you met, especially on trips. Identify your research with some big question, on every possible occasion. Don’t wait until all the data you think you need have come in before analyzing, at least enough to decide what the story is. Don’t print out even a few sample plots to test your plotting program, unless you label them with every relevant parameter; assume they will be kept, will get into the wrong folder, and, if unlabelled, will puzzle the stuffing out of you. Don’t exaggerate, even in conversation, except when telling jokes. Here I stop, before the negative slope of wisdom becomes a cliff.

La Jolla, Medicine, and Marine Biology, R/V Alpha Helix, NRP, SFN, IBRO, and ISN

I don’t know just why we moved to La Jolla; I was happy at UCLA, associated with the Department of Biology and the Brain Research Institute. The prospect of being a bridge between marine biology and medicine, of helping my old UCLA friend Bob Livingston realize his dream of creating the first Department of Neurosciences, and the unconventional plan of the medical school were all appealing. The so-called Bonner plan, now officially abandoned, actually accomplished a great deal, though not all of its promise. The plan provided that every department of the medical school had clinical responsibilities and most departments had nonclinical faculty. Many faculty positions budgeted in the medical school were farmed out to nonmedical departments and those departments participated in the preclinical teaching. Core courses were controlled by committees, not departments, and there were no departments of anatomy, physiology, or biochemistry.

The curriculum was not quite so unusual but provided free time for elective courses and a required thesis or creative project to give each student the experience of investigation. The boundary between the medical school and the rest of the campus was appreciably fuzzier than elsewhere. All these features were positive, and I enjoyed being the first chairman of the electives committee and spending time on self-paced learning resources, tutorial sessions, and optional exams. Many meetings and beautifully uninhibited planning went into designing the Ph.D. programs in neurosciences and in physiology-pharmacology, writing training grants, formalizing a program in marine biomedicine, and recruiting faculty, as well as into committees on the design of new buildings, on privilege and tenure, university-wide coordination, and others.

Locally, we maintained for years the Marine Neurobiology Facility (MNF), a joint operation of the UCLA BRI and UCSD SIO, in the third floor of a new building, called the Physiological Research Laboratory, built from joint NSF grants to Per Scholander for SIO and J.D. French for the BRI. The same grants also covered large outdoor pools and the R/V Alpha Helix. The first chairman of the MNF was Susumu Hagiwara, who was recruited in 1965 as the first neuroscientist at UCSD; he had been a postdoc in my laboratory at UCLA and gradually developed his own space, grants, and group. He brought a large and brilliant group to La Jolla and spent four productive years there. After he was lured back to UCLA in 1969, I managed the MNF as a group of laboratories for visiting scientists from UCLA and elsewhere, plus the larger entity, called the Neurobiology Unit of SIO (officially an “Affinity Group”), which included the MNF, plus my own laboratory and eventually those of Walter Heiligenberg, Jim Enright, Adrianus Kalmijn, and Glenn Northcutt.

SIO is a stimulating place and it keeps one’s perspective not only global but cosmic. Despite an omnipresent, fortunately minority view that only those working on blue water oceanic problems belong, a large faculty of broad and deep thinkers could be encountered in the corridors or the lunch line at Snackropolis on Bikini Plaza. I will mention just a few whom I saw frequently: P.F. Scholander and J.D. Isaacs (both of whom left stimulating memoirs), A.A. Benson, G. Arrhenius, W. Munk, W.A. Nierenberg, F. Azam, and E.D. Goldberg.

The R/V Alpha Helix was near completion in the shipyard when I was invited to join the National Advisory Board for the Physiological Research Laboratory, which included its shore facilities and the ship, all regarded by UCSD and NSF as national facilities. Under the chairmanship of A. Baird Hastings, this board solicited and evaluated proposals for comparative physiology and biochemistry that justified the trip, exotic locations, and floating platform. Each selected proposal became a one- to three-month program—a segment of an expedition of 12 to 18 months. The principal investigator or proposer became the chief scientist of that segment and chose about 10 colleagues from anywhere in the world, including students and senior scientists, all concentrating on projects in the same broad field—normally 15 or 20 projects with different combinations of coworkers. Joining the vessel and each other in some remote port, these people experienced a magical process by which new projects sprang up, in addition to those that had been well prepared.

The ship operated in this mode, as Scholander had envisioned and described in his original application for funds, for about five years, completing some 30 programs, involving more than 300 scientists. I was chairman of the National Advisory Board for several of those years and chief scientist for two programs in neuroethology, one on the Great Barrier Reef and one on the Rio Negro, the fifth tributary of the Amazon. This innovative and successful concept of Scholander’s could not, however, be maintained at this rate, for lack of high-quality proposals. Having skimmed the cream, it became harder to find nonoceanographic, nonecological proposals high in merit and also in justification for both the remote location and the floating platform, because these depend on biochemists and physiologists, most of whom have ongoing programs at home and have never thought about working on exotic species unavailable at home or even at existing shore laboratories. At SIO’s initiative, the vessel was transferred to and is still operated by the University of Alaska, in quite another mode.

The times were ripe in the late 1960s for the field that came to be called neuroscience. Crossing disciplinary lines began with anatomy and physiology– H.W. Magoun and many colleagues had been doing physiology in anatomy departments, notably UCLA. Some psychologists had started what grew into a mass movement into neurophysiology. The International Brain Research Organization (IBRO) had been dreamed up by a small multinational group at a meeting in Moscow and was eventually chartered in Canada in 1958. Francis O. Schmitt’s Neuroscience Research Program (NRP) at the Massachusetts Institute of Technology (MIT) had put the word neuroscience on the map and explicitly included all the disciplines dealing with nervous systems. He had staged a carefully orchestrated symposium at a National Academy of Science meeting in 1967. The first of the mammoth NRP Intensive Study Programs ranging over the whole field, was held in Boulder, Colorado for a month in midsummer 1966, involving several hundred people and producing a weighty and influential tome, the first of four.

The National Research Council set up a Brain Science Committee (BSC), partly to provide U.S. representation on the IBRO Central Council and partly to think up what needed to be done for brain science, procedurally as well as substantively. At the instigation of Ralph Gerard, the committee took steps to create the Society for Neuroscience (SFN), which convened its first meeting in Washington, D.C. in 1970. I was involved in most of these events, from the recruitment of Magoun to UCLA, to the NRP, ISP, and BSC. Later I joined the IBRO Council and headed its Visiting Lecture Team Program and Workshop Program, which had significant budgets from UNESCO. By the time I became president of SFN in 1973 to 1974, it was a smoothly running operation under a superb executive secretary, Marjorie Wilson, but was financially vulnerable. Among our campaigns was one to persuade the neurochemists, anatomists, and clinical neurologists that they were wanted, another to elect Canadian and Mexican members to solidify the status of SFN as regional and multinational. We then helped local chapters to form in those countries and in many cities in the United States. With this background, it is understandable that I felt truly honored when SFN awarded the Gerard Prize jointly to my long-time friend and coworker, Susumu Hagiwara, and me in 1984. I had known and admired Ralph Gerard through many of his phases—in Chicago, Ann Arbor, and Irvine—and knew his personal role in the founding of the society.

One other organizational caper may be of interest. In 1981 J.-P. Ewert of Kassel, Germany, invited a large number of worthies to a NATO-sponsored symposium on recent advances in vertebrate neuroethology, and staged a memorable meeting. Near the end, some of us saw the opportunity and asked for a business meeting to think about the future. Probably the rank and file thought there would be polite thank-yous and a suggestion that we meet again in a few years. By prearrangement, however, a few plotters had a preamble and a motion ready to propose setting up a steering committee to create a permanent, new society, to be called the International Society for Neuroethology (ISN). We had to do some quick-stepping to prevent its being dedicated to vertebrate animals. An organizing committee under Masakazu Konishi was authorized to assemble a list of invitees to charter membership and to conduct an election. Eventually I was elected the first president (1984–87), by a statistically insignificant majority. I was saved from presiding over a stillbirth by the magnificent response of Kiyoshi Aoki of Sophia University in Tokyo and his many colleagues in Japan, who raised money and organized the first congress in 1986. ISN has weathered not so much storms as calms, and just held its fourth congress.

Meetings, Lectures, Intussuscepting, Pontificating, and Globe-trotting

It suffices to say but little about the many trips taken to regular and to irregular meetings and to give lectures, colloquia, or seminars. The meetings, both the giant and the cozy, are major pauses along the way. The regular ones, like milestones, permit periodic reports of your progress; the sporadic symposia, conferences, and workshops allow extended presentations and discussion with fellow specialists. Both types bring old and new friends and, increasingly in the last few decades, overseas colleagues. A feature of science that we tend to take for granted but should appreciate as different from most other walks of life is the instant friendship and ease of meeting people from other countries and cultures. Side trips to visit laboratories and give lectures double the value, both scientifically and personally. I have a long list of hosts and hostesses I should like to acknowledge for an even longer list of first experiences in interesting venues.

In a category by itself belong the meetings of the NRP: “stated meetings,” “work sessions,” and ISPs. This instrumentality of MIT, created and operated by Francis Schmitt was a highly successful experiment in scientific communication. A core group of diverse people willing to come together several times a year to think about the nervous system included mathematicians, physicists, anatomists, psychologists, chemists, physiologists, and others, from half a dozen countries. Four to six meetings a year were held on special topics and a dozen or more world experts were invited to each, producing a Work Session Bulletin on the status of the topic. I was privileged to be an early (1962) member and went to three or four meetings a year for 16 years. These were rich privileges in substance and in learning how difficult serious interdisciplinary dialogue can be and how shaggy dog stories can help.

Working for national and international organizations can add up to a lot of trips—planning, evaluating, and advising—which are usually interesting and often constructive. One makes splendid friends and pays some dues for all the beneficence one owes to others. Besides the lofty angles suitable for reports, there are the memories—like shopping for saffron in the bazaar in Kuwait with Sir John Eccles, trailing his eager and qualityconscious wife, while David Ottoson and I deploy as bodyguards.

Invited lectures have meant another wide range of experiences. Some are intimidating occasions for trying out a brainchild on a hypercritical audience; others are inspiring visits to liberal arts colleges. Altogether they have formed a major part of my teaching and, from spirited feedback, a substantial source of broadening my own research and thinking. With or without honored names attached (the Jacques Loeb, George Bishop, Ralph Gerard, Alexander Forbes, Robert Dow, Clinton Woolsey, Albert Grass, Arturo Rosenblueth Lectures, and others), they are also gratifying honors that I have appreciated greatly. Being constitutionally unable to give the same lecture more than a few times, I have trod where angels fear to, over a range of topics: evolution of the brain, reliability of neurons, redundancy and equivalence classes of nerve cells, animal rights, aspects of recent history in neuroscience, integrative mechanisms, recognition by neurons, electroreception, and others.

Some of these subjects have grown into books. The 1965 treatise with Adrian Horridge on Structure and Function in the Nervous Systems of Invertebrates summarized about 10 kiloreferences before the age of many modulators, transmitters, and channels. This work even missed by a few years the recognition of many identifiable cells in insects, crustaceans, opisthobranchs, leeches, and other taxa. Despite its being out of date, our sentimental investment in this two-volume work was severely rocked when it went out of print, without our knowledge, in a warehouse cleaning that destroyed a good many sets before we had a chance to purchase them! One feels impelled to a slightly mutated dictum: caveat auctor. Skipping over a textbook and a multiauthored monograph on electroreception, I will mention only the 1993 book, titled How Do Brains Work? Without pretending to answer the question globally, I had a lot of fun talking about major aspects of it, updating old essays, placing bets and picking a selection of reprints—the publisher’s raison d’etre for the volume.

Today the driving motivation continues: what’s going on; how does it work; what’s the principle of the thing; there must be a good idea waiting to be recognized– think! At this writing I am surrounded by plots of human, turtle, and ray EEGs analyzed for higher moments of nonlinear interactions among frequency components, called bicoherence, a hitherto almost untried descriptor of different states, brain parts, and species. I am nearing the end of a labor of love, keeping the Walter Heiligenberg laboratory open and active for nearly three years after his tragic death in a plane crash. My wife Martha and I enjoy our children, grandchildren, friends, church, walk-in aviary, and bonsai. We appreciate every day as a gift.

Selected Publications

Bullock TH. Neuromuscular facilitation in scyphomedusae. J Cell Comp Physiol 1943;22:251–272.

Bullock TH. A preparation for the physiological study of the unit synapse. Nature 1946;158:555–556.

Bullock TH. Predator recognition and escape responses of some intertidal gastropods in presence of starfish. Behaviour 1953;5:130–140.

Rao KP, Bullock TH. Q₁₀ as a function of size and habitat temperature in poikilotherms. Am Nat 1954;88:33–44.

Bullock TH. Compensation for temperature in the metabolism and activity of poikilotherms. Biol Rev 1955;30:311–341.

Bullock TH, Diecke FPJ. Properties of an infra-red receptor. J Physiol 1956;134:47–87.

Bullock TH, Hagiwara S. Intracellular recording from the giant synapse of the squid. J Gen Physiol 1957;40:565–577.

Bullock TH, Terzuolo CA. Diverse forms of activity in the somata of spontaneous and integrating ganglion cells. J Physiol 1957;138:341–364.

Bullock TH. Homeostatic mechanisms in marine organisms. In: Buzzati-Traverso AA, ed. Perspectives in marine biology. Berkeley: University of California Press, 1958a;199–210.

Bullock TH. Evolution of neurophysiological mechanisms. In: Simpson GG, Roe A, eds. Behavior and evolution. New Haven, CT: Yale University Press, 1958b;165–177.

Bullock TH. Neuron doctrine and electrophysiology. Science 1959;129:997–1002.

Watanabe A, Bullock TH. Modulation of activity of one neuron by subthreshold slow potentials in another in lobster cardiac ganglion. J Gen Physiol 1960;43:1031–1045.

Bullock TH. The origins of patterned nervous discharge. Behaviour 1961a;17:48–59.

Bullock TH. The problem of recognition in an analyzer made of neurons. In: Rosenblith WA, ed. Sensory communication. Cambridge: Technology Press, 1961b;717–724.

Bullock TH, Hagiwara S, Kusano K, Negishi K. Evidence for a category of electroreceptors in the lateral line of gymnotid fishes. Science 1961;134:1426–1427.

Grüsser-Cornehls U, Grüsser O-J, Bullock TH. Unit responses in the frog’s tectum to moving and nonmoving visual stimuli. Science 1963;141:820–822.

Bullock TH, Horridge GA. Structure and function in the nervous systems of invertebrates, 2 Vols. San Francisco: WH Freeman, 1965.

Enger PS, Bullock TH. Physiological basis of slothfulness in the sloth. Hvalradets Skrifter (Scientific results of marine biological research). 1965;48:143–160.

Bullock TH, with Quarton CG. Simple systems for the study of learning mechanisms. Neurosci Res Program Bull 1966;4:105–233.

Fehmi LG, Bullock TH. Discrimination among temporal patterns of stimulation in a computer model of a coelenterate nerve net. Kybernetik 1967;3:240–249.

Perkel DH, Bullock TH. Neural coding. Neurosci Res Program Bull 1968;6:221–348.

Bullock TH. The reliability of neurons. J Gen Physiol 1970;55:565–584.

Bullock TH, Ridgway SH. Evoked potentials in the central auditory system of alert porpoises to their own and artificial sounds. J Neurobiol 1972;3:79–99.

Scheich H, Bullock TH, Hamstra RH Jr. Coding properties of two classes of afferent nerve fibers: high-frequency electroreceptors in the electric fish, Eigenmannia. J Neurophysiol 1973;36:39–60.

Bullock TH. Recognition of Complex Acoustic Signals. Dahlem Workshop. Life Sciences Research Report 5. Dahlem, Germany: Dahlem Konferenzen, 1977.

Bullock TH, Orkand R, Grinnell AD. Introduction to nervous systems. San Francisco: WH Freeman, 1977.

Bullock TH, Corwin JT. Acoustic evoked activity in the brain in sharks. J Comp Physiol 1979;129:223–234.

Bullock TH. Reassessment of neural connectivity and its specification. In: HM Pinsker, WD Willis Jr, eds. Information processing in the nervous system. New York: Raven Press, 1980;199–220.

Corwin JT, Bullock TH, Schweitzer J. Auditory brainstem response in five vertebrate classes. Electroencephalogr Clin Neurophysiol 1982;54:629–641.

Bullock TH. Neuroethological role of dynamic traits of excitable cells: a proposal for the physiological basis of slothfulness in the sloth. In: Grinnell AD, Moody WJ Jr, eds. The Physiology of Excitable Cells. New York: Alan R Liss, 1983;587–596.

Bullock TH, Bodznick DA, Northcutt RG. The phylogenetic distribution of electroreception: evidence for convergent evolution of a primitive vertebrate sense modality. Brain Res Rev 1983;6:25–46.

Bullock TH. Comparative neuroscience holds promise for quiet revolutions. Science 1984a;225:473–477.

Bullock TH. The application of scientific evidence to the issues of use of animals in research: the evolutionary dimension in the problem of animal awareness. IBRO News 1984b;12:9–11.

Bullock TH. ’Simple’ model systems need comparative studies: differences are as important as commonalities. Trends Neurosci 1986a;9:470–472.

Bullock TH. Suggestions for research on ethological and comparative cognition. In: Schusterman RJ, Thomas JA, Wood FG, eds. Dolphin cognition and behavior: A comparative approach. Hillsdale, NJ: Lawrence Erlbaum Associates, 1986b;207–219.

Bullock TH, Heiligenberg W. Electroreception. New York: John Wiley, 1986.

Bullock TH, Basar E. Comparison of ongoing compound field potentials in the brains of invertebrates and vertebrates. Brain Res Rev 1988;13:57–75.

Smith DPB, Bullock TH. Model nerve net can produce rectilinear, non-diffuse propagation as seen in the skin plexus of sea urchins. J Theor Biol 1990;143:14–40.

Bullock TH. Introduction to induced rhythms: a widespread, heterogeneous class of oscillations. In: Basar E, Bullock TH, eds. Induced rhythms in the brain. Boston: Birkhäuser, 1992;1–26.

Bullock TH. How Do Brains Work? Papers of a Neurophysiologist. Boston: Birkhäuser, 1993a.

Bullock TH. How are more complex brains different? One view and an agenda for comparative neurobiology. Brain Behav Evol 1993b;41:88–96.

Bullock TH, Karamürsel S, Hofmann MH. Interval-specific event related potentials to omitted stimuli in the electrosensory pathway in elasmobranchs: an elementary form of expectation. J Comp Physiol [Al 1993;172:501–510.

Bullock TH. Neural integration at the mesoscopic level: the advent of some ideas in the last half century. J Hist Neurosci 1995;4:219–235.

Additional Publications

Alexandrowicz JS. The innervation of the heart of the Crustacea. I. Decapoda. Q J Microsc Sci 1932;75:182–249.

Gesell R. Forces driving the respiratory act. A fundamental concept of the integration of motor activity. Science 1940;91:229–233.

Horridge GA. The co-ordination of the protective retraction of coral polyps. Philos Trans R Soc Lond B Biol Sci 1957;240:495–529.

Josephson RK, Reiss RF, Worthy RM. A simulation study of a diffuse conducting system based on coelenterate nerve nets. J Theor Biol 1961;1:460–487.

Jahn TL, Crescitelli F. The electrical response of the grasshopper eye under conditions of light and dark adaptation. J Cell Comp Physiol 1938;12:39–55.

McCulloch WS, Pitts W. A logical calculus for ideas immanent in nervous activity. Bull Math Biophys 1943;5:115–133.

Pantin CFA. The nerve net of the Actinoza. I. Facilitation. J Exp Biol 1935;12:119–138.

Schultz R, Berkowitz EC, Pease DC. The electron microscopy of the lamprey spinal cord. J Morphol 1956;98:251–274.

Wiersma CAG, Van Harreveld A. A comparative study of the double motor innervation in marine crustaceans. J Exp Biol 1938;15:18–31.

*Space does not permit listing them or citing theses and publications. A bibliography can be found in Bullock (1993a).

Irving T. Diamond

BORN:

Chicago, Illinois

September 17, 1922

EDUCATION:

University of Chicago, B.A., 1943

University of Chicago, Ph.D. (Psychology, with W.D. Neff, 1953)

APPOINTMENTS:

University of Chicago (1948)

Duke University (1958)

Professor of Neurobiology, Duke University (1988)

HONORS AND AWARDS:

James B. Duke Professor, Duke University (1971)

National Academy of Sciences USA (1982)

Distinguished Scientific Contribution Award, American Psychological Association (1988)

William James Fellow, American Psychological Society (1989)

Irving Diamond pioneered the anatomical and functional study of auditory cortex, and carried out fundamental studies of the organization of sensory and association cortex, thalamocortical pathways, and the superior colliculus.

Irving T. Diamond*

I enrolled in a Chicago high school (Hyde Park, 1934) not far from the University of Chicago. At Hyde Park, the faculty and students were considered above average and I recall classes in differential calculus and college-level chemistry. Foreign languages were hardly touched, certainly not by me; I think I studied Latin for a year at most.

My parents were eager to see me choose the University of Chicago, which was taken to be the best university in the Western world, matched only by Oxford and Cambridge. I entered in 1938 and was serious about and excited by all or most of the classes. Teachers—such as Anton Carlson, the Swedish physiologist—were thrilling and often amusing. I remember Carlson picking up a beaker of urine and, after taking a sip, insisting it was just a glass of water—the point being that urine is as benign as a glass of water. Heinrich Kluver, Ralph Gerard, Sewell Wright, and Anton Carlson were all my teachers and members of the National Academy of Sciences. Each one was a specialist in either neurology, physiology, or genetics. Robert Maynard Hutchins, the president of the University, was tall and handsome, as well as charming and witty. He was unwilling to spend money to recruit top football candidates. All Chicago players were devoted to academic life. I remember that one year Chicago remained scoreless in an 80-point loss to Michigan at Stagg Field. I believe it was shortly thereafter that intercollegiate football was dropped at Chicago.

I was pleased by the camaraderie of fellow students, and was even a member of a fraternity. I recall many social events such as dances with white ties and tails. The shock of World War II led to a new and different climate. I was just 19 on Pearl Harbor Day; most of the males and some females enlisted, but we were permitted another year at the university.

In 1946 I was released from Army service, and returned to the University of Chicago. The atmosphere had changed completely—at least that was how I saw it, but perhaps I had changed. I became acquainted with the dean of humanities, a well-known philosopher, Richard McKeon. I enrolled in his courses and read, in English, the works of Aristotle, such as Ethics, the Politics, and De Anima. This experience, in turn, led to an acquaintance with “the great books.”

In 1948, well before I qualified for the Ph.D. degree, I was presented with the modest title of assistant instructor in the college of biology, with a salary of $2,400 for the year. I was not alone in teaching the original papers from scientists such as Harvey (1628), Darwin (1859), Mendel (1865), Bernard (1877), and Sherrington (1906). Once a week I joined a small group of three or four other instructors for the purpose of improving our teaching. We would discuss the major papers in evolution, genetics, ecology, physiology, and anatomy, and we learned more about teaching undergraduates. We agreed to lecture occasionally to the students but, for the most part, our goal was to ask crucial questions of the class. For example: “How did Harvey identify the transport of blood from arteries to veins? From the right ventricle to the lungs? From the left ventricle to the aorta?” “Why did Mendel use the ratio of 3 to 1 when, in fact, the number of two distinct lines (for example, red and white, or round and angular) was 2.98 to 1?” (The answer to this question, of course, is that in the F2 generation the genotypes could be viewed as 1/4 A:1/2 Aa:1/4 a. Mendel did not use double letter notation such as AA:Aa:aa.)

Darwin’s basic principles were given a poetic description:

The entangled bank clothed with many plants of many kinds, with birds singing on bushes, with various insects fluttering about, with worms crawling through the damp earth, and to reflect that these elaborately constructed forms, so different from each other and so dependent on each other, have all been produced by the laws of growth, reproduction, external conditions of life, use and disuse, and a ratio of increases so high as to lead to a struggle for life (Darwin, 1859).

Darwin’s concepts of inheritance, variation, and selection were his way to explain evolution. We also read how his effort to deal with gemmules as the mechanism in heredity fell short of the chromosome.

Not every great biologist need be a poet like Darwin. We taught the work of Claude Bernard, who in 1877 identified the significance of the liver—to retain sugar and to transport blood in the portal vein. We also read the works of Walter S. Sutton and Edward Murray East. Sutton recognized the brilliance of Mendel’s principles of hereditary units, and from these developed his concepts of cell division, germ cells, and cytology. He determined that the chromosome group of pre-synaptic germ cells was made up of two equivalent chromosomes, one paternal and one maternal. East recognized that the continuous variation that he found in corn hybrids could be explained in Mendelian terms. He crossed 8-rowed corn (that is, corn with ears having eight rows of kernels) with 20-rowed corn and produced a hybrid having 14 rows per ear (Fl). Then he showed that with self-fertilization of the Fl population, there is a new population, F2, that includes corn of 8, 10, 12, 14, 16, 18, and 20 rows of kernels per ear. The F2 population follows a normal frequency distribution—that is, the 14-rowed com occurs most frequently.

In each case, the achievements of these great biologists could only be fully appreciated by reading their original works.

My Introduction to the Thalamus and Cortex

Although I began teaching college students with trepidation, experience ultimately led to confidence, but something was still missing. I needed to become a scientist; just reading about the great scientists was not sufficient. I required a Ph.D. thesis, and a warm friendship with W.D. Neff led to his supervision. Dewey Neff had already found his niche at the University of Chicago and had developed methods to train cats to jump over a barrier when there was a change in pitch or sound location (Neff et al., 1956). He was devoted to the auditory cortex and was attempting to identify its subdivisions. I was a helping partner in these efforts, concentrating on the brain and especially the cortex and thalamus.

At the turn of the century, the Spanish genius Santiago Ramón y Cajal drew countless pictures of the cortex and traced sensory pathways to it (see Figure 1). In England, Campbell wrote a long and detailed description of the visual cortex (1905). In 1910, George Elliot-Smith gave a series of lectures on the evolution of the cortex. His first principle was clear: “The key to understanding the cortex depends on an intensive study of the thalamus.” Some 20 years later, W.E. LeGros Clark—a friend of Smith’s—offered a similar principle: “The neocortex depends entirely on the thalamus for sensory information.”

Figure 1.    Sensory pathways to the neocortex as drawn in the spirit of Cajal and published in his 1906 Nobel Prize lecture. Note three sensory pathways.

LeGros Clark’s 1932b paper begins with a long paragraph and then turns to classifying distinctive features in the various thalamic nuclei. I quote the beginning:

With the solitary exception of olfactory impulses, all sensory impulses which are destined to reach the cerebral cortex have first to be filtered through the mass of grey matter which is found in the walls of the third ventricle. From the thalamus such impulses are projected on to the cortex by thalamo-cortical fibres, and their mode of distribution to topographical cortical areas is no doubt determined in large part by the spatial relationship of the thalamic nuclei from which these fibres arise. This fundamental fact has been emphasized by Cajal and Elliot-Smith and rests on the observation that projection fibres take the most direct and shortest route from the thalamic centres to the cortex…. The neocortex must depend entirely on the thalamus for the precise nature of sensory material that it receives indirectly from peripheral receptors.

In his 1932b monograph, LeGros Clark classified distinctive features in the various nuclei of the dorsal thalamus. The sensory relay nuclei are the most prominent and especially striking in “primitive” (LeGros Clark’s term) mammals. The three primitive species discussed by LeGros Clark are the common shrew (Sorex), the hedgehog (Erinaceus), and the Virginia opossum (Didelphis). The three prominent sensory nuclei constitute what LeGros Clark called “the lower level”: the ventral posterior nucleus (VP), the lateral geniculate nucleus (GL), and the medial geniculate nucleus (GM). The “upper level” comprises the lateral group and the mediodorsal nucleus. LeGros Clark recognized that in primates, even in prosimian primates such as the lemurs, the upper level of the thalamus had become larger than the sensory relay nuclei.

In the early 1950s, I recognized a giant in the field of neuroanatomy, Jerzy Rose. Rose teamed with Clinton Woolsey in the late 1940s, and they were a perfect pair, first at Johns Hopkins University and later at the University of Wisconsin. Rose’s experiments with Woolsey (1949) relied on two methods, each supporting the other: (1) retrograde degeneration in the thalamus after restricted cortical lesions; and (2) evoked potentials in the auditory, visual, and somatic areas of the cortex. The borders of maps using the evoked potentials in sensory areas were meticulously precise, and when small lesions were made, degeneration was identified, as expected, in the lateral geniculate nucleus, the medial geniculate nucleus, and the ventral posterior nucleus-the three “extrinsic” nuclei.

Rose and Woolsey argued that a second class of nuclei, called “intrinsic,” represented a higher functional level because they appeared to depend on projections from the extrinsic nuclei. The intrinsic nuclei include the pulvinar nucleus and the lateral, posterior, and medio-dorsal nuclei; their projections to the cortex terminate in the association areas intercalated between the sensory areas. Rose and Woolsey demonstrated that in small, lower mammals like the rabbit, the area of the association cortex is much less than that of the sensory cortex. In primates, of course, the association areas have greatly expanded. This synopsis emerges in a 1949 paper by Rose and Woolsey.

A further step in Rose and Woolsey’s inquiry was probably the result of an accidental reduction in anesthesia which increased the responsiveness of cortical neurons. They discovered that a second topographic sensory map is adjacent to each sensory area and is a mirror image of the first area. As a result, the nomenclature for cortical areas became SI and SII, AI and AII, and VI and VII. These “second” areas created a special problem. Do the extrinsic nuclei project only to AI, VI, and SI, or do they also project to All, VII, and SII? Rose and Woolsey found that isolated lesions in the second auditory area (All) of the cat produced degeneration neither in the medial geniculate nucleus nor in any other thalamic nucleus. Small lesions in the second visual area (VII) also failed to produce thalamic degeneration. This finding could mean that there is some sparse projection from an extrinsic nucleus or a collateral projection from an intrinsic nucleus. Larger lesions showed that the intrinsic nuclei—for example, the pulvinar nucleus—project to the regions intercalated between the sensory areas. In a rabbit, the strips intercalated between visual and auditory areas or auditory and somatic areas are narrow; the strips are larger in the cat and larger still in the monkey. The result is that an extensive area of the cortex in the primate is devoted to the pulvinar nucleus.

In addition to extrinsic and intrinsic nuclei, another region of the dorsal thalamus remained that, Rose and Woolsey insisted, did not project to the neocortex at all, let alone to the entire neocortex. That region consists of the midline and intralaminar nuclei. However, Moruzzi and Magoun (1949), using a new and quite effective method—stimulation of the reticular formation—speculated that the reticular formation influenced the neocortex by means of a relay in the intralaminar and midline nuclei. Ironically, the two papers (Rose and Woolsey’s, and Moruzzi and Magoun’s) were published back to back in the first volume of the Journal of Electroencephalography and Clinical Neurophysiology (1949).

The Auditory Thalamus and Cortex in the Cat

In the 1950s Neff and I focused on AI and AII in the cat and expected that removal of these subdivisions would handicap auditory discriminations, just as removal of VI and VII apparently destroyed visual discrimination. After several years of training cats to discriminate changes in pitch or temporal patterns of pitch or location of sound, we concluded that ablation of AI and AII did not result in permanent deficits (Butler et al., 1957; Diamond and Neff, 1957). However, significant behavioral deficits appeared if the lesion extended caudally to the posterior ectosylvian gyrus (Ep) and ventrally to the rhinal fissure, thus including the insular-temporal areas. The results indicated that auditory information could reach the cortex through pathways in addition to the well-recognized pathway to the primary auditory area.

It was natural to look at the thalamus to explain the differences between the behavioral effects of ablating AI alone and ablating both AI and the extensive belt around AI—that is, Ep, AII, the insular area, and the temporal area. The time was right for me to learn histology—microscopic anatomy. I sectioned the brains of several cats and stained each section with Cresyl violet, looking for degeneration of cells. I sought advice from Jerzy Rose, and he invited me to take a train from Chicago to Baltimore to visit. I was surprised to spend the night in his home. His wife, who was born and trained in Europe (and a member of the faculty in a women’s college), prepared a wonderful dinner and we had a pleasant evening. The next morning Jerzy looked at the stained sections. His response was: “Do you want me to be nice, or should I tell the truth?” And he made his point: “It is the poorest Nissl stain I have ever seen.” His eyes twinkled, and in that second I knew Jerzy Rose. With an excellent histologist like him helping me, the following findings were made: with small lesions in AI, small patches of degeneration would be located in the rostral half of the principal division of the medial geniculate nucleus, now called GMv; with all of AI ablated, GMv showed severe degeneration; after large lesions of AII, the insular and temporal areas, and ventral Ep, GMv is spared, but degeneration covers the caudal medial geniculate nucleus (GMc) and the magnocellular medial geniculate nucleus (GMmc) (Figure 2) (Diamond et al., 1958).

Figure 2.    Summary diagram showing that the ablation of AI (in black) leads to degeneration only to GMv.

In summary, the caudal division of the medial geniculate nucleus had the greatest amount of degeneration when the lesion was close to the rhinal fissure and behind the pseudosylvian gyrus. A comparison of GMv to GMmc is striking: GMv projects topographically just to AI, whereas GMmc projects all over the auditory field from the middle suprasylvian to the rhinal fissure. The extensive projections of the medial geniculate to areas well beyond the borders of AI and AII led me to question for the first time the fundamental distinction between sensory and association cortex—the “association cortex” was also a target of sensory relay nuclei in the thalamus.

A Change in Life

In December of 1957 my wife and I traded the snow and sleet of Chicago for a vacation among the orange and palm trees of Beverly Hills, California. I had just begun sunbathing in the garden of my wife’s grandmother’s home when I received a telegram from the University of Chicago Board of Trustees: I had been promoted to “associate professor with indefinite tenure.” I recognized the honor but, nevertheless, I had been thinking of leaving Chicago and Duke University had recently offered me a postion. I had scarcely heard of Duke University at the time and was not even aware that Duke was in the state of North Carolina. I visited Duke twice and decided against moving to a town with just two sites for bed and breakfast: one downtown hotel and a Howard Johnson’s Motor Inn. However, with Duke’s promise of tenure and new opportunities for science and collaboration, I was finally persuaded to make the move.

Besides transferring equipment, the most significant part of the move was transferring my former Chicago students, John Jane, Bruce Masterton, and John Utley. Masterton and Jane took on a number of projects, including the function of tectum for attention to auditory stimuli, the effects of auditory cortex ablation, and the role of auditory structures such as the superior olive and lateral lemniscus in sound localization. Utley worked hard on the analysis of retrograde thalamic degeneration after cortical lesions in the opossum (Diamond and Utley, 1963).

Bill Hall was finishing an undergraduate degree and joined our team, developing skills at an exponential rate. When Jon Kaas appeared from the northern border of Wisconsin he was quite shy to the point of being almost speechless. However, his skills and scientific judgment developed at a great rate and remain a power. The hedgehog became the central species of study inasmuch as its neocortex is small and primitive. Hall and Kaas concentrated on the visual cortex. Removal of the entire striate cortex of the hedgehog failed to produce complete degeneration of the lateral geniculate nucleus and, indeed, it showed only moderate degeneration. To produce severe degeneration in the lateral geniculate nucleus it was neeessary to ablate both the striate cortex and the surrounding belt of cortex. The belt could be named VII, the striate VI. The lateral posterior nucleus clearly projects to both VI and VII, and only when both are destroyed does the lateral posterior nucleus show severe degeneration.

A new phase began at Duke with the arrival of the tree shrew. The next section will identify a group of students with both post- and predoctoral degrees who initiated the study of this remarkable species: Vivien Casagrande, John Harting, Herb Killackey, and Marvin Snyder.

The Visual Thalamus in the Tree Shrew

When LeGros Clark served in the British Army in Burma, Malaya, and Siam, he could hardly escape the jungles and especially could not escape the tree shrew. I believe he communicated regularly with Elliot-Smith, chairman at University College of London, and both agreed that the Tupaia brain was primate-like, albeit primitive. I saw many of LeGros Clark’s slides in Oxford, and I was aware of the striking appearance of the striate cortex and the lamination of the lateral geniculate nucleus of the shrew (Figures 3a and 3b).

Figure 3a.    Photomicrograph showing the lateral geniculate body and the pulvinar nucleus in Tupaia glis.

Figure 3b.    Photomicrograph of the striate and extrastriate cortex in Tupaia glis.

LeGros Clark was no longer chairman of Anatomy but still had a position at Oxford when I was there on sabbatical in 1964 to 1965. We had lunch about once every other week in his office. What a fine man! He knew I had worked with the hedgehog and opossum. He also included the tree shrew in our discussions. His first paper about this species was “The Thalamus of Tupaia” in 1929.

After the papers by Casagrande, Glendenning, Harting, Killackey, and Snyder, the tree shrew became our laboratory’s central topic of study. We reasoned that if the cortex of the tree shrew fit the traditional view of sensory and association cortex, the lateral geniculate nucleus would project only to the striate cortices, and the pulvinar nucleus would project only to the association areas between VII and the auditory field. The surprising result was the ability of the tree shrew to discriminate between different patterns and different colors after complete removal of the striate cortex; the completeness of the lesion was verified by the complete degeneration of the lateral geniculate nucleus! Only when the rest of the occipital cortex (areas 18 and 19) plus the temporal cortex were ablated in addition to area 17 was the tree shrew unable to discriminate between upright and inverted triangles (Figures 4a and 4b) (Snyder et al., 1966; Snyder and Diamond, 1968).

Figure 4a.    Learning curves for the tree shrew before and after complete removal of the striate cortex.

Figure 4b.    Failure to attain visual discriminations after ablation of both the striate and temporal cortex.

After long and tedious training, some vision remained as indicated by better than chance discrimination between horizontal and vertical stripes. As a result of these huge cortical lesions, the pulvinar nucleus was severely degenerated in addition to the lateral geniculate nucleus. The results immediately showed that the pulvinar nucleus does not depend solely on fibers from the lateral geniculate. This conclusion convinced us that the pulvinar nucleus is not intrinsic, and that some part of the visual brain stem must be a source of a visual pathway to the pulvinar nucleus (Diamond and Hall, 1969). These results were reminiscent of earlier ones from the auditory cortex in the cat. It followed that much of the cortex between the primary visual and auditory areas of the tree shrew was the target of a visual pathway and should be classified as sensory rather than association cortex, according to the traditional definition.

A good starting point was the tecto-thalamic pathway projections that had been identified in lower vertebrates. In 1966, use of the Nauta method allowed tracing fibers from the tectum to the nucleus rotundus in birds (Karten and Revzin, 1966). In tree shrews, small lesions were made in the superficial layers of the superior colliculus, which revealed a strong projection to the pulvinar nucleus (Harting et al., 1973a,b). The well-established pathway from the optic nerve to the superficial superior colliculus (SC) explained the role of the pulvinar nucleus and the temporal cortex in the tree shrew’s vision; it also seemed likely that at least some part of the pulvinar nucleus in all mammals receives visual impulses from the superior colliculus (Diamond, 1973, 1982).

Whereas the two pathways from the retina, one to the lateral geniculate nucleus and the other to the superior colliculus, forced a major revision of our view of cortical organization, further experiments in Tupaia have subsequently revealed increased complexity. First, the pulvinar is not the only target of a superior colliculus projection. Two of the six geniculate layers are also destinations of superior colliculus fibers. These two layers, 3 and 6, have smaller cells and project above layer IV in the striate cortex. The lateral geniculate layer 3 is particularly striking as its projection reaches cortical layer I. Two methods support this finding: anterograde transport by the Nauta method shows that the lateral geniculate projects strongly to layer I of the striate cortex and retrograde transport after applying horseradish peroxidase (HRP) on the surface of the striate cortex labeled cells in lateral geniculate layer 3 (Carey et al., 1979a,b). The conclusion was clear that the simple distinction between sensory and association areas fell far short of accounting for the multiple pathways through which the visual system influences the cortex.

Visual Pathways and Fiber Size: Cat and Galago

Just 10 years after Rose and Woolsey’s 1949 paper, George Bishop (1959) proposed a new way of explaining the significance of fiber size. The prevailing view was initiated by studies of Gasser and Erlanger (1929), who showed that fiber size was a function of modality or submodality; large fibers convey touch and small fibers pain. Later, Bishop (1959) turned to the visual system and was convinced that only the large fibers of the optic tract reach the lateral geniculate nucleus in the cat. The small fibers of the optic tract project instead to the tectum, and this seems to hold for all vertebrates. Bishop then made his major point that fiber size differences are a reflection of stages in the evolution of sensory pathways. Newer, large fibers bypass the older centers in the brain stem. In contrast, older, small fibers synapse step-by-step through the brain stem. Bishop showed that C fibers in the lateral columns project to the reticular formation and, with further synapses, the pathway continues to the intralaminar nuclei. This proposal is compatible with that of Giuseppe Moruzzi and Horace Magoun, who had inferred a diffuse projection from intralaminar nuclei to the superficial layers of the entire cortex. Their stimulation of the reticular formation had the important result of a change from sleep to a waking state. However, Bishop took an alternative, but not necessarily contradictory, view: the diffuse projection from the intralaminar nuclei to the cortex produces the experience of burning pain characteristic of C fibers.

Bishop identified still another path by recording visual impulses in the pulvinar nucleus. The impulses were produced by stimulating the optic tract but were delayed by a synapse, which Bishop attributed to a relay in the lateral geniculate nucleus. If visual input reached the pulvinar from a source inside the thalamus, the pulvinar would be intrinsic in Rose’s sense of the term. As it turned out, the delay could be attributed to the superior colliculus, so the pulvinar is not intrinsic, but instead falls into Rose’s extrinsic class. There still was a third class of thalamic nuclei according to Rose: those nuclei that are not relays in any sensory path and receive fibers only from the association cortex. This third class may include larger portions of the primate pulvinar and provide the basis for the higher level of thalamic processing envisioned by both LeGros Clark and Rose.

The role of cell size and fiber size became important in my laboratory as well. We found that the lateral geniculate of Galago has three pairs of layers: magnocellular, parvocellular, and layers 4 and 5, with small pale cells (Figure 5) (Itoh et al., 1981; Diamond, 1993).

Figure 5.    Photomicrograph of a frontal section of the lateral geniculate body of Galago senegalensis. Note the small cells filling layers 4 and 5.

The visual thalamus is not the only sensory relay to show a relation between fiber size and modality. Our laboratory demonstrated that cells of different sizes in the ventral posterior nucleus of the cat project to different layers of somatic cortex (Penny et al., 1982).

One might expect that there also would be a close correspondence in Galago between the sizes of afferent fibers in the optic tract and the sizes of the cells in the three lateral geniculate layers of a set. Large axons project to the pair of magnocellular layers, and small fibers project to the pair of layers with the small cells, layers 4 and 5. This small cell pair projects to the cortex above layer IV (Itoh et al., 1982).

I began this section with Bishop’s rejection of modality as the significance of fiber size; instead, he regarded the larger fibers as phylogenetically more recent pathways that bypass older brain stem centers. Fiber size may turn out to have some relation to submodality after all. The information conveyed from the retina to the lateral geniculate layers 4 and 5 in Galago is surely not the same as that received in the big cell layers by large axons (Conley et al., 1987).

Summary: There have been advances in our understanding of thalamocortical organization as research methods have been refined and improved. The idea of intrinsic thalamic nuclei has given way to the discovery of multiple pathways from the retina and from both deep and superficial layers of the superior colliculus to the thalamus. The sizes of axons projecting to a thalamic nucleus are not uniform. On the contrary, large cells in the lateral geniculate receive large fibers and small cells receive small fibers. Large and small cells in a single thalamic nucleus send fibers to different layers of the cortex. The superior colliculus is important for understanding the organization of the thalamus and the cortex and, in particular, makes an important contribution to the visual pathways to the cortex. I have tried to show that my own research relied heavily on many major figures in neuroanatomy and neurophysiology and in the evolution and development of the thalamus: Ramón y Cajal, Campbell, Sherrington, Elliot-Smith, LeGros Clark, Rose, Woolsey, and Bishop. George Bishop and I made a promise to work together—he visited Durham and I St. Louis. I enjoyed his large farm house and the seemingly rural surroundings of his many acres. Fences and shrubs isolated him from the middle-class neighborhood that had sprung up around him. His laboratory was small, and he shared an office with his assistant. No one presented a more humble view of a science laboratory. When I said good-bye to George Bishop in St. Louis in 1971, he was elderly and quite ill. We both knew we would not see each other again.

The Role of Universities—Inside and Outside the United States

Over the years I have had a chance to lecture at many universities and have learned much, especially when I have been invited to speak at academic institutions in foreign countries.

I begin by telling a moving experience that taught me the meaning of “chairman.” In 1970, I visited the Institute of Neurophysiology in Pisa. When the time came for my lecture, Dr. Giovanni Berlucchi introduced me first in Italian, then in English. I stood behind a large table in a traditional European auditorium, looking up at the steep rows of students and staff. To my surprise and disappointment, I could not find Professor Moruzzi, chairman of Physiology. Just as I began to talk, I heard some noises at the side of the auditorium. Some students were carrying in an ancient leather chair. Moruzzi followed them in, nodded to me, and sat down—in his chair! The meaning of a “chairman” finally took on significance. After the lecture, Moruzzi showed me his private library in his apartment above the laboratories of the institute. The books were bound in ancient white leather, one of which was the great treasure of an original edition of William Harvey.

In the fall of 1980, I was invited to lecture at the Sechenov Institute of Evolutionary Physiology in Leningrad. At that time, traveling to the USSR and lecturing to the Russian Academy of Science was not recommended by the U.S. State Department, but it was left up to me to decide whether to proceed. My wife accompanied me. Leningrad was dismal in many ways, but I felt the warmth and sincerity of my hosts, especially Dr. Margareta Belekhova, who continued to write and send photographs long after I returned from this trip.

My lectures required three hours because each of my sentences in English was followed by translation into Russian. My wife sat in the large audience of well over 200 people. At one intermission, she called my attention to someone who was sitting nearby—a physicist, Adolph Lev—who had spent time in the physiology department at Duke University. Adolph turned his head away from me and in a low voice gave me his telephone number. How could I find a telephone? There was no telephone in our hotel room because Soviet policy decreed that “guests” could not telephone. I suggested to the young KGB assistant, who was assigned to escort us everywhere, that he need not accompany my wife and me to the ballet that evening. Later, during the intermission, I walked alone to find a telephone booth. I had just one kopeck in my pocket. I telephoned and planned a way of meeting Adolph. One week later, it was pitch dark and cold when my wife and I left the hotel and walked six blocks to find Adolph waiting for us in an old automobile. He drove for an hour and stopped in front of his home in a 10-story building just two years old. The building was cracked, the elevator weak. In his flat the shades were drawn and his words to us were these: “They can’t make a fool of me.” The frustration of Dr. Lev was apparent. We could now, finally, discuss our lives as scientists openly without KGB monitoring or censure.

Another recollection from this trip was the darkness that fell early in the evening and lasted late into the morning. I would leave the hotel to take a walk before breakfast and see lines of people two blocks long waiting to get into a shop; each person left the shop carrying one loaf of bread. Two years after my Russian trip my wife and I visited China. This tour began in Hong Kong where the university was entirely devoted to English. Doctors Hwang and Wong helped prepare our visit there and Dr. Paul Poon, who spent a couple of years with Dewey Neff, arranged everything before and during our stay. The hotels had every luxury, the restaurants were excellent, and Rolls Royce automobiles were in abundance.

A short train trip from Hong Kong brought us to Guangzhou (Canton). During my lecture I sat at a large table covered with a white cloth, everyone wore open-necked white shirts, and tea was served throughout. Dinner was in Canton’s oldest restaurant, where the service was superb. We left Canton by plane for Shanghai during a torrential rainstorm that came close to a typhoon. We were met at the airport by Professors T.P. Feng and H. Chang, along with other senior members of the two institutes they headed. Chang had spent several years in Washington D.C. He was optimistic about future plans for building a research facility in Shanghai. Feng was remarkable—old enough to have known Sir Charles Sherrington and Lord Adrian in England.

The research laboratory at the University in Peking (Beijing) focused on the physiology and psychophysics of vision. In addition to touring the Great Wall, we had considerable time to walk through the Forbidden City. A final experience was learning how the Chinese suffered during the Cultural Revolution. With stoicism, resignation, and even good humor, they related stories about sentences to hard labor, separation from families, seeing libraries pillaged and schools closed.

I have visited Japan, a complex place, several times. Japanese scientists have worked in my laboratory and one, Kazuo Itoh, was here for three years. I spent a year at Oxford in the 1960s and I have spent many summers in the Cotswolds since that time. Italy is a place of my close friends, Drs. G. Maachi in Rome, G. Berlucchi and M. Bentivoglio in Verona, R. Spreafico in Milan, and G. Rizzolatti in Parma. Several Italian scientists have also worked in my laboratory, Drs. G. Luppino, M. Matelli, and M. Molinari.

In May 1992, I discovered to my complete surprise a special issue of the Journal of Comparative Neurology. This issue had been published in my honor. The editor-in-chief was Sanford Palay and the contributors were my former students—Jeff Winer, Pete Casseday, Karen Glendenning, David Fitzpatrick, and others I have identified in the above text. An article by my youngest son, Mathew, a neurobiologist in Trieste, Italy, can also be found in this issue of the journal.

Finally, my laboratory at Duke University has had many rotations of students and postdoctoral fellows through the years. At a recent Society for Neuroscience meeting, a session was given in my honor. I went to the session without any notion of what was to follow, which turned out to be presentations by Vivien Casagrande, John Harting, Jon Kaas, David Hubel, David Fitzpatrick, and Bill Hall. This event was the highest moment of my career. I was touched and delighted, as were my children who attended, Mathew, Nancy, and Thomas.

Selected Publications

Bernard C. Lectures in diabetes and animal glycogenesis. Paris: Bailliere, 1877.

Bishop GH. The relation between nerve fiber size and sensory modality: phylogenetic implications of the afferent innervation of cortex. J Nerv Ment Dis 1959;128:89–114.

Butler RA, Diamond IT, Neff WD. Role of auditory cortex in discrimination of changes in frequency. J Neurophysiol 1957;20:108–120.

Campbell AW. Visuo-sensory and visuo-psychic areas (Chapter V). Histological studies on the localization of cerebral function. Cambridge: Cambridge University Press, 1905.

Carey RG, Fitzpatrick D, Diamond IT. Layer I of striate cortex of Tupaia glis and Galago senegalensis: projections from thalamus and claustrum revealed by retrograde transport of horseradish peroxidase. J Comp Neurol 1979a;186:393–438.

Carey RG, Fitzpatrick D, Diamond IT. Thalamic projections to layer I of striate cortex shown by retrograde transport of horseradish peroxidase. Science 1979b;203:556–559.

Casagrande V, Harting JK, Hall WC, Diamond IT, Martin GF. Superior colliculus of the tree shrew: evidence for a structural and functional subdivision into superficial and deep layers. Science 1972;177:444–447.

Conley M, Penny GR, Diamond IT. Terminations of individual optic tract fibers in the lateral geniculate nuclei of Galago crassicaudatus and Tupaia belangeri. J Comp Neurol 1987;256:71–87.

Darwin C. The origin of species. (Originally published in 1859.) New York: Mentor Books, 1958.

Diamond IT. The evolution of the tectal-pulvinar system in mammals: structure and behavioral studies of the visual system. Symp Zool Soc Land 1973;33:205–233.

Diamond IT. Changing views of the organization and evolution of the visual pathways. In: Morrison AR, Strick PL, eds. Changing concepts of the nervous system. New York: Academic Press, 1982;201–233.

Diamond IT. Parallel pathways and fibre size. In: Minciacchi D, Molinari M, Macchi G, Jones EG, eds. Thalamic networks for relay and modulation. New York: Pergamon, 1993;3–15.

Diamond IT, Hall WC. Evolution of neocortex. Science 1969;164:251–262.

Diamond IT, Neff WD. Ablation of temporal cortex and discrimination of auditory patterns. J Neurophysiol 1957;20:300–315.

Diamond IT, Utley JD. Thalamic retrograde degeneration study of sensory cortex in opossum. J Comp Neurol 1963;120:129–160.

Diamond IT, Chow KL, Neff WD. Degeneration of caudal medial geniculate body following cortical lesion ventral to auditory area II in the cat. J Comp Neurol 1958;109:349–362.

Diamond IT, Fitzpatrick D, Conley M. A projection from the parabigeminal nucleus to the pulvinar nucleus in Galago. J Comp Neurol 1992;316:375–382.

East EM. A Mendelian interpretation of variation that is apparently continuous. The American Naturalist 1910;44:65–82.

Elliot-Smith G. Some problems relating to the evolution of the brain. Lancet 1910;1:1–6, 147–153, 221–227.

Gasser HS, Erlanger J. The role of fiber size in the establishment of a nerve block by pressure or cocaine. Am J Physiol 1929;88:581–591.

Harting JK, Hall WC, Diamond IT, Martin GF. Anterograde degeneration study of the superior colliculus in Tupaia glis: evidence for a subdivision between superficial and deep layers. J Comp Neurol 1973a;148:361–386.

Harting JK, Diamond IT, Hall WC. Anterograde degeneration study of the cortical projections of the lateral geniculate and pulvinar nuclei in the tree shrew (Tupaia glis). J Comp Neurol 1973b;150:393–440.

Harting JK, Glendenning KK, Diamond IT, Hall WC. Evolution of the primate visual system: anterograde degeneration studies of the tecto-pulvinar system. Am J Phys Anthropol 1973c;38:383–392.

Harvey W. An anatomical disquisition on the motion of the heart and blood in animals. (Originally published in 1628; translated from Latin by Robert Willis.) New York: Dutton, 1908.

Itoh K, Conley M, Diamond IT. Different distributions of large and small retinal ganglion cells in the cat after HRP injections of single layers of the lateral geniculate body and the superior colliculus. Brain Res 1981;207:147–152.

Itoh K, Conley M, Diamond IT. Retinal ganglion cell projections to individual layers of the lateral geniculate body in Galago crassicaudatus. J Comp Neurol 1982;205:282–290.

Karten HJ, Revzin AM. The afferent connections of the nucleus rotund us in the pigeon. Brain Res 1966;2:368–377.

LeGros Clark WE. The thalamus of Tupaia. J Anat 1929;63:117–206.

LeGros Clark WE. A morphological study of the lateral geniculate body. Br J Ophthalmol 1932a;16:264–284.

LeGros Clark WE. The structure and connections of the thalamus. Brain 1932b;55:406–470.

LeGros Clark WE. The medial geniculate body and the nucleus isthmi. J Anat 1933;67:536–548.

Mendel G. Experiments in plant hybridization. (Originally published in 1865.) Cambridge: Harvard University Press, 1960.

Moruzzi G, Magoun HW. Brain stem reticular formation and activation of the EEG. Electroencephalogr Clin Neurophysiol 1949;1:455–473.

Neff WD, Fisher JF, Diamond IT, Yela N. Role of auditory cortex requiring localization of sound in space. J Neurophysiol 1956;19:500–512.

Penny GR, Itoh K, Diamond IT. Cells of different sizes in the ventral nuclei project to different layers of the somatic cortex in the cat. Brain Res 1982;252:55–65.

Ramón y Cajal S. Comparative study of sensory areas, sensory pathways to the neocortex. Clark University 1889–1899 decennial celebration. Worcester, MA, 1899;311–382.

Ramón y Cajal S. The structure and connections of neurons. Physiology or medicine: Nobel lectures including presentation speeches and laureates’ biographies 1901–1921 (Nobel Foundation). (Originally published, 1906). New York: Elsevier, 1967.

Rose JE, Woolsey CN. Organization of the mammalian thalamus and its relationships to the cerebral cortex. Electroencephalogr Clin Neurophysiol 1949;1:391–403.

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*I thank Bill Hall for discussions about this chapter. Our collaboration over the last 30 years has been very important to me.

Robert Galambos

BORN:

Lorain, Ohio

April 20, 1914

EDUCATION:

Oberlin College, B.A., 1935

Harvard University, M.A., Ph.D. (Biology, 1941)

University of Rochester, M.D., 1946

APPOINTMENTS:

Harvard Medical School (1942)

Emory University (1946)

Harvard University (1947)

Walter Reed Army Institute of Research (1951)

Yale University (1962)

University of California, San Diego (1968)

Professor of Neurosciences Emeritus, University of California, San Diego (1981)

HONORS AND AWARDS:

American Academy of Arts and Sciences (1958)

National Academy of Sciences USA (1960)

Robert Galambos discovered, with Donald Griffin, the phenomenon of echolocation in bats. During his career he carried out fundamental physiological studies of the auditory system using microelectrodes in cats, and later studied brain waves and auditory evoked potentials in humans. He was an early and forceful protagonist for the importance of glia in the function of the nervous system.

Robert Galambos

Introduction

The subject was born in Lorain, Ohio, on April 20, 1914, not long after the vacuum tube was invented. At the age of 6, and in the first grade of a Cleveland, Ohio public school, he heard his first radio message through an earphone connected to a crystal radio receiver his older brother had built. He was about 40 years old when television sets first appeared for sale in the stores; by that time he had obtained A.B. and M.A. degrees in Zoology at Oberlin College (1936); M.A. and Ph.D. degrees in Biology at Harvard University (1941); and the M.D. degree at Rochester University (1945). Also, penicillin had been discovered, Hitler and Hirohito defeated, and a remarkable expansion of research on the brain was just getting under way throughout the world. This essay provides some details about the subject’s participation in that effort.

In autobiographies this use of the third person past tense is the way writers inform readers they feel uncomfortable with the topic being discussed. My problem is that I have already published one of these self-portraits (Galambos, 1992), which is probably all the world needs. How will I cover the same old ground in a new way? The questions I asked in search of the answer may be worth preserving.

Who writes an autobiography? Among modern scientists, almost invariably, someone who has been asked. Benjamin Franklin, our first great scientist, wrote a long one, and Abraham Lincoln wrote a very short one, but we don’t remember either man because of what he wrote about himself. If what you produce during your lifetime is really worthwhile others see to it the world does not forget.

Why does a person agree to write one? If you have grandchildren, which most autobiographers do, the immortality your genes clamor for is already assured. Duty? Vanity?

For whom do we write? I have yet to find someone who makes this explicit, but I will aim my autobiography at the young person about to submit a manuscript reporting his or her first successful experiment, knowing full well that when I was at that point in my own career the bottommost item on my reading list was an account of someone’s life.

What should I write about? I asked several friends, and their answers clustered around two themes. Many wanted to know how I decided what I was going to do, both as a student before committing myself to a research career, and then every morning as I opened the door of my place of business and walked inside. Students often raised practical matters, such as how to write a good scientific paper, how many mistakes are you allowed to make during a career, and so on.

I finally settled on what follows, which has three parts: my background, my work, and what I would do in the future if I had one. It is a story about people, ideas, what we accomplished together, and the environments in which we worked during the most remarkable 60 years in the history of science, so far.

Personal Matters

I was the third of four brothers. My father (1880–1954) and mother (1885–1969) came through Ellis Island from northeast Hungary around 1895 and met for the first time in Lorain about 10 years later. My paternal grandfather (1844–1907) was a peasant who died in the same farmhouse where he had raised two daughters and four sons, of whom my father was the youngest. (I have a copy of the von Galambos coat of arms and once exchanged letters with the last nobleman of the line; there is no evidence whatever our families are related.) My mother, Julia Peti (Petty), was the oldest of five siblings; her father was a schoolteacher who taught her to read and write before she was brought to America by a relative at the age of 12 or 13. It is interesting and sad that I retain nothing that I may have been told about my grandmothers.

My father said his first purchase was an English dictionary, and that he set himself the task of learning to spell, pronounce, and use three new words every day. By 1905 he had apprenticed as a carpenter and was taking a correspondence school course covering the building trades, and would soon set himself up in the house-building business he successfully conducted throughout his life. He was proud that his word and handshake were all anyone needed to close a business deal.

My mother was a small woman—perhaps five feet tall—who took nonsense from no one. She attended night school to improve her English skills, and I retain dozens of letters she wrote in a curiously antique hand. She taught her sons promptness because the early bird catches the worm, frugality because a penny saved is a penny earned, and honesty because it is the best policy—teachings many young people today never even encounter, let alone learn. As an adult I spent a day or two with her whenever possible, managing this once or twice every year at her home in Florida. She told me during my last visit she had delayed going to the hospital because she was certain she would come out “feet first” the next time. An inoperable gastric carcinoma had finally blocked her digestive tract. My mother was much loved; three of her doctors helped carry her casket and, as she had instructed, we drank champagne during the goodbye party at my brother’s house afterwards.

My parents were intelligent but not intellectuals; there were few if any family discussions about books, religion, poetry, or politics. My father did once outline for me his theory of vision; it involved particles emitted by the eye that reach targets in the environment. My mother listened proudly while I described my research results, but she still wondered how soon I was going to go to work when I was almost 40 years old.

Physical Well-Being; Financial Security, Domestic Tranquility

Prior to a mild heart attack at age 78, my most serious medical problems had been a tonsillectomy at 19, a frequently aching back, and an occasionally painful knee corrected by arthroscopic surgery at age 69. At 65 I quit smoking after 50 years, began jogging, and kept an almost daily log of distance run for the next 10 years. Its entries occasionally note what a godsend this exercise was for me physically and mentally, and they also trace, inadvertently, the order in which my genes have progressively turned off one bodily process after another. At 81 I have finally accepted the fact that a few years at most remain for completing what I still want to do, and am mildly amused at how, like so many other aging people, I stubbornly refused to accept my mortality.

Money has never been much of a problem, although I was close to 40 before repaying what I had borrowed from parents and others. Throughout my adulthood, the national economy expanded, salaries increased regularly, and inflation boosted the value of the homes I sold. As a result, I found it possible to live well with my family and to do such extra things as pay the salary of a collaborator for a month or two between grants, commute to Budapest to work with colleagues on an experiment, and assemble a collection of old pocket watches and Navajo rugs.

I have had three wives, each a strong person who meshed her career plan with my own. My first wife, now Jeannette Wright Stone, is widely known for her contributions to the field of early childhood education; after more than 30 years, she chose to divorce me for another man. The second, Carol Armstrong Schulman, a neuroscientist in her own right, left me by committing suicide during one of her bouts of depression. The third, Phyllis Johnson, joined me in 1977, and since then I have known more peace, order, comfort, and companionship than a person has any right to expect. Jeannette and I have three daughters, who, between them, have given us five grandchildren.

Awards and Prizes

My honorary degrees include the M.A. routinely awarded all Yale professors who do not already have a Yale degree and the M.D. awarded by the Swedish University of Göteborg, for which its then-rector, my friend Holger Hyden, the glia specialist, is probably responsible. I also have several meritorious performance commendations from the Army. A former colleague, George Moushegian, told me recently that during the past 20 to 30 years he has repeatedly submitted my name for various honors given specialists in hearing matters and is frustrated that none has ever been awarded. Perhaps he overestimates my qualifications, but certainly my ability to say no when offered jobs that would take me away from the laboratory has played a part. My own view is that I am often arrogant and cranky, and this turns people off.

Introduction to Research, Oberlin College, 1934-38

I first systematically encountered biological facts and concepts as a college junior in 1934 and found them surprisingly easy to grasp, remember, and manipulate. My math and physics grades were B with a sprinkling of C. I was delighted by my special knack for Biology, which in retrospect seems easy to interpret in the context of Howard Gardner’s idea of multiple innate intelligences (Gardner, 1983). Undergraduates in 1935 were strongly inclined toward J.B. Watson’s behaviorism, sometimes illustrated by the fantasy that a given baby can be fashioned into either a musician or a mathematician by selecting the proper stimuli to create its repertoire of reflex responses.

The conceptual distance is immense between such ideas and the current explanations, which assign a huge contribution to the genome (“nature”) and whatever remains to “nurture.” Gardner’s Seven Intelligences account much more aptly than J.B. Watson’s reflexes for the musical genius of Mozart and Bach, the mathematical genius of Turing and Leibnitz, the verbal genius of Shakespeare, and the athletic genius of ballet dancers and basketball players. It seems believable to me that each of us arrives with a unique mix of Gardner’s seven, and we thereafter develop these to the extent permitted by where, and how long, we happen to live. Of course, people still take sides on the nature-nurture dichotomy, but my quaint behavioristic view disappeared forever following the publication by J. D. Watson and Crick, in 1953, of what Watson has called their “insight into the nature of life itself.”

About the Scientific Paper

My first encounter with one of these took place in my junior year in the departmental library as I was preparing my first seminar report for C. G. Rogers, a professor of Comparative Physiology. The paper, by W. R. Hess, dealt with the nervous system of the earthworm, and it ended with a complete summary of the paper’s objectives and results! What a stunning surprise! How informative and helpful! I gushed on like this in my presentation.

I have never read an account of how the scientific paper, that unique creation of the scientific community, evolved to reach its modern form. The mathematician Mark Kac once called them five-part Scientific Sonatas: Summary, Introduction, Methods, Results, Discussion. It is clearly the best known way to organize a scientific message; try to invent something different and be convinced. Meanwhile, here are two tips if you need help: first, study a few published examples you admire and note how often the writers follow the rules you will find in Strunk and White’s The Elements of Style. Second, edit ruthlessly; you can always improve what you have already written.

My First Laboratory

Raymond Herbert Stetson, professor of psychology at Oberlin College in 1935, was one of those unsung heros of American science: the small-college professor who inspires and guides its recruits at the time they are most vulnerable and educable. He introduced me to the research plan, the research lab, and the research discovery. In my two years with him (September 1935-37) I learned all the fundamentals: how to formulate the problem, plan the work, collect the apparatus, do the experiments, analyze the data, make the figures, write the paper, get it published, and, finally, how to teach what you know about all this to others. See Kelso and Munhall (1988) for biographies of this remarkable man.

Roger Sperry and I graduated together in 1935 and then did our master’s degree research in Stetson’s Oscillograph Laboratory, which, thanks to its chief technician, James M. Snodgrass, was about as well equipped for electrophysiological measurements as the Forbes-Davis Harvard Medical School laboratory to which I would shortly go. Stetson’s lab regularly included a few senior visitors who had come to work on the mechanisms of speech production, or motor phonetics, Stetson’s special field of interest. It was there that I joined the first of many such small, intimate fellowships that unite for the purpose of discovery. Members of every healthy lab bond closely together, like all comrades who seek the same goal. Years later, at Yale, I created similar temporary groups by organizing summer-long, six-days-a-week opportunities (five in all) where young people gained hands-on experience with electrophysiological instruments and developed a certain skill in using them. Still later, in San Diego, this became a three- to four-day annual symposia (seven in all) on the then-new auditory brainstem response; the attendees listened to lectures, but more importantly they carried home tracings of the responses made with their own hands. I have always wanted my own laboratory to be like Stetson’s, a place where people take pleasure in creating their own experiments and discoveries in the company of others doing the same.

Don Lindsley introduced me to single units when he visited Stetson’s lab in the spring of 1936. While at Harvard (1933–35), Don had inserted electrodes consisting of a fine insulated wire inside a hypodermic needle into arm and leg muscles of human subjects to isolate single motor units, which he defined as the collection of muscle fibres innervated by a single motor neuron. Stetson had heard of these measurements and asked Lindsley, who by then was at the Western Reserve Medical School in Cleveland 30 miles away, to come and demonstrate his technique. Don arrived and connected his electrodes to Snodgrass amplifiers, while the lab group (Sperry, Joe Miller, H. D. Bouman, and I) watched. I can still hear those individual loud pops the loudspeaker emitted, which Don predictably adjusted down and up in rate by exerting less or more effort. In Stetson’s opinon, “motor unit” meant one of the opposing muscle groups reciprocally activated around some joint to produce a ballistic movement, and Lindsley’s different definition troubled him. But Sperry, whose master’s thesis experiments mapped the sequence of the shoulder girdle muscle activations during such ballistic movements, welcomed the new techniques and ideas Lindsley brought.

After Lindsley’s visit, Sperry and I fabricated concentric needle electrodes and invented new ones, the most successful of which was a strand of fine copper wire with a single line cut across its insulation with a scalpel blade. We threaded this wire into the eye of a surgical needle, passed the needle through our skin into a muscle and back out, and connected it to the Snodgrass amplifier and loudspeaker. When our muscle contractions caused the loudspeaker to emit loud pops, similar to Lindsley’s, we knew the bared surface rested upon one or a few muscle fibers. I also found that an ordinary brainwave electrode placed on the skin over the first dorsal interosseous muscle—the one connecting thumb and forefinger—will readily pick up single units if one carefully adjusts the tension exerted.

My master’s thesis proposal to the zoology department was the analysis of earthworm locomotion using muscle action currents recorded in Stetson’s lab. Step one was to build a direct coupled amplifier; Snodgrass designed it, I built it, and it successfully amplified the potentials associated with earthworm movements, which we displayed with both a Westinghouse oscillograph and a smoked drum kymograph. My thesis was accepted in 1936, but it fell far short of what I had in mind. Stetson agreed to my remaining another year, at the end of which, still dissatisfied, I wrote my first paper, which was published in the Festschrift honoring him on his retirement (Galambos, 1939).

Throughout my six-year Oberlin stay I played saxophone in a dance band to help pay my bills, and when I left in the fall of 1937 for Harvard with the fellowship that made going there possible, I was a member of the musician’s union abandoning a possible musical career for what I thought was going to be the life of a smooth-muscle physiologist.

Introduction to Neuroscience, Harvard I, 1938-42

At the Biological Laboratories I met my advisor, A. C. Redfield, a distinguished physiologist and oceanographer, and we worked out a course of study that included mycology and its delightful teacher, Cap Weston, and physiology, where George Wald made memorable comments such as “the Napoleon of smell has yet to be born,” which I guess may still be true. Redfield gave me an office where I set up simple instruments for measuring the dynamic properties of invertebrate smooth muscles, and later arranged for me to spend the summer of 1939 at the Biological Station in Bermuda where my second, and last, contribution to smooth muscle physiology originated (Galambos, 1941a).

I told Redfield very early about my interest in electrophysiology, and with his blessing visited the Forbes-Davis Harvard Medical School laboratory for the first time during the 1937-38 winter. Alexander Forbes and Hallowell Davis welcomed me warmly, and before long I was making the trip from Cambridge to Boston at least once a week to serve as a subject in EEG experiments, or to watch other experiments underway, and even to lend a hand from time to time.

In the late 1930s the Harvard Medical School physiology department was one of a very small number of places in the world where students could learn electrophysiological techniques. For several years Forbes and Davis had aggressively supported development of the vacuum-tube amplifiers and stimulators that were propelling the department into the modern era of brain and peripheral nerve electrophysiology. Albert Grass, who designed and built all the physiological amplifiers and stimulators I used, succeeded E. Lovett Garceau, who had built the laboratory’s first cathode ray oscillograph and EEG machine. Albert arrived a year or two before I did, and left in the early 1940s to found his famous Grass Instrument Company.

Several graduate students and postdoctoral fellows were measuring brain waves, evoked and cochlear potentials, and single cell responses (I recall A.J. Derbyshire, J.E. Hawkins, Jr., H.O. Parrack, B. Renshaw, and P.O. Therman). Birdsey Renshaw showed me my first fluid-filled glass pipette electrodes and explained how he had used them to record responses of single hippocampal brain cells in situ (Renshaw et al., 1940); he left, his thesis finished, shortly after I arrived. His equipment passed first to a postdoctoral fellow from Sweden, P.O. Therman, to whom Forbes apprenticed me in the 1938-39 winter. I inherited this set-up and used it with Hal Davis to produce data for the first two of our three papers on the cochlear nucleus-the ones erroneously called auditory nerve studies (Galambos and Davis, 1943; 1944). Our third paper is a disclaimer, four years later, that showed many of our electrodes must have been located in the cochlear nucleus (Galambos and Davis, 1948). To the detailed account of these experiments which appears elsewhere (Galambos, 1992a), I would add only the following advice to the eager graduate student or postdoc at an early stage of his or her career in neuroscience:

Do exactly what I did. Find yourself welcomed into a laboratory where, for the first time, one of the most important techniques of the century has just been shown to work. Learn to use the method from its pioneers. Then listen carefully as the laboratory director tells you the space and equipment will be exclusively yours into the indefinite future, and instructs you to make whatever measurements you wish. Your success is assured provided you remain, or become, diligent and attentive.

Micropipette Electrodes

I know of no scholarly history of the glass pipette microelectrode, but one or more may in fact exist (Stetson gauged the goodness of a paper by the quality of its literature review). Don Lindsley says the Forbes-Davis lab did not have them when he left the place in 1935, but two years later it certainly did, because Forbes, Renshaw, and Rempel described experiments using them at the 1938 meeting of the American Physiological Society (Renshaw et al., 1938).

Renshaw’s pipettes were “pulled by hand or with a machine devised and kindly loaned by Dr. L. G. Livingston from thoroughly clean pyrex capillary tubing.” After breaking the 3-5 micron tips to sizes “upward from 15μ,” he filled them by suction with a warm agar-saline solution, inserted a chlorided silver wire into the cooled and hardened agar, and drove the electrode with a manipulator into the brain (cortex, hippocampus) of anesthetized or decorticated rabbits or cats, and chicken embryos (Renshaw et al., 1940). His microelectrode measurements may be the first ever made inside a living brain. In 1939, using Renshaw’s technique, I prepared identical pipettes with 3-5 micron tips, filled them by sucking Ringer’s solution up into them using a 20 cc syringe with its plunger coated with Vaseline, and inserted them into the cochlear nucleus area of anesthetized cats.

Ralph Gerard claims to have discovered, in 1936 with Judith Graham, the “true microelectrode” which he defines as “a salt-filled capillary with a tip small enough (up to five microns) that a muscle fiber could be impaled without excessive damage” (Gerard, 1975, p 468). The 1940 historical review in Renshaw et al. references the microelectrodes of Gelfan dated 1927, and of Ettick and Peterfi dated 1925, among others, but, curiously, not the Gerard and Graham version. A reprint Ted Melnechuk recently sent me describes a 3-micron saline-filled pipette used in 1918 by its author, I.H. Hyde; she calls hers a modification of one described in 1910 by Chambers, which in turn was based on the even earlier one of M.A. Barber (Hyde, 1921).

Gerard, in summarizing his career, says “I am probably best known for the microelectrode” (Gerard, 1975, p 474). Not by me. I remember him for the remarkable Gerard, Marshall, and Saul paper, the first comprehensive exploration of the cortical evoked potentials Richard Caton first described in 1875 (Gerard et al., 1936).

Bats

The collaboration with fellow graduate student Donald R. Griffin that produced my thesis experiments took place between May 1939 and November 1940, sandwiched in between a summer in Bermuda and the Davis auditory microelectrode studies. It yielded six papers covered in my earlier autobiography (Galambos, 1941b;1942;1943a,b; Galambos and Griffin, 1942; Griffin and Galambos, 1941). A paper just published adds details of possible historical interest (Galambos, 1995a) and I am happy to say we recently found the sound movies of flying bats taken in 1941, thought for many years to be lost forever. Some advice: if your experiment is photogenic, take the pictures and remember where you stored them afterward.

By 1940, investigators had tried vainly for 150 years to discover the mechanism by which blind bats avoid obstacles when flying. Today, in hindsight, it is easy to identify the two completely unrelated technical advances that made the solution inevitable. One was the cochlear microphonic method for testing animal hearing, which Hal Davis was teaching me; the other was the development of the instruments that generate, detect, and analyze high-frequency sounds inaudible to man. Don Griffin, a graduate student already an authority on bats, had just published a paper reporting they utter high-frequency cries inaudible to man; his co-author, G.W. Pierce, a physics professor, had just invented the ultrasonic sound generating and recording instruments essential for the demonstration. Don asked me to test bat ears with the Davis method and within a month I had convinced myself that the bat’s upper hearing limit was an octave or more above that of other animals. Don and I then designed and performed the behavioral experiments that convinced us we had solved the problem. My recent historical account of those experiments concludes as follows:

Griffin and I were lucky, first of all, to have found each other, for it is not likely that either of us would or could have made the measurements alone. Then there are the facts that the laboratories of Professors Pierce and Davis were separated by a few miles, and that their doors opened wide to us the moment we knocked. And finally, every one of our experiments worked out exactly as planned, and they all pointed directly at the ear hypothesis Jurine, and then Spallanzani, knew to be correct (in 1795 they both agreed that bats with plugged ears collide with obstacles, but neither could say why this was so). At the moment we were united with our professors there was only one place in the world where two graduate students could demonstrate that flying bats emit sounds we cannot hear, and that the animals hear and act upon the echoes—and we happened to be there (Galambos, 1996).

A graduate student once asked how I found the bat problem that became my Ph.D. thesis. Frankly, I cannot decide whether I found the problem or the problem found me. I favor the explanation that countless interrelated events, accumulated over 150 years, finally converged on the two of us, and that we, like bubbles in the vortex twisting around the drain of an emptying bathtub, swirled faster and faster along with Spallanzani, our two Harvard professors, and the many others who have left a mark in the literature. In this figure of speech, the problem disappears when the drain empties; however, 55 years later, according to my Medline search, about 25 bat hearing papers are being published every year.

Alexander Forbes

It is not easy to find words to describe the enormous changes in research methods my generation has seen. Let me try with the story of how one of my mentors, Alexander Forbes, came to work, and the equipment he used when he got there.

Alex was about to become emeritus professor of physiology at the Harvard Medical School when we met. He lived in the Blue Hills section of Milton, a Boston suburb. Around 1910, as a young faculty member, he rode to work on horseback, stabling his animal during working hours in a barn on Huntington Avenue near the medical school. During the wartime 1940s, as a member of a mapping expedition organized by the U.S. Geological Survey, he piloted his own plane while taking pictures over Nova Scotia.

He was middle-aged when someone discovered how to amplify small electrical signals using the vacuum tube, one of the most significant events in the history of technology, an advance ranked by some even higher than the microscope and telescope in its importance to science. Every discipline from astronomy through zoology entered its modern era as soon as its measuring instruments included electronic circuits that create large voltages out of small ones. Certainly neuroscience would not be what we know without the voltage amplifiers in electron microscopes, computers, physiological stimulators, and so on.

Hal Davis states that in 1923 Alex “had already developed a capacitycoupled vacuum tube amplifier to increase the sensitivity of his string galvanometer, and was the first to employ an amplifier in a physiological experiment” (Davis, 1991). Around 1930, when Alex decided to modernize his system, his options were another string galvanometer or the new vacuum tube amplifier-plus-cathode-ray-oscilloscope system being used by adventurous neurophysiologists like Gasser and Erlanger in St. Louis. According to Davis, the deficiencies of the then-available cathode ray tube, whose moving spot of light could be seen only by a partially dark-adapted eye, led Forbes to select the string galvanometer, but Don Lindsley has told me it had no amplifier when Forbes used it in 1933. When I arrived five years later, a string galvanometer was nowhere to be seen in the Harvard laboratory.

In 1939, when Alex added my name to the report that introduced me to glass microelectrodes, Albert Grass had only recently completed our stimulus and recording systems, a “thyratron set similar to the one used by Renshaw” and “a capacity-coupled push-pull amplifier connected with a cathode-ray oscillograph” (Therman et al., 1941). I measured the bat cochlear potentials with this amplifier, and within a week it was clear the bat ear generated frequencies well above the upper limit of Albert’s amplifier response. A few days later, as I was moving the bat experiment to the Cruft Physics laboratory and G.W. Pierce’s unique high-frequency system (Noyes and Pierce, 1938), Albert told me he felt betrayed. He had asked Davis and Forbes what the upper frequency limit of the new amplifier should be, and when they said 20,000 cycles per second he knew they would shortly want more, so he arbitrarily raised the upper limit to 40,000, which, as the bats revealed, was still not enough.

What about funding? Who paid for salaries, supplies, overhead? Alex bought his own equipment and supplies, and donated his $600 yearly salary along with even more princely sums to the department anonymously. The word overhead entered my vocabulary in the late 1940s, at which time universities considered one percent a welcome bonanza. In the mid-1950s, when I was doing my duty on study sections, I sometimes saw the same proposal twice, once at a meeting of the agency that paid overhead on salaries only, and again at the meeting of the agency calculating it on equipment and supplies only. Dishonest people turn up everywhere, but in a long career I have actually known only two crooks who invented their data.

Alex Forbes was a pioneer American electrophysiologist; like me, he loved the laboratory and continued working in one long after official retirement. Wallace Fenn’s summary of this gentle man’s many contributions is a beautiful tribute (see it in the National Academy of Sciences Memoirs, Vol. 40).

Hallowell Davis—Loud Sounds and Hearing Loss

In 1942, just after the Pearl Harbor attack, Hal Davis was offered the following assignment: find out how much and what kind of sound it takes to injure or incapacitate a man. A lifetime conscientious objector, he resigned his membership in the Society of Friends and accepted the assignment (Davis, 1991, p. 12). Hal collected the four of us listed as co-authors of his 1950 monograph “Temporary deafness following exposure to loud tones and noise” (Davis et al., 1950), and we proceeded to expose our ears to the sound waves emitted by a so-called bullhorn, the kind of loudspeaker the Navy used to deliver messages to personnel wearing earplugs on the busy flight deck of an aircraft carrier. We systematically varied the three sound variables—intensity, frequency, and duration—producing in ourselves increasingly larger temporary hearing losses, until we neared combinations we thought might cause a permanent loss. At the end of the project, Hal decided to find out if our predictions were correct, and told us to expose his right ear—we always protected his left ear—to a wideband noise at 130 dB for 32 minutes. As predicted, this exposure permanently sliced a few hundred Hz off the high end of his existing congenital hearing loss in the 3500–3800 Hz region. The monograph that summarizes this work is still quoted in the literature.

Hal began wearing hearing aids in 1979, I in 1985. We agreed those wartime exposures had nothing to do with our presbycousis. My evidence seems particularly strong: we exposed only my left ear, but my measured losses have always been symmetrical, and I invariably put the telephone to my left ear, the one that took all the beating, because I “hear better” on that side. Hal called his last research project “Old Time Ears.” In 1990, he convinced 15 aging hearing specialists to join him in systematically documenting the progress of their hearing losses by all available tests, and recruited Charles I. Berlin and Linda Hood at the Kresge Hearing Research Institute of the South in New Orleans to administer them. In late 1995, all of us except Hal had our hearing tested once again in New Orleans. Hal discharged his final obligation to the project in 1992 when his temporal bones reached the Temporal Bone Bank in Boston for histological analysis.

The Origins of Neuroscience—Clifford T. Morgan and F. O. Schmitt

Morgan is one of the co-authors of the Davis temporary hearing loss monograph. In the summer of 1942, Hal sent the two of us to Woods Hole to find out whether underwater explosions are hazardous for the ears. Some physicists were exploding bombs in the harbor there, and we were supposed to jump in and have our heads submerged when this happened. We spent several beautiful summer days taking turns jumping off the pier at the Oceanographic Institute. The plan required comparing before and after audiograms, and we began with blasting caps detonated at 50 feet or so. When we detected no losses following detonations so close that we were afraid we might be wounded by shrapnel, we began jumping in when the blasters signalled a bomb of theirs was about to go off. They supplied us with pressure data from their sensors, and I recall really impressive shock waves compressing my body, but neither of us ever recorded a hearing loss.

Morgan came to Harvard with his new psychology Ph.D. from Rochester University to work with Karl Lashley, but before long he was traveling throughout the country for the National Defense Research Council helping coordinate the efforts of different laboratories working on the same or similar wartime problems. We were close personal friends and laboratory colleagues. Morgan’s Ph.D. thesis had shown certain behavioral seizures in rats to be audiogenic, not the product of frustration or anxiety as N.R.F. Maier had claimed; two of our joint papers used the bullhorn, outside of official hours, to confirm and expand this point (Morgan and Galambos, 1942, 1943). We also made pitch and loudness measurements in man (Morgan et al., 1951), and in 1957-58 worked out a long and difficult chapter on the neural basis of learning for the first Handbook of Neurophysiology (Galambos and Morgan, 1960).

Cliff went to Johns Hopkins to chair its Psychology department in 1947 and resigned in 1958 when he could no longer tolerate the tedium of administration. A few years later, royalties from his Introduction to Psychology (1961) made him rich. He became peripatetic, and served without pay on the psychology faculties at the University of Wisconsin and the University of California at Santa Barbara. In Austin, Texas he was loosely associated with the University of Texas, helped found the Psychonomic Society, named it, and established and edited its journal until his untimely death there in 1976.

His Physiological Psychology, written in spare time during his war work, was published in 1943. In it he says, “the primary goal of physiological psychology is to establish the physiological mechanisms of normal human and animal behavior” (Morgan 1943, p vii). Its 26 chapters cover, in some 600 pages, nothing but, and essentially everything known then about, what we call neuroscience today. The following paragraph comes from the introduction to his third, 1965, edition:

Perhaps no subject draws upon so many different sciences and their methods as does physiological psychology. Every sort of pure and applied scientist—mathematician, physicist, chemist, physiologist, pharmacologist, anatomist, neurologist, psychiatrist, electrical engineer, as well as psychologist– has been taking part in our subject in one way or another (Morgan, 1965, p 9).

It can be argued, and I do, that when Frank Schmitt three years earlier coined the word “neuroscience,” he merely renamed an existing discipline hard at work doing exactly what he had in mind (the first Physiologische Psychologie was published by Wilhelm Wundt in 1873). Schmitt’s early Neuroscience Research Program Associates, of whom I was one, are all specific examples of the physicists, chemists, and biologists on Morgan’s list (Schmitt, 1990, p. 218). Frank and Cliff looked at the same thing through different goggles. I can imagine Cliff congratulating Frank on having recruited all those Nobel Prize winners to join the ordinary biologists, chemists, and physicists already trying their best to describe the brain correlates of learning, memory, thinking, motivation, and so on. Of course, this takes away nothing from Frank Schmitt’s contribution to the effort; this remarkable man organized, promoted, and catalyzed much of what subsequently transpired. But let history note he was not, as some claim, the first to discover the need for extensive interdisciplinary collaborations.

By 1962, when Frank Schmitt invited me to join his about-to-be-organized Neuroscience Research Program (NRP), I had spent 10 years as a member of Dave Rioch’s Walter Reed group, a historically important prototype of the modern neuroscience laboratory where department lines were deliberately blurred, and cross-discipline thinking, the hallmark of physiological psychologist and neuroscientist alike, was the rule. Furthermore, I had found a similar spirit of interdisciplinary interaction to be the way of life in the Magoun group in Los Angeles where I spent the summer of 1955.

Neuroscience at the conceptual, textbook, and laboratory levels may not have been new in 1962, but Frank’s NRP certainly was. Its faculty, the Associates, spoke often and eloquently from the platforms he created for them. The electron microscope had just come of age; the molecular biology revolution was barely underway; neurochemistry was at its threshold of unprecedented growth; and the first cognitive evoked potentials had just been averaged by computers. Nothing like this had ever happened before, and the Associates told each other at Work Sessions and Annual Meetings how the new methods and data were transforming old concepts and creating new ones. Each was a world-class expert in his field, and the authority and elegance of their presentations made for memorable learning experiences.

The origins and goals of Schmitt’s NRP can be traced directly to his earlier response, in the mid-1950s, to the National Institutes of Health authorities who asked him “What is biophysics?” He answered, in 1958, by organizing a month-long “Intensive Study Program” (ISP) in Boulder, Colorado, at which 61 experts delivered lectures which were published in 1959 as the Biophysical Sciences-A Study Program. This book defined the field for the first time and was instrumental in the creation of the Biophysical Society.

A few years later, Schmitt found himself “interested in the possibility that information might be transferred in the brain and central nervous system not only by electrical action waves along neural nets, but also by fast transport, possibly through extracellular substances” (Schmitt, 1990, p. 201). In order to organize the effort to find out whether the brain actually does work this way, he simply elaborated and extended the procedures that had so successfully settled the question, “What is biophysics?” He conceived, organized, and funded what came to be called the Neuroscience Research Program. He selected experts, the Associates, to advise him on how to proceed, assembled a staff, and installed it in excellent quarters. Because “fast transport” was prominent in his hypothesis, his original 27 Associates included many with special knowledge of, or interest in, the fast transfer of elementary particles (electrons and protons) in solids and water solutions; five of them were pure physical chemists, and fully two-thirds were primarily physicists or chemists. He also began planning a month-long neuroscience ISP at Boulder and convened it in 1966. This time he raised the number of experts delivering lectures to 65. Their contributions appeared a year later in what has been called the bible of Neuroscience, the first of the four volumes of The Neurosciences: A Study Program. Interestingly, only about a third of the book deals with the particular molecular biology questions that initially attracted Schmitt to the field.

The four Study Program volumes received world-wide acclaim as authoritative definitions and periodic updates of the field of neuroscience. Schmitt’s NRP will also be remembered for its NRP Bulletins, which were conceived by Ted Melnechuk, an interdisciplinary writer who joined the staff in 1963 as director of publications to help plan the Boulder ISP. Ted immediately suggested that the Associates pinpoint the new findings and ideas that might become topics on the Boulder program; then invite a dozen world-class experts to a Work Session where one of the topics would be discussed; and then prepare and disseminate an edited version of their deliberations and conclusions. His ideas were accepted, and six such Work Sessions per year were promptly authorized; the first ones covered such neuroscientific vanguards as biomolecular information storage, the synapse, cell membranes, glial cells, brain correlates of memory, mathematical concepts of CNS function, and immunoneurology (a word, like “neuroscience” itself, first promulgated in the NRP Bulletin). Between 1963 and 1972 the Bulletins clarified the conceptual and empirical state of research in 75 such neuroscience subfields. The Bulletins became very popular, and reached thousands of practicing and potential neuroscientists and science libraries around the world (few know about the two-day Work Session on Extrasensory Perception I attended in the early days of the NRP; a Bulletin reporting it out was considered but rejected. Frank would try almost anything in his search for enlightenment).

During my 20-years as an NRP Associate I attended all four Boulder meetings and coauthored three of the Bulletins, all made possible by Frank’s vision, hard work and extraordinary executive abilities.

Medical School and Military Service

My best friend, when I was 10 years old, was named Wilfred Earl Allyn, Jr. His father was a doctor, and we occasionally snuck into his home library to look at the pictures in his books. It was during this period of my life that I first wanted to be a doctor. Later, after reading Paul DeKruif’s Microbe Hunters, I had to be.

At Oberlin I was a premed major, but on graduation, in 1935, in the middle of the depression, financing a medical school education was out of the question. But the yearning would not go away, and finally, in 1942, my wife Jeannette and I decided it was now or never. Obviously the dream could come true only if she went to work to support three of us, which she did. I was accepted at the University of Rochester School of Medicine. World War II was on, and I enlisted as a First Lieutenant in the Army Medical Service Corps. The war and my medical school education ended at almost the same time without my ever serving a day in uniform.

But there is more to this military history. In 1952, during the Korean War, the draft board called my number. I reported for the physical examination, passed it, and prepared to receive marching orders. These never came, and I later found out why. The Army had neglected to discharge me from the Medical Service Corps, which meant I had technically been a soldier for more than 10 years. The automatic advances in rank along with other perks due me would mean inducting me as perhaps a Lt. Colonel entitled to a bundle of accumulated back pay, which made sense to no one.

At Rochester I was involved in several experiments, of which only one reached publication (Fenn et al., 1949). Other experiments included microelectrode penetrations of the cat optic nerve with Karl Lowy in the psychology department; rectal feeding of paralyzed poliomyelitis patients in the iron lung; and, with Jose Barchilon, the treatment of acute poisoning by the mushroom Amanita phalloides.

I interned in medicine at Emory University Hospital in Atlanta, and for another year debated, while teaching anatomy to medical students there with Harlow Ades, whether to practice medicine or return to the laboratory. The laboratory won out, and I had to choose between the Wilmer Institute in Baltimore and the Psychoacoustic Laboratory (PAL). The PAL was S.S. (Smitty) Stevens’ wartime lab in the basement of Harvard’s Memorial Hall, now newly civilianized but still funded by the Office of Naval Research. When I asked Smitty why he wanted me to come, he said that the war had consumed all our basic knowledge about hearing, and we needed pure research to generate more before the fighting began again.

Harvard II, 1947–51

My plan was simple. The cats and I would converse, with me asking the questions by delivering clicks and tones to their eardrums, and they replying, one brain cell at a time, through a microelectrode. No theory, no preconceptions; just simple experimental facts. I adopted this stern position because, as recounted elsewhere (Galambos, 1992a), Hal Davis and I had found inhibition in the auditory nerve, a totally unexpected event neither teachers nor textbooks had prepared me for. A pox on both their houses. Teachers and books peddle dogma, the enemy of discovery, and from now on I would believe only what I could coax the cats to tell me (actually, as will become clear shortly, most of our electrodes had certainly rested in the cochlear nucleus, not the nerve, and had I known this there would have been no reason for disillusion).

A dozen publications came out of my second Harvard period, one or more with collaborators Reg Bromiley, Ira Hirsh, John R. Hughes, Larry Kahana, Cliff Morgan, Jerzy Rose, Walter Rosenblith, Mark Rosenzweig, and Carroll L. Williams. Of these, the three with Jerzy Rose on the medial geniculate consumed the most time and effort. We mapped the location of responding units in that nucleus, and whether they responded to clicks, noise, or tones delivered monaurally and binaurally. Jerzy liked my microelectrodes and carried samples back to Baltimore scotch-taped inside the rear window of his car. Vernon Mountcastle told me recently those highimpedance pipettes did not work with the Baltimore low input-impedance amplifiers, whereupon Jerzy devised the famous Dowben-Rose metal version and the Johns Hopkins laboratory entered the single unit business.

I did most of the writing on the medial geniculate papers, and when we sent them to the editor in 1951 I told Jerzy I was deeply disappointed at how little we had learned after so much effort. Jerzy, who had practiced psychiatry in the Pacific during World War II, sought to soothe me with this reply: “Maybe so, but these will soon be the best papers on the medial geniculate ever published.” He knew they had to be, because for several years there were no others.

Cat experiments were a small fraction of what went on at PAL. E.G. Boring, the department chairman, invited us to bring our brown bags and join him at lunch every day around a huge oval table. George A. Miller, J.C.R. Licklider, and Ira Hirsh, among others, were beginning to become famous. My youngest daughter spent her first year in the Skinner crib George and I built, more or less overseen by B.F. Skinner himself, in the laboratory shop. Rufus Grason and Steve Stadler soon graduated from that shop to form their company that sold the amplifiers and audiometers they had learned to perfect, and along with another graduate, Ralph Gerbrands, the first generation of operant conditioning timing and recording equipment. Walter Rosenblith kept talking about the NIH-financed computer being built nearby, at MIT’s Lincoln Laboratory, to process physiological data like what he, Mark Rosenzweig, and I were coaxing out of our cats, but to me the computer was an unnecessary distraction. I was still trying to find the data worth processing.

Bekesy

Georg von Bekesy was brought to PAL in 1947 by Smitty and E.B. Newman from Sweden, where he had gone after leaving Budapest at the end of World War II. When I arrived, he was setting up to continue the basilar membrane measurements for which he would receive the Nobel Prize. He was a quiet man, a bachelor, who rarely contributed to the wordy interplay at Boring’s table. His 83-item bibliography cites only three co-authored papers. I remember him laughing only once. We were talking with a visiting scientist for whom I tried to explain something in my high-school German. I noticed Bekesy laughing, with his hand held over his mouth, and when I asked him later what had been funny he said my German has a strong Hungarian accent (I learned my limited vocabulary of Hungarian words as a child overhearing conversations between my parents and others).

Don Griffin says the Yale bat man, Alvin Novick, visited Bekesy in 1953 or 1954 to seek advice on bat hearing matters but left without any. Bekesy was skeptical about the whole echolocation idea and said the emitted sounds were probably just noise bursts. A few years later after attending a seminar given by a visiting bat man from Brown University, Jim Simmons, Bekesy was heard to say maybe there was something to the idea after all. Bekesy and I saw each other almost daily for four years, but we never once talked about bats. Is it possible he had not read the bat papers published 10 years earlier?

Another strange thing. In 1947, I came upon a brief report (in a journal I have since been unable to find) of microelectrode experiments Bekesy and a person named Hamburger had done on the cat cochlear nucleus in Sweden. They confirmed our 1943 results and in addition demonstrated histologically that their electrodes had been in the cochlear nucleus, not the auditory nerve as Hal Davis and I had claimed. Our note in Science saying we had discovered this embarrassing fact ourselves had just appeared (Galambos and Davis, 1948). When I asked Bekesy why he had not told us he knew it all along, he said our experimental findings had been correctly reported, and he believed one should not emphasize the mistakes in a publication unless they alter the data.

We collaborated in only one measurement. His question was what an eardrum looks like as it ruptures. I exposed the eardrum of an anesthetized guinea pig from the inside by removing the wall of the bulla, and we adjusted the lens of a Fastax camera so that the eardrum filled a 35mm movie film frame. Fastax cameras can run thousands of frames past the lens every second. Bekesy fixed things so that the camera began rolling a moment before a starter’s pistol fired a cartridge next to the pig’s ear. Everything worked. The eardrum shatters into fragments that fly in all directions. The pictures were spectacular, but I don’t remember why Bekesy wanted them or what has happened to them.

One Sunday afternoon I accompanied him to the Boston Fine Arts Museum. He had an appointment with the egyptologist, who took us to a basement storage area to see the items Bekesy had in mind. Bekesy collected such things and willed them all to the Nobel Foundation. He told me that when he received his Prize he visited the King of Sweden in his office, as was customary, and when he saw an Egyptian artifact on the shelf behind the King’s head he commented on it, whereupon the two of them spent an hour talking about the hobby they shared.

Bekesy was also a historian-philosopher of science. For instance, he classified experimental problems in the following concise and amusing way:

Problems arise in a variety of ways, and it is often worthwhile to list the forms that they may take. Thus we can distinguish the following:

The classical problem, which has had much effort expended upon it, but without any acceptable solution.

The premature problem, which often is poorly formulated, or is not susceptible to attack.

The strategic problem, which seeks data on which a choice may be made between two or more basic assumptions or principles.

The stimulating problem, which may lead to reexamination of accepted principles and may open up new areas for exploration.

The statistical question, which may be only a survey of possibilities.

The unimportant problem, which is easy to formulate and easy to solve.

The embarrassing question, commonly arising at meetings in discussion of a paper, and rarely serving any useful purpose.

The pseudo problem, usually the consequence of different definitions or methods of approach. Another form of pseudo problem is a statement made in the form of a question. It also is often the result of discussions in meetings (von Bekesy, 1960, p 5).

The most personally gratifying of my experiments fit into every one of Bekesy’s first four groups. His ‘classical’ means to me that many people have already tried without success; his ‘premature’ means those unsuccessful predecessors had been denied an essential fact, concept, technique, or instrument without which the problem cannot be solved or even posed; his ‘strategic’ means you suddenly realize you can lay your hands at last on exactly what those predecessors needed and did not have; and his ‘stimulating’ means your contemporaries contemplate, replicate, and extend your findings. Here are two that fit this description.

The bat hearing experiment with Griffin was premature for fully 150 years, but when instruments that generate and detect ultrasonic sounds finally joined hands with the cochlear microphonics method, the experiment became strategic. This is the scientific equivalent of saying you can’t win a horse race if you don’t have a horse, and then finding the horse.

The idea of studying single auditory neurons changed from premature to strategic as soon as someone could lock a newish tool, the microelectrode, into a micromanipulator, then connect it to another new tool, the right kind of amplifier, and then insert the electrode into the cochlear nucleus of an anesthetized animal. The first of those measurements converted some long-standing theoretical controversies into matters of historical interest.

Industry? Government? Academe?

The Harvard “up-or-out” edict hit PAL hard when the administration ruled that researchers not promoted “up” to permanent positions from temporary ones, like ours, would be “out” at age 35. We didn’t want to go, but of course we did, seeding the entire U.S.A. with Smitty Stevens’ ideas. We had no trouble finding jobs; very few with our training were available to fill the increasing number of post-war openings. My final choices narrowed down to either a government civil service job in Washington, D.C., or a position near the bottom of the academic ladder at either Iowa City or New York City.

Then, and now, most scientists blend various amounts of research, teaching, and administration within an industrial, governmental, or university setting. I chose the Walter Reed Army Institute of Research for three reasons: to gain experience in administration (ultimately for a staff of some 30 anatomists, physiologists, and technicians); to do research with abundant support in the company of productive colleagues; and to spend time, as a citizen, on my country’s business. All these expectations were abundantly met during more than ten productive and exciting years.

David McK. Rioch and His Division of Neuropsychiatry—An Early Multidiscipline Laboratory, 1950–61

The Rioch organization came into being because the Army wanted to solve a pressing practical problem. The Commandant of the Walter Reed Army Institute of Research, Col. William Stone, defined it when he interviewed me for the job. He said, in effect, psychiatric casualties had reached the top of the Army’s list of medical problems, and Rioch’s mission was to supervise the basic research effort that would drop it to the bottom (Col. Walter Reed had done exactly that for yellow fever 50 years earlier in Panama). Dave Rioch was a practicing psychiatrist highly respected in the Washington, D.C. area, a Johns Hopkins M.D. known for his anatomical studies of the cat thalamus, and a natural person for the army to select. Rioch, interpreting his mandate in the broadest biological terms, put on paper a Neuropsychiatry Division with, initially, departments of psychiatry; clinical psychology; experimental psychology; and neurophysiology, and began to recruit the department heads. At our peak, we totaled well over 100 bodies, including technical help; we were an interdisciplinary group of practicing neuroscientists (not yet so-named), part civilian, part military, bent on making important contributions to knowledge about the brain.

I was one of Rioch’s first appointments, in neurophysiology, followed within months by Capt. Joseph V. Brady (experimental psychology), and Capt. Harold L. Williams (clinical psychology). Rioch selected my first recruit, the young neuroanatomist Walle J.H. Nauta, imported from Switzerland. Rioch was a superb administrator, and therefore an expert at bending bureaucratic regulations; Civil Service had no classification called neuroanatomy, so he identified Walle as a “neurophysiologist (neuroanatomy)”. Rioch filled many research positions by obtaining the names of M.D. and Ph.D. draftees from headquarters and telling his department heads to choose the ones they wanted. This meant many excellent young investigators spent their two-year dutytours as Army officers assigned to do postdoctoral brain research.

Microelectrodes Again

Rioch hired me to do microelectrode experiments, but only about a third of the more than 180 papers and abstracts my group published fell into this category (the microelectrode group included Michelangelo G.F. Fuortes, Robert G. Grossman, David H. Hubel, George Moushegian, Allen Rupert, Johann Schwartzkopff, Guy Sheatz, Felix Strumwasser, and Vernon G. Vernier). I was particularly pleased with the superior olive study with Schwartzkopff and Rupert (Galambos et al., 1959), but surely the most notable of them all are the first six of David Hubel’s visual cortex papers that later impressed the Nobel Prize committee. Hubel and I co-authored a different one: it describes auditory cortical cells that respond only to the sounds the cat is attending (Hubel et al., 1959).

Jerzy Rose and I returned to the cochlear nucleus study begun at PAL with John Hughes. During 1956-57 Jerzy would commute from Baltimore every week or so, often driving back after midnight; he insisted on perfusing the cat himself, to be sure the electrode tracks would show up well. The cochlear nucleus is a complicated structure divisible into three morphological regions in each of which the cochlea is unrolled systematically. Our report, which matches the nucleus itself in complexity, includes 29 figures, was published in a journal few libraries carry, and has been relatively infrequently referenced. Papers can be too difficult for readers to find, and, once found, too prolix and complex (Rose et al., 1959).

Implanted Animals—Labile Event Related Potentials (ERPs)

In 1953, when we learned of James Olds’ self-stimulating rats, Brady and I went to Rioch with the suggestion that we take up that line of investigation. His comment: “You two are running this show; if that’s what you want to do, do it.” We promptly invited Olds to come to Washington, and after he told us what he knew, Walle Nauta introduced him to the limbic system, the part of the brain into which he was placing his electrodes. The Olds visit was responsible for the dozens of studies on implanted rats, cats, and monkeys that became the trademark of Rioch’s unit. As my fascination with the electrical responses delivered by these unanesthetized, intact brains grew, my interest in the microelectrode experiments on which I had spent 20 years declined. Rioch once pointedly told me he regretted this.

For some six years thereafter Guy Sheatz, Allen Rupert, and I implanted electrodes in monkey cortex and throughout the cat auditory system from the round window to the cortex, publishing more than 30 accounts of the various results. Toward the end I discovered computers at last, and with Sheatz, demonstrated a brain response I was sure deserved documenting-the transformations in amplitude and configuration of the cortical potentials evoked during behavioral conditioning in monkeys. As noted elsewhere, the Russians discovered the labile event-related brain potentials, but we were very close by when it happened (Galambos, 1995b).

Lesions

An early recruit to my unit was Capt. Leon Schreiner, a neurosurgeon plucked out of the Magoun group while it was still at Northwestern University in Chicago. Rioch soon had him removing the amygdalae of cats and monkeys to produce and study the Kluver-Bucy syndrome, a bizarre “psychiatric” disorder characterized by docility, hypersexuality, and odd, compulsive oral behaviors. The Johns Hopkins physiologists Philip Bard and Vernon Mountcastle had for some time been making such lesions and reporting their animals became more aggressive, not more docile. After a particularly vexing interchange with the Hopkins group, Schreiner queried some animal trainers who told him the only animal too aggressive to handle was the southern lynx, a cat about half the size of a lion. He ordered our Army veterinarians get him one, removed its amygdalae bilaterally and took moving pictures a few days later showing the animal wandering sedately and unrestrained through the hallway, rubbing against his leg in the typical feline manner, and eating chunks ofraw hamburger out of his hand. The pictures settled the matter, as far as Schreiner was concerned, and he and Pvt. Arthur Kling, his draftee collaborator, published the experimental results (Schreiner and Kling, 1956).

Another drafted lesion maker was Capt. Ronald E. Myers, who arrived just after receiving his Ph.D. from Roger Sperry in Chicago. In his thesis he reported that cats with midline transections of both optic chiasm and corpus callosum could not perform a visual pattern discrimination learned through one eye when tested through the other eye; normal cats do this with ease. At the Walter Reed, Myers extended this finding to the chimpanzee and to tactile learning. He taught them to use one hand to open the door of a small box containing a piece of banana; the task was difficult because hooks had to be unhooked, latches unlatched, knobs turned, and so on, and the animal was prevented from seeing what was going on. The normal animal could immediately open a mirror-image of the box with its untrained hand, but the chimpanzee with corpus callosum sectioned had to learn the task all over again.

Myers, Allen Rupert, and I collaborated on a different problem: what electrophysiological and behavioral changes follow cutting Cajal’s classical auditory pathway at the point where it enters the thalamus? The remarkable answer is very few (Galambos et al., 1961; 1992a), a conclusion I still find difficult to believe. At Yale, as will be described shortly, we uncovered equally surprising facts following the comparable visual lesion.

Miscellaneous

The Olivocochlear Bundle (OCB). In 1949 I visited Grant Rasmussen in Buffalo to learn more about this collection nerve fibers he had discovered leaving the brain to innervate the cochlea. Anatomists generally ridiculed his claim, and he was always happy to talk to someone, even a physiologist, who did not. As already noted in detail (Galambos, 1992a), my Walter Reed research produced some physiological ammunition he could lob at the disbelievers (Galambos, 1956), but Moushegian, Rupert, and I failed, after several years of trying, to describe the role Rasmussen’s feedback fibers play in converting basilar membrane mechanical movements into sensations of sound. Apparently their function is still poorly understood. My recent literature review reveals that the system is complex, not simple. Its feedback loops are now known to be multiple and to originate as high up as the cortical level; the efferent bundle delivered into a given cochlea contains fibers from at least four different places in the brain. It terminates differently around the inner and outer hair cells where it produces both slow and fast effects. Worst of all, a patient could hear equally well through each ear on a large and sophisticated battery of tests after the bundle entering one of the ears had been completely cut across. If ever a classical problem awaited the insights of the person who will make it strategic, this is it.

The Moscow Colloquium. October 6-11, 1958. The Academy of Sciences of the USSR organized and financed this meeting attended by 49 representatives from 17 countries to discuss “electroencephalography of the higher nervous system.” A supplement to the EEG Journal published the 28 papers presented (Jasper and Smirnov, 1960). The official U.S. delegation consisted of M.A. Brazier, H.W. Magoun, Frank Morrell, and me; Herbert Jasper was Canada’s representative. We participated in the first face-to-face encounter between Soviet and Western physiologists in decades. The Soviet physiologists, despite years of government-dictated isolation, were familiar with our new ideas; it was instructive to hear them incorporate these into Pavlov’s framework in public and to learn what they really thought in private conversations. Important as these interpersonal encounters were for the participants, perhaps the meeting will be remembered longest as the birthplace of the International Brain Research Organization, IBRO.

The Aplysia Parabolic Burster. The circadian rhythm in this single cell was discovered by Felix Strumwasser in 1961 at the Walter Reed Institute. It is, I believe, the first glia-neuronal system shown to continue its diurnal cycling when transferred into a petri dish (Strumwasser, 1963). In a modern version of his experiment the rat suprachiasmatic nucleus clock similarly survives in vitro, producing its 24-hour rhythm spontaneously for at least three cycles (Prosser et al., 1994). The possible glial contributions to this mammalian circadian clock is under active investigation (Prosser et al., 1993).

Sleep Deprivation. Rioch favored interdisciplinary research and his department chairmen delivered it enthusiastically. When someone suggested studying people deprived of sleep in the mid-1950s, his entire organization mobilized behind the proposal. Seymour Fisher and I were the guinea pigs who went through the entire procedure before formal testing began. We stayed awake 53 hours, enduring repeated psychiatric interviews, behavioral and EEG testing, and the frequent drawing of blood samples for endocrine level and other measurements. At about this time, a disc jockey in New York logged 200 sleepless hours in a booth in the middle of Times Square; our Capt. Williams interviewed him and followed his progress as part of the study. The reports that came from this effort, in which several small platoons of army privates typically stayed awake for 100 hours in the successive replications, are a classic in the literature of sleep research.

Anesthetics. S.N. Pradhan was a pharmacologist at Howard University College of Medicine, an institution a few miles away in downtown Washington, D.C. He asked to join our research enterprise, and we welcomed him, as we did many others. The resulting publication may record the first use of an averaging computer to study brain changes during anesthetic induction and the subsequent recovery. Our stable of implanted animals were ideal subjects, and his expertise and interest added the necessary motivation (Pradhan and Galambos, 1963).

Other Research. My neurophysiology department included Nauta’s neuroanatomy unit and, for a time, John Mason’s neuroendocrinology unit; both of which were outstandingly productive. Joe Brady and Hal Williams, my counterpart heads of experimental and of clinical psychology, were close companions and confidantes. We were young and enjoyed each others’ company; we almost never disagreed on administrative decisions important to us all, and co-authored several papers combining behavioral, anatomical, and physiological measurements.

Glia I

I left the Walter Reed Institute after a falling-out with Dave Rioch over my sudden interest in glial cells. This is what happened.

During the afternoon of Friday, October 28, 1960, on an airplane somewhere between Chicago and the Grand Canyon, I turned to my companion, Harvey Savely, and announced, “I know how the brain works,” and for the next hour or so bent his ear with the ideas published two months later in the paper, “A Glia-Neural Theory of Brain Function” (Galambos, 1961).

I share with everyone else the occasional experience of having the solution to a problem suddenly arrive unasked. This particular vision appeared at the end of some 15 Harvard and Walter Reed years occupied by work along four different lines—microelectrode recordings; brain changes during learning by implanted animals; auditory pathway lesions; and the efferent olivocochlear bundle. We had discovered many interesting things, but none of them seemed to bring me at all close to what I really wanted to know, which is the way animal brains store and retrieve phylogenetic and ontogenetic memories (Galambos and Morgan, 1960). My revelation both ended the frustration and pointed a way to the fresh ideas and experiments that might give answers at last.

What followed had for me profound personal and scientific consequences. Six months later I had found another job because my boss became so angry we could no longer work together. A week after the insight flashed into my head, I laid a draft of the paper I proposed to publish on Rioch’s desk. He returned it promptly with a six-paragraph note suggesting I first do this with the paper, then that, and still something else. A few days later he had a copy of the final draft, which I saw sitting in the in-box on his desk, untouched, for over a week. We had several warm discussions during this period marked, among other things, by an order that I not discuss my idea at an upcoming seminar, as well as a prediction that my scientific career was over because I now had a theory and would spend the rest of my life proving it. After two months of this kind of thing, I was actively looking for another job.

Autobiographies sometimes tell of confrontations over teaching load, politics, bad habits, or personality differences. My confrontation with Rioch was over an idea. We had worked together harmoniously for a decade. His vision and administrative skill had conceived, created, and sustained the archetypical neuroscience laboratory; his department chiefs had put together a factory which, in less than a decade, had churned out dozens of first-class papers on topics ranging from microscopic anatomy to clinical psychiatry. Like everyone else at the time, and many still, we had extrapolated Cajal’s neuron doctrine to mean that neurons were the only cells in the brain worthy of study. I could at that time understand, and still do, how difficult it is to entertain a major challenge to one’s dogma, but when Rioch ordered me not to talk in public about my new idea, I knew it was time for me to leave. I once told a student not to do a particular experiment, but he knew me well enough to go ahead anyway, and we were both pleased when it worked. But I didn’t demand that he hide the idea, nor will I ever think highly of someone who would.

An attempt to transfer from the Walter Reed to another government job at the NIH failed when an unrelated (I think it was unrelated) confrontation not worth recounting here intervened. What remained were academic and industrial jobs. During the previous 15 years, I had turned down several university offers using the following reasoning: students come first in the university job, research comes first in the research institute job, so if you put research first you turn down the academic job. I went, finally, to Yale as the Eugene Higgins Professor of Psychology and Physiology, content to give second priority to what pleased me most. It consoled me to remember those bright and capable Ph.D. and M.D. draftees assigned to us at the Walter Reed—those people were once the golden eggs universities hatch, and this was my opportunity to incubate a few of my own.

Yale, 1962–68

Physiological Psychology (aka Neuroscience)

In 1962, the stimulus-locked electrical events recorded from the brain, ERPs, were called evoked potentials (EPs), and the manufacturer of the first commercial hard-wired computer designed to average them, the Mnemetron CAT (Computer of Average Transients), quickly became very busy indeed. My first act at Yale was to buy one—a wonderful, dependable device with several annoying features—and very soon after that I bought a second one. A year of so later, I bought a FabriTek Model 1052 (serial #2, and as of 1995 it still worked). These three computers were so popular you had to sign up to use one days in advance.

I favored hard-wired computers over general-purpose computers because they were easy to learn to use. I had noted that whenever a lab hired a programmer, he instantly became a kind of king who dispensed favors, whereas when my students and I obtained evoked-response averages by pushing buttons, we were the kings. Tools should work for you, not the other way around. I did encourage students to build at least one amplifier just to get a feel for instrumental complexities, but the amplifier they used in their thesis research was the finest commercial instrument I could buy.

The following is a list of the Yale research projects that used Grass amplifiers, both the free-standing and the EEG machine varieties, connected to these hard-wired computers:

ERP Lability. Warren O. Wickelgren’s thesis became three papers demonstrating that ERP lability is confined to thalamus, cortex, and cerebellum. His cats were implanted from cochlear nucleus through auditory and visual cortex; they wore earphones and learned to walk on a treadmill in one of the most carefully controlled animal experiments I have known (Wickelgren, 1968).

Brain Refractory Periods. Luke M. Kitahata and Yoshikuri Amakata were postdoctoral fellows in Yale’s department of medicine. They produced a successor to Pradahn’s Walter Reed pharmacological study; they anesthetized implanted cats with halothane and measured the ensuing prolongations of refractory periods at brainstem, thalamic, and cortical levels (Kitahata et al., 1969). Recovery is prompt at the brainstem level and progressively slower at higher levels.

The Contingent Negative Variation (CNV). Steven A. Hillyard’s CNV thesis yielded the publications that launched a distinguished career (for example, Hillyard and Galambos, 1967). He is one of those golden eggs I had expected to encounter as a professor.

The following entries identify the Yale experiments that turned out beautifully but left behind the conviction that brains still hide their best secrets. Two of these studies are typical classical problems awaiting the explorer unafraid to take big chances in hopes of big rewards.

The Evoked Resistance Shift (ERS). Kenneth A. Klivington’s Ph.D. thesis satisfied both the engineering and the psychology department requirements. He delivered clicks to cats and measured differences in resistance between the two cortical recording electrodes in addition to the conventional ERP. A small resistance shift, with a slightly different time course, approximates the shape and duration of the ERP. Ricardo Velluti obtained similar results in subcortical nuclei of both the auditory and visual systems. We could not explain the ERS mechanism then, but today the flux of potassium ions through astrocyte membranes during synaptic activity seems likely. However, the problem still sits untouched a quarter century after it was defined (Klivington and Galambos, 1967; Galambos and Velluti, 1968).

Optic Tract Lesions. Thomas T. Norton and Gabriel P. Frommer, undergraduate and postdoctoral fellow, respectively, cut cat optic tracts in experiments aimed to discover the largest lesion that fails to impair performance on pattern discrimination tasks. To everyone’s surprise, cats with less than two percent of the normal input to the lateral geniculate performed perfectly, a startling contradiction of the conventional expectations that remains unexplained. Completely severing both optic tracts produced total blindness, of course (Galambos et al., 1967; Norton et al., 1967). In a related study, Eli Osman used computer-averaged data to redo and confirm the Walter Reed finding that unanesthetized cats with and without input to the medial geniculates produce the same cortical click responses. I discuss these visual and auditory findings elsewhere in detail (Galambos, 1992a). These results suggest to me is that functional visual and auditory wiring diagrams differ greatly from the anatomical wiring diagrams our students learn.

An Implantable High Power Microscope. In 1964 the triumvirate, Mojmir Petran, Milan Hadravsky, and David Egger joined me, supported by my National Aeronautics and Space Administration (NASA) grant, in attempting to devise a microscope through which we would view the movements of normal cat brain cells in situ. I was powerfully motivated to accept this challenge after viewing the remarkable time-lapse moving pictures of cultured glial cells Gerald Pomerat had produced and was widely displaying. Needless to say, we did not reach our goal, but we approached it (Petran et al., 1968). In today’s world the confocal microscope with its laser illumination (we used sunlight admitted through a hole in the laboratory ceiling) approaches what we had in mind.

Glia II

Before leaving the Walter Reed, I had considered several possible glial research projects and settled on producing anti-glial antibodies which, when introduced into the cerebrospinal fluid of cats with indwelling electrodes, had been reported to produce morphological and EEG changes in the recipient (Mihailovic and Jankovic, 1961). I initiated these antibody experiments in 1963 at Yale, and invested close to half of my time, effort, and NASA grant funds on them for almost six years. Exactly one abstract (Galambos et al., 1966), one Ph.D. thesis (John Chimienti), and two student term papers (Martin Stein, Robert Humphries) represent the tangible results. To the graduate student who asked how many mistakes one is allowed to make during his career, I answer none at all, and then add that if you must make one have it be really big, and save it until you hold a tenured faculty position.

Goodbye Yale, Hello La Jolla

In all, my laboratory group published 41 papers during my seven-year tenure as a Yale psychologist and physiologist. I also conducted the five summer-long teaching sessions previously mentioned during which at least 50 students ranging from undergraduate to associate professor in rank learned some rudiments of electrophysiological techniques. Denis Baylor was one of several golden eggs in this group.

I also joined with Jerome Sutin and a few younger members of the Yale anatomy, pharmacology, and physiology departments in an attempt to create a university-wide coalition ofneuro-anatomists, neuro-pharmacologists, and neuro-physiologists along the Walter Reed model. We failed; every department head refused to relinquish the neuro-portion of his turf. Meanwhile, in 1967 Robert B. Livingston began telling me about the department of neuroscience he was creating at the new University of California campus in La Jolla. He and Theodore H. Bullock described just the kind of cross-discipline organization I had in mind, and at their new Medical School there were no entrenched department chairmen with turf to protect. They urged me to join them; I was reluctant to leave my Yale responsibilities so soon after taking them on, but I did.

The University of California, San Diego, 1968–82

The Department of Neuroscience

The first neuroscience department in the world was conceived by its first Chairman, Robert B. Livingston, in 1964-65. Its responsibilities include medical and graduate student instruction, the neurology resident program, and the clinical neurology services in the hospitals operated by the university. Its organizational details were worked out during 1967-69 by the chair along with Theodore H. Bullock, A. Baird Hastings, Charles E. Spooner, Charles Bridgeman, Theodore Melnechuk, and me. In due course, the department also became the administrative unit of the Neurosciences Group, which is now a university-wide voluntary consortium made up of more than 80 professors from 14 university departments who will accept graduate students seeking degrees in some aspect of brain science. For its first dozen years, I was the group’s director of graduate studies.

From the beginning, the department was planned to have equal and interacting clinical and basic science arms, a controversial organization scheme many predicted could not survive; a quarter century later it remains in place, largely unchanged. In 1995, the National Research Council rated our neuroscience graduate program number one in the United States.

Auditory Event Related Potentials (ERPs), Again

I moved all my research grants and paraphernalia from Yale to San Diego and promptly put together a new animal laboratory. However, within a few years I had abandoned animals, left microelectrodes, and embraced human ERPs. There were three reasons for this move. First, the local antivivisection opposition became increasingly strident, aggressive, and annoying. Second, at a time grant money was becoming more difficult to get, I added together the cost of maintaining an animal house, buying cats, caging and feeding them for months, and paying the fees for mandated university veterinarian services, and compared this sum with the $5 per hour pocketed happily by the already-trained college sophomore who houses, feeds, beds, and doctors himself. Third, Terry Picton delivered a seminar presentation in which he plotted, for the first time on the same time base, the auditory brainstem, middle latency, and late slow waves, whereupon we all realized what we had thought of as three separate events was actually a kind of single unit consisting of some 15 distinct waveshapes awaiting dissection and analysis. For this kind of enterprise college sophomores would make ideal subjects.

In 1972 we decided to divide the auditory ERP into two parts, one including the newly-discovered auditory brainstem response (ABR), the other containing the waves beyond about 50 msec. The boundary was flexible. I fell heir to the ABR while Terrance Picton and Steve Hillyard took charge of the late waves (along with, as time passed, Eric Courchesne, Robert Hink, Howard Krausz, Robert Knight, Marta Kutas, Helen Neville, Vince Schwent, Kenneth and Nancy Squires, Elaine Snyder, and David Woods). When I retired in 1981, this late-wave group, which initially focused on the CNV and selective attention, had published cognitive ERP papers at a rate of six to eight per year and ranked with the best in the field anywhere. The ABR work at the Children’s Hospital is described below.

Loudness Enhancement

Teaching a seminar on the auditory system was one of my responsibilities. Following our discussion of the mysterious olivocochlear bundle, my 1971 seminar group designed, performed, and published the following experiment. A listener receives, monaurally, two tones separated by an interval of a second or two, and learns to adjust the loudness of the second one to equal that of the first. This task is then repeated immediately after a short noise burst stimulates the opposite ear. Our idea was that the noise burst will deliver a transient olivocochlear pulse into the test ear, and this will change the apparent loudness of the first of the two tones. The result: subjects report the first tone sounds much louder (up to 35 dB) or much fainter, depending on the strength and timing of the contralateral noise burst (Galambos et al., 1972). Unfortunately, we failed in several subsequent studies to show the olivocochlear bundle is responsible for the phenomenon, and at the present time loudness enhancement and diminution remain unexplained in neuronal terms, another of Bekesy’s classical premature problems. Robert Elmasian’s thesis contains the relevant experiments, most of which have been published (Elmasian et al., 1980).

Microwave Hearing

I worked for several months during a 1975 sabbatical year at the University of Washington with C.-K Chou and A. W. Guy on a number of the experiments Chou included in his thesis (Chou et al., 1982). Thirty years earlier, during the war, it had became known that the pulsed microwaves emitted by a radar antenna are heard as a series of clicks by a person who puts his head in their path. The phenomenon was explained by some to be a result of direct stimulation of nerve cells, and by others as the perception of a miniscule pressure wave set up in the head as the absorbed microwave pulses are converted to thermal energy. My hosts, who were physicists, favored the thermoelastic expansion hypothesis, but they sought my counsel to discover whether they might be making a mistake. There was no mistake, as we established by cochlear microphonic and ABR experiments on cats and guinea pigs, and by demonstrating that the rat trained to press a lever for a reward when it hears clicks will press equally enthusiastically when its head is in the path of pulsed microwaves. The matter was finally settled when I realized I did not myself hear the microwave pulses the rats detected and visited the university audiology department, where an audiogram revealed my high frequency hearing loss.

My wife Carol Schulman and I spent five weeks of this sabbatical year in Japan as guests of several Japanese scientific organizations, introducing the ABR, which was so new no one there was using it yet. Jun-Ichi Suzuki, our host at the Teikyo University in Tokyo, provided us with an office in which we wrote the first manual to describe the ABR methods and illustrate its typical results. We distributed copies of the manual there and back in the United States on our return. At more than a dozen universities between Tokyo in the north and Fukuoka in the south, I wired together whatever local apparatus was available and successfully demonstrated the ABR, always using a young woman subject because we had already discovered that women’s ABRs are almost always large and easy to obtain.

The Speech and Hearing Center at San Diego’s Children’s Hospital, 1972–92

Not long after arriving in San Diego in 1969, I paid a get-acquainted visit to the Speech and Hearing Center (which is not connected in any way to the university) and was warmly greeted by its director, Donald Krebs, and his assistant, Bob Sandlin. Both were interested in research and showed me their Princeton Applied Research Waveform Eductor, the first commercial computer designed to estimate auditory thresholds by averaging cortical late waves. A year or so later, they supplied the space in which Carol Schulman estimated the hearing thresholds of hard-of-hearing and difficult-to-test children using her experimental heart-rate audiometer. When in 1972 I could find no clinical research space anywhere in the university for my graduate student Kurt Hecox, Carol suggested I take my problem to Krebs and Sandlin; within days, Kurt was setting up equipment in one of their soundproof rooms, and the extraordinarily happy arrangement that supported and nourished my laboratory for the next 20 years had begun.

The Auditory Brainstem Response (ABR)

As described elsewhere (Galambos, 1992a), my interest in objective tests of hearing dates from my Walter Reed days. While there, I helped develop two procedures aimed at identifying the malingerer who feigns hearing loss at the time of discharge in hopes of drawing an undeserved Army pension for life. Both of these tests reached the goal, but they were too complex to administer in busy clinical settings. A few years later, in 1963, Don Jewett, while my postdoc at Yale, discovered the cat ABR, and in 1971 published his classical paper with Williston on the human ABR in the journal Brain. When a preprint of this Brain paper circulated through our laboratory in 1970, my reaction was immediate. Was this ABR the objective hearing test I had been looking for—the way to resolve another one of those classical, premature problems?

The Children’s Hospital wards and the Speech and Hearing Center, which are connected physically and administratively, are about 10 miles away from the La Jolla campus, but Kurt and Carol moved easily between them. They began ABR-testing babies in their Speech and Hearing Center sound booth, but before long Carol was also using a small room adjacent to the normal newborn nursery at Sharp Memorial Hospital, which is connected to Children’s by a tunnel, and where some 6000 babies were being born every year. In 1973, Paul Despland joined the group from Lausanne, Switzerland, where he was the neurologist in charge of the EEG department. For a year he almost literally worked day and night in the Intensive Care Nursery (ICN) at Children’s Hospital, which is a regional third-level intensive care center, a place to which the sickest babies born in the county are transported. It took the four of us several years to collect the basic science information needed to design and validate the clinical hearing tests we finally installed. We eventually published 19 papers that, among other things, established the age-dependent ABR norms for babies as young as 12 weeks premature, differentiated conductive from sensorineural hearing loss using the ABR, estimated the prevalence of hearing loss in the normal and intensive care populations, and convinced the audiologists that the ABR is a trustworthy way to approximate thresholds in difficult-to-test children.

By 1976, our pilot studies had repeatedly demonstrated that hearing loss is common in the ICN and exceedingly rare in the normal newborn nursery. Armed with these facts, we proposed to deliver the ABR test to all ICN graduates and to follow-up those found to have hearing loss at the Speech and Hearing Center. The hospital administration agreed, and in 1977 we installed the clinical program that has continued without interuption to the present day (Galambos et al., 1994). In 1996, our ABR program celebrates its 25th birthday, its original data acquisition methods unchanged, and the clinical program still under the supervision of Mary Jo Wilson, who has run it since 1979.

40 Hz

In 1978, when no commercial ABR machine was as yet for sale, an MDPh.D. candidate, Peter Talmachoff, designed and built one as his thesis project. When he first tested it on human volunteers, in 1980, he delivered clicks at a rate of 40 Hz and recorded the physiological responses through an amplifier with a bandpass wider than was customary; the recordings contained what we thought at first must be an artifact at the stimulus rate but turned out to be the 40 Hz physiological phenomenon we described in 1981 (Galambos et al., 1981). Scott Makeig, the last of my Ph.D. students, picked up where Talmachoff left off, produced his SteadyState Response (SSR) thesis in 1985, and in the process introduced me to the power of frequency analysis methods. We abandoned an attempt to develop an infant audiometer using 40-Hz tone bursts at the audiometric frequencies in 1988 when we discovered newborns do not reliably produce 40 Hz responses. Recently, the use of more sophisticated stimulus delivery and response analysis procedures by others has revived hopes that 40 Hz audiograms may soon be obtained from small babies after all.

What do these 40 Hz frequencies tell us about the brain’s operations? I have written what I know, and it is not much (Galambos, 1992b). The 40 Hz contribution to that mysterious band of spontaneous and driven brain wave frequencies is small compared to the alpha-wave contribution, and my inability to answer the most basic questions about what generates either of them is a major embarrassment. I think it disgraceful that we all remain only a bit less ignorant of the mechanisms that create and modulate brain waves than was Berger, their discoverer, 65 years ago. Do they convey something interesting about brain functions or, as someone has suggested, is their message irrelevant, like the noise of the toilet as it flushes? Perhaps some useful answers will be forthcoming from the current research attention Makeig and others like Ted Bullock and Erol Basar are giving the problem.

Tending to Unfinished Business, 1992–Present

In 1992 I closed the door of my own laboratory for the last time, and no longer had a place to go after having worked in one almost daily for over 50 years. My domain is now a small room at home. Most of my books and journals have been donated to others, and the bulk of my papers are locked up in rented storage space several miles away. Since I have no secretary, I finally learned to type, and with my word processor have managed to get nine papers (five of them refereed) published from this place. Thanks to e-mail, I communicate almost daily with Gabor Juhasz in his Budapest laboratory to which I commuted three times in a recent year. His group and I are doing experiments on glial cells, and we are getting interesting results at last.

Glia III

Shortly after arriving in San Diego in 1968, I abandoned the Yale antibrain antibody project after failing to ignite any interest in the several Salk Institute immunologists who listened politely to my presentation. In retrospect, there were two strikes against the idea from the start—I did not know enough about immunology, and the purified astrocyte antigens essential for quantitative results did not exist. Today, specific anti-astrocyte antibodies could conceivably be prepared which, after injection into the cerebrospinal fluid of experimental animals, might produce the behavioral deficits and astrocyte lesions we were hoping to see 35 years ago, but more precise and elegant genetic methods would probably be used instead.

For almost 20 years I laid low, followed the glia literature, wrote two glia papers, one of them for a Rioch festschrift (Galambos, 1971), and waited for something to happen. It did, in 1986, when Juhasz approached me during the IBRO meeting in Budapest and suggested we work together on a glia problem. As already reported at length (Galambos, 1992a), our first experiments were inconclusive, but perseverance paid off in late 1993, when we prepared rats with electrodes implanted around the eyeball for recording the electroretinogram (ERG) and in the cortex for recording visual cortical ERPs. We also implanted a light-emitting diode under the skin over one eye for producing flash stimuli. The result is a normal, freely moving animal restrained only by the bundle of wires connecting a plug on its head to the distant stimulating and recording devices. Whenever we push the button that activates the rat’s built-in stimulator, a flash of light evokes two potentials, one generated where the animal’s visual system begins, the other where it ends.

The preparation is interesting because the first potential, the ERG, is widely conceded to index the intracellular transport of potassium ions in the Müller (glial) cells. The evidence supporting this conclusion, which others began accumulating some 30 years ago, can be very briefly summarized as follows: synaptic activity in retinal neurons raises extracellular potassium ion concentration; Müller cells uptake this excess and transport it away; the resulting intracellular-extracellular ion current loop appears outside the eyeball as the ERG. Does the rat’s second potential, the cortical ERP, index a similar potassium ion flux through cortical astrocytes? We are attempting to answer this question by comparing the way the two responses change as we vary stimulus parameters and/or the state of the animal. Our first publication concluded that one cannot exclude the possibility that cortical astrocytes contribute to ERPs what Müller cells contribute to ERGs (Galambos et al., 1994). In reports now being prepared, we make additional comparisons that continue to support this conclusion. It actually seems possible that evoked potentials generated in synaptic regions throughout the brain will all turn out to be the joint product of the neurons and the glial cells that are invariably located nearby.

These results take me back to my 1961 glia paper which, in essence, is a suggestion that brain scientists should include the glia in the models they take into the laboratory. Increasing numbers of them appear to be doing this, to judge from the recent proliferation of glia papers. It may soon be neither wise nor tenable to think of the brain as an interacting collection of neurons. Electron microscope images show every brain to be a single system consisting of three interlinked compartments—neurons, glia, and extracellular space. The system does not function the way its genes intend unless all three parts are in place, at work, and in an unanesthetized animal. Much can be learned from drugged or dead brains, and from parts of it living in test tubes, but the most obvious message is that the operations responsible for integrated behavioral responses do not exist under such conditions. One sees behavior only when the real thing, its three compartments interacting harmoniously, works inside the container the genes have prepared for it. If behavior is what interests you, study the system out of which it comes.

Having delivered myself of this somewhat controversial theoretical position, let me continue with two more points of view some find even more distasteful. Let me identify, first, the preparations I think are most likely to yield answers to that lofty goal encapsulated in that hackneyed phrase “how the brain works,” and then, second, say what I think we need to know about those behaving systems if we are to reach the answers we seek. It is customary today to single out the human cortex as the place to study how the brain works, but I do not share that view. I would work with the phylogenetic memories if my research career stretched out in front of me instead of behind me. Phylogenetic memories, like all memories, are products of the neuropil, where all behavior originates out of the interactions between its three compartments.

The Phylogenetic Memory

If I were to ask you to give me your mother’s maiden name, you could do it, and then I could recite it back to you. Such commonplace exchanges show our cerebral cortexes are normal, and that we share the mechanisms that retrieve learned facts and deposit them into our unique memory stores. We also share what have been called phylogenetic memories, the species-specific behavioral repertoire created, like the shape of a finger, by our genes (Galambos and Morgan, 1960). Human newborns display dozens of these phylogenetic memories: babies start breathing at once, and know how to cry out when cold or hungry; they can suckle, swallow, digest food, circulate blood, empty the bladder, and do still other things. Later on, with little or no special training, they display the behaviors on which species survival depends—courtship, mating, and the care of the young.

For some animals the behavioral repertoire is almost entirely the product of these phylogenetic memories. Cockroach genes put together a nervous system that requires them all to scurry away when the kitchen light comes on in the middle of the night. Spider genes build a brain that creates what we call hunger, and makes possible the web-spinning that entangles the dinner, and the eating, digesting, and excreting behaviors that follow. Genes securely build good habits like these into the nervous system of every animal that takes in air and delivers it throughout the body; and for every ability to become thirsty, find water, and drink. The list of things animals do without instruction is very long, and it includes the ability to learn from experience, a habit so well developed in ourselves.

Most of us now writing autobiographies first grasped the connection between genes and all this biological behavioral machinery as adults, thanks largely to the gene technology elaborated after Watson and Crick’s great discovery in 1953. Today the evidence for the primacy of the genes in determining form and function is overwhelming; it seems highly unlikely that any future disclosure will seriously challenge the proposition that genes create a brain for each animal that produces exactly the behavior patterns needed for survival in its ecological niche.

The Dedicated Neuropil

Neuropil is the term C. Judson Herrick used in the early years of this century for “the intricate tangle of thin unmyelinated fibers” his light microscope revealed in every synaptic region. Today he might agree to define neuropil as an organized system in which the three brain compartments interact harmoniously. Herrick considered neuropil to be the brain’s “primary apparatus of integration” and its product to be “a total pattern of behavior.” Today he might agree that samples of behavior such as drinking, digesting, defecation, and so on, are products of specialized regions of this neuropil—call them centers—within which unique interactions take place between inputs and outputs. The most obvious such center I can name is the retina, a typical neuropil made up of neuron and glial terminals separated by extracellular space, the whole of it dedicated to meet a specific biological need. Eyeballs containing a lens and retina similar to ours are found throughout the vertebrate phylum, which suggests that once genes devise a superb solution to a given problem they simply duplicate it, with small changes introduced here and there. My recent study of the rat retina has given me considerable respect for the contributions glial cells can make to such a functioning unit; the well-known neuron-neuron interactions in retinal neuropil play a key role in converting light waves into optic-nerve discharges, as do the Müller cell-neuron interactions going on at the same time.

A second example of the dedicated neuropil is the suprachiasmatic nucleus clock, which, as noted above, continues its 24-hour cycling in a test tube when dissected out of the rat brain. I anticipate that, as in the retina, future measurements will uncover essential contributions from the glial compartment in this neuropil also, and further, that the glial cells around Strumwasser’s parabolic burster Aplysia neuron will be found to make a similar contribution to the diurnal cycling found there.

Other dedicated neuropils include temperature center, respiratory center, hunger center, drinking center, sleep center—in fact, every neuropil region created by the genes to do a particular job well, such as the spinal cord territories where reflexes organize, and even the cortical columns, the neuropils of which have been prepared by the genes to store and release our “real” ontogenetic memories. In short, the typical speciesspecific behavioral response is a phylogenetic habit laid down by the genes in the form of organized neuropil. This thought can be extrapolated to its ultimate—the neuropil organization responsible for my sensations of hunger may well resemble the one in the spider that prompts the webspinning that entangles its dinner, and the brain mechanism that causes air to leave and enter my body may have a recognizable counterpart in the insect neuropil that controls the same process.

In Herrick’s time, there was no way to test ideas like these experimentally. He did not have the tool, the concept, that would make empirical testing reasonable; this was provided only a decade or so ago by the discovery of the homeotic and segmentation genes. That the same homeobox gene family determines the segmental organization of species as distant as Drosophila and mouse makes it reasonable to ask whether the two species similarly share one gene family that creates their ability to breathe in and out, and another that makes it possible for them to find food and eat. Can it be that the mechanism responsible for morphological universals has much in common with the mechanism responsible for behavioral universals? We will know the answer one day.

Coda

I greatly admire Ted Bullock, a close colleague for almost 30 years, in my opinion the wisest and most erudite of living neuroscientists. Both of us are what I call systems people, willing to take brains apart and even examine them cell by cell with microelectrodes, but the question of how the parts fit together in the behaving organism is never far from our thoughts. Interestingly, Ted says he looks for what is different as he does his work; by contrast, I look for what is the same. In seminar situations it is predictable that he will identify and contrast the opposites whereas I will grope for a thread to connect the pieces together, as the paragraphs immediately above this one illustrate.

This dedicated neuropil idea has features to please us both. All neuropil samples are nothing more than extracellular fluid surrounded by neuron and glial terminals, which means they can look alike to observers even at the electron microscope level. However, a neuropil sample such as the vomiting center in the medulla must have a very different organization from that of the respiratory center located nearby. Someone some day will surely find the way to measure these differences, and, if still around, I will congratulate Bullock for having been right all along. Vive la difference!

Acknowledgements

My thanks go to the following good friends, who read parts of the manuscript, and to Phyllis, my wife, who read the whole of it, for important suggestions, additions, and corrections: Joe Brady, Steve Hillyard, Don Lindsley, Ted Melnechuk, George Moushegian, Allen Rupert, Bob Sandlin, and Liz Yoder.

Selected Publications

Potentials from the body wall of the earthworm. J Gen Psychol 1939;20:339–348.

Characteristics of the loss of tension by smooth muscle during relaxation and following stretch. J Cell and Comp Physiol 1941a;17:85–95.

Cochlear potentials from the bat. Science 1941b;93:215.

(with Griffin DR) The sensory basis of obstacle avoidance by flying bats. J Exp Zool 1941;86:481–506.

(with Therman PO, Forbes A) Electric responses derived from the superior cervical ganglion with microelectrodes. J Neurophysiol 1941;3:191–200.

(with Griffin DR) Obstacle avoidance by flying bats: The cries of bats. J Exp Zool 1942;89:475–490.

The avoidance of obstacles by flying bats: Spallanzani’s ideas (1794) and later theories. Isis 1942;34:132–140.

(with Morgan CT) Production of audiogenic seizures by tones of low frequency. Am J Psychol 1942;55:555–559.

Cochlear potentials elicited from bats by supersonic sounds. J Acoust Soc Am 1943a;14:41–49.

Flight in the dark: A study of bats. Scientific Monthly 1943b;56:155–162.

(with Morgan CT) Production of audiogenic seizures by interrupted tones. J Exp Psychol 1943;32:435–442.

(with Davis H) The response of single auditory nerve fibers to acoustic stimulation. J Neurophysiol 1943;6:39–58.

(with Davis H) Inhibition of activity in single auditory nerve fibers by acoustic stimulation. J Neurophysiol 1944;7:287–304.

(with Davis H) Action potentials from auditory-nerve fibers? Science 1948; 108:(2810):513.

(with Fenn WO, Otis AB, Rahn H) Corneo-retinal potentials in anoxia and acapnia. J Appl Physiol 1949;1:710–716.

(with Davis H, Morgan CT, Hawkins J, Smith FW) Temporary deafness following exposure to loud tones and noise. Acta Otolaryngol 1950;Suppl. 88:1–57.

(with Morgan CT, Garner WR) Pitch and intensity. J Acoust Soc Am 1951;23:658–663.

Suppression of auditory nerve activity by stimulation of efferent fibers to cochlea. J Neurophysiol 1956;19:424–437.

(with Hubel DH, Henson CO, Rupert A) “Attention” units in the auditory cortex. Science 1959;129:1279–1280.

(with Rose JE, Hughes JR) Microelectrode studies of the cochlear nuclei of the cat. Bull J Hopkins Hosp 1959;104:211–251.

(with Schwartzkopff J, Rupert A) Microelectrode study of superior olivary nuclei. Am J Physiol 1959;197:527–536.

(with Morgan CT) The neural basis oflearning. In: Field J, Magoun H, Hall VE, eds. Handbook of Physiology-Neurophysiology III. Washington, D.C.: Am Physiol Soc 1960: 1471–1499.

(with Myers RE, Sheatz GC) Extralemniscal activation of auditory cortex in cats. Am J Physiol 1961;200:(1):23–28.

A glia-neural theory of brain function. Proc Natl Acad Sci USA 1961;47:129–136.

(with Pradhan SN) Some effects of anesthetics on the evoked responses in the auditory cortex of the cat. J Pharmacol Exp Ther 1963;139:97–106.

(with Manuelidis E, Fischer D, Chimienti J, Stein M) Observations on antibrain antibodies. Science 1966;152:673–674.

(with Norton T, Frommer G) Optic tract lesions sparing pattern vision in cats. Exp Neurol 1967;18:8–25.

(with Hillyard SA) Effects of stimulus and response contingencies on a surface negative slow potential shift in man. Electroenceph Clin Neurophysiol 1967;22:297–304.

(with Klivington K) Resistance shifts accompanying the evoked cortical response in cat. Science 1967;157:211–213.

(with Norton T, Frommer G) Optic tract lesions destroying pattern vision in cats. Exp Neurol 1967;18:26–37.

(with Petran M, Hadravsky M, Egger MD) Tandem-scanning reflected-light microscope. J Opt Soc Am 1968;58:661–664.

(with Kitahata L, Amakata Y) Effects of halothane upon auditory recovery functions in cats. J Pharmacol Exp Ther 1969;167:14–25.

The glia-neuronal interaction: some observations. J Psychiatr Res 1971;8:219–224.

(with Velluti R, Klivington K) Evoked resistance shifts in subcortical nuclei. Curr Mod Biol 1968;2:78–80.

(with Bauer J, Picton T, Squires K, Squires N) Loudness enhancement following contralateral stimulation. J Acoust Soc Am 1972;52:1127–1130.

(with Elmasian R, Bernheim A) Loudness enhancement and decrement in four paradigms. J Acoust Soc Am 1980;67:601–607.

(with Makeig S, Talmachoff P) A 40 Hz auditory potential recorded from the human scalp. Proc Natl Acad Sci USA 1981;78:(4):2643–2647.

(with Chou C-K, Guy AW) Auditory perception ofradio-frequency electromagnetic fields. J Acoust Soc Am 1982;71:(6):1321–1334.

A Career Retrospective. In: Samson FE and Adelman G, eds. The Neurosciences: Paths of Discovery II. Boston: Birkhauser, 1992a: 261–280.

A comparison of certain gamma band (40 Hz) brain rhythms in cat and man. In: Basar E and Bullock TH, eds. Induced Rhythms in the Brain. Boston: Birkhauser, 1992b: 201–217.

(with Wilson M-J, Silva PD) Diagnosing hearing loss in the intensive care nursery: A 20-year summary. J Am Acad Audiol 1994;5:151–162.

(with Juhasz G, Kekesi AK, Nyitrai G, Szilagyi N) Natural sleep modifies the rat electroretinogram. Proc Natl Acad Sci USA 1994;91:5153–5157.

The 1939--40 experiments that validated Jurine’s claim. Le Rhinolophe 1996;11: (Symposium Jurine) 17–25.

Epic X: Past, present, future. In: Karmos G, et al., eds. Perspectives in Event-Related Potentials Research. Amsterdam: Elsevier, 1995b: 1–20.

Additional Publications

Davis H. The Professional Memoirs of Hallowell Davis. St. Louis MO: The Central Institute for the Deaf, 1991.

Gardner H. Frames of mind: the theory of multiple intelligences. New York: Basic Books, 1983.

Gerard RW, Marshall WH, Saul, LJ. Electrical activity of the cat’s brain. Arch Neural Psychiatry 1936;36:675–735.

Gerard RW. The minute experiment and the large picture. In: Worden FC, Swazey JP, Adelman G, eds. The Neurosciences: Paths of Discovery. Cambridge MA: MIT Press, 1975:457–474.

Hyde IH. A micro-electrode and unicellular stimulation. Biol Bull 1921;40:130–133.

Jasper RH, Smirnov GD, eds. The Moscow Colloquium on Electroencephalography of Higher Nervous Activity. Montreal: The EEG Journal 1960.

Kelso JAS, Munhall KG. RH Stetson’s Motor Phonetics: A Retrospective Edition. 1988: Boston: Little, Brown.

Mihailovic L, Jankovic BD. Effects of intraventricularly injected anti-N caudatus antibody on the electrical activity of the cat brain. Nature 1961;1962:665–666.

Morgan CT. Physiological Psychology. (1st ed.). New York: McGraw Hill, 1943.

Morgan CT. Physiological Psychology. (3rd ed.). New York: McGraw Hill, 1965.

Noyes A, Pierce GW. Apparatus for acoustic research in the supersonic frequency range. J Acoust Soc Amer 1938;9:205–211.

Prosser RA, et al. Serotonin and the mammalian circadian system: I. In vitro phase shifts by serotonergic agonists and antagonists. J Biol Rhythms 1993;8:(1):1–16.

Prosser RA, et al. A possible glial role in the mammalian circadian clock. Brain Res 1994;643:(1–2):296–301.

Renshaw B, Forbes A, Drury C. Electrical activity recorded with microelectrodes from the hippocampus. Amer J Physiol 1938;123:169–170.

Renshaw B, Forbes A, Morison BR. The activity of the isocortex and hippocampus: electrical studies with micro-electrodes. J Neurophysiol 1940;3:74–105.

Schmitt FO. The never-ceasing search. Philadelphia: American Philosophical Society, 1990.

Schreiner L, Kling A. Rhinencephalon and behavior. Amer J Physiol 1956;181:486–490.

Strumwasser F. A circadian rhythm of activity and its endogenous origin in a neuron. Fed Proc 1963;22:220.

von Bekesy G. Experiments in hearing. (EG Wever, Trans.). (Acoustical Society of America ed.). New York: McGraw-Hill, 1960.

Wickelgren WO. Effects of walking and flash stimulation on click-evoked responses in cats. J Neurophysiol 1968;31:(5):769–76.

Viktor Hamburger

BORN:

Landeshut Silesia, Germany (now Poland)

July 9, 1900

EDUCATION:

University of Heidelberg, 1919

University of Freiburg, Ph.D., 1920 (Zoology with H. Spemann, 1925)

APPOINTMENTS:

University of Göttingen (1925)

Kaiser-Wilhelm Institute for Biology, Berlin-Dahlem, Germany (1926)

University of Freiburg (1928)

University of Chicago (1932)

Washington University, St. Louis (1935)

Mallinkrodt Distinguished Professor Emeritus, Washington University (1969)

HONORS AND AWARDS (SELECTED):

Society for Developmental Biology (President, 1950, 1951)

National Academy of Sciences USA (1953)

American Society of Biologists (President, 1955)

Ralph W. Gerard Prize, Society for Neuroscience (1985)

National Medal of Science (1989)

Karl Lashley Award, American Philosophical Society (1990)

Viktor Hamburger is best known for his pioneering work in experimental neuroembryology, including the effects of peripheral tissue on the development of the central nervous system, and the emergence of behavior in the embryo.

Viktor Hamburger

Childhood and Youth

I grew up in a small town, Landeshut, Germany, in the remote southeastern corner of the Prussian province of Silesia, which is now Polish. Landeshut had about 12,000 inhabitants, half of whom were textile factory workers. My father was the owner of one of several textile plants. I was born in 1900 in the comfortable house of my parents, and was the eldest of three boys. My parents had grown up in Breslau, the capital of Silesia, about two hours by train from Landeshut. They had moved to Landeshut in the late 1890s when my father, Max Hamburger, took over the family business. He was married to Else Gradenwitz, the daughter of a banker. The family ties to both grandparents were tight, and mutual visits were frequent. As a teenager, I spent many vacations in Breslau and I became acquainted with city life, visited the art museum, and attended concerts and theater performances.

Our two-story house was a block away from the textile factory. The house had a large veranda in the back, overlooking a flower garden. Near the factory was a large vegetable garden with cherry and pear trees, and a tennis court. Next to our house was a large office building that included storage rooms used for shipping merchandise to all parts of the country. The building housed the offices of my father, the co-director, and the bookkeepers. The textile business flourished in the early part of the 19th century, the number of looms grew from 150 to about 600, and auxiliary facilities were built.

Father was a leader in the business community and for many years the chairman of the local chamber of commerce. He was also active in politics, in the liberal Democratic Party, a stronghold of the Weimar Republic that otherwise had few friends in the upper middle class. My parents were sociable; business friends, artists, writers, and politicians were frequent house guests. The house was decorated with original paintings by contemporary artists. A few miles from Landeshut, in the countryside, was a Benedictine monastery and a large Baroque church next to it. The church’s facade was praised as one of the most beautiful in Germany. My memories of its grandiose interior and the frescoes of angels on the ceiling are still vivid. Thus, early on, art became part of my life. We were frequent visitors of the church and my parents befriended the abbot and Pater Luterotti, the art historian of the monastery.

My mother was the gentle, warm-hearted, and circumspect mistress of a large household. She cared particularly for the women working in our factory; she provided a kindergarten for their children. I grew up with two younger brothers: Rudi became an architect and Otto entered our father’s business. Early on, I took a strong interest in nature: plants, animals, and rocks. Landeshut and its environs were ideally suited to nourish this disposition. Beyond the villages and meadows were forested hillsides, rock formations, and brooks at the foothills of the Riesengebirge (Giant Mountains). The highest peak, rising above timberline, is visible from the outskirts of the town. Mother took us many times in the horse-drawn carriage to see this beautiful scenery.

Before I was 10 years old, I started collecting plants and preserving them in an herbarium. In a freshwater pond, I found mussels and water beetles, and in the spring the eggs of frogs and salamanders. I took the eggs home to watch them develop in large aquaria. At age 13, I exhibited native amphibians and reptiles, including a poisonous viper, at the annual show of the local Aquarium and Terrarium Society. In a nearby quarry, I collected carboniferous fossils. I had the good fortune to have two excellent biology teachers in the Gymnasium. I befriended the younger one, with whom I explored the subalpine flora of the Giant Mountains. Another friend, Walther Arndt, somewhat older than I, introduced me to some rare animal species in our county. He later became a distinguished taxonomist at the Berlin Museum of Natural History. All this happened before and during World War I.

In the spring of 1918, I passed the Abitur, the graduation from the Gymnasium, with honors. A few months later, I was drafted into the army and sent to Breslau, but I was discharged in November when the war ended.

Much later, when I spent the years 1926 to 1928 in Berlin-Dahlem at the Kaiser Wilhelm Institute for Biology, Walther and I embarked on an ambitious enterprise: we planned and edited a two-volume book about our homeland, the county of Landeshut (Heimatbuch des Kreises Landeshut). It was a comprehensive account of nature, history, art, local dialect, folk lore, industry, and agriculture, including vignettes of small towns and villages, with many illustrations. Walther wrote the chapter on zoology and I the one on geology. The book was published in 1929. We were deeply rooted in our homeland (Heimat). Four years later, I was exiled by the Nazis. In 1944, Walther Arndt made some disparaging remarks about Hitler to a trusted friend who betrayed him; at his trial Walther refused to recant, and he was executed. In 1946, Silesia was annexed by Poland, and all its inhabitants were forced to emigrate.

University Life

There had never been any doubt in my mind about having an academic career in the natural sciences. For the winter semester of 1918 to 1919, I enrolled at the University of Breslau to study zoology, botany, geology, and mathematics. The only memory I have of those days is that of getting acquainted with the Mendelian laws in a botany course, which fascinated me. But now it was time to reach out. Apart from a few summer vacations at the shore of the Baltic Sea and perhaps a visit to Berlin, I had never crossed the border of Silesia. My parents suggested I attend the University of Heidelberg, where my aunt, Dr. Clara Hamburger, was a senior assistant at the Zoological Institute and the right hand of the then well-known Professor Otto Bütschli. My parents thought that my aunt would take care of me, which she did. I spent two semesters there, from 1919 to 1920. When Bütschli died, the experimental embryologist, Curt Herbst, became his successor.

Besides zoology, I studied botany and geology. Professor Salomon, the geologist, was an excellent teacher. During a field trip to the Swabian Alb, a mountainous region in South Germany in the summer of 1920, I became acquainted with a variety of colorful stratified rocks containing a wealth of fossils. That experience almost converted me to a career in geology. But when I discussed this prospect with my mother, she said: “Do you really want to spend your life with rocks?” With that comment, she laid my doubts to rest.

Shortly thereafter, Professor Herbst admitted me, a beginner, to an advanced seminar on experimental embryology. We read and discussed some of the works of Wilhelm Roux, the founder of experimental embryology, which Roux called “developmental mechanics.” Although Roux’s writings are dense, opaque, and long-winded, I became intrigued by the causal-analytical, experimental approach to the study of development, and I envisioned a future of doing experiments on embryos; however, I was not interested in the experimental work that Herbst and his students did at that time.

In the spring of 1920, a friend and I spent a vacation in Freiburg and the Black Forest, which reminded me of the Giant Mountains where I had grown up. I was enchanted by the medieval spirit of Freiburg, which the center of the city had preserved. The city’s narrow, winding streets were lined by small brooklets. In the center, the large cathedral square (Münsterplatz) was flanked by Renaissance, Baroque, and modern buildings. The large gothic cathedral (Münster) is one of the most beautiful in Germany, decorated with sculptures, altar paintings, and stained glass windows by famous artists. The environs of Freiburg are unique. To the west extends the Rhine Valley, populated by prosperous villages surrounded by vineyards. To the east rises the Black Forest. We climbed the highest peak, the Feldberg. Clearly this region appeared much better to me for hiking and skiing than the hills near Heidelberg. When I found out that Professor Hans Spemann, who already had a sound reputation as an experimental embryologist, had become the chairman of the zoology department of the University of Freiburg, I made up my mind to transfer to that university. I arrived there in the spring of 1920. The salamander breeding season was approaching, and preparations for the experiments were in full swing.

The department was dominated by experimental embryology. Spemann soon became the leader in that field in Germany and all of Europe. Dr. Otto Mangold was Spemann’s oldest and favorite student. He was a skillful experimentalist, and he did some original work. The only other prominent figure was Professor Fritz Baltzer, a geneticist and, like Spemann, a student of the famous cytogeneticist, Theodor Boveri. Through Baltzer’s lecture courses and some private instruction, he instilled in me a deep interest in developmental genetics, a field to which I later devoted several years of experimental work. Baltzer left in 1922 to become the chairman of zoology at the university of his hometown, Bern, in Switzerland; he was not replaced by another geneticist. Spemann had recruited Dr. Bruno Geinitz, an entomologist, for experimental embryological work, but Geinitz soon returned to his specialty. The remaining faculty consisted of an undistinguished ornithologist and another lecturer, whose courses I did not take. In 1924, Dr. Fritz Süffert, an excellent scientist with original ideas, joined the department. His field was the study of adaptive coloration in butterflies and moths. We became friends, particularly after my return to Freiburg in 1928.

We students attended lecture courses in the sciences, philosophy, and literature, and laboratory courses in our minor fields (mine were botany and geology). Most of our time was spent in the Grosse Praktikum, an allday laboratory course, in which we each studied, at our own tempo, representatives of all phyla, from protozoa to mammals, using preserved specimens and microscope slides. There were no examinations in either lecture or laboratory courses. We were responsible for our own progress in scientific proficiency.

Hilde Proescholdt and Johannes Holtfreter had also joined the department in 1920. We were assigned adjacent tables, and I befriended both of them. Hilde was somewhat older and more advanced than Hannes and I, and had already started her Ph.D. project in the spring of 1921. She transplanted the upper lip of the blastopore of salamander embryos to the belly region. The experiment became famous later as the “organizer experiment.” I still remember the excitement of Spemann and all of us, one morning in May 1921, when Hilde showed us the first induced secondary embryo. She married Otto Mangold later that year, and they moved to Berlin-Dahlem, where Mangold became Spemann’s successor at the Kaiser-Wilhelm Institute for Biology. Hilde was not destined to enjoy her success. She died of severe burns after an accident at her home in 1924, the year in which her article with Spemann on the organizer was published. Holtfreter and I remained lifelong friends. He became the most imaginative and most productive experimental embryologist of his generation.

The atmosphere in the department was relaxed. Spemann was not the stern Herr Geheimrat (Privy Councillor) as he is sometimes portrayed. He had a subtle sense of humor. In seminars he could be very critical, but his criticism was usually softened by a touch of humor. We came closest to knowing him when the staff and students working on their Ph.D. dissertations, the Doktoranden, met in the afternoon for tea in the reprint room. There were lively discussions of ongoing research, discoveries in our field, evolution, and philosophical themes, but rarely of politics. Life in the department was animated by many guests from abroad. Fritz Lehmann and Oscar Schotté from Switzerland worked there for several years. Ross Harrison from Yale, who was close to Spemann, visited frequently during the summer. Sam Detwiler, Elmer Butler, and Charles Parmenter came from the United States; John Runnstroem came from Sweden; Martin Woerdeman from Holland; Tadao Sato from Japan; and Georg Schmidt from Russia.

In all those years, Spemann had instilled in all of us an understanding of the intricacies of embryonic development as a sequence of inductive interactions and morphogenetic movements—and a great respect for the living embryo that integrates all these interactions. On the other hand, he gave us confidence that our minds could unravel this complex interplay of forces by the well-thought-out analytical experiment. I think we were not then fully aware of our limitations. We had at our disposal only two methods: extirpation and transplantation. The scope of the latter had been broadened by Spemann’s introduction of hetero- and xenoplastic transplantation. In retrospect, it seems remarkable how much information was obtained by these modest methods.

In the spring of 1923, I asked Spemann to assign a topic for my Ph.D. dissertation. He suggested a topic that was remote from his own major interests. I think his idea was to create for me a field of research independent of his own, which would later facilitate my academic career. I was to settle a dubious claim by Bernhard Dürken that the normal development of frog larvae depends on a normal supply of innervation. Dürken had extirpated the right eye of young larvae and found more or less severe abnormalities of the hind limbs in a high percentage of cases. He had assumed that the defects were neurogenic in nature. He had observed, as expected, a hypoplasia of the left midbrain and hypothesized a cascade of neural deficiencies all the way down to the lumbar spinal cord and the leg innervation. I did many hundreds of eye extirpations, with several variants, such as the stage of development at which the operation was done, and obtained a small percentage of defects limited to the toes. These defects were minimal compared to those in Dürken’s experiments; the leg abnormalities were probably due to nutritional deficiencies. Although my results had been equivocal, my dissertation had two notable consequences: it launched my lifelong career in neuroembryology, and it led to the design of my first original experiment, the production of nerveless legs, which I discuss below. I also derived a valuable personal benefit from my first exercise: self-sufficiency. There was nobody around with whom I could discuss my project. Experimental neuroembryology was then a modest side branch of experimental embryology and was practiced almost exclusively by Professor Harrison and his students at Yale.

I received the Ph.D. degree (summa cum laude) in June of 1925. The months of January to April 1925 I spent at the Zoological Station in Naples. In preparation for an academic career in zoology, I was supposed to become familiar with the marine fauna. The Mediterranean fauna was rich and beautiful. Every morning I awaited the return of the fishing boats. Most of the catch was destined for the international group of researchers, but enough was left for us beginners. My particular favorites were the transparent coelenterates and mollusks. I filled several notebooks with sketches. And in the company of my friend, Hannes Holtfreter, I explored the beautiful environs of Naples. This was my first trip abroad, and I made the acquaintance of a number of distinguished European and American biologists.

Göttingen, Winter 1925–1926

To broaden my proficiency in biology further, Spemann provided me the opportunity to work in the laboratory of his friend, Professor Alfred Kühn, in Göttingen. Kuhn was a polymath, equally at home in genetics, comparative physiology, embryology, and systematics. His textbook of zoology had practically a monopoly. He worked at that time on the development of pigment patterns, such as eye spots, in the scales of butterflies and moths, in collaboration with his senior assistant, Karl Henke. Kühn suggested that I work on a topic that he and several of his students had dealt with: color vision in fish. He had refined these studies by the use of spectroscopy. I was to test whether superimposed complementary colors would be seen as white, as in higher vertebrates. I trained minnows to jump for food presented in front of a white strip at the wall of the aquarium. Indeed, they responded when superimposed complementary colors were presented. Their performance improved when ultraviolet light was added; hence, their visual color spectrum was shown to extend further than that of higher vertebrates.

I profited greatly from discussions with Kühn and Henke, and I befriended Henke and his family. At their house, I became reacquainted with my future wife, Martha Fricke, whom I had met when she visited a friend in Freiburg. At that time, she was studying for a state examination that would qualify her to teach biology at a Gymnasium. We married in 1928. We had two daughters: Doris, born in 1930, who became a geologist and environmentalist at Berkeley; and Carola, born in 1937, who became a professor of ancient languages and literature at Wesleyan University in Connecticut and then switched to medicine. Carola practiced at several clinics in New York and is now connected with Yale Medical School; her major concern is AIDS in women.

Berlin-Dahlem, 1926–1928

In the spring of 1926, Otto Mangold offered me an assistantship in his department of experimental embryology at the Kaiser Wilhelm (later called the Max Planck) Institute for Biology in Berlin-Dahlem. This was an ideal position; I could devote all my time to research. Mangold was supportive; we respected each other but did not get very close. I completed the experiment of producing nerveless legs in frog larvae. The unilateral and bilateral extirpations of the lumbar segments of the spinal cord were done at the neurula stage. I had to do hundreds of experiments because I had to cope with two predicaments: after unilateral extirpation, the neural tube frequently regenerated to different degrees; and the bilateral extirpation incapacitated the mobility of the tail, and swimming. Fortunately, the few specimens that went through metamorphosis provided an unequivocal conclusion: the morphology, skeleton, and musculature of the nerveless legs were completely normal, except that the muscles had atrophied. Thus Dürken’s hypothesis that the normal development of legs depends on the normal supply of innervation was disproved. My results were published in Roux’s Archiv in 1928. The specimens with partially regenerated spinal cords showed various degrees of incomplete nerve patterns in the leg. I had no help, so I did all the sectioning and staining myself.

My interest in genetics was fostered by a group of young geneticists in the genetics department, the director of which was Professor Richard Goldschmidt. I participated in their seminars and befriended Curt Stern, his assistant. One summer, I spent several weeks in Stern’s laboratory. I learned how to cross Drosophila mutants, and I actually identified a new mutant. Stern later became one of the leaders in the field. Our friendship continued after we emigrated to the United States.

Berlin was then the vibrant cultural center of the Weimar Republic; theater, music, dance, and expressionist painting flourished. I was too busy to participate actively, but I remember Max Reinhardt, who dominated the theater, the dancer Mary Wigman, the plays of Bert Brecht, and outstanding cabarets. The Depression and inflation were behind us, the country was fairly prosperous, and the political scene was still rather peaceful.

Instructor in Freiburg

In 1927, Spemann offered me an instructorship, and later that year I returned to my alma mater. My duties were to supervise the elementary and advanced laboratory courses. In my spare time, I continued a project in developmental genetics that I had started in Dahlem. I shall deal with it only briefly because it was discontinued, unfinished when I moved to the United States. Although most experimental embryologists showed no interest in the role of genes in development, I considered the analysis of gene action as important as the analysis of induction or regulation. My view was reinforced by my contact with the Goldschmidt group in Dahlem. I had in mind to combine the methods of experimental embryology and genetics. This plan meant that I would stay with amphibians and cope with a serious drawback: no mutants were known so I was confined to species hybridization. The obvious choices were the two common salamander species, Triturus cristatus and Triturus taeniatus. These species differ significantly in the growth rate of the forelimbs and particularly of the four digits. I spent several breeding seasons constructing growth curves for the parent species and the reciprocal hybrids. These data were supposed to be the basis for planned transplantation experiments, but I never got to the point of doing these experiments and I terminated the project.

Chicago, 1932–1935

In the fall of 1932, I received a one-year Rockefeller Fellowship to work in the laboratory of Dr. Frank R. Lillie, a friend of Spemann’s, at the zoology department of the University of Chicago. Lillie’s classic book, The Development of the Chick, had introduced the use of the chick embryo in research and teaching; but at that time, experimentation had been limited to chorioallantoic grafts and hormone injections. Spemann suggested that I try his microsurgical technique on chick embryos. I arrived in Chicago late in October 1932. Lillie was then the dean of biological and medical sciences, and Dr. Benjamin Willier had taken his position as professor of embryology in the zoology department. At my first meeting with Lillie, he reminded me that 25 years earlier his student, Dr. M.C. Shorey, had removed leg buds by electrocautery, which resulted in severe deficiencies of the lumbar spinal ganglia and lateral motor columns. Sam Detwiler, a student of Ross G. Harrison, had repeated the experiment on salamander embryos; the spinal ganglia were reduced in size, but the motor centers seemed to be unaffected. Lillie thought that this experiment would be a good starter for a beginner, that it met with my interest in neuroembryology, and that I might resolve the discrepancy between the observations of Shorey and Detwiler.

Willier and his research associate, Dr. Mary Rawles, taught me how to handle chick embryos, how to saw a window in a shell, and how to remove the membranes. Within a few months, I had mastered the craft of extirpation and transplantation of limb buds to the flank. My mentors and the graduate students were much impressed by the sight of perfectly normal supernumerary wings and legs between the normal ones. The transplants were even motile, if they were connected with the brachial or lumbar plexus.

The wing bud extirpation experiment was done with glass needles on 3-day embryos; the embryos were fixed five to six days later. Both brachial spinal ganglia and lateral motor columns were greatly reduced, compared with those on the contralateral side, confirming Shorey’s findings. I was intrigued by the idea that I was now facing the problem of nerve influence on limb development in reverse: how do the structures of the limb regulate the nerve centers which innervate them? The first step of the analysis would be to find out whether there was a quantitative relationship between the loss of target structures and the hypoplasia of the nerve centers which innervate them. I counted the number of motor neurons and measured the volume of spinal ganglia on both sides. At this point, the inaccuracy of my operations, as a beginner, turned out to be a blessing in disguise. In addition to removing the wing musculature, I had removed a varying degree of pectoral muscles, ranging from 90 to 30 percent. The loss of the number of motor neurons corresponded exactly to the muscle loss in every case. On the other hand, the loss of sense organs in the skin and the reduced volume of spinal ganglia showed little variation. The loss amounted to about 50 percent in both. This finding suggested “the idea that each peripheral field controls the quantitative development of its own nerve center,” and, furthermore, that “the stimuli going from the peripheral fields to their nerve centers are probably transmitted centripetally by the nerve fibers” (Hamburger, 1934, p. 491).

Thus, the foundation was laid for a deeper understanding of the relationship between the target structures and their nerve centers. I stated this in a three-point paradigm:

1) The targets, that is, the musculature and the sense organs, generate two specific agents, one controlling the spinal ganglia and the other controlling the lateral motor columns.

2) The agents travel retrogradely in the nerves to their respective nerve centers, the lateral motor columns and the spinal ganglia.

3) The agents regulate the development of the nerve centers in a quantitative way.

The paradigm has stood the test of time well; two decades later, the discovery of nerve growth factor (NGF) identified one of the two agents postulated in the first point.

The third point, the mode of action of the agents, was not obvious. I suggested a hypothesis based on my familiarity with the notion of embryonic induction. I assumed that in early stages the nerve centers would contain a reservoir of undifferentiated neuroblasts; that early differentiating neurons would send out pioneer fibers that would explore the size of the targets; and that the neurons from which the pioneer fibers had emerged would induce an appropriate number of neuroblasts to differentiate into neurons and join them. This recruitment hypothesis would explain the hypoplasia of nerve centers in the absence of limbs and their hyperplasia in the presence of transplanted supernumerary limbs. The hypothesis turned out to be erroneous, but, as we shall see, my error was a blessing in disguise. This, my first publication in English, appeared in 1934. My first venture with the chick embryo proved its superiority over amphibian embryos in neuroembryology: the motor units are more clearly defined, and one gets results in days rather than weeks or months, and all year round.

My transition from amphibian to chick embryos coincided with my move from the Old World to the New World. Before, I had spent most of my life in idyllic small towns. On first arriving in the New World in October 1932, the skyscrapers of New York called for a readiness to forget the past for a while, and to adjust to a powerful, impressive, but somewhat scary new scenery. In the company of several other Rockefeller Fellows who had crossed the ocean with me, I called on the headquarters of the Rockefeller Foundation and then did several days of sightseeing, visited museums, and climbed the Woolworth Tower, then the tallest building in the world.

Then I traveled by train to Chicago and stayed for a while in the International House, a donation of the Rockefeller Foundation to the University of Chicago. The university is located on the South Side of Chicago, which was then a quiet neighborhood. I went downtown infrequently, to purchase materials for my experiments, or for movies and occasional dinners in a German restaurant in the company of some other German inhabitants of the International House. From the beginning, I was most impressed by the friendliness of everybody and the informality of all human relationships, reflecting an easy-going acceptance of others that one did not find in Germany. I was soon on a first-name basis with the graduate students around me, and before long Dr. Willier was “Benjie” and Dr. Rawles was “Mary.”

The most striking difference between the zoological institutes in Freiburg and Chicago was the narrow specialization in the former and the wide range of special fields represented in the latter. Of course, the University of Chicago was many times the size of the University of Freiburg; but, as I have mentioned, specialization was typical of German university departments. In Chicago, Willier represented embryology; Sewall Wright was already a famous geneticist; and Charles M. Child, the originator of the gradient theory, was also prominent. Also present were Warden C. Allee, one of the founders of modern ecology; Carl Moore, a distinguished endocrinologist; Ralph Emerson, an entomologist; and several others. Now, for the first time, I could “talk shop” with prominent neurobiologists and behaviorists. I became acquainted with Dr. C. Judson Herrick, with Dr. Karl Lashley, whose seminar on comparative psychology I attended, and with his colleague, Heinrich Klüver. They all took an interest in my experiments.

The tranquillity of life in Chicago was disrupted when the Nazis came to power in January 1933. In April, I received a letter from the dean in Freiburg, telling me that I was discharged from my assistantship. Naturally, I was shaken by this sudden uprooting, the separation from family and friends, and an uncertain future in a foreign country. But I was lucky in that the Rockefeller Foundation immediately created an emergency fund for displaced German scholars, which supported me for another two years. I became an assistant and participated in the teaching and laboratory work in the comparative anatomy and embryology courses that were then a requirement for premedical students in the United States.

In Chicago, I became acquainted with the routine of the college curriculum of American universities. Thus, I was well prepared when I received an offer of an assistant professorship in the zoology department of Washington University in St. Louis in 1934 which, of course, I accepted. In the meantime, I had returned to Germany for a short visit early in 1934. My wife had already dissolved our household in Freiburg. Back in Chicago we lived in a small apartment. Our four-year-old daughter was enrolled in the university kindergarten, and she soon surpassed her parents in spoken English.

St. Louis

We moved to St. Louis in September 1935. The zoology department occupied a large building on the Hill Campus together with botany. The campus overlooks the large Forest Park; the medical school and hospitals are just visible at the other end of the park. While the medical school already had a reputation as one of the best in the country, the college and graduate school were just average; they were populated mostly by local students. Their quality improved markedly when, many years later, dormitories were built, and the physicist Arthur Compton, a Nobel Laureate, became chancellor after World War II. He brought with him and recruited faculty of very high standards. The chairman of the zoology department, Dr. Caswell Grave, was an elderly gentleman, kind and unpretentious, a benevolent administrator.

The greatest asset of the department was a young biophysicist, Frank Schmitt, one of the best minds on the campus and one of the pioneers in the study of cell structure with the polarization microscope and by x-ray diffraction. His vitality and enthusiasm were contagious. My encounter with him broadened my scientific outlook profoundly. For the first time, I came in contact with a strictly reductionist, physico-chemical approach to biology. We were both open-minded and profited from our exchange of ideas. Frank had probably never seen an embryo before, but he soon realized that the processes with which I dealt might provide the biophysicist with intriguing opportunities. Our discussions led to a joint project on tissue density in amphibian gastrulae and neurulae, which was executed by a competent research assistant, Dr. Morden Brown. We organized a weekly seminar for advanced students in which theoretical and philosophical books by Julian Huxley, J.B.S. Haldane, Erwin Schroedinger, and others were read and discussed. Frank had also organized the Schmitty Verein, which included all prominent scientists of the Hill Campus and the medical school and met once a month to report on their latest discoveries and other events. One evening, Carl Cori gave the first demonstration of the enzyme that earned him and his wife Gerty the Nobel Prize.

I was promoted to associate professor with tenure in 1939. In the meantime, Dr. Grave had retired, and Frank Schmitt became the chairman, but not for long. In 1941, he moved to the Massachusetts Institute of Technology as the chairman of a newly established biology department. I became his successor and a full professor. Around the same time, two younger staff members had left, and I had the challenging opportunity to rebuild the department practically from the ground up. Through friends and colleagues, I recruited three recent Ph.D.s: the geneticist Harry Stalker, the cytologist Hampton Carson, and the biochemist Florence Moog. We were joined later by a more seasoned physiologist, Burr Steinbach. I was lucky in that all of them became prominent in their fields and highly regarded teachers. We all were exceptionally compatible and became friends. Carson and Stalker soon formed a successful research team. We all had lunch together in the conference room, and much of the department business, the curriculum, and new appointments were discussed there.

In 1945, another stroke of good luck came my way. I received a letter from Dr. Tom Hall inquiring about an opening in the department. He taught at Purdue and wished to return to his family in St. Louis. He had excellent credentials and turned out to be a brilliant educator with original ideas. He took over the elementary zoology course and redesigned it completely. He made the students think! Tom shared my interest in wildlife, in the arts, and in literature, and we became close friends. We spent weeks together in the Colorado and California mountains. Soon the administration discovered his propensity for general education ideas; he became the dean of the Faculty of Arts and Sciences and stayed in the administration for 13 years. In 1955, Owen Sexton joined the zoology department as an ecologist. He complemented the strongly experimental, laboratory-oriented faculty by his teaching, his field trips, and his research in a forested wildlife reserve owned by the university. Five of us—Stalker, Moog, Sexton, Hall, and I—stayed at Washington University until our retirement; Carson stayed for three decades. This tenacity is testimony to an unusual compatibility and also the favorable academic and living conditions in St. Louis.

The Marine Biological Laboratory in Woods Hole, Massachusetts

I think the MBL needs no introduction. Dr. Grave spent all his summers there. He owned a house in Woods Hole, did his research on ascidians, and was a member of the Board of Trustees. He did me a great favor by providing me with an instructorship in the embryology course. I started it in 1936 and carried on for 10 years. When its director, Dr. Hubert Goodrich, retired in 1941, I became his successor. Until then, the course had dealt with the description of the development of fishes and marine invertebrates. I initiated a radical change and placed experimentation on eggs and embryos at the core of the course work, and I found competent and enthusiastic colleagues to help me.

For me, the fairly isolated newcomer from the midwest, the contact with colleagues from other parts of the country, who met regularly every summer, was of incalculable value. The daily conversations, shop talk, and exchange of ideas created strong bonds. We visited each other in the laboratories and had meals together in the Mess Hall. Many of us brought our families along. Our spouses and children enjoyed the two beaches, and there was a Nature Study School for older children. Lasting friendships were formed. Dr. Lillie was at that time one of the most respected figures. He had been director of the MBL for many years; during his tenure, the laboratory had attained its great national reputation. I got together with him much more frequently there than in Chicago.

The atmosphere of the MBL was conducive to all kinds of gatherings of people who shared interests in special fields. A group of about a dozen experimental embryologists met every few weeks in the dunes of Truro Beach in Barnstable, northwest of Woods Hole. We brought our lunch and talked for hours; each time, the discussions focused on a different topic. We became known as the “sandpipers,” after the birds that shared the dunes with us. These meetings generated a tangible product: three of us—Benjie Willier, Paul Weiss, and I—got the idea of producing a comprehensive survey of the state-of-the-art of experimental embryology. We recruited over 20 colleagues, who contributed chapters on special topics. The book, Analysis of Development, under the editorship of the three of us, appeared in 1955. For quite a while, it was the standard book in the field. My contribution was a chapter, jointly with Holtfreter, on amphibians which, at that time, still played the key role in the field. The collaboration with Hannes, who was then at the University of Rochester, was not easy because our styles of thinking and writing were very different. We exchanged many drafts and letters, criticizing each other; but in the end, Hannes conceded that our chapter had considerable merit.

Back in St. Louis

Now back to St. Louis and chick embryos. I turned my attention to limb bud transplantations. First, I asked whether nerve centers would show a hyperplasia when their target area was enlarged. Because limb buds transplanted to the flank received little innervation, I used wing buds transplanted immediately behind the normal wing buds, and leg buds transplanted in front of the normal leg buds. The transplants were innervated predominantly by brachial and lumbar plexuses, respectively. The hyperplasia in the lateral motor columns was only slight, and that in the spinal ganglia somewhat greater. The most significant observation was that only motor segments and ganglia that actually sent nerves to the transplants were affected, whereas neighboring segments that did not contribute to their innervation showed no hyperplasia. This finding proved beyond a doubt that the hypothetical agents produced by the targets were transported to their nerve centers by retrograde transport in the nerves, as postulated in my paradigm, and not by diffusion (Hamburger, 1939).

Harrison had shown by transplantation of the left limb anlage to the right side, and by rotation, that in tail bud stages of salamander embryos the anterior-posterior axis is determined earlier than the dorso-ventral axis. I repeated these experiments on 2- to 2.5-day chick embryos in which the limb anlagen were either not yet elevated or recognizable as narrow ridges. In all 50 cases that were raised to advanced stages, both wings and legs developed according to their original axial orientation; that is, both axes were programmed at the earliest stages used for my experiments (Hamburger, 1938).

Inadvertently, I obtained nerveless limbs; in some cases, the limb primordia had not healed where placed but had slipped into the coelomic cavity where they differentiated in complete isolation. Later, I produced nerveless wings and legs on a large scale and showed that all structures had differentiated normally, thus confirming my earlier observations on the nerveless legs of frog larvae.

A chance observation directed my attention to the mitotic activity in the spinal cord. It was known that all dividing cells are assembled at the inner lining of the central canal. One day, in the laboratory course of embryology, I looked through the microscope of a student who studied sections of a 10 mm pig embryo. I was struck by the observation that all mitotic figures were concentrated in the (dorsal) alar plate, whereas there were very few in the (ventral) basal plate. I turned to my collection of chick embryos and found that there was indeed a remarkable temporal shift of mitotic activity from ventral to dorsal. Mitotic activity in the ventral plate that produces motor neurons, among other types, peaks at three days of incubation, whereas the peak in the alar plate that produces internuncial neurons occurs three days later. All proliferation is near its end on the eighth day. As a result, the motor neurons mature three days earlier than the interneurons, which then connect with the spinal ganglia. This pattern applies also to mammals, and probably to all vertebrates. I was surprised to find that it had never been described before. The observations were published in 1948. Fifteen years later, when I began to study motility in chick embryos, one of my first findings was that motility starts three days before the first reflexes can be elicited. That was exactly what I might have predicted in 1948—if I had been smart enough.

My interest in developmental genetics was still alive; I taught an advanced course on this topic. In the early 1940s, I returned to this field, motivated by the fact that mutants were available in chicks—a great advantage over amphibians. Moreover, I had access to these mutants through Walter Landauer, whom I had befriended during our student years in Heidelberg in the laboratory of Professor Herbst. Landauer had emigrated to the United States long before I did and was then in charge of poultry science at the Agricultural Experiment Station located on the campus of the University of Connecticut in Storrs, then a small village in the countryside, with a few buildings for agricultural sciences. One of the mutants that he had studied in detail was the Creeper fowl. It attracted my attention because the legs of the heterozygotes showed severe abnormalities, and the eyes of homozygotes showed an abnormality called coloboma. Transplants of Creeper leg and eye primordia to the flank of normal embryos gave rise to the expected abnormalities. But the transplantation of a potentially colobomatous eye primordium to the site of an eye primordium of a normal embryo brought a surprise: a perfectly normal eye was formed. This meant that we were dealing with an indirect gene effect. The gene was probably responsible for a deficiency in the vascular layer surrounding the eye. The outcome of the experiment showed that experimental embryology can contribute in a modest way to the analysis of gene action. But I realized the limitation of this approach, and I returned to neuroembyrology. A general account on the work with the Creeper fowl was published in 1942.

The Discovery of Nerve Growth Factor

I had sent a reprint of my article on wing bud extirpation (1934) to Professor Guiseppe Levi, director of the anatomy department of the medical school of the University of Turin, Italy, who was well known for his studies of nerve cells in tissue culture. He had given the reprint to his research associate, Dr. Rita Levi-Montalcini, who had also done experiments on chick embryos. The idea that the target structures influence the development of the nerve centers which innervate them, and my paradigm, intrigued her. But intuitively, she felt that my recruitment hypothesis, which tried to explain this influence, was improbable. In her previous work, she had become familiar with spinal ganglia. She did hind limb bud extirpations and then counted the numbers of undifferentiated and differentiated neurons in a lumbar ganglion. Up to the sixth day of incubation, the cell numbers were the same in the left and right ganglion. In the following two days, the number of differentiated neurons decreased substantially on the operated side, and only a few neurons remained toward the end of incubation. She concluded that neurons differentiate normally up to a certain point, but then they perish if their axons fail to establish contact with their target structures. Thus my recruitment hypothesis was replaced by one which had a solid foundation in facts; and my paradigm, on which her study was based, was strengthened. The results were published by Levi-Montalcini during World War II.

I became acquainted with her papers after the war. Of course, I accepted her version, but I felt that the analysis of the effect of limb extirpation could be carried further and that a collaboration with Levi-Montalcini might lead to the clarification of still unresolved issues, such as the nature of the target-produced agents that had been postulated in my paradigm. I wrote to Dr. Levi and asked whether Dr. Levi-Montalcini would be interested in working in my laboratory for a year. She consented and arrived in St. Louis in the fall of 1947. We agreed to repeat the limb bud extirpation experiment once more and, as the first step, to pay special attention to the finest details in the response of the spinal ganglia. Fortunately, we chose her preference; if my preference of the motor columns, which are more homogeneous than the ganglia, had prevailed, NGF would not have been discovered in my laboratory. The experiments and observations on the slides were done by Dr. Levi-Montalcini. I followed her work and discoveries with intense interest, and we were in close communication all the time. The one year originally planned was extended, and eventually she stayed in the department for 25 years; in due time, she was promoted to a full professorship.

Within a short time, Rita had made an important observation: beginning at 4.5 days of incubation, pyknotic neurons appeared in the brachial ganglia on the side of the operation. Degeneration reached its peak at days 5 and 6, and declined thereafter. The peak period coincided with the arrival of the axons at the target area. Few healthy neurons were left in pre-hatching stages. This finding was a welcome confirmation of the conclusions she had reached on the basis of her earlier work. But a much more exciting surprise was in the offing: when she surveyed other regions, she found the same pattern of neuronal degeneration in cervical and thoracic spinal ganglia that had not been affected by the operation. This was the momentous discovery of naturally occurring neuronal death. In our joint publication (Hamburger and Levi-Montalcini, 1949), we stated: “Substances necessary for neuroblast growth and maintenance would not be provided in adequate quantities, when the limb bud is removed” (p. 493), and “in early stages, cervical and thoracic neurons send out more neurites than the periphery can support. They are highly susceptible to environmental conditions” (p. 495). We mentioned in passing that cell death was found also in the normal brachial lateral motor column.

The obvious next project was to identify the maintenance factor for spinal ganglia, presumably a chemical agent. We looked for tissues that were more homogeneous than limb tissue and implanted skin, muscle, brain, and liver fragments in the place of limb buds. The results were not conclusive. At this critical moment, I received a reprint from my former student, Elmer Bueker, who was then at the anatomy department of Georgetown University. In his Ph.D. dissertation, he had learned to implant limb buds with and without the adjacent spinal cord into the coelomic cavity. In his publication, he described the implantation of mouse sarcomas 180 and 37 into the coelomic cavity. The tumors had been invaded by axons from adjacent spinal ganglia (which were hyperplastic), but bypassed by motor nerves. We could not have asked for a more favorable answer to our plight. The tumors were homogeneous and available in large quantities, and they shared our interest in spinal ganglia.

We obtained mice with these sarcomas from the Jackson Laboratory in Maine and, with the consent of Dr. Bueker, Rita repeated his experiment on a large scale. Beginning at day seven, the tumors were invaded by massive bundles of sensory and sympathetic nerve fibers, but motor axons bypassed the tumors. In several cases, volume measurements of paravertebral sympathetic ganglia of 13- to 15-day embryos involved in tumor neurotization, showed a 5- to 6-fold enlargement. Area measurements of spinal ganglia that sent axon bundles to the tumors in 9- to 13-day embryos showed a 2- to 3-fold increase. Again, motor fibers did not enter the tumors. “All available data indicate that the sarcomas 180 and 37 produce specific growth promoting agents which stimulate selectively the growth of some types of nerve fibers but not of others” (Levi-Montalcini and Hamburger, 1951, p. 349). In a subsequent publication (Levi-Montalcini and Hamburger, 1953), we reported that tumors implanted in the chick chorioallantoic membrane (a vascularized membrane underneath the shell) likewise induced great enlargements of sympathetic ganglia, although they were far removed from nerve centers. Hence, the hypothetical agent can be transported by diffusion, though in normal development it is transported retrogradely in axons, as shown in the earlier experiment.

At this point, identifying the chemical agent produced by the tumor became our highest priority. We realized that we needed the collaboration of a biochemist. In 1953 we were joined by a young postdoc, Stanley Cohen, who was recommended to us by a friend in the medical school, Martin Kamen. We could not have wished for a more brilliant or more congenial collaborator. He isolated NGF protein in the late 1950s. As is well known, it became the progenitor of a large family of growth factors. The Nobel Prize was awarded to Dr. Levi-Montalcini in 1986. Stanley Cohen shared it for the discovery of the epidermal growth factor, which had its roots in observations he had made on newborn mice treated with a tumor fraction. In the mid-1950s, I withdrew from the project. I could no longer contribute to it because of its biochemical nature; but of course, I followed its progress with keen interest. I think that the collaboration of an experimental embryologist, a neurologist, and a biochemist contributed a great deal to the success of this project in which NGF was discovered and characterized.

Spontaneous Motility

Early on, I had been interested in problems of animal behavior. In fact, I had planned experiments on birds before I left Freiburg for Chicago. In the many years of experimentation on chick embryos, I had noticed that their motility showed strange features. In the 1960s, I decided to make a systematic study of this phenomenon, which had not received much attention so far. A lively interest in embryonic behavior had existed in the 1920s to 1940s, but it had faded. According to the behaviorists, who dominated psychology at that time, behavior begins, by definition, with the first responses of the embryo to stimulation, and the stimulus-response mode is maintained throughout development. A lone outsider, Dr. George Coghill, who at that time studied the behavior of salamander larvae, maintained that behavior is integrated from the first movements of the head eventually to swimming and feeding, and that local reflexes originate secondarily by what he called “individuation.” His findings were supported by detailed parallel studies of the development of neural structures and synapse formation. I had met Dr. Coghill in Woods Hole in the 1930s and had long discussions with him and admired him, but at that time I was deeply involved in other scientific questions.

A glance at undisturbed chick embryos shows that they do not conform to either one of the two models. A closer inspection reveals two characteristic features. The first characteristic is that the movements of the different parts—head, body, wings, legs, beak, and eyelids—are uncoordinated until late in the incubation period. Any part can move simultaneously with any other part. The wings do not move simultaneously, nor do the legs alternate. The other characteristic is periodicity; activity periods alternate with inactivity periods. When motility begins at 3.5 days of incubation, the activity periods are brief, followed by long periods of quiescence. Gradually, the activity phases lengthen, and after day 13, motility is interrupted only by short inactivity periods. This pattern suggests that stimulation plays no role in the motility. It seems that we are dealing with nonreflexogenic, spontaneous motility.

Together with a group of capable and enthusiastic doctoral and postdoctoral fellows, I spent the 1960s analyzing spontaneous motility. This concept received strong support from the observation that motility begins at 3.5 days of incubation with the bending of the head, but the first response to stimulation cannot be elicited until 7.5 days of incubation. This finding agrees with the observation on mitotic activity. I found that we had not been the first to discover prereflexogenic motility in the chick embryo. The distinguished German psychologist, William Preyer, had reported in his book Spezielle Physiologie des Embryo (1885) exactly the same finding, that chick embryos become responsive to stimulation four days after the onset of motility. He had called the prereflexogenic movements “impulsive.”

The obvious next step was to design a deafferentation experiment. We chose the right leg for this purpose. In 2- to 2.5-day embryos, the dorsal half of the lumbar spinal cord, which includes the precursors of the spinal ganglia, was extirpated. To exclude sensory input from the brain and rostral spinal cord, a segment of the posterior thoracic spinal cord was also removed. The motility of the deafferented legs was tested in 8.5- to 17-day embryos; of course, they were not responsive to stimulation. The controls were embryos in which only the posterior thoracic segments had been excised. The activity phases of the embryos were about 40 percent shorter than those of normal embryos. The completely deafferented embryos showed a pattern of activity exactly identical to that of the controls. Thus, spontaneous motility extends throughout most of the incubation period. We concluded: “The experiment proves that the overt cyclic motility of the leg is the result of discharges generated in the ventral part of the spinal cord, and that sensory input neither initiates nor sustains the motility” (Hamburger et al., 1966, p. 148). The experiments were done in collaboration with Eleanor Wenger and Ron Oppenheim.

We did follow up the idea that spontaneous motility is the result of electrical discharges of spinal cord motor neurons. This experiment required electrophysiological equipment that was not available in my laboratory. I enlisted the help of Dr. Tom Sandel, chairman of the psychology department. Drs. Ron Oppenheim, Robert Provine, and Sansar Sharma did the experiments, which were done again on the legs. An electrode was placed on the dorsal surface of the lumbar spinal cord and then lowered in incremental steps. Polyneuronal burst activity was highest in the ventral region. The bursts were exactly synchronous with the activity phases of the leg all the way from four to 21 days of incubation. To ascertain that the electrical discharges caused the motility, and not vice versa, Provine curarized the embryos and recorded from the sciatic nerve; the periodic bursts persisted. Thus, our paradigm was confirmed beyond doubt. Finally, in collaboration with C.H. Narayanan and Michael Fox, I did a thorough study of motility in rat fetuses. We found the same pattern of periodic random movements as in chick embryos. The main differences are that the rat fetus is more advanced; it has legs with toes when motility begins, and it has no prereflexogenic period (see general review in Hamburger, 1973). Spontaneous motility had been observed occasionally in earlier times, but it was ignored because it was in conflict with the basic tenet of the behaviorists. I assume that the paradigm of uncoordinated, periodic spontaneous motility has now been adopted for all embryos and fetuses of warm-blooded vertebrates.

It is obvious that the uncoordinated movements of the chick embryo are not suitable for its escape from the shell. Hatching requires a coordinated, goal-directed activity. A search of the literature revealed, to our astonishment, that bits and pieces of the hatching process had been described, but no coherent picture of it had ever been presented. The best description so far dated back to de Reaumur in the 1750s! Why had no poultry scientist found it worthwhile to study this critical event? Ron Oppenheim and I spent several months of intense concentration on what turned out to be a very complex sequence of integrated movements that begins at incubation day 17 and ends with hatching on day 21. Our observations were published in 1967.

Return to Trophic Interactions

Strangely enough, the discovery of neuronal death in normal spinal ganglia by Dr. Levi-Montalcini in the late 1940s remained almost unnoticed for several decades. Levi-Montalcini herself never returned to this topic. I decided to set the record straight for the lateral motor columns. I studied first the effects of leg bud extirpation (Hamburger, 1958) and then the loss of neurons in normal embryos (Hamburger, 1975). I made counts of neurons and of degenerating cells on both sides of the lumbar motor columns. The pattern was strikingly similar in both instances: the maximum number of mature motor neurons was present on the fifth day of incubation. Shortly thereafter, degeneration began, reached its peak on the sixth to eighth day, and was nearly completed on the ninth day. The neuron loss amounted to about 40 percent in normal embryos and to more than 90 percent in embryos in which the leg bud had been removed. Thus the conclusions derived from the corresponding analysis of spinal ganglia were confirmed for another neural unit. In the meantime, it has been established that most units in the central and peripheral nervous system lose 40 to 50 percent of differentiated neurons in the course of normal development. As a rule, this happens when their axons reach their target structures. This finding means that my paradigm of 1934 has universal validity. While one of the two agents postulated in the paradigm, the one regulating the size of the spinal ganglia has been identified as the NGF protein, the ongoing search for the trophic agent sustaining motor neurons is also close to a solution.

The last phase of my activity in the laboratory, between 1976 and 1981, was devoted to an extension of the analysis of trophic interactions. I shall give a brief account of the results. In an experiment with Margaret Hollyday (1976), leg buds were transplanted in front of the normal leg buds. The transplants were sparsely innervated by thoracic and anterior lumbar nerves. Cell counts of the lateral motor column showed that from 11 to 17 percent of the motor neurons that would have died, were rescued. In an experiment with Judy Brunso-Bechtold (1979), gel pellets impregnated with labeled NGF were implanted subcutaneously in the leg of 10-day embryos. The embryos were processed for autoradiography eight hours later. All lumbar dorsal root ganglia on the side of injection were labeled selectively, showing once more that growth factors travel retrogradely in axons to their perikarya. Finally, we subjected the capacity of NGF to sustain the survival of sensory neurons to a particularly stringent test; in collaboration with Joe Yip, wing buds were extirpated in two-day embryos and small doses of NGF were injected into the coelomic cavity. The dosage was increased with advancing age of the embryos. Again, the majority of sensory neurons were kept alive (Hamburger and Yip, 1984). All these findings, together with similar results obtained in mammals, prove convincingly that NGF is the naturally occurring trophic maintenance factor for dorsal root ganglia.

The Stage Series of Chick Embryos

The Hamburger-Hamilton stage series of the chick embryo, published in 1951 and republished in 1992, has been adopted by most developmental biologists who work on chick embryos. It was conceived at a meeting of the Society of Zoologists in Chapel Hill, N.C., when Howard Hamilton told me that he was preparing a new edition of F.R. Lillie’s widely used Development of the Chick. I already knew Hamilton well; he had been a student of my friend, Benjie Willier, and was then a professor of zoology at Iowa State College in Ames, Iowa. I pointed out to him that the description of stages in Lillie’s book was entirely inadequate—it was based on chronology, that is, days and hours of incubation. The pitfalls of this method are discussed in the introduction to the stage series. We agreed to prepare a description that would be based on readily recognizable morphological criteria. I quote from my afterword to the 1992 edition: “Development is a continuum and all stage series are frames taken from a film, as Dr. Harrison once put it. The major issue is to decide which frames to designate as stages. The two ground rules are: that the stages can be identified unequivocally by one or more morphological features, and that successive stages are spaced as closely as possible…. In the first week, the changes are so rapid that the stages are only hours apart. During the second half of incubation, the stages are a day apart” (Hamburger, 1992, p. 275). I identified the stages of 2- to 9-day embryos and Howard identified the others. A good deal of the success can be ascribed to the excellent photographs, done by our students and collaborators.

The idea of a stage series was not new to me. Since my student days, I had been made aware of one of the basic tenets in experimental embryology: to be precise in identifying the stage of development at which a particular event or interaction occurs. And we were familiar with the prototype: Harrison’s stage series of the salamander, Ambystoma.

The Hamburger-Hamilton stage series is still one of the most frequently quoted publications in developmental biology. It owes this record to two facts: it is a tool, and not a report of a new discovery; and the number of investigators using chick embryos is still rising. For me, the greatest reward is the fact that in all these years, nobody has suggested to me a change or improvement.

Teaching

Teaching has been an essential part of my academic life. I tried to convey to students the satisfaction one gets from the mastery of a broad field and from the elucidation of the complex interplay of forces in evolution and development. And I enjoyed the contact with young people. I prepared my lectures carefully. For advanced courses, I read the pertinent literature before each lecture. I had complete notes, but usually I spoke freely. I think students liked my style of lecturing because it was lucid and, at the same time, exacting.

I regularly taught the course in comparative anatomy and embryology which was then obligatory for premedical students. In this, I was joined by my colleague, Florence Moog. At first we taught it in the traditional way: one semester comparative anatomy and one semester embryology. Then Florence had the idea to integrate the two fields and to deal with each organ system, such as the skeleton, first from the developmental and then from the evolutionary point of view. At my suggestion, she wrote a manual for the course which was adopted widely. Florence was a congenial partner for several decades.

An innovation of far greater impact was my design of a laboratory course in experimental embryology shortly after my arrival in St. Louis. It was taught to a small group of 10 to 12 advanced undergraduate and graduate students every other year. I knew that doing experiments on living amphibian embryos and watching the outcome was one of the most exciting experiences imaginable. I realized also that the course required a high degree of manual skills and perseverance, and much extra time, because water had to be changed, drawings and protocols had to be made at short intervals, the larvae had to be fed, and the high mortality, for which we then had no remedy, made it necessary to do many experiments. I was careful in the selection of students and, despite all the difficulties, the course became a great success.

The semester began a few weeks before the amphibian breeding season, and all instruments were prepared when, early in March, we made field trips to ponds at the outskirts of St. Louis to collect salamander and frog eggs, the mainstay of the course. In addition, we used planarians for regeneration experiments. After a few years, I decided to share my innovation with my colleagues; I wrote A Manual of Experimental Embryology that was published in 1942, and a revised edition appeared in 1960 (Hamburger, 1942, 1960). The detailed description of each experiment was preceded by the theoretical and conceptual premises of that experiment. Apparently many institutions introduced a similar course; when the manual went out of print in the 1980s, it had sold more than 10,000 copies.

Administration

The central administration of Washington University has always been liberal and broadminded. Throughout my tenure as chairman of the zoology department, from 1941 to 1966, I was on good terms with a succession of chancellors and deans. As I have mentioned, my friend Tom Hall was dean of the Faculty of Arts and Sciences during half of that period. He was unique in that he involved the entire faculty in lively discussions of fundamental issues in teaching and general education; he created several committees for this purpose, which met regularly for a year or two. I served on this and numerous other committees and attended endless faculty meetings, most of them of little consequence.

One of the outstanding scholars whom Tom Hall, as dean, brought to Washington University was Tom Eliot, who became chairman of the department of political science. We happened to be neighbors in a suburb; our families became friends, and our children were playmates. Everybody recognized Eliot’s superior administrative abilities, and he became chancellor when that position became vacant. He was instrumental in a substantial strengthening of the zoology department, by adding a large new building dedicated to research. He obtained half of the required funds from the Monsanto Chemical Company in St. Louis, after which the building is named. I obtained the other half from the National Institutes of Health (NIH). I introduced Tom Eliot to the NIH authorities in Washington, D.C. who were in charge of funding. They were familiar with my work and the discoveries that had been made in my laboratory, and we had no difficulty in getting what we needed. Thus, Monsanto Biological Laboratories were opened in 1964.

I do not remember details of my considerable administrative work; that means that all went smoothly, thanks primarily to my congenial colleagues. Mine was the first department in which two women, Florence Moog and Rita Levi-Montalcini, became full professors; and the first laboratory in which the work of two Nobel Laureates was initiated. Until the mid-1950s, all research was funded by the Rockefeller Foundation; thereafter NIH took over. In those golden days, the majority of grant applications were funded; I never had a rejection. I was the last chairman of zoology. After my retirement, the zoology and botany departments were combined to form the biology department.

Historical Writings

When my experimental work came to an end in the early 1980s, I turned to the history of my special fields of interest, experimental embryology and neuroembryology. I do not know when and how I acquired my historical perspective. But early on, I was aware of the fact that significant changes and innovations in the continuum of the history of biology are brought about by creative minds who combine intuition with profound thought, keen powers of observation, and mastery of a particular methodology. Names like Carl Ernst von Baer, Santiago Ramón y Cajal, Wilhelm Roux, and in my own orbit, Hans Spemann, Ross Harrison, Rita LeviMontalcini, and Johannes Holtfreter come to mind.

My most ambitious project was the book The Heritage of Experimental Embryology (Hamburger, 1988). Several considerations attracted me to this enterprise. First and foremost, I saw the German contributions to experimental embryology during the first half of this century as an exciting story with a modest beginning, several highlights, and an ending that was actually a transformation of Spemann’s organismic approach to a reductionist, cellular, and eventually a molecular approach. I was an eyewitness to some of the most important discoveries in Spemann’s laboratory, but not an active participant because my Ph.D. dissertation was not in the mainstream of the Spemann school; hence I could be objective and critical. I knew all and befriended some of the main participants and developed a close personal relationship with Spemann and Holtfreter, the key players in this saga. Another motive was the consideration that the literature I dealt with was written in German and that my book would make the prevailing ideas and experiments accessible to a readership not conversant with the German language.

Of my contributions to the history of neuroembryology, I mention only one essay, which I think contains an original idea: a lecture given at the annual meeting of the Society for Neuroscience in 1987 and published in The Journal of Neuroscience (Hamburger, 1988), titled “Ontogeny of Neuroembryology”. I suggested that modern developmental neurology represents the confluence of two originally very different currents of inquiry that were based on different frames of reference and different methodologies. The histogenetic approach was founded by the German histologist, Wilhelm His, and the Spanish histologist, Santiago Ramón y Cajal, in the late 1880s and the 1890s. They established the neuron and axonal outgrowth theories and thus refuted the then prevailing reticular theory of axon formation. In doing so they created modern neuroanatomy and an understanding of the wiring of the central nervous system. The mastery of the silver impregnation method by Ramón y Cajal was crucial in this enterprise.

The causal-analytical, experimental approach was introduced by Ross Harrison of Yale University in the early 1900s, using amphibian embryos. He made two crucial contributions: the invention of the tissue culture method, by which he confirmed the axon outgrowth theory; and the introduction of the limb transplantation experiment, which became the model for the analysis of nerve pattern formation and of the interactions between nerve centers and their target structures. He provided his many students and followers, including myself, with challenges for a lifetime. I was fortunate, indeed, to have two men of this stature, Spemann and Harrison, as my guides.

Travels

A short trip to Berlin in 1937 turned out to be my last crossing of the Atlantic Ocean for two decades. My family spent the summers of 1936 to 1945 in Woods Hole, where I taught in the embryology course. This left no time to travel elsewhere. In the summer of 1947, I taught a course in the zoology department of the University of Chicago. At last in 1948, we got a chance to spend a carefree vacation in the Colorado Rockies and to visit Mesa Verde. In 1950, I taught summer school in Berkeley, and we had an opportunity to get acquainted with the attractions of the West Coast—the redwoods and the Sierra Nevada—truly a New World to the European immigrants.

In the spring of 1951, my family suffered a severe setback. My wife was struck with schizophrenia and was hospitalized for a decade. I visited her regularly and avoided long absences. But in the summer of 1954 I accepted an invitation to attend a meeting of embryologists in Oxford, where I reported on the spectacular effects of mouse tumors on spinal and sympathetic ganglia. I used the opportunity to visit the continent, and after two decades was reunited with colleagues and friends in Germany and Switzerland. In 1958, an international group of biologists gathered in London to celebrate the centennial of Darwin’s Origin of Species. I gave a talk and had the unpleasant experience of having my briefcase, including notes and slides, stolen shortly before my lecture. I managed to improvise and to make my point with the aid of a blackboard. Then I spent several weeks in Germany, Austria, and Switzerland, in the company of my younger daughter, in a newly acquired Volkswagen. I finally saw Freiburg again, and I hiked in the Alps with my brother and his wife.

In 1960, I spent six weeks in Japan. I think that the first contact of Westerners with Japanese culture makes them aware of its much more formal style. But, of course, I found myself immediately at home in the laboratories of my fellow embryologists. In Tokyo, I spent several weeks with Dr. T. Fujii and his many students, among them the son of the emperor. The large museum introduced me to Japanese art which made an enduring impression on me. My hosts in Nagoya were two friends from my German past, Drs. Tuneo Yamada and Tadao Sato. Of several other places I saw, Kyoto was by far the most impressive; its temples and shrines, and the oldest temples in nearby Nara, are unsurpassed. A unique event was an audience with Emperor Hirohito at his biological laboratory on the palace grounds; he was an ardent marine zoologist. I was introduced to him by Dr. Sato, who had been his assistant years ago. For almost an hour, the emperor was an interested listener to my report on my research, and he inquired about my visits to the Japanese laboratories. He was anything but imperious; he was cordial and professional in the conversation translated by Sato. I later published an account of this visit (Hamburger, 1962).

In 1961, my wife was discharged from the hospital and moved to be near our daughter in California. Now I was free to travel, and I took full advantage of the opportunity. In the 1960s and 1970s I spent most summers in Europe. The most vivid memories are visits with my friend Fritz Baltzer in Bern and with Professor Karl von Frisch, well known for his studies on honey bees and their language, at his Austrian summer residence in Brunnwinkel.

My second trip to Japan, in 1965, was to a joint meeting of American and Japanese embryologists that I had helped to organize. About 20 Americans and 40 Japanese met in Tokyo for several days. I do not want to go into detail, but mention only that Howard Schneiderman gave the welcoming address in Japanese. Afterward, we Americans visited the laboratory in Fukuoka on the island of Kiu-shu, and the active volcano of Mount Aso, with red lava—a rare sight.

My friend Ernst Hadorn in Zürich arranged two trips to Africa for about 20 of his academic colleagues and me in 1972 and 1974. We traveled in two buses across the wildlife preserves of Kenya and Tanzania. The encounters with herds of elephants, zebras and giraffes, baboons, packs of lions, and thousands of flamingos populating the lakes are unforgettable.

Concluding Remarks

In retrospect, I realize the extent to which my scientific perspective has been shaped by my mentor, Hans Spemann. I do not share his vitalistic world view (Weltanschauung), but I do share his organismic creed, which implies that everything developmental biologists explore occurs in the context of the living, developing organism. This creed is entirely compatible with a rigorous reductionist analysis of development, all the way down to the molecular level.

Selected Publications

A manual of experimental embryology. Chicago: University of Chicago Press, 1942. 2nd ed., 1960.

Analysis of development. Willier B, Weiss P, Hamburger V, eds. Philadelphia and London: W.B. Saunders Company, 1955.

The heritage of experimental embryology. Hans Spemann and the organizer. Oxford, UK: Oxford University Press, 1988.

Neuroembryology: The selected papers. Boston: Birkhäuser, 1990.

Die Entwicklung experimentall erzeugter nervenloser and schwach innervierter Extremitäten von Anuren. W Roux’s Archiv 1928;114:272–363.

The effects of wing bud extirpation in chick embryos on the development of the central nervous system. J Exp Zool 1934;68:449–494.

Morphogenetic and axial self-differentiation of transplanted limb primordia of two-day chick embryos. J Exp Zool 1938;77:379–397.

The development and innervation of transplanted limb primordia of chick embryos. J Exp Zool 1939;80:347–389.

The developmental dynamics of hereditary abnormalities in the chick. Biol Symposia 1942;6:311–334.

The mitotic patterns in the spinal cord of the chick embryo and their relation to histogenetic processes. J Comp Neurol 1948;88:221–284.

(with Levi-Montalcini R) Proliferation, differentiation and degeneration in the spinal ganglia of the chick embryo under normal and experimental conditions. J Exp Zool 1949;111:457–502.

(with Levi-Montalcini R) Selective growth stimulating effects of mouse sarcoma on the sensory and sympathetic nervous system of the chick embryo. J Exp Zool 1951;116:321–362.

(with Hamilton H) A series of normal stages in the development of the chick embryo. J Morph 1951;88:49–92. Republished in Dev Dyn 1992;195:229–275.

(with Levi-Montalcini R) A diffusible agent of mouse sarcoma, producing hyperplasia of sympathetic ganglia and hyperneurotization of viscera in the chick embryo. J Exp Zool 1953;123:233–288.

(with Holtfreter J) Amphibians. In: Willier B, Weiss P, Hamburger V, eds. Analysis of development. Philadelphia and London: W.B. Saunders Company, 1955;230–296.

Regression versus peripheral control of differentiation in motor hypoplasia. Am J Anat 1958;102:365–410.

An embryologist visits Japan. Am Zoologist 1962;2:119–125.

(with Wenger E, Oppenheim R) Motility in the chick embryo in the absence of sensory input. J Exp Zool 1966;162:133–160.

(with Oppenheim R) Prehatching motility and hatching behavior in the chick. J Exp Zool 1967;166:171–204.

(with Narayanan CH, Fox MW) Prenatal development of spontaneous and evoked activity in the rat (Rattus norwegicus albus). Behavior 1971;40:100–134.

Anatomical and physiological basis of embryonic motility in birds and mammals. In: Studies on the development of behavior and the nervous system, Vol. 1. New York and London: Academic Press, 1973;63–76.

Cell death in the development of the lateral motor column of the chick embryo. J Comp Neurol 1975;160:535–546.

(with Hollyday M) Reduction of the normally occurring motor neuron loss by enlargement of the periphery. J Comp Neurol 1976;170:311–320.

(with Brunso-Bechtold J) Retrograde transport of nerve growth factor in chicken embryos. Proc Natl Acad Sci USA 1979;76:1494–1496.

(with Yip J) Reduction of experimentally induced neuronal death in spinal ganglia of the chick embryo by nerve growth factor. J Neurosci 1984;4:767–774.

Ontogeny of neuroembyrology. J Neurosci 1988;8:3535–3540.

The rise of experimental neuroembryology (The Kuffler Lecture). Int J Dev Neuroscience 1990;8:121–131.

Sir Alan L. Hodgkin

BORN:

Banbury, Oxfordshire, England

February 5, 1914

EDUCATION:

University of Cambridge: Trinity College (1932), Sc.D. (1963)

APPOINTMENTS:

Fellow, Trinity College, Cambridge (1936 to date)

Foulerton Research Professor, Royal Society (1952)

Plummer Professor of Biophysics, University of Cambridge (1970)

Master of Trinity College, Cambridge (1978)

HONORS AND AWARDS:

Fellow, Royal Society of London (1948)

Royal Medal, Royal Society (1958)

Nobel Prize for Medicine or Physiology (1963)

Copley Medal, Royal Society (1965)

President, Royal Society (1970–1975)

Knight of the British Empire (1972)

Order of Merit (1973)

Foreign Associate, American Academy of Arts and Sciences (1974)

Foreign Associate, National Academy of Sciences USA (1974)

Sir Alan Hodgkin, together with Andrew Huxley, established the ionic basis of the resting potential in nerve cells and the ionic basis of nerve conduction. Later, he studied the biophysics of sensory transduction in the photoreceptors of vertebrates.

Sir Alan L. Hodgkin

I come from a long line of Quakers, some of whom were scientists and others historians. But until about 1870 the Universities of Oxford and Cambridge were not open to nonconformists, so scientists such as the meteorologist Luke Howard, my great-great grandfather, or the historian Thomas Hodgkin, my grandfather, relied on a profession—like banking—for financial support and pursued their academic interests in their spare time or, when they had made enough money, after early retirement. This may have had some indirect effect on my attempts to do scientific research because it encouraged me to try experiments at home with simple equipment. More generally it gave me the feeling that research was something one did for fun rather than part of a “9 to 5” profession.

It is customary to divide research into the pure and applied categories. Such a distinction is plainly unsatisfactory because pure research like that of Sir Alexander Fleming’s may lead to results of great practical importance such as the discovery of penicillin, and applied plant breeding experiments may generate new ideas about genetic theories. I have no real quarrel with this classification, but think it incomplete because it says nothing about the actual motivation of scientists. If pure scientists were motivated by curiosity alone, they should be delighted when someone else solves the problem they are working on—but this is not the usual reaction. And of course the same is true of applied research: engineers or inventors are naturally upset if their designs are anticipated.

I mention these rather obvious points about motivation because they were strong influences on my own research. I certainly was curious about how a nerve conducts electrical impulses or an eye catches light quanta and am delighted that we have gone a long way toward solving both problems. But a good deal of my satisfaction comes from the fact that my colleagues and I helped to put theories for such problems on a firm footing and eventually came to see them taken for granted. Yet establishing a firm base for a scientific theory or discovering something new does seem to me a possible way of answering A.E. Housman’s moving but melancholy question:

Here, on the level sand,

Between the sea and land,

What shall I build or write

Against the fall of night?

Tell me of runes to grave

That hold the bursting wave,

Or bastions to design

For longer date than mine.

Shall it be Troy or Rome

I fence against the foam,

Or my own name, to stay

When I depart for aye?

Nothing: too near at hand,

Planing the figured sand,

Effacing clean and fast

Cities not built to last

And charms devised in vain,

Pours the confounding main.

Family Background

As a Quaker and pacifist my father, George, took no direct part in military activities during World War I. Instead he joined two expeditions which attempted, with some success, to bring relief to Armenian refugees in the Middle East. On the second expedition he died of dysentery in Baghdad on June 24, 1918. This left my mother with three small boys—ages four, two, and one month—of whom I was the eldest.

One might have expected George’s death to have made my mother, who then was only 26, unduly protective of her young family. But it seemed to have had the opposite effect, perhaps because she was buoyed up by some inner faith or because she recognized the danger of being overprotective. At any rate, when we were old enough she encouraged us to walk long distances on our own in the pleasant country round Banbury or Oxford, England, where we lived until I was 18. Or, after we had learned to use a map and compass, she allowed us to make all-day expeditions in the snow-covered hills in the Lake District, where we occasionally spent a winter holiday.

My mother also encouraged my interest in natural history, in which she was helped by my Aunt Katie—a talented but eccentric ornithologist with whom we stayed on the Northumbrian coast opposite Holy Island. Aunt Katie taught me to keep a bird diary and to hunt for the nests of rare birds. The nest most prized was that of the golden plover, of which there were one or two on some neighboring hills. We found our first nest in April 1928, having hunted without success in the same area in the two preceding years. The search followed a standard pattern not unlike scientific research. The strange creaking whistle of the plovers provided initial evidence of the likelihood of a nest in the vicinity, and one collected further clues by watching the behavior of the birds. The resulting hypothesis as to the whereabouts of a nest was confirmed by finding the four beautifully marked but well-camouflaged eggs. But sometimes one had misread the evidence and there were no eggs because one had been watching the male, not the female, and it had been sitting on a “scrape” or dummy nest.

Starting a Scientific Career

At the end of 1931 I got a major scholarship at Trinity College, Cambridge. This came as a surprise to my school which had not thought I was was of that caliber. My main subjects at school were zoology, botany, and chemistry, in the first two of which I was helped greatly by my interest in natural history. I was to go to Cambridge in the autumn of 1932, and my mother had sensibly arranged for me to spend some time before then learning German in Frankfurt. I also was keen to have a shot at some research problem before going to Trinity.

Getting a scholarship encouraged me to visit one of my future teachers in Cambridge, Carl Pantin, a distinguished experimental zoologist who gave me some good advice which I had the sense to follow. He said that in my last term at school I should do no more biology but should concentrate on mathematics, physics, and German. He also told me that I must continue to learn mathematics—something that I have tried to do during the rest of my life, or at any rate until a few years ago. One of my bibles was Piaggio’s Differential Equations, though I cannot claim to have done all the examples as I probably should have done.

As to a short-term research project, Pantin was doubtful about my attempting something at Plymouth Marine Biological Laboratory, which was my initial idea and where I had once been on a schoolboy course. He suggested that I work at the Freshwater Biological Station on Lake Windermere that had just been set up under the direction of two young zoologists, Philip Ullyott and R.S.A. Beauchamp. I jumped at the idea, not least because it provided an opportunity of spending May in one of the most beautiful parts of the Lake District. I lived in the tiny village of High Wray and many years later I found that my ancestors, Rachel and Isaac Wilson, had lived there two centuries earlier.

For my research project, Ullyott suggested that I study the effect of temperature on the freshwater planarian Polycelis nigra and in particular should see if they congregated in the cold end of a temperature gradient. I found that they did, and that this was only partly explained by their higher rate of movement in the warm end. Six months later I tried to continue the experiments in the spare bathroom at home, but nothing came of this apart from the disturbance to our guests.

I went up to Trinity in the autumn of 1932. During full term in Cambridge there was no time to attempt even the simplest kind of research An opportunity came during the much more leisurely, Long Vacation term, July to September, when a few optional courses are held. The first experiments I tried were aimed at comparing the effects of changes in external and internal pH on amoeboid motion. This research did not get anywhere but increased my interest in cell membranes, which I read about in James Gray’s Experimental Cytology and A.V. Hill’s Chemical Wave Transmission in Nerve. I had also read W.J.V. Osterhout’s Physiological Studies of Large Plant Cells and was impressed by the evidence obtained by L.R. Blinks that an increase in membrane conductivity occurred when an electrical impulse traveled along one of the large cells of the water plant Nitella.

I felt that it would be nice to know whether the nerve impulse was accompanied and perhaps caused by a similar increase in membrane conductivity. It seemed to me that evidence for this crucial point was lacking and might be obtained by the experiment illustrated in Figure 1, which could be carried out with simple apparatus. I arranged to block a frog nerve locally by freezing a short length and applied two appropriately timed shocks on either side of the block. I argued that if the membrane conductivity increased during activity, then arrival of an appropriately timed impulse at the block should help the stimulating current to enter the nerve and so increase excitability—provided that the shock and impulse coincided.

Figure 1. Diagram of method of testing the effect on excitability of a blocked nerve impulse, using sciatic gastrocnemius preparation [Source: Hodgkin (1976) J Physiol 263:1-21].

To begin with, I got a negative result but on trying again in October 1934 the experiment worked well, and I was pleased. However, after several weeks I got a horrid surprise. I switched the anode from just above the block to a position beyond it—from position C in Figure 1A to position E in Figure 1B—and found that the facilitating effect of the blocked impulse persisted. The effect therefore had nothing to do with an increase in conductivity at position C and was simply explained by local electric currents spreading through the block and raising excitability beyond it, as shown in Figure 2.

Figure 2. Diagram illustrating local electric circuits spreading through block and increasing excitability beyond it (from Hodgkin, 1936, 1937a,b) [Source: Hodgkin (1976) J Physiol 263.1-21].

More generally, the effect might be attributed to whatever agent is responsible for the conduction of the nerve impulse. The effect did not provide any evidence for electrical transmission, but it offered a neat way of testing the theory, and it was this subject that I chose when starting whole-time research in the following year, at the end of my undergraduate studies.

By mid-July 1936 I had been through the main experiments which strongly supported the idea that nerve impulses are propagated by electric currents spreading in a local circuit ahead of the active region. I wrote up these and other results in a thesis which brought me a fellowship at Trinity College in October 1936 and a Rockefeller Fellowship in New York for the following year. Both influenced my life in many ways, and for both I am deeply grateful.

During my last few months in Cambridge before going to America, I found that it was surprisingly easy to dissect single nerve fibers from the shore crab Carcinus maenas. I had also shown that there were transitional stages in the initiation of the nerve impulse as expected from the work of William Rushton and Bernard Katz. To begin with, H.S. Gasser and several other senior neurophysiologists were skeptical about this result, but Gasser did not mind my continuing on my own and provided me with a room and splendid equipment in the Rockefeller Institute in New York.

The Rockefeller Foundation encouraged travel and in the early summer of 1937 I worked with K.S. Cole and H.J. Curtis at the Woods Hole Marine Biological Laboratory in Massachusetts, where they introduced me to work on the giant nerve fiber of the squid, which was to have a major effect on my scientific life.

In New York and on the personal side, far and away the most important contact that I made was with Marni Rous whom I first met in 1937 at a tea party given by her father, the distinguished and delightful scientist Peyton Rous, then working at the Rockefeller. Six months later I got to know her well while she was staying with her cousins in Connemara, Ireland, where I joined her on my return from America. I had fallen deeply in love and wanted to marry her, but she said no quite firmly and it was seven years before we met again and she changed her mind.

Someone, probably H.S. Gasser, suggested that the Rockefeller Foundation might help me buy or build a modern set of electronic equipment for my lab in the Physiological Laboratory, Cambridge. Dr. Toennies, the Institute’s electronics man, suggested a list of things I might need, and before leaving New York in 1938 I learned that I would receive an equipment grant of £300, a large sum in those days.

When I got back to Cambridge and started work in the Physiological Laboratory, I joined forces with three psychologists, A.F. Rawdon-Smith, Rowan Sturdy, and Kenneth Craik, who were interested in building new electronic equipment. Among us we built three or four sets of equipment, some of which were still in use 25 years later. In addition to building equipment I gave a course of lectures in the laboratory and tutorials at Trinity College where I had the good fortune to teach some brilliant people, including Andrew Huxley in his fourth year and Richard Keynes in his first year.

I got my laboratory equipment going by January 1939 and started to measure the relative size of resting and action potentials in crustacean nerve, using external electrodes. This work led to my internal electrode experiments on squid nerve, carried out with Andrew Huxley at Plymouth, which showed that the action potential might exceed the resting potential by some 40 mV. In other words, the membrane potential at the peak of the nerve impulse reversed by 40 mV instead of falling to zero as assumed in the classical theory.

There obviously was much to be done with the exciting new technique, but it had to be abandoned when Hitler marched into Poland and war was declared on September 3, 1939. We left the equipment at Plymouth in the faint hope that the war would be short and that we could soon continue the experiments. However, the war lasted six years, Plymouth was badly bombed, and it was eight years before I could return. There also was a major disappointment on the personal side as Marni Rous, who had planned to be in Cambridge 1939 to 1940 on a Henry Fellowship, had to cancel her visit. We did not meet again until 1944 in New York when I was sent to the U.S. on a radar mission and we then lost little time in getting married.

I spent most of the war in Britain working extremely hard on 9-cm radar in night-fighters, Beaufighters and Mosquitoes, for the Royal Air Force. The most important and interesting job in which we collaborated with the (British) General Electric Company and several other firms, was to design an air interception set capable of bringing a night-fighter within about 500 feet of an enemy bomber in darkness, at which range the night-fighter’s pilot should be able to see and shoot down the bomber.

Return to Cambridge

Toward the end of 1944 my work on radar grew less urgent, and I started working again on neurophysiology at home in the evenings and on weekends. I was released from military service soon after the end of the German war, and Marni and I, with our baby daughter, returned to Cambridge from Malvern on the Hereford/Worcestershire border at the end of July 1945. I was keen to start experimental research again but it was as difficult to get going in the Physiological Laboratory as it was to set up house. We had managed to buy a pleasant, smallish house, but there was a £10 limit on any unauthorized repairs. In six months the universities were to be flooded with war-surplus equipment, but to begin with there was nothing in the laboratory and little in the shops.

Some of the equipment that I had left at Plymouth was damaged in a major air raid, but I managed to salvage a good deal. Fortunately I had lent the main racks to Rawdon-Smith and Sturdy, and they had removed them before the main air raids began. Somehow I managed to collect everything and get the equipment going well enough to start experiments on Carcinus again.

E.D. Adrian, the professor of physiology at Cambridge University, had obtained my early release from military service on the grounds that he needed help with teaching. This was true, as we still had our full quota of medical students. One of my first jobs was to lecture on human physiology to student nurses. This job was good practice for me, but the nurses were under the charge of a fearsome-looking matron, and I could not get a flicker of interest out of them. I felt better when Adrian, who had given the lectures originally, said that he had had the same experience. Adrian let me off with a light teaching load, but I found it much harder to give tutorials than before the war. This difficulty was partly because I had forgotten a good deal and partly because I no longer believed in many of the principles that once seemed to hold physiology together. Thus the constancy of the internal environment was as important as ever, but the way in which it was achieved had grown more complicated. I suppose that after five years working as a physicist, I had little use for biological generalizations and preferred physicochemical approaches to physiology. This did not go down well with most medical students.

After a rocky start my experiments on crab nerve fibers began to go well. These experiments went even better after Andrew Huxley returned to Cambridge from the Admiralty in 1945. Professor Adrian obtained a grant of £3,000 per annum from the Rockefeller Foundation, which helped to support a group working mainly on nerve and muscle. The original members of this group were D.K. Hill, Andrew Huxley, and myself. We were soon joined by distinguished visitors from abroad, among whom R. Stampfli and S. Weidmann were some of the first.

In 1948 I was encouraged greatly by my election to the Royal Society. This was welcome recognition, as the ionic hypothesis of nerve conduction then was not widely accepted outside Britain. Four years later the Society helped me in a more material way by appointing me to a Foulerton Research Professorship, which allowed me to concentrate on research with little teaching. More widespread recognition came with the award of the Nobel Prize in 1963 to Jack Eccles, Andrew Huxley, and myself.

Our work was influenced strongly by a number of new techniques, some of which had arisen during the war and others which we developed for ourselves. Huxley and I had obtained strong but indirect evidence that each nerve impulse was associated with a minute but rapid outflow of potassium ions. We also thought it likely, but had little evidence, that the potassium outflow was preceded by an entry of sodium ions.

It clearly was important to measure the sodium entry and potassium loss in a single nerve fiber. Richard Keynes was keen to have a go at this ambitious project, which he did successfully when he returned to Cambridge in 1945. In the end, he used several methods, including radioactive tracers, flame photometry, and activation analysis, but happily all three provided results that were in reasonable agreement. The quantity turned out to be exceedingly small, and a single nerve fiber loses only about one 100,000th of its potassium and gains a similar quantity of sodium in one impulse. However, this quantity is equivalent to several times the charge on the resting membrane, so sodium entry and potassium exit are a satisfactory basis for the nerve impulse.

For this scheme to work efficiently it is important that the sodium and potassium movements are separated in time. Ideally the sequence of events when the impulse passes a particular point on the nerve should be something like this: as the active region approaches, the membrane will be depolarized, i.e., grow less negative. This depolarization will raise the sodium permeability of the membrane, which in turn will cause sodium ions to enter the nerve and lead to further rapid depolarization. As a result of this regenerative process, the membrane potential will move from somewhere near the potassium equilibrium potential to a new value near the sodium equilibrium potential: say from –70 to +40 mV. In addition to changing the charge on the membrane capacity, the early entry of sodium to the nerve provides the inward current, which depolarizes the next section of the nerve and makes a wave of high sodium permeability spread along it.

If this were all that occurred, once the nerve were activated it would remain in a state of high sodium permeability indefinitely and so would be useless for further signaling. However, at the crest of the impulse slower processes begin to take effect. In the first place the sodium permeability does not remain at a high value but declines with a time constant of about 1 msec when the membrane is depolarized. This process is known as inactivation. Recovery of the original resting potential in the nerve is greatly accelerated by an increase in potassium permeability, which takes place with an S-shaped delay near the crest of the impulse. The mechanism responsible for the initial rise of sodium permeability is reversible. Hence any sodium conductance that has not been inactivated is cut off, and repolarization is accelerated.

After its resting potential has been restored, the membrane is ready to conduct another impulse, but it only does so with difficulty. In this condition, which is known as the relative refractory period and which lasts for a few milliseconds, a second impulse is harder to set up and is conducted more slowly. In the initial part of the refractory period, a second impulse cannot be set up at all and the nerve is said to be in the absolute refractory period.

In the years after the war my colleagues and I obtained much evidence for the essential correctness of the theory outlined above. So far as we could see, it applied to all nerves and to skeletal muscle, which also conducts something similar to a nerve action potential. However, it is necessary to make a reservation because in some cases—crab muscle is an example—the inward current that drives the action potential along the muscle is carried by calcium rather than by sodium ions.

One satisfactory point for us was that the evidence for the sodium theory of the nerve impulse was quantitative. Thus we found that the reversed membrane potential at the crest of the impulse varied as 58 mV log[Na]o, as it should if the membrane is selectively permeable to sodium ions.

In analyzing the behavior of nerve and other excitable tissues, much progress was made by using the voltage-clamp technique in which the membrane potential is displaced to a new value and held there by electronic feedback. The current, which flows through a definite area of membrane under the influence of the impressed voltage, is measured with a separate amplifier. The early work using this technique was done on squid axons, first by Cole and later by Huxley, Katz, and myself.

When an impulse propagates along a nerve fiber, the internal potential changes with time and distance, as does the membrane current. In the original voltage-clamp method, about a centimeter of the interior of the nerve was pierced by a long metal electrode and could be treated as an isolated patch of membrane.

A further advantage of the voltage-clamp method is that the experimenters control the voltage across the membrane and can make it do what they want. They can for example make the feedback apparatus suddenly reduce the membrane potential to zero, a procedure equivalent to suddenly short-circuiting the membrane. If this is done the membrane capacity is discharged at once, and thereafter only ionic flow through the membrane contributes to the current. If the membrane is suddenly depolarized to some value between 20 and 110 mV below the resting potential, the ionic current consists of two phases. To begin with, sodium ions flowing down their concentration gradient give an inward current. This component is transient and after about 1 msec (at 10°C) is replaced by an outward potassium current. The two components of the current vary with the concentrations of sodium and potassium ions. By changing these concentrations the ionic current can be separated into its two components. From there it is a short step to calculate the sodium and potassium conductances and see how they change with time (Figure 3).

Figure 3. Separation of membrane current into components carried by Na and K; outward current upwards. A, Current with axon in sea water = INa+ IK-B, Current with most of external Na replaced by choline = IK − C, Difference between A and B = INa. Temperature 8.5°C (from Hodgkin and Huxley, 1952a) [Source: Hodgkin, 1964a].

We made a few voltage-clamp experiments in the late summer of 1948, but nearly all the results on which we relied for our analysis were obtained a year later. After that it took a further two years to analyze and write up the results. I have sometimes been asked why this took so long. The reasons were multiple. In the first place we had other things to do, notably teaching and working with research students or visitors. Much of the analysis had to be done by hand, and we had no suitable computers to assist us. Fortunately for us, no one else was particularly interested in voltage-clamp analysis, and we were able to take our time.

Our conclusions could be summarized by saying that nerve conduction was brought about by changes in sodium- and potassium-selective channels. Both changes were graded and reversible in the sense that if the original resting potential of the nerve was restored, both channels reverted rapidly to their closed condition. For both channels the turn-on rate was increased and the turn-off rate decreased by depolarization. In addition the system controlling the sodium permeability was reduced more slowly by the inactivation mechanism, which was primarily responsible for the transient nature of the rise in sodium permeability.

At first it might be thought that the response of a nerve to different electrical stimuli is too complicated and varied to be explained by these relatively simple conclusions. Partly for this reason Huxley and I spent a long time developing what are sometimes known as the Hodgkin-Huxley equations, which are given in outline below. In using the equations it should be emphasized that there are no arbitrary constants, as the voltage-clamp results were used to supply the numerical data required.

The main features that had to be built into our theory are shown in Figure 4. A striking point that caused some initial difficulty was that both conductances were turned on with an S-shaped delay but were turned off sharply along an exponential curve. We dealt with this fact by assuming that each conductance was proportional to the third or fourth power of a variable which obeyed a first-order equation. A fourth power was used for potassium, and in this case, the rise of conductance was described by [1-e-t]⁴ and showed a marked inflection, whereas the fall was given by e-4t and remained exponential with a faster rate constant.

Figure 4. Time course of sodium and potassium conductance for different displacements at 6°C; the numbers give the depolarization used. The circles are experimental estimates and the smooth curves are solutions of equations (1) and (2) (from Hodgkin and Huxley 1952d) [Source: Hodgkin (1964a) or Hodgkin (1957) Proc R Soc Lond B Biol Sci 148,1-37].

A tentative picture of what might be going on, is that a path for potassium ions is formed when four charged particles have moved to the right place under the influence of the electric field. The probability of a single particle being correctly placed, denoted by n, obeys first-order kinetics, i.e.,

dn/dt = α(1−n)−ßn      (1)

where α increases and ß decreases as the inside of the nerve fiber becomes more positive. The potassium conductance is assumed proportional to the fourth power of n.

For the sodium channel, we assumed that three simultaneous events, each of probability m, opened the channel to sodium and that a single event of probability (1–h) blocked it. These events were not specified, but could be thought of as the movements of three activating particles and one blocking particle to a certain region of the membrane. The probability that there will be three activating particles and no blocking particle is then given by m³h, and the sodium conductance is proportional to that quantity. Both m and h obey first-order equations similar to (1). However, both the rate constants and the way they are affected by membrane potential are different for the m and h variables. Thus the effect of making the inside of the nerve fiber more positive is to increase m by raising a and lowering ß; this effect on the h rate constant is the opposite, so that h decreases with V.

A striking feature of the nerve membrane is the extreme steepness of the relation between ionic conductance and membrane potential. Thus both sodium and potassium conductances may be increased e-fold by a change of only 4 to 5 mV in membrane potential. The corresponding figure for most physical devices at room temperature is 25 mV. Our model allows for the steep relation of the membrane by making the rate constants increase sharply with membrane potential and by involving several particles at each site.

The steepness of the conductance-voltage relation must be of value to the animal because it enables the nervous system to work at much lower voltages than those of our computers. On the other hand, although efficient in this respect, ionic gating systems are much slower than their electronic counterparts.

Although partly empirical, our equations did account satisfactorily for many aspects of a nerve’s behavior. A simple case to deal with was the membrane action potential in which all parts of the membrane are activated simultaneously by applying a brief shock to a length of nerve. In the upper part of Figure 5 are theoretical curves for different initial displacements, and the lower curves are membrane action potentials recorded in an actual nerve. The agreement between real and model nerves is clearly satisfactory.

Figure 5. Upper curves, theoretical solution for different initial depolarizations of a uniform area of membrane. Lower curves, tracings of membrane action potential at 6°C obtained on same axon as that which gave Figure 4. The numbers attached to the curve give the strength of the shock in nanocoulomb/cm² (from Hodgkin and Huxley, 1952d) [Source: Hodgkin 1964a].

The form and velocity of the propagated action potential can be obtained by combining the equations for m, n, and h with the wellknown relation between membrane current density (I) and membrane potential (V). For a wave propagating with velocity θ in an axon of radius a and resistivity R, this is:

I = a/2Rθ²        ×        d²V/dt²      (2)

In the resulting second-order equation, the velocity is unknown at the beginning of the computation but can be found by guessing a value and running a trial solution. V then goes to ±∞ according to whether θ has been chosen too high or too low. The correct value that corresponds to the natural velocity brings the potential back to its resting value at the end of the run.

A solution of this kind was worked out by Huxley in 1950 and was found to agree with a real nerve in the following respects: the form, amplitude, and velocity of the action potential (Figures 6 and 7) and of the conductance changes, as do the total movements of sodium and potassium during the impulse. The equations also accounted satisfactorily for the refractory period and for a wide range of phenomena associated with the excitation of nerve under different conditions. A striking example was the oscillatory responses seen in response to a rectangular current in both model and real nerve.

Figure 6. Propagated action potentials in A, theoretical model, and B, squid axon, at 18.5°C. The calculated velocity was 18.8 msec and the experimental velocity 21.2 msec (from Hodgkin and Huxley, 1952d) [Source: Hodgkin 1964a].

Figure 7. Theoretical solution for propagated action potential and conductances at 18.5°C (From Hodgkin and Huxley 1952d). Total entry of sodium = 4.33 pmole/cm²; total exit of potassium = 4.26 pmole/cm² [Source: Hodgkin 1964a or 1957].

The immediate effect of carrying a train of impulses is that a nerve gains a small amount of sodium and loses a similar quantity of potassium ions. In large nerve fibers the changes in concentration of both ions resulting from a single impulse are extremely small, and a 500-μm diameter fiber might be able to conduct half-a-million impulses without recharging its batteries by metabolism. But whether large or small, nerve fibers would be of no value unless they could use metabolic energy to extrude sodium and reabsorb potassium after a train of impulses.

We guessed that nerve, like other tissues, would contain a sodium pump for extruding sodium and that it would be interesting to characterize the system using radioactive tracers. To begin with, Keynes and I, who worked together on this project, used cuttlefish axons. These were large enough to give us the necessary sensitivity and had the advantage that we could do the experiments in Cambridge. Later when we needed larger cells, we moved to Plymouth to do certain key experiments on squid axons.

This joint work with Keynes, which I enjoyed very much, lasted intermittently for more than 10 years. In the latter part of the work we were joined by P.F. Baker, T.I. Shaw, and P.C. Caldwell who contributed a great deal on both the theoretical and practical sides of the project. It has been a great sadness to me that all three of these brilliant and attractive people died relatively young: Caldwell and Baker from heart disease, and Shaw from an accident during a period of depression.

Although we were not able to give a full biochemical description of the sodium/potassium pump, we found out many interesting things about the way in which it works. In the first place it soon became clear that the downhill movements of sodium and potassium which take place during the impulse have completely different properties from the reverse, uphill movements that occur during recovery. For example, metabolic inhibitors which knock out the pump have no immediate effect on the action potential whereas tetrodotoxin, which blocks the action potential, has no effect on the pump. The systems also differ in their ionic selectivity. For example, lithium, which can replace sodium in the action potential, is not moved at all effectively by the pump. As might be expected, the downhill movements through sodium channels during the action potential are much faster than the uphill movements during recovery.

In the early 1950s it was clear that there had to be some kind of metabolic pump to drive out the sodium ions that leaked into the nerve or entered it during the impulse. However, the theory with regard to potassium was less clear, as these ions might be drawn in passively by the electrical negativity created by the sodium pump rather than by some chemical linkage between sodium and potassium movements. It also was not clear how the hydrolysis of ATP was involved with the pumping mechanism.

Our work at Plymouth clearly fitted well with the experiments of Skou (1957) in Denmark who showed that an essential component of the sodium pump was a membrane protein which catalyzed the hydrolysis of ATP into ADP and inorganic phosphate. This enzyme, which is widely distributed, is known as an Na,K,-ATPase. It is catalyzed by sodium inside and potassium outside the cell. We were able to obtain evidence for several of these points by restoring the sodium/potassium pump with injections of ATP or ATP generators. The quantity of sodium ions extruded was roughly proportional to the amount of ATP injected. The theory now generally accepted is that two potassium ions are absorbed and three sodium ions extruded for each ATP split.

I worked at Plymouth nearly every year between 1958 and 1970, usually in the late autumn when large squid were in good supply. I found, as others have done, that it is easier to keep going with experiments when you are away from home and the laboratory has priority. My scientific partners during that period included P.F. Baker, T.I. Shaw, H. Meves, W.K. Chandler, M. Blaustein, and E.B. Ridgway. At first we worked mainly on perfused fibers, but later we studied calcium movements using radioactive calcium or the calcium-sensitive protein aequorin, extracted from certain jellyfish that emit light in the presence of calcium ions. Some of this work helped to advance the idea that internal calcium ions might be kept at a low level by a system in which several external sodium ions are exchanged for one internal calcium ion.

Move to Visual Research

The autumn of 1970 ended my experiments at Plymouth. After that I switched my interest to visual research which I could do in Cambridge with the help of colleagues or visitors. In the end I thoroughly enjoyed the change, but at the time I sometimes felt that in the middle of my scientific life “I found myself in a dark wood with no straight path before me.” The main reason for the change was that in December I was to become president of the Royal Society in London with a tenure of five years. I thought that with the right colleague I could keep experiments going in Cambridge and combine a London life with a Cambridge one, but saw no way that I could add in Plymouth as well.

As a student in Cambridge I had been influenced by Adrian’s work on the retina and by H.K. Hartline’s work on the eyes of Limulus. Later, I was impressed by the work that Hartline and his colleagues were doing on generator potentials, which I heard about at the 1952 Cold Spring Harbor Conference.

In making the move to visual research I was helped by my friendship with M.G. Fuortes, an Italian physiologist whom I had met in Cambridge before his move to the United States in 1950. In 1961 we started to correspond about work that he was doing on the eye of Limulus. I was to lecture at Woods Hole in 1962, and Fuortes asked me to join him in experiments on Limulus eyes. We were interested in the long delay between a light flash and the electrical response, which we thought might arise from the time taken for a signal to pass through a cascade of intermediate chemical reactions, possibly stages of chemical amplification. We also wanted to know how the delay might change with light adaptation. It turned out that in the Limulus eye, as in most eyes, there is a trade-off between time resolution and sensitivity: the eye loses sensitivity but gains time resolution as it adapts to light. There was something in both these ideas, but looking back after 30 years, they seem absurdly amateur and oversimplified.

Fuortes, who was known as Mike (an abbreviation of Michelangelo), was one of the first people to get satisfactory readings from microelectrodes inserted into photoreceptors. Before that he had worked mainly on motoneurons, a subject which he had studied with Bryan Matthews in Cambridge. I am not sure what caused Mike to switch to vision and have the temerity to work on Limulus, an animal generally regarded by workers at Rockefeller University as their property despite its great antiquity. But I can guess that one factor was the 1952 Cold Spring Harbor Conference, where we listened to an excellent paper by Hartline’s team, illustrated by records of generator potentials in single ommatidia. This research showed that much could be done if microelectrodes could be inserted into photoreceptors without damaging them. By 1962 Mike had been doing this for several years, and I was familiar with his work as he sometimes sent his manuscripts to William Rushton and me for comments.

I found Mike a pleasant collaborator—patient, tolerant of other people’s mistakes, and good at getting difficult experiments to work. I kept asking questions about generator potentials and he would reply, “Yes, I have done experiments on that but the films are back at NIH.” When he came to Cambridge early in 1963 he brought a lot of films with him which we spent a long time analyzing. This work led to a paper published a year later. At Woods Hole we had also done experiments on the quantal bumps which Yeandle had discovered. These experiments never got published but they had a considerable influence on Mike’s pupil, and my subsequent colleague, Denis Baylor.

The idea about a cascade of chemical reactions proved to be broadly correct, but the conjecture was too vague to be useful and it was some time before the nature of the intervening chemistry began to be understood. There also had to be a minor revolution in our understanding of the way in which vertebrate and invertebrate animals perceive light and dark.

Closure of Ionic Channels by Light in the Photoreceptors of Vertebrates

By 1965 a number of invertebrate photoreceptors had been studied, and the general pattern conformed to that in Limulus. In all cases, light was absorbed by rhodopsin and then, by a chain of events that was still unknown, the conductivity of the cell membrane was increased. The result was that the cell was depolarized—that is, the cell interior became less negative than in the resting condition. This result is what one would expect because the photoreceptor is electrically connected to the nerve fiber. A positive-going change (depolarization) is what is needed to activate the nerve, and one would expect light to set up a wave of this polarity in the cell.

Therefore many of us were surprised when A. Bortoff in Russia and T. Tomita in Japan and their colleagues showed that in the receptors of vertebrates light decreases membrane conductivity and makes the inside of the cell more negative. This finding breaks the general rule that sensory stimulation depolarizes cells and increases conductivity. One may find it unreasonable to be disturbed by a simple change of polarity or to think that all animals should contain the same basic mechanism. But there is more in it than that. Electrical changes in the nervous system are usually conveyed from one cell to the next by a mechanism that involves the release of a chemical transmitter. Because transmitters are normally released by a positivegoing change in the internal potential of the cell, it seems that vertebrate rods and cones must release transmitter continuously in the dark, and that light suppresses this release by making the inside of the cell negative.

There is nothing really surprising about this. Physiologists and psychologists often test the eye with flashing lights, but these are not the natural stimuli which an animal encounters in its everyday life. A dark object against a light background, which may be either predator or prey, may be a more important stimulus than a bright spot of light.

Figure 8 summarizes the position reached as a result of the work of several schools, notably those of Bortoff, Tomita, Fuortes, and W. Hagins.

Figure 8. Effect of illumination in suppressing the dark current of retinal rods.

In the dark, the outer segment of a rod or cone is permeable to sodium ions and there is a steady circulating current with sodium ions entering the outer segment and potassium ions leaving the cell from the more concentrated internal solution. A steady state is maintained by a sodium/potassium pump located in the inner segment. The resting potential is about–35 mV, and the pedicle at the base of the cell is liberating a chemical transmitter (probably glutamate) at a high rate. All this is stopped by light. The sodium channels are closed; the resting potential rises to –60 mV and the release of transmitter is greatly reduced.

The electrical signal produced by a flash of light has a remarkable waveform which has repaid detailed study. Figure 9, which is from Baylor, Fuortes, and O’Bryan (1971), shows the signals produced by a turtle cone in response to 10 msec flashes varying in strength over a 1,000-fold range.

Figure 9. Response of turtle cone to flashes of light of different intensity; the numbers on each curve give the logarithm to base 10 of the light intensity relative to the unattenuated beam. The vertical scale gives the internal potential of the cone.

As can be seen, the response to a strong light saturates when the potential has increased from –35mV to –53 mV, but it continues to get longer as the brightness of the flash is increased so information about the strength of the flash is not lost. The upper level of –53 mV corresponds to the potential at which the variable sodium conductance is almost completely suppressed; the potential then becomes equal to that of the potassium battery.

A curious feature of the response, which is even more conspicuous in rods, is the initial hump before the plateau. It later became clear that this was a secondary event introduced by voltage-dependent changes in the inner segment of a rod or cone. When current was recorded from the outer segment, where the light quanta are caught, the effect was not seen. By saying that the effect is secondary, I mean that it happens later, not that it is unimportant. We now know that signals undergo several stages of processing as they are handed from one cell to the next in the retina. It is now clear that the first stage of processing happens when currents are transformed into voltage in the rod itself.

My first laboratory contact with the vertebrate retina was in the autumn of 1970 when Denis Baylor, who had worked for several years with Fuortes at the National Institutes of Health in Bethesda, Maryland, came for a two-year visit to Cambridge. This was the beginning of an alliance between Baylor’s group in Stanford, California, and mine in Cambridge, which has led to several productive collaborations.

After some preliminary experiments and a long period assembling optical equipment (with much help from Andrew Huxley), Baylor and I settled down to study cones, and occasionally rods, in the retina of the turtle Pseudemys, a preparation on which Baylor, Fuortes, and O’Bryan had already done important experiments.

As in other vertebrates with color vision, there are three main types of cone in the turtle eye, each with a different visual pigment and a different spectral sensitivity. We confirmed the division into red-, green-, and blue-sensitive cones and extended it by showing that the colored oil droplets, which are present in turtles and many other animals, sharpened the spectral sensitivity as well as helped to channel light into the outer segment of the cone.

Unlike most higher vertebrates, no placental mammal has oil droplets. One cannot help wondering whether turtles, birds, and other animals that do may not see the world in brighter, or at any rate different, colors than we do. But this raises doubts about the admissibility of such questions, and it is safer to stick to the experimental approach.

One useful result of our experiments was the demonstration that turtle cones obeyed a generalization enunciated by Rushton, sometimes known as the principal of univariance. This principle states that the output of a receptor depends only on the number of quanta absorbed and not on their wavelength. To put this in another way, a green-sensitive cone is poor at catching quanta in the red end of the spectrum, but when it does absorb a long-wave quantum it gives precisely the same signal as it would for a quantum of shorter wavelength. Figure 10 illustrates this result using the voltage response of a red-sensitive cone as a criterion and a small spot of different wavelength as a stimulus. One can see that all three colors give exactly the same shaped response and can be scaled onto a common curve.

Figure 10. Linear response of a red-sensitive cone to 10 msec flashes of light of different wavelengths, scaled to give the same amplitude. The scaling factor Rq, the relative quantum sensitivity, was 1 for 644 nm, 8 ¥ 10⁻⁴ for 805 nm, and 0.24 for 400 nm. Vertical lines are ±1 SEM. Zero time corresponds to the midpoint of the flash. The recording was obtained from a microelectrode inserted into a cone in the isolated retina of the turtle Pseudemys scripta elegans. The diameter of the light spot on the retina was 150 μm (from Baylor and Hodgkin, 1973).

When the internal potential of the cone is used to measure the response, univariance holds only if a small spot is employed. This is because a large spot activates surrounding cones of different spectral sensitivity which affect the impaled cone through horizontal cells. A better method of measuring spectral sensitivity is to record the current produced by the outer segment. This has now been done by Baylor’s group using the rods and cones of the Macaque monkey, which are known to be similar to those of humans.

About 50 years ago Hecht, Schlaer, and Pirenne concluded that a dark-adapted human can detect a flash in which something like 10 quanta fall on an area containing about 500 rods. This observation made it highly likely that a single quantum would have a detectable electrical effect on a rod. This observation was made satisfactorily when recording current from the outer segment with the suction electrode developed by Baylor, Lamb, and Yau (1979), who found quantal bumps of about 1 pA in amplitude and three seconds in duration. However, an apparent paradox appeared when an attempt was made to perform the same type of experiment with microelectrodes.

Figure 11 illustrates an experiment in which we introduced a microelectrode into a dark-adapted turtle rod and then applied a series of diffuse flashes of a strength such that on average each rod would absorb a quantum on about 70 percent of occasions. If rods were isolated one would expect such responses to be extremely variable. A simple calculation shows that one would expect to get nothing on 50 percent of occasions, 1 unit of 3 mV on 35 percent of occasions, 2 units of 6 mV on 12 percent of occasions, and so on.

Figure 11. Voltage response of turtle rod to series of weak, diffuse, 500 nm flashes repeated at 10 sec intervals. On average each rod should have absorbed 1 quantum on about 70 percent of occasions. The trace shows the internal potential of a rod measured with a microelectrode inserted into the inner segment. The resting potential was –42 mV and the maximum response to a strong flash was 40 mV; flash duration 20 msec. Note that the variability of these voltage responses was small compared with the variability of the response when current was measured as in Figure 12 (from a record of Detwiler, Hodgkin, and McNaughton, 1980).

As can be seen from Figure 11 there is some variation, but nothing like this. In some way rods seem to have cheated the quantum theory. Physicists will know that this is impossible and may think that we and others who have observed the same discrepancy have got our calibrations wrong. But that is not the case. The answer is that rods are coupled so that the effects of one photon are averaged over about 100 rods. One does not get something for nothing because coupling reduces the acuity of the rods, and detail is seen less well than it would be if cells were isolated. In this connection I should mention experiments on darkadapted turtle rods, which show that the effects of an absorbed photon spread out over a large area initially which then contracts down to a smaller one at long times (Detwiler, Hodgkin, and McNaughton, 1980). This must help to increase early awareness at short times while preserving some visual acuity for later.

Partly to get around the difficulty introduced by coupling, Baylor, Lamb, and Yau developed the suction method of recording, in which the outer segment of a single rod is sucked into a narrow, tightly fitting capillary (Figure 12). The potential difference across the tip of the capillary then gives the photocurrent.

Figure 12. Arrangements for recording membrane current of rod outer segment. A, Original Stanford method of Baylor et al. B and C, Modifications introduced at Cambridge by McNaughton, Yau, Nunn, and the author to measure effect of ions on rod currents. In B, the inner segment of an isolated rod is sucked into a capillary and the outer segment is in flowing solution. C shows the reverse arrangement with the inner segment in flowing solution.

The method, or variants of it, showed that in a dark-adapted toad or salamander rod each absorbed quantum reduced the standing current in a single rod by 1 pA for about three seconds and that such events occurred in the expected random manner (Figure 13).

Figure 13. Current response of rod outer segment to 40 consecutive dim flashes repeated at eight second intervals; flashes of strength such that on average 1 quantum was successfully absorbed per flash on 53 percent of occasions. 20 msec flashes of wavelength 500 nm; flash timing monitored below [from Baylor, Lamb, and Yau (1979)].

The Nature of the Internal Transmitter

Since the work of Baylor and Fuortes in 1970, researchers have agreed that in rods and cones there has to be some kind of internal linkage which connects the activated rhodopsin inside the cell with the surface membrane. The position is clearest in rods where a single photon absorbed anywhere inside the outer segment can stop the movement of about 10 million sodium ions per second for a period of one to two seconds.

For some time there were two main candidates for the internal messenger. In 1975 Hagins and Yoshikami suggested that light released calcium ions from disks, and that these ions then blocked channels. The rival theory, now thought to be correct, is that cyclic GMP is present at a fairly high concentration and keeps the light-sensitive channels open in the dark. Rhodopsin activated by light catalyzes a G-protein which in turn activates the enzyme phosphodiesterase that hydrolyzes cyclic GMP. The turnover number of this enzyme is high, about 2,000/second, so that a strong flash causes a rapid fall in cyclic GMP and hence a rapid decrease in the inward current of sodium ions.

In 1985 opinion swung strongly against calcium and in favor of the cyclic GMP theory. There were several kinds of evidence but the one that I found most convincing was that of E.E. Fesenko, S.S. Kolesnikov, and A.L. Lyubarsky, who submitted an article to Nature in the summer of 1984. The Russian workers showed that the concentration of an isolated patch of membrane was not reduced by raising calcium, but that it was increased in a rapid and reversible manner by applying a physiological concentration of cyclic GMP to the inner surface membrane obtained from a rod outer segment. Cyclic GMP appears to act directly on the ionic channels rather than by turning on a cascade of phosphorylating enzymes as biochemists originally thought. Details of the mechanism and of the names of some of those who worked it out can be found in the excellent review by Stryer (1986).

Apart from the positive evidence that cyclic GMP is the internal transmitter, there were good reasons for thinking that all was not well with the calcium theory. For example Yau and Nakatani (1984) showed that a light flash decreased rather than increased internal calcium. Another result obtained by McNaughton and Nunn (1985), which is incompatible with the calcium theory, was that transferring the rod to isotonic calcium chloride caused a large transient increase in light-sensitive current. A further strong objection to the calcium theory was the demonstration that the introduction of the calcium chelator BAPTA had little effect on the rising phase of the response (Lamb, Matthews, and Torre, 1986).

The conclusion from these and other experiments was that a rise in internal calcium did not close channels, but acted indirectly, perhaps blocking guanylate cyclase and interfering with the supply of cyclic GMP.

Ionic Movements and the Cyclic Nucleotide Cascade

Although calcium ions are no longer considered to be the internal transmitter it is clear that they play an important part in controlling the ionic currents underlying photoreception. Some of my experiments with Brian Nunn are concerned with this subject and are summarized in a review written shortly before his death (Hodgkin, 1988; Hodgkin and Nunn, 1988).

I entered this field with some trepidation as I knew little modern biochemistry, and it is hard to learn anything new when you are over 70. However, I cheered up when I found that our experiments would involve the sodium/calcium exchange mechanism on which Baker, Blaustein, and I had worked at Plymouth some years before. This system maintains a low internal calcium ion concentration at the expense of the sodium and potassium gradients, which are themselves maintained by the sodium/potassium pump (Cervetto et al., 1987; McNaughton, 1990).

The main chemical and electrical events in the cascade that follows the absorption of a quantum of light are summarized by the highly simplified diagram in Figure 14. With a salamander rod in the dark there is an inward sodium current of about 50 pA, which is only 5 percent of the maximum light-sensitive current that the cell is capable of producing. This effect occurs because a large number of channels are closed, some by external calcium and others because the concentration of cyclic GMP is not high enough to keep the whole population open. At first it seems wasteful to have most of the channels closed, but it may be helpful to stabilize cyclic GMP at a low level. If there were a high concentration of cyclic GMP, many molecules would need to be hydrolyzed and the system would be insensitive to light.

Figure 14. Scheme showing possible interactions of Ca²⁺ with ionic channels and with cyclic nucleotide cascade. Rh is rhodopsin, Rh* is rhodopsin activated by light. T is transducin, a G-protein, and T* is the activated form produced by GTP replacing GDP in the G-protein in a cyclical reaction catalyzed by Rh*. PDE is the phosphodiesterase which, when activated by T*, catalyzes the hydrolysis of cyclic GMP to GMP. The figures in brackets give the number of rhodopsin, transducin, or PDE molecules in a toad rod; other figures give the number per photoisomerization. Instead of prolonging the life of activated PDE, Ca²⁺ might act by increasing the number of T* per Rh*, perhaps by prolonging the life of Rh*. For further details see Stryer, 1986.

In a toad or salamander rod there are about 2 × 10⁹ molecules of rhodopsin. Absorption of a light quantum by a rhodopsin molecule causes its retinal chromophore to isomerize from the 11-cis to the all-trans form, a change that leads neighboring parts of the molecule to become enzymatically active and catalyze the production of activated transducin, a G-protein. Considerable amplification occurs at this stage and roughly 1,000 active transducin molecules may be produced by one photoisomerization. Activation of transducin involves the replacement of GDP by GTP in the G-protein and is a cyclical process driven by GTP. In vivo, the activated transducin has a lifetime of one or two seconds in rods and less in cones. However, the quenching of transducin is still the subject of active research (see reviews by McNaughton (1990) and by Lagnado and Baylor (1992)). From transducin, activation is handed on to phosphodiesterase, which can rapidly hydrolyze cyclic GMP and close channels in a fraction of a millisecond. The number of cyclic GMP molecules hydrolyzed by one quantum is the order of 103, which suppresses the entry of between 10⁶ and 10⁷ sodium ions—this being the overall amplification of the system in ions per quantum. The amplification in terms of energy is less because the system transforms down from 2.5 electron volts—the energy of a quantum of 500 nm light—to about 0.1 electron volts—the energy saved by stopping one sodium ion from moving down its electrochemical gradient.

Lagnado and Baylor (1992) and others have pointed out that if the high gain of the transduction mechanism were constant, a steady background of moderate intensity would close all the light-sensitive channels and prevent any additional signals from being encoded. However, a gain-control mechanism automatically reduces sensitivity so that some channels remain open in the presence of a background. The drop in sensitivity depends to a considerable extent on the fact that the light-sensitive channels are permeable to calcium as well as sodium ions. Measurements with a rapid solution change method suggest that calcium is about 10 times more permeable than sodium. The internal calcium level depends on the balance of entry through light-sensitive channels and extrusion through the sodium/calcium potassium exchanger. When calcium influx is blocked by closure of channels by light, internal calcium is pumped down by the exchanger with the result that many channels reopen and the eye becomes light-adapted. The same mechanism helps to keep the response to a flash short, as was shown later by Brian Nunn and myself (Hodgkin and Nunn, 1988). Further evidence that the drop in internal calcium is partly responsible for light-adaptation, is that clamping the internal calcium with buffers blocks the reduction in sensitivity normally associated with background light (Yau and Nakatani, 1985; Lamb et al., 1986).

In 1986 McNaughton, Nunn, and I came across the interesting phenomenon illustrated by Figure 15. We found that raising external calcium immediately before a flash had the effect of sensitizing the rod, in that recovery from the flash was delayed by an amount equivalent to a 2.3-fold increase in flash strength. If the same pulse of raised calcium was given more than about 1 second before the flash, the effect disappeared, presumably because internal calcium was pumped out with a time constant of 0.5 second or so. If given on top of the response the effect again disappeared, probably because all calcium channels were closed and no calcium could get in. Later as channels reopened, calcium had a rapid and reversible effect in shutting off the current, but there was no prolongation of the current, such as that observed immediately after the flash.

Figure 15. Effect of one second pulse of raised external calcium in lengthening the response of a salamander rod when applied immediately before a strong flash. Record b (left) shows the effect of the flash by itself, applied at time 0. Record a shows the effect of preceding the flash (and in practice overlapping it) with a one second pulse of raised calcium (10 mM instead of 1 mM) applied from –1 to 0 seconds; note the prolongation of the response. The right-hand records show the effect of the flash by itself and with the pulse of raised calcium applied on the plateau and during the falling phase; note that there is no prolongation of the response (Hodgkin, McNaughton, and Nunn 1986).

These effects are consistent with a sensitizing effect of elevated calcium at an early stage in the transduction chain. It also seems that the levels of ionized calcium and cyclic GMP must be in rapid equilibrium during recovery from the flash.

Just before Brian Nunn left Cambridge we obtained evidence that reducing internal calcium accelerates recovery in two ways: (1) by turning on guanylate cyclase and accelerating the supply of cyclic GMP, and (2) by reducing the lifetime or number of active transducin molecules and decreasing the activity of phosphodiesterase, so lowering the rate of hydrolysis of cyclic GMP.

At the Helmerich conference in 1986 I wrote the following:

…it will be aesthetically pleasing when the various interactions between ions and the nucleotide cascade can be summarized in a set of differential equations that describe the complicated responses to light or chemical and ionic changes. At one time I had hoped to be in on this myself but as things have turned out, all I can do is to gaze from Pisgah to the promised land where I hope you will enjoy yourselves.

Although much has been discovered during the last 10 years we are still a long way from fully understanding how the retina transforms visual into neural signals.

Retrospective

To my great sorrow Brian Nunn died in September 1987, which put an end to some plans we had made for future research. Our last paper was published in 1988 and since then I have devoted much of my energy to writing, in particular to Chance and Design, an autobiography dealing mainly with the first part of my life.

Royal Society Presidency, 1970–1975

In 1970 when I became president, the Royal Society had been in Carlton House Terrace, London, for three years and the former president and his wife, the Blacketts, had furnished and lived in the president’s flat on the third floor. This flat contained one large room with a splendid view looking across St. James Park to Westminster. David Martin, the executive secretary, thought that after I took office I would need to spend two or three nights in London—an estimate which proved about right. At that time my wife, Marni, was running children’s books at Macmillan and usually commuted to London four days a week from Cambridge. She welcomed the idea that the Royal Society should be our London pied-a-terre and we lived there happily in the midweek for the next five years. I was keen to keep my experimental work going in Cambridge, both because it was going well and because unless I have some research to think about, I become too obsessively involved with administration—and too upset when things go wrong, as they often do. With the help of Denis Baylor and other visiting scientists I managed to do my research reasonably successfully, though it often meant working for much of the weekend.

When I had become president, David Martin had asked me rather nervously whether I had a policy. I said I had not but thought that my predecessors, Lord Florey and Lord Blackett, had formulated objectives which would keep us busy for the next five years. Briefly, these objectives were that the Society should take a greater part in promoting research, particularly in its international aspects or in connection with appointments of outstanding distinction, such as Royal Society research professorships; also that the Society should aim to make its meetings more interesting and accessible to all concerned with pure and applied science. This had been difficult at the Society’s former home, Burlington House, but would be much easier in our new premises in Carlton House Terrace with its large lecture hall. When asked what I had enjoyed most during my five years as president, my answer was “entertaining friends and colleagues in this beautiful building.” Next to that, and on a more serious plane, I put the sense of historical continuity and of taking part in scientific discussions in a Society that counted Robert Boyle and Sir Isaac Newton among its earliest members.

International relations were prominent in the Society’s activities, and I found myself bombarded with invitations from different countries. During the next six years I visited Japan, India, Canada, Australia, China, Kenya, and Iran (the last two after my presidency but on Royal Society business). A delegation was going to Moscow in 1975 but at the last moment was postponed to a date that I could not manage. However, I had already spent May 1967 in Russia and the neighboring country, Georgia, and did not particularly mind missing this trip.

The Royal Society attached high priority to restoring the links with Chinese science which had flourished before the Cultural Revolution but disappeared completely after it. One or two Fellows did manage to go to China, and we helped them to get visas. But the Chargé d’Affaires hated to put anything on paper and preferred to make a solemn declaration that it was perfectly in order for Dr. X to visit China.

Eventually the Chinese Academy of Science invited a small delegation from the Royal Society to visit China and discuss scientific exchanges. In May 1972, Kingsley Dunham (our new foreign secretary), Martin, and I accepted at once and booked tickets on the overland air route through Siberia. However, at the last minute we were told by the Chargé d’Affaires that permission was withdrawn and we must cancel our visit. This we refused to do, cabled the Academy that we were coming, and went ahead on the flight through Moscow, Omsk, and Irkutsk to Beijing. In Beijing we were greeted in a friendly way, put up in a comfortable hotel, taken sightseeing and shown various university departments, which seemed more disorganized by the Cultural Revolution than most other institutions in China. This was not surprising because one of the aims of the Cultural Revolution was to prevent the re-emergence of an intellectual elite.

The sightseeing was interesting, but not what we came to accomplish. After several days it became evident that the Cultural Revolution was still much in force, and that members of the Chinese Academy were frightened of arranging any sort of meeting with our delegation. After consulting the British ambassador we sent a letter asking for a meeting to the right man at the Chinese Academy. This was written in the grandest handwriting and phrased in the politest language we could manage. It did the trick. An evening meeting was arranged, and an exchange arrangement between Britain and China was discussed and supported on the understanding that it would be developed later by a Chinese delegation to the Royal Society—an event that took place in October and formed the basis of the numerous visits that have been made since by both British and Chinese participants.

On our last evening in Beijing we went to a formal banquet in the Hall of the Peoples, where we were received by the president of the academy, Ko-Mo-Jo, with whom gifts of books were exchanged, and where he stated that the academy looked to United Kingdom scientists for help in developing the study of fundamental sciences in China.

Trinity College, Cambridge, 1978–1984

As a Trinity College scholarship in 1931 was the event that opened up a career in science for me, there was something appropriate about ending my academic life as Master of Trinity, the college where so many distinguished scholars had found interest and happiness. So, in 1978, I had no hesitation in accepting the Mastership, although it meant a great change in our way of life. My wife gave up her publishing job with Macmillan, and we sold our over-large but much loved house in Newton Road. This saddened our children and grandchildren, who were deeply attached to our old home although they no longer lived there. However, they soon came round to the view expressed by an American friend that the Master’s Lodge in Trinity was “not a bad pad.”

Even if you do not love grandeur, you would have to be unromantic not to feel the charm of living in the splendid house described by the historian G.M. Trevelyan as “built by Nevile’s love and Bentley’s pride.” It is true that in summer the courts are full of tourists, and one wishes that more visitors would accept Baedeker’s advice that “Cambridge is less attractive than Oxford and may be omitted altogether if the visitor is short of time.” But even at the height of the tourist season, peace returned in the evening, and in the early morning a kingfisher or a heron could occasionally be seen on the river wall at the end of the Master’s garden.

Transcending these details was the feeling that the Master’s Lodge was part of Trinity College and belonged to its history, or even its prehistory. In the Comedy Room wall, to quote Trevelyan again, “the bees have made their hives in blocked-up windows that once looked out on the Wars of the Roses.”

Most country houses or palaces are lived in for only months of the year and are often empty for long periods of time. But Trinity Lodge has been lived in more or less continuously for nearly four centuries and must have seen some 50,000 undergraduates come and go in Trinity Great Court. Partly for that reason we adopted the practice of keeping the picturelights on in the lodge, so that on winter evenings undergraduates crossing Great Court could catch glimpses of the portraits of Elizabeth I and famous Trinity men like Isaac Newton and the poet Andrew Marvell.

One change that I remember with satisfaction was the coincidence of my Mastership with the entry of female undergraduates to Trinity College in 1978. I believe that this change, about which many people were nervous, has been a resounding success and will be of enduring benefit to the college.

Another satisfying development was the continued growth of the Trinity Science Park on land given to Trinity’s precursor, King’s Hall, in 1443. Both the creation and development of this major enterprise were the work of the senior burser of Trinity, John Bradfield. I am glad that I was able to help him with this project which is important in bridging the gap between science and industry—not only in Cambridge but in the country as a whole.

We were told that on leaving a master’s lodge in Cambridge, one must either move into the country or stay as near the center of the city as possible. We chose the latter course and found an oldish house between the Fitzwilliam Museum and the Botanical Garden. Although quite unlike our previous homes, it suits us down to the ground.

Selected Publications

Adrian ED. The basis of sensation. London: Christophers, 1928.

Adrian ED. The physical background of perception. Oxford: Clarendon Press, 1947.

Adrian RH, Chandler WK, Hodgkin AL. Voltage clamp experiments in striated muscle fibres. J Physiol (Lond) 1970;208:607–644.

Aidley DJ. The physiology of excitable cells. 3rd ed. Cambridge: Cambridge University Press, 1989.

Armstrong CM, Bezanilla FM. Charge movement associated with the opening and closing of the activation gates of the Na channels. J Gen Physiol 1974;63:675–689.

Atwater I, Bezanilla F, Rojas E. Sodium influxes in internally perfused squid giant axons during voltage clamp. J Physiol (Lond) 1969;201:657–664.

Baker PF, Blaustein MP, Hodgkin AL, Steinhardt RA. The influence of calcium on sodium in squid axons. J Physiol (Lond) 1969;200:431–458.

Baker PF, Hodgkin AL, Meves H. The effects of diluting the internal solution on the electrical properties of a perfused giant axon. J Physiol (Lond) 1964;170:541–560.

Baker PF, Hodgkin AL, Shaw TI. Replacement of the protoplasm of a giant nerve fibre with artificial solutions. Nature 1961;190:885–887.

Baker PF, Hodgkin AL, Shaw TI. Replacement of the axoplasm of giant nerve fibres with artificial solutions. J Physiol (Lond) 1962a;164:330–354.

Baker PF, Hodgkin AL, Shaw TI. The effects of changes in internal ionic concentrations on the electrical properties of perfused giant nerve fibres. J Physiol (Lond) 1962b;164:355–374.

Baker PF, Shaw TI. A comparison of the phosphorus metabolism of intact squid nerve with that of the isolated axoplasm and sheath. J Physiol (Lond) 1965;180:439–447.

Baylor DA, Fuortes MGF. Electrical responses of single cones in the responses of the turtle. J Physiol (Lond) 1970;207:77–92.

Baylor DA, Fuortes MGF, O’Bryan PM. Receptive fields of cones in the retina of the turtle. J Physiol (Lond) 1971;214:265–294.

Baylor DA, Hodgkin AL, Lamb TD. The electrical response of turtle cones to flashes and steps of light. J Physiol (Lond) 1974a;242:685–727.

Baylor DA, Hodgkin AL, Lamb TD. Reconstruction of the electrical responses of turtle cones to flashes and steps of light. J Physiol (Lond) 1974b;242:759–791.

Baylor DA, Hodgkin AL. Detection and resolution of visual stimuli by turtle photoreceptors. J Physiol (Lond) 1973;234:163–198.

Baylor DA, Hodgkin AL. Changes in time scale and sensitivity in turtle photoreceptors. J Physiol (Lond) 1974;242:729–758.

Baylor DA, Lamb TD, Yau K-W. Responses of retinal rods to single photons. J Physiol (Lond) 1979;288:613–634.

Blaustein MP, Hodgkin AL. The effect of cyanide on the efflux of calcium from squid axons. J Physiol (Lond) 1969;200:467–527.

Blinks LR. The direct current resistance of Nitella. J Gen Physiol 1930;13:495–508.

Blinks LR. The effect of current flow on bioelectric potential III. Nitella. J Gen Physiol 1936;20;495–508.

Bortoff A. Localisation of slow potential responses in the Necturus retina. Vision Res 1964;4:627–635.

Brinley FJ, Mullins LJ. Sodium extrusion by internally dialysed squid axons. J Gen Physiol 1967;50:2303–2332.

Caldwell PC, Hodgkin AL, Keynes RD, Shaw TI. The effects of injecting “energyrich” phosphate compounds on the active transport of ions in the giant axons of Loligo. J Physiol (Lond) 1960;152:561–590.

Caldwell PC, Keynes RD. The utilization of phosphate bond energy for sodium extrusion from giant axons. J Physiol (Lond) 1957;137:12P.

Caldwell PC. The phosphorus metabolism of squid axons and its relationship to the active transport of sodium. J Physiol (Lond) 1960;152:545–560.

Catterall WA. Voltage-dependent gating of sodium channels: Correlating structure and function. Trends Neurosci 1986;9:7–10.

Cervetto L, Lagnado L, McNaughton PA. Activation of the Na:Ca exchange in Salamander rods by intracellular Ca. J Physiol (Lond) 1987;382:135P.

Chandler WK, Hodgkin AL, Meves H. The effect of changing the internal solution on sodium inactivation and related phenomena in giant axons. J Physiol (Lond) 1965;180:821–836.

Clay JR, DeFelice LJ. Relationship between membrane excitability and single channel open-close kinetics. Biophys J 1983;42:151–157.

Cole KS, Curtis HJ. Electric impedance of the squid giant axon during activity. J Gen Physiol 1939;22:649–670.

Cole KS, Hodgkin AL. Membrane and protoplasm resistance in the squid giant axon. J Gen Physiol 1939;22:671–687.

Cole KS. Dynamic electrical characteristics of the squid axon membrane. Arch Sci Physiol 1949;3:253–258.

Cole KS. Membranes, ions, and impulses. Berkeley: University of California Press, 1972.

Cole KS. Rectification and inductance in the squid giant axon. J Gen Physiol 1941;25:29–51.

Curtis HJ, Cole KS. Membrane action potentials from the squid giant axon. J Cell Physiol 1940;15:145–157.

Curtis HJ, Cole KS. Membrane resting and action potentials from the squid giant axon. J Cell Physiol 1942;19:135–144.

Detwiler PB, Hodgkin AL, Lamb TD. A note on the synaptic events in hyperpolarizing bipolar cells of the turtle’s retina. In: Borsellino A, Cervetto L, eds. Photoreceptors. Plenum, 1984;285–293.

Detwiler PB, Hodgkin AL, McNaughton PA. A surprising property of electrical spread in the network of rods in the turtle’s retina. Nature 1978;274:562–568.

Detwiler PB, Hodgkin AL, McNaughton PA. Temporal and spatial characteristics of the voltage response of rods in the retina of the snapping turtle. J Physiol (Lond) 1980;300:213–250.

Detwiler PB, Hodgkin AL. Electrical coupling between cones in turtle retina. J Physiol (Lond) 1979;201;75–100.

Draper MH, Weidmann S. Cardiac resting and action potentials recorded with an intracellular electrode. J Physiol (Lond) 1951;115:74–94.

Feng TP, Liu YM. The connective tissue sheath of the nerve as effective diffusion barrier. J Cell Physiol 1949;34:1–16.

Fesenko EE, Kolesnikov SS, Lyubarsky AL. Induction by cyclic GMP of cationic conductance in plasma membrane of retinal rod outer segment. Nature 1985;313:310–313.

Frankenhaeuser B. A method for recording resting and action potentials in the isolated myelinated nerve fibres of the frog. J Physiol (Lond) 1957;135:550–559.

Frankenhaeuser B, Hodgkin AL. The action of calcium on the electrical properties of squid axons. J Physiol (Lond) 1957;137:218–244.

Fuortes MGF, Hodgkin AL. Changes in time scale and sensitivity in the ommatidia of Limulus. J Physiol (Lond) 1964;172:239–263.

Gray J. A text-book of experimental cytology. Cambridge: Cambridge University Press, 1931.

Hill AV. Chemical wave transmission in nerve. Cambridge: Cambridge University Press, 1932.

Hille B. Ionic channels of excitable membranes. Sunderland, MA: Sinauer, 1984.

Hodgkin AL, Horowicz P. Movements of Na and K in single muscle fibres. J Physiol (Lond) 1959a;145,405–432.

Hodgkin AL, Horowicz P. Potassium contractures in single muscle fibres. J Physiol (Lond) 1960b;153:386–403.

Hodgkin AL, Horowicz P. The differential action of hypertonic solutions on the twitch and action potential of a muscle fibre. J Physiol (Lond) 1957;136:17—18P.

Hodgkin AL, Horowicz P. The effect of nitrate and other anions on the mechanical response of single muscle fibres. J Physiol (Lond) 1960c;153:404–412.

Hodgkin AL, Horowicz P. The effect of sudden changes in ionic concentration on the membrane potential of single muscle fibres. J Physiol (Lond) 1960a;153:370–385.

Hodgkin AL, Horowicz P. The influence of potassium and chloride ions on the membrane potential of single muscle fibres. J Physiol (Lond) 1959b;148:127—160.

Hodgkin AL, Huxley AF, Katz B. Ionic currents underlying activity in the giant axon of the squid. Arch Sci Physiol 1949;3:129–150.

Hodgkin AL, Huxley AF, Katz B. Measurement of current-voltage relations in the giant axon of Loligo. J Physiol (Lond) 1952;116:424–448.

Hodgkin AL, Huxley AF. A discussion on excitation and inhibition. Propagation of electric signals along giant nerve fibres. Proc R Soc Lond B Biol Sci 1952e;140:177–183.

Hodgkin AL, Huxley AF. A quantitative description of membrane current and its application to conduction and excitation in nerve. J Physiol (Lond) 1952d;117:500–544.

Hodgkin AL, Huxley AF. Action potentials recorded from inside a nerve fibre. Nature 1939;144:710–711.

Hodgkin AL, Huxley AF. Currents carried by sodium and potassium ions through the membrane of the giant axon of Loligo. J Physiol (Lond) 1952a;116:449–472.

Hodgkin AL, Huxley AF. Ionic exchange and electrical activity in nerve and muscle. Copenhagen: Abstr XVIII Int Physiol Congress, 1950;36–38.

Hodgkin AL, Huxley AF. Movement of sodium and potassium ions during nervous activity. Cold Spring Harb Symp Quant Biol 1952f;17:43–52.

Hodgkin AL, Huxley AF. Potassium leakage from an active nerve fibre. J Physiol (Lond) 1947;106:341–367.

Hodgkin AL, Huxley AF. Resting and action potentials in single nerve fibres. J Physiol (Lond) 1945;104:176–195.

Hodgkin AL, Huxley AF. The components of membrane conductance in the giant axon of Loligo. J Physiol (Lond) 1952b;116:473–496.

Hodgkin AL, Huxley AF. The dual effect of membrane potential on sodium conductance in the giant axon of Loligo. J Physiol (Lond) 1952c;116:497–506.

Hodgkin AL, Katz B. The effect of sodium ions on the electrical activity of the giant axon of the squid. J Physiol (Lond) 1949a;108:37–77.

Hodgkin AL, Katz B. The effect of temperature on the electrical activity of the giant axon of the squid. J Physiol (Lond) 1949b;109:240–249.

Hodgkin AL, Keynes RD. Active transport of cations in giant axons from Sepia and Loligo. J Physiol (Lond) 1955a;128:28–60.

Hodgkin AL, Keynes RD. Experiments on the injection of substances into squid giant axons by means of a micro-syringe. J Physiol (Lond) 1956;131:592–616.

Hodgkin AL, Keynes RD. The potassium permeability of a giant nerve fibre. J Physiol (Lond) 1955b;128:61–88.

Hodgkin AL, McNaughton PA, Nunn BJ, Yau K-W. Effect of ions on retinal rods from Bufo marinus. J Physiol (Lond) 1984;350:649–680.

Hodgkin AL, McNaughton PA, Nunn BJ. Effect of changing calcium before and after light flashes in salamander rods. J Physiol (Lond) 1986;372:54P.

Hodgkin AL, McNaughton PA, Nunn BJ. Measurement of sodium-calcium exchange in salamander rods. J Physiol (Lond) 1987;391:347–370.

Hodgkin AL, McNaughton PA, Nunn BJ. The ionic selectivity and calcium dependence of the light-sensitive pathway in toad rods. J Physiol (Lond) 1985;358:447–468.

Hodgkin AL, Nakajima S. Analysis of the membrane capacity in frog muscle. J Physiol (Lond) 1972b;221:121–136.

Hodgkin AL, Nakajima S. The effect of diameter on the electrical constants of frog skeletal muscle fibres. J Physiol (Lond) 1972a;221:105–120.

Hodgkin AL, Nunn BJ. Control of light-sensitive current in salamander rods. J Physiol (Lond) 1988;403:439–471.

Hodgkin AL, Nunn BJ. The effect of ions on sodium-calcium exchange in salamander rods. J Physiol (Lond) 1987;391:371–398.

Hodgkin AL, O’Bryan PM. Internal recording of the early receptor potential in turtle cones. J Physiol (Lond) 1977;267:737–766.

Hodgkin AL, Rushton WAH. The electrical constants of a crustacean nerve fibre. Proc R Soc Land B Biol Sci 1946;133:444–479.

Hodgkin AL. A local electric response in crustacean nerve. J Physiol (Lond) 1937c;91: 5–6P.

Hodgkin AL. A note on conduction velocity. J Physiol (Lond) 1954;125:221–224.

Hodgkin AL. Anniversary Address of the Royal Society. (30 November 1971) Proc R Soc Lond A 1971;326:v—xx.

Hodgkin AL. Anniversary Address of the Royal Society. (30 November 1973) Proc R Soc Lond B Biol Sci 1974;185:v—xx.

Hodgkin AL. Beginning: some reminiscences of my early life. Ann Rev Physiol 1983;45: 1–16.

Hodgkin AL. Chance and design in electrophysiology: An informal account of certain experiments on nerve carried out between 1934 and 1952. J Physiol (Lond) 1976;263:1–21.

Hodgkin AL. Chance and design; reminiscences of science in peace and war. Cambridge: Cambridge University Press, 1992.

Hodgkin AL. Edgar Douglas Adrian: Baron Adrian of Cambridge. Biogr Mem Fellows R Soc Lond 1979;25:1–73.

Hodgkin AL. Evidence for electrical transmission in nerve I. J Physiol (Lond) 1937a;90:183–210.

Hodgkin AL. Evidence for electrical transmission in nerve II. J Physiol (Lond) 1937b;90:211–232.

Hodgkin AL. Ionic exchange and electrical activity in nerve and muscle. Arch Sci Physiol 1949;3:151–163.

Hodgkin AL. Les Prix Nobel en 1963. The ionic basis of nervous conduction. Stockholm: Kungl. Boktr. 1964b;224–241.

Hodgkin AL. Modulation of ionic currents in vertebrate photoreceptors. The Helmerich Lecture. In: Lam DMK, ed. Proceedings of the Retina Research Foundation Symposium, Vol. 1. The Woodlands, TX: Portfolio Publishing Co., 1988;6–30.

Hodgkin AL. The conduction of the nervous impulse. Liverpool: Liverpool University Press, 1964a.

Hodgkin AL. The Croonian Lecture. Ionic movements and electrical activity in giant nerve fibres. Proc R Soc Lond B Biol Sci 1957;148:1–37.

Hodgkin AL. The effect of potassium on the surface membrane of an isolated axon. J Physiol (Lond) 1947;106:341–367.

Hodgkin AL. The electrical basis of nervous conduction. Fellowship dissertation, Library of Trinity College, Cambridge, 1936.

Hodgkin AL. The ionic basis of electrical activity in nerve and muscle. Biol Rev 1951;26:339–409.

Hodgkin AL. The optimum density of sodium channels in an unmyelinated nerve. Philos Trans R Soc Lond B Biol Sci 1975;270:297–300.

Hodgkin AL. The physical basis of vision. Royal Institution Proc 1982;54:7–27.

Hodgkin AL. The relation between conduction velocity and the electrical resistance outside a nerve fibre. J Physiol (Lond) 1939;94:560–570.

Hodgkin AL. The subthreshold potentials in a crustacean nerve fibre. Proc R Soc Land B Biol Sci 1938;126:87–121.

Huxley AF, Niedergerke R. Interference microscopy of living muscle fibres. Nature 1954;173:971–973.

Huxley AF, Stämpfli R. Direct determination of membrane resting and action potential in single myelinated nerve fibres. J Physiol (Lond) 1951a;112:476–495.

Huxley AF, Stämpfli R. Effect of potassium and sodium on resting and action potentials of single myelinated nerve fibres. J Physiol (Lond) 1951b;112:496–508.

Huxley AF, Stämpfli R. Evidence for saltatory conduction in peripheral myelinated nerve fibres. J Physiol (Lond) 1949a;108:315–339.

Huxley AF, Stämpfli R. Saltatory transmission of the nervous impulse. Arch Sci Physiol 1949b;3:435–448.

Huxley AF, Taylor RE. Local activation of striated muscle fibres. J Physiol (Lond) 1958;144:426–441.

Huxley AF. Ion movements during nerve activity. Ann N Y Acad Sci 1959;81:221–246.

Huxley AF. Muscle structure and theories of contraction. Prog Biophys 1957;7:255–318.

Huxley HE, Hanson J. Changes in the cross-striations of muscle during contraction and stretch and their structural interpretation. Nature 1954;173:973–976.

Katz B, Schmitt, OH. Electric interaction between two adjacent nerve fibres. J Physiol (Lond) 1940;97:471–488.

Katz B. Experimental evidence for a non-conducted response of nerve to subthreshold stimulation. Proc R Soc Lond B Biol Sci 1937;124:244–276.

Katz B. The effect of electrolyte deficiency on the rate of conduction in a single nerve fibre. J Physiol (Lond) 1947;106:411–417.

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Keynes RD, Lewis PR. The sodium and potassium content of cephalopod nerve fibres. J Physiol (Lond) 1951;114:151–182.

Keynes RD, Martins-Ferreira H. Membrane potentials in the electroplates of the electric eel. J Physiol (Lond) 1953;119:315–351.

Keynes RD, Rojas E. Kinetics and steady-state properties of the charged system controlling sodium conductance in the squid giant axon. J Physiol (Lond) 1974;239:393–434.

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Keynes RD. The ionic movements during nervous activity. J Physiol (Lond) 1951b;114:119–150.

Keynes RD. The leakage of radioactive potassium from stimulated nerve. J Physiol (Lond) 1948;107:35P.

Keynes RD. The leakage of radioactive potassium from stimulated nerve. J Physiol (Lond) 1951a;113:99–114.

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Lamb TD, Matthews HR, Torre V. Incorporation of calcium buffers into salamander retinal rods: a rejection of the calcium theory of phototransduction. J Physiol (Lond) 1986;372:315–349.

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David H. Hubel

BORN:

Windsor, Ontario

February 27, 1926

EDUCATION:

McGill University, B.Sc., 1947

McGill University, M.D., 1951

APPOINTMENTS:

Montréal General Hospital (1951)

Montréal Neurological Institute (1952)

Johns Hopkins Hospital (1954)

Walter Reed Army Institute of Research (1955)

Johns Hopkins University (1958)

Harvard Medical School (1959)

John Franklin Enders University Professor of Neurobiology, Harvard University (1982)

HONORS AND AWARDS (SELECTED):

American Academy of Arts and Sciences (1965)

National Academy of Sciences USA (1971)

Karl Spencer Lashley Award, American Philosophical Society (1977)

Nobel Prize for Physiology or Medicine (1981)

Foreign Member, Royal Society of London (1982)

American Philosophical Society (1982)

Royal Society of Medicine (1991)

Ralph W. Gerard Prize, Society for Neuroscience (1993)

David Hubel carried out fundamental studies of the physiology and anatomy of mammalian visual cortex. Together with Torsten Wiesel, he identified the ocular dominance columns, the simple and complex cells of visual cortex, and demonstrated plasticity in the visual cortex following monocular deprivation.

David H. Hubel

I was born in Windsor, Ontario, in 1926. Both my parents were American citizens, born and raised across the river in Detroit. They had moved to Canada a few years before I was born, when my father got a job as chemical engineer for Windsor Salt Company. From the start my citizenship was complicated because the citizenship laws in Canada and the United States are different; I was considered Canadian by Canada because I was born there, and American by the United States because my parents registered me at birth as a U.S. citizen. Consequently, I had dual citizenship most of my life. All this had practical consequences: when in college, in the late stages of World War II, I had to serve in an Officers Training Corps in Canada, and in 1954 I had to serve in the U.S. Army because of the doctors’ draft. In 1982 the Royal Society discussed making me a member but, by their rules, American citizenship precluded my becoming a regular member, and because of my Canadian citizenship I couldn’t be a foreign member. Finally, after much correspondence and committee meetings on their part it was decided that for practical purposes I was an American. This meant I could append to my signature “For. Mem. R. S.” instead of simply “FRS”.

In 1929 my parents, my older sister and I moved to Montreal when Canadian Industries, Ltd., took over Windsor Salt. We settled in Outremont, in a middle-income neighborhood that was then about twothirds French speaking and one-third English. “English”, in Outremont, meant four-fifths Jewish, one-fifth Protestant (mainly Scotch origin). In our duplex the French landlord’s family lived downstairs and their little boy and I played together constantly for about five years. The first French word I learned, at the sandbox behind the house, was “sable” (pronounced “sawb,” meaning sand). We boys developed a half-French Canadian half English polyglot which no one else could understand-I can still see our mothers shaking their heads and laughing as we jabbered away. In our lingo, “Pokapab” meant “I can’t” (a corruption of “Je ne suis pas capable”), and “petayt” meant “perhaps”. I have wonderful memories of our French neighbors, and Quebec still seems a great example of two cultures living in harmony and friendship, blighted mainly by trouble-making politicians plus a certain unwillingness of the English to work at another language. In promoting French-English relationships our Outremont Protestant schools were, if anything, a hindrance. We started French in grade three and slugged away at French grammar, but absolutely no effort was made to teach us to speak or comprehend spoken French Canadian. The Quebec laws said that Roman Catholic teachers could not teach in Protestant schools, and so our French teachers were mainly Huguenots from France.

To a French Canadian our accents were ridiculous, and we could not buy a streetcar ticket using French without being laughed at. Some of the French did sink in however, and now I read French with pleasure. I can do reasonably well in a conversation, probably because the patients at the hospital where I interned were mainly French speaking. I, as the doctor, being as it were in the driver’s seat, refused to talk to them in English and managed at last to get some practice in French. In the past few years I have even lectured in French, in Paris and in Montreal. The first time when asked over the phone for a lecture title by my University of Montreal host, I proposed “Oeil, Cervelle, et Vision”. After a slight pause he politely said “Perhaps cerveau?” I asked what the difference was and he answered “Cervelle, c’est quelque chose a manger”. I think the audience followed everything in the lecture (they laughed at the jokes, which I put in as controls), but they also laughed when for blood vessels I used “vaisseau saignant”—which means “bloody vessel”.

Except for the deficient French teaching, our schools in Outremont were excellent. Most of the students were first-generation JewishEuropean, and there was a seriousness of purpose that complemented the absence of television at home or computers at school. After school, during the winter, it was light enough to ski on the mountain for about an hour. Otherwise we went home and studied.

I got interested in science very early. I plagued my father with questions about chemistry, and a wonderful Lott’s chemistry set (British made) slowly developed into a small basement laboratory. There I perfected an explosive based on potassium chlorate, sugar and potassium ferricyanide, that could be heard over all Outremont, rocked the neighborhood houses and brought two burly French policemen to our door. I told them I had simply put firecrackers in a toy brass cannon, and it must have all seemed innocent to them.

My other passion was electronics. Over what must have been an unselective crystal set I picked up the transmissions of a neighboring radio amateur, whom I got to know. I built a small one-tube radio that worked immediately, but then spent months trying to get a more ambitious short-wave radio to work. It produced a roar like a motorboat which I never succeeded in curing. Years later I finally learned that the trouble was feedback through the power supply, which could have been remedied in minutes with a capacitor and resistor in parallel. Not having anyone nearby to help, and no book besides a 1937 American Radio Relay Handbook which was about as easy to read as swimming through molasses (the 1993 edition is just as bad) and with no good libraries in Montreal, my electronics had to wait until I got to college. Four years ago I finally did become a licensed ham, with a call AAlFG, of which I am inordinately proud.

Like most families in those days we had a piano at home, and both of my parents played a little and my sister took lessons. I learned from them, and started formal lessons at the age of five, before I could even read. I kept the lessons up through high school and much of college, and still play about an hour each day. My main teacher was one of the best organists in Montreal, and to him I owe a love of Bach that I would not trade for any amount of success in science.

In high school, 10 subjects were compulsory. In addition one had the option of choosing among biology, advanced mathematics and Latin. Mathematics was considered appropriate for future engineers, Latin for future doctors, and biology for dumb students. I chose Latin, not wanting to preclude medicine and having no interest in engineering, but I found the math so easy that I learned it by myself. Latin was not at all easy; I loved it and worked hard at it, harder than at any other subject except history. That was taught by the best teacher in the school, a tiny red-haired Irish woman named Miss Bradshaw, who made the students work like slaves and assigned an essay each week which she then covered with red ink, demanding that we produce ideas as well as facts.

I wanted to go to college in the United States, and went to Boston for an interview at the Massachusetts Institute of Technology (MIT) (my interviewer was a young enthusiastic man named F.O. Schmitt, whom I got to know well many years later). Because of World War II it became impossible to send money out of Canada, so I stayed in Montreal and went to McGill University. I commuted, which was not much fun, since taking the streetcar swallowed up 90 minutes a day. I decided to take Honors in mathematics and physics because these subjects fascinated me and there was almost nothing to memorize. That left time to attend every concert in the city and keep up the piano. Mathematics at McGill was excellent, physics was bad. Modern physics (relativity and quantum physics) was not taught at all to undergraduates. Instead we learned classical physics, including such utterly stultifying subjects as statics. Luckily it was classical physics, especially optics and electronics, that I ended up needing in my work.

After four years of undergraduate college I had to confront my first big decision. I had applied to graduate school in physics and had been accepted. More or less on a whim—and never having taken a course in biology even in high school—I also applied to medical school at McGill. Almost to my dismay I was accepted. Registration day arrived and I still hadn’t made up my mind. When I finally decided on medicine I went to tell the professor who was to have been my advisor in physics. I can still hear him saying, “Well, I admire your courage. I wish I could say the same for your judgment!”

In the back of my mind, I suppose, was the idea that I might be able to apply my physics to medical research, and that if there were no opportunities in research, practicing medicine might be fun. I had been seriously intimidated when I attended an international meeting in physics in Montreal, while I was still an undergraduate: it was clear that my physics training had not got me off to a flying start, and I was shaken to see how crowded a field it was.

Medical school, on the other hand, was like a blow to the jaw. It took the first year, and four Cs at midterm to teach me that medical school requires work. Biochemistry was the only subject I really enjoyed and I did very well in it. Near the end of the first year, with all the class hopelessly behind, a kind anatomy professor told us that if we were really up against it we should remember that head and neck made up about half the work but could be the topic of only one of the five exam questions. The obvious solution was to skip head and neck. Ironically, I took his advice.

Near the middle of that first year I began to wonder if I had made a mistake; I had not made any effort to talk to people in research, to find out what the opportunities were. One day I went to one of the few professors at McGill who was actually doing research, a man who had, like myself, majored in math and physics. His comments shook me. He said, as part of a long soliloquy, that I should realize that the opportunities to do medical research in Canada were statistically almost nil, amounting perhaps to one job a year. But, he added, if I were to get that one job, the statistics wouldn’t matter. One simply had to clench one’s teeth and take a chance.

By second year medical school I began to develop a strong interest in the brain. Luckily for me the Montreal Neurological Institute (MNI) was part of McGill. It was one of the most celebrated neurological institutes in the world, best known for work on epilepsy by Wilder Penfield and Herbert Jasper. The MNI was perched high on the hill to the southeast of Mount Royal, a sort of ivory tower that medical students seldom climbed. I decided to grab the bull by the horns and made an appointment to see Penfield himself. Finally the day arrived. I borrowed the family car, parked it on University Street, and in a state of some terror climbed up to the fourth floor of the institute. Penfield was at his most charming, and when I told him of my physics background he immediately took me up to see Herbert Jasper, who in turn, immediately offered me a summer job doing electronics in his physiology group. (When I got back to the car I found it running, with the keys locked inside. I took the streetcar home to get a spare key, and 90 minutes later was back. It was a stressful afternoon.)

To my surprise, I enjoyed clinical medicine and even led the class in, of all subjects, obstetrics, which I liked even if it was free of intellectual content. By the end of medical school I had become interested enough in clinical medicine not to want to give it up, at least not so soon, so I decided to do a residency in neurology and in preparation did a rotating internship (medicine, outpatient surgery, gynecology and mental-hospital psychiatry) at the old Montreal General Hospital, which was then in a slum, with mostly French patients and a wonderful atmosphere. I probably enjoyed that year more than any other, before or since.

The two summers I spent doing electronics for Jasper at the MNI were the start of a long association. After graduation and my internship, I did a year’s neurology residency, followed by a year with Jasper doing clinical electroencephalography (EEG). Completely empirical, EEG was of great use in those days, long before neurology had become revolutionized by modern computer-aided imaging methods. Then, to diagnose brain disease, one did the usual history-plus-physical, an EEG, and finally, a hideous procedure called a “pneumogram”, in which one drained off the poor patient’s spinal fluid (about a tumbler full) and replaced it by air, causing a violent headache: x-ray might then show up such things as tumors, provided they were the size of a tennis ball. Of course, EEG found its main use in epilepsy, and Jasper was the undoubted world expert in that field, besides being one of the leading clinical neurophysiologists of his time. His scientific outlook was wonderfully broad and he had a clarity of mind and skepticism that made him stand out among brain scientists. The first time we spoke, the day of the locked car, he asked me what I had read in the field. I told him I had just read Cybernetics, by Norbert Wiener. He gave me an odd look, and said, “Did you understand it?” I thought I had, even if through a glass, darkly, and when I said so, he grinned. It was clear that he thought that Wiener’s brain science was off the wall, but he was nice enough not to want to put me down.

I began learning EEG from Cosimo Ajmone-Marsan, who was then a teaching fellow at the MNI, and Jasper’s main assistant. Ajmone-Marsan was a wonderful teacher, bright and witty, and I felt privileged to work with him. It didn’t last: after three months he accepted a position at the National Institutes of Health (NIH) in Bethesda, Maryland, in clinical neurophysiology. The Clinical Center at NIH was just getting into full swing, and that year several of the best people at the MNI took jobs there. Suddenly I found myself Jasper’s main assistant, having to read most of the EEGs of the institute and attending all the Penfield temporal lobe excisions. It was a busy year, which was to have been half research, but the research fell by the wayside.

All the fellows at the institute took part in a seminar series that covered neurophysiology. By some lucky chance Jasper assigned me the visual system, and by an equally lucky chance I came upon the 1952 volume of the Cold Spring Harbor Symposia, which was devoted to neurophysiology, and there discovered two great papers by Keffer Hartline and by Stephen Kufller. These came like a sudden ray of light, as they seemed to be getting at the question of what the nervous system was doing to encode sensory information. I had no idea then that I would ultimately get to know Hartline fairly well, and that Kuffler would become one of my closest friends and my main mentor.

One day, a young neurologist named Charles Luttrell showed up from Johns Hopkins, in Baltimore, to learn EEG, and Jasper assigned him to me. Luttrell must have found me a good teacher, because on returning to Hopkins he arranged for me to be offered the residency in neurology there. The time was certainly ripe for me to get out of Montréal and see something else, even though it meant again postponing starting research (I was 28, and still had not done any research even during summers—if you don’t include my work on explosives in the 1930s). I was sure that with my dual citizenship I would be subject to the doctors’ draft as soon as I set foot in the United States, but that didn’t seem to be a valid reason not to accept (this was between the Korean and Vietnam Wars, but M.D.s were still subject to two years of military service).

I was married in 1954, the summer before the EEG fellowship. My wife, Ruth, had just graduated from Hebb’s psychology department at McGill. We kept body and soul together by her taking a job as a technician in clinical psychology. Even for that time my income from the MNI, $1,800 a year, seemed meager and prospects then, in research in Canada, were far from brilliant. In Baltimore our finances were even grimmer—my pay as a neurology resident was $35 per month, of which $18 was wangled through the kindness of Jack Magladery, then chief of neurology at Hopkins. Clinically, the high points of that year were the informal teaching of Frank Ford, the country’s leading pediatric neurologist and a brilliant, thoroughly eccentric clinician, and the weekly Saturday morning clinics run by Frank Walsh, the world’s leading neuro-ophthalmologist.

In 1954 Johns Hopkins was an exciting place. Everyone in the area, house staff, attending staff, people in research at the hospital and medical school, had lunch at the Doctor’s Dining Room. At these informal meals, surrounded. by dark paneled walls, people in neurologically related fields tended to sit together, and it was there that I first met Stephen Kuffler, whose lab was in the basement of the Wilmer Ophthalmology Institute. Despite his friendliness, it never occurred to me to visit his lab: I was much too shy and felt I had nothing much to offer. He was at that time working on synaptic transmission but kept up a vision project that was run by postdoctoral fellows.

My first meeting with the other Hopkins celebrity in neurophysiology, Vernon Mountcastle, occurred when a neurosurgery resident asked him over to the hospital to give an informal research seminar to the house staff. Vernon was, I think, dismayed by the neurophysiological naïveté of the neurosurgeons; I was the only one there who asked questions, which must have impressed him, as he still remembers that occasion.

The doctors’ draft loomed and it seemed certain I would be grabbed after my neurology residency year was up. I made several trips to Bethesda, hoping to get assigned to NIH. Luckily, I also visited the Walter Reed Army Institute of Research, where I first met Michelangelo Fuortes and Robert Galambos, who assured me that I would be assigned there if I volunteered for the Army. I did so, and after a close call in which I nearly found myself in Japan, I arrived at Walter Reed, an Army captain, finally about to begin doing research, at age 30.

In retrospect, I doubt that I could have found a better place to begin research on the central nervous system. Neuropsychiatry at Walter Reed consisted of a small group led by David Rioch, an authority on the thalamus and a well-known psychiatrist with a background in neuroanatomy. The group he had assembled included Robert Galambos, one of the foremost people in auditory neurophysiology and a close collaborator of the neuroanatomist, Jerzy Rose, who was then at Hopkins; Mike Fuortes, then working with Karl Frank at NIH; and Walle Nauta, recently arrived from Holland, the main forerunner of the dawning revolution in neuroanatomy. It was a small, close-knit and exciting group.

My first day at Walter Reed was unforgettable. I arrived in the morning and was greeted by Mike Fuortes, who was to be my advisor while I got started. Mike was preparing to set up a decerebrate cat for a spinal cord experiment. He began by asking if I had any experience anesthetizing cats. The answer was no. Had I ever set up a cat for recording? No. Had I done any experiments in neurophysiology? To every question, the answer was no. Mike walked calmly over to the window and gazed out for a few minutes. He then said, “Well, here is what I suggest. We’ll postpone the cat to this afternoon, and this morning we’ll set up a frog sciatic nerve preparation”. So that was my crash laboratory course in neurophysiology—peripheral nerve physiology in the morning, and in the afternoon mammalian decerebration followed by one of the most difficult neurophysiological procedures: unroofing the spinal cord, dissecting the nerves to leg flexors and extensors and teasing apart a dorsal root to record from single isolated root fibers. It was a big day.

Mike had to go away for a day a few weeks later and it fell to me to run an experiment by myself. To be exact: by myself with massive help from a wizard technician named Calvin Henson, a wonderful, generous, witty man, and a friend of Duke Ellington, who could do anything surgical that anyone else could do, only better. Calvin and I were to work together for three years, and it is to him and Mike that I owe my research training in neurophysiology. “Doc, ya holler before you’re hurt”, Calvin would say when I would groan in anticipation of some terrible catastrophe like drilling into a cat’s cortex.

Mike and I collaborated for about three months, and the work resulted in a modest single-unit study in the Journal of Physiology that compared flexor and extensor reflexes in decerebrate cats. Mike had a rare sixth sense for biology, and a breadth of outlook and tolerance of others’ ideas that made him a delight to work with. Before our paper was mailed off he commented, almost as an aside, that I should realize that the order of names on a paper in the Journal of Physiology was determined strictly alphabetically. I felt enormously flattered at this generous and slightly backhanded compliment, for it had never entered my mind that I should be first author.

Later that first year, the time came for me to get started on a project of my own. I had no specific ideas, though my years at the MNI had given me an interest in cerebral cortex and sleep. At that time, the world of neurophysiology was much smaller, and brain physiology was heavily preoccupied by studies of consciousness, sleep, the reticular system and something mysterious called “recruiting”. Single-cell recording from cortex had only barely begun in the labs of Herbert Jasper and Cho-Luh Li in Montreal, Richard Jung in Freiburg and Vernon Mountcastle in Baltimore, and we hoped that these new methods would soon help us understand consciousness. Alas, studies of consciousness languished, perhaps for want of adequate methods or ideas.

Mike Fuortes made several suggestions as to possible projects. One seemed rather outrageous, but certainly adventurous. This was to expose the cortex of a cat and, using fine forceps, insert small wires (as E.D. Adrian had in the spinal cord) and then sew the animal up, hoping to record single cells after it had recovered and was wide awake and moving about freely. We made one or two attempts, but they were complete failures.

I decided that this project was well worth taking on but would require some serious tooling up. My first efforts went into making a microelectrode that would reliably record cells extracellularly without breaking or bending into hooks. Harry Grundfest had published a paper describing a stainlesssteel electrode electrolytically pointed by raising and lowering it into a polishing bath and insulated with a coating called Formvar. I decided that stainless steel was not stiff enough, but I had no idea what other metals to try. By a great stroke of luck, the head of the instrument shop at Walter Reed was a physicist named Leon Levin, who had done his thesis in electrochemistry. He suggested I try tungsten, gave me a roll of it and said I should sharpen it with alternating current in a bath of concentrated sodium nitrite. The results were spectacular; within days I was able to make a pointed wire that looked ideal and was strong enough to pierce, with a little care, my thumbnail. It only remained to find a way of insulating the wire down close to the tip. That was not easy. I tried every coating I could find but nothing seemed adherent enough or viscous enough. Formvar did not adhere and in any case was available only in tank-car amounts.A solution of Lucite in chloroform came close to working. One day while I was playing with this my neighbor in the next lab walked in with a can of something called “Insulex” and said, “Why not try this?” I soon found that when Insulex was thickened by evaporation it became viscous enough to adhere to the wire, and suddenly I had an electrode that was recording sensational single units. I spent the next few months recording everything in the anesthetized cat’s nervous system, from spinal cord to cochlear nucleus to olfactory bulb, almost forgetting the original plan to record from awake behaving animals.

Jasper had got wind of the electrode and came down from Montreal to see it for himself and to learn how to make it. It turned out that his group was also working on a system for chronic single-unit recording and had come up with the idea of implanting a hollow screw into the cat’s skull, to which the electrode advancer could be attached. The competition got my efforts into focus, as competition often does, and I began to work on an advancer. The problem was not entirely simple. There were no stepping motors then, and a hydraulic system seemed to be the best bet, but one had to make the piston-and-cylinder compatible with a chamber closed to the atmosphere, which was necessary to prevent cortical movements caused by pulsations, as Phil Davies and Vernon Mountcastle had discovered a few years before. I found myself having continually to mollify machinists who were outraged whenever I would come back to them to explain why my latest model, which they had just skillfully built for me, could not possibly work. Finally I decided I must learn how to operate a lathe, and went to night school in downtown Washington, D.C. In the years that followed, the small investment I made in learning machining paid huge dividends, both in equipment and in occupational therapy.

My system worked. The Montreal group, with the help of my electrode, got there first, however, and for a time I wished I hadn’t taken so much time recording from so many parts of cats’ brains. It has always surprised me how few attempts are made to devise new methods—perhaps it is because one is generally rewarded not for inventing new methods but for the research that results from their use. One’s new method is in any case soon modified by someone else whose name then becomes attached to the modified version (I got tired of this happening to the tungsten electrode and, more or less as a joke, began to make electrodes of molybdenum, which is just as stiff as tungsten, confers no electrical advantage, but is a lot more expensive and carries more prestige). I think the time I spent groping around in the nervous system was not wasted even if it delayed my main objective for a few months. The chance to play around at an early stage in one’s training is a luxury denied to most beginning graduate students, who often start in on a specialized problem assigned by an advisor, before having a chance to try a few things for themselves.

One day Torsten Wiesel and Ken Brown came over to Walter Reed from the Hopkins Wilmer Institute to find out how to make tungsten electrodes, to try them out in the cat retina. Stephen Kuffler had stopped working on vision some years before but had kept his vision lab going, and Torsten and Ken were collaborating on retinal intracellular recordings. This was my first meeting with Torsten (the electrode turned out to be useless in the retina, because it could not pierce the inner limiting membrane).

I worked with alert cats for the rest of my stay at Walter Reed but abandoned it when Torsten Wiesel and I joined forces, as it became clear that the next steps in studying visual cortex would require eye stabilization. The technique was taken up by Ed Evarts, who adapted it to monkeys at NIH. Evarts’ methods ultimately became standard worldwide. My final contribution to the field of chronic microelectrode recording was to adapt the method for depth recording using stereotaxic methods. This allowed me to map the first receptive fields of lateral geniculate cells.

At Walter Reed, in alert animals, I began by focusing on the effects of sleep on cat cerebral cortex. I recorded from striate cortex because there I could hope to identify cells in terms of their specific sensory responses. When I told some of my colleagues that I was going to record from visual cortex they reacted by saying “Why striate cortex? I thought Richard Jung had worked that all out?” That didn’t bother me too much: my interest at that point was mainly sleep; vision was a sideline.

Jung and his collaborators were indeed among the world’s leading figures in visual cortex physiology, and the only group that had recorded responses from single cells in the visual cortex. They certainly seemed to have everything worked out. Cells fell into four groups which they termed A, B, C, D and E. B-, D- and E-cells responded to one-second diffuse flashes of light at onset, termination and at both onset and termination of the flash. C-cells were inhibited by light. A-cells, strangely, did not respond at all. They were something of a mystery, but the Freiburg group, perhaps because of its interest in epilepsy, regarded them as exerting a dampening or braking effect on cortical activity, as though they existed for the purpose of preventing epileptiform activity.

I quickly confirmed their main results. Stimulating the retinas was easy—the room lights could be turned on and off by pulling on a cord hanging from the ceiling and monitored by a photoelectric cell. I could compare the awake state with sleep, using the EEG to monitor arousal level (REM sleep was still unknown, or had just been discovered).

Jerzy Rose, in one of his visits to Bob Galambos, had made clear to me the importance of histologically monitoring the electrode positions, and luckily Walle Nauta was generous enough to have his technician process my blocks of brain tissue. I had little hope of finding the tracks of these slender wires, much less their tip positions, so I decided to mark tip position by passing current and making lesions. Passing direct current did no harm to the electrode as long as it was made negative, and I estimated how much charge to pass by breaking an egg into a dish, putting the electrode into the egg white and observing its denaturation as current was passed. The first trials, in a real brain rather than an egg, were spectacular, with tiny lesions about 50–100 μm, easily small enough to allow me to tell what cortical layer a cell was in.

One of the first results of using this technique came like a bombshell. One of my lesions, made after recording a B-cell (an on-cell), was in white matter! The importance of this was that no one had realized that in cortex, extracellular recordings could be made from fibers (probably the exceedingly sharp electrode tip was piercing the myelin sheath). Now one had to consider seriously the possibility that some of Jung’s cortical units were myelinated fibers, perhaps including fibers of geniculate origin.

Cell after cell, meanwhile, refused to react to my flashlight or to my pulling the cord that hung from the ceiling light. This certainly confirmed the existence of Jung’s A-cells. Thinking that a moving object might have more visual significance than mere light, I began waving my hands in front of the cat. Figure 1 shows the result. One of the cells in this two-unit recording responded to leftward movement, the other to rightward movement (the cat’s eyes gave no hint of following the movements—cats soon lose interest and just gaze into space). On another occasion I showed that such cells could respond selectively to up versus down, but for some reason it did not occur to me to try oblique movement. The idea of orientation selectivity was still several years away. These responses to movement were the first indication from a single-cell recording that the cortex might be doing something interesting, something that transcended what the geniculate could do.

Figure 1. A two-unit recording from area 17 of an awake alert cat showing responses to to-and-fro movements of my hand. One cell responded to left-toright movement, the other to right-to-left. The upper beam in each of the four traces indicates the movement by deflections produced each time my hand passed in front of a photocell.

I finally became convinced that Jung’s A-cells, the ones that had been thought to be unresponsive to visual stimuli and to prevent epilepsy, were actually the cortical cells, the other classes, B, C, D and E, the geniculate inputs. The “unresponsiveness” was a delusion: the cells were unresponsive to changes in diffuse light intensity, not to visual stimuli in general.

The sleep studies meanwhile soon showed that resting activity is profoundly affected by arousal level, and is far more irregular in slow-wave sleep. But I had no way of comparing responses to visual inputs in different arousal states, because the cat slept with its eyes closed. As I saw no easy way of pushing the study further my growing interest in vision took over. Meanwhile, my time at Walter Reed was running out.

I stayed at Walter Reed for a year after my Army service, to get my research to a logical stopping point. Vernon Mountcastle had meanwhile arranged for me to set up a lab in physiology at Hopkins, and the matter seemed to be settled except for the fact that the physiology labs were being remodeled, with an expected delay of about a year from the time of my leaving Walter Reed. One day Steve Kuffler called to ask if I would be interested in coming to his lab to work with Torsten (Ken Brown had left to take a job in San Francisco). That seemed to be a good solution, and a great chance to learn about receptive fields, so I didn’t hesitate. I went over to Baltimore one day, and Torsten, Steve and I sat in the lunch room and made plans. It was clear that Torsten and I should try to extend the work Steve had done in the retina to the visual cortex, using the same retinal stimulation techniques that Steve had developed, and adapting my recording methods to acute, anesthetized animals. It was not clear how much the anesthetics might impair the cortical responses, though Mountcastle had shown that somatosensory cortical cells could respond actively provided the anesthesia was kept light.

My family and I moved back to Baltimore in the summer of 1958 and rented an apartment in Rogers Forge, just to the north of the city. By then our oldest child had been born, and Ruth was no longer working. My captain’s pay of $10,000 a year had supported us handsomely and now I had a fellowship that Steve had arranged together with my own R01 NIH research grant and some support from the Air Force. Our row house was clean and comfortable. There are basically two styles of row houses in Baltimore, the old and the newer, and there are a million indistinguishable specimens of each. For this second stint in Baltimore we had the newer type—more comfortable, and fewer cockroaches. Three years before we had lived just five minute’s walk from the hospital and socially it was fun as our neighbors were mostly house staff. Now our neighbors were all junior executives, and all were exactly the same brand of Christian (I believe it was Roman Catholic). As Protestant Unitarians we felt like outcasts. It was dull, both socially and architecturally. One night I arrived back in Rogers Forge, parked the car, came up to the front door, and sensed that something was not quite right. The number, 232, was correct, but it took a few seconds to realize that I was at the right house but on the wrong street. That is Baltimore.

Torsten and I wasted no time getting going. It was clear (or so it seemed) that our time was limited to about a year, so we started experimenting immediately, using whatever equipment we could scrounge. We began by using the Talbot-Kuffler ophthalmoscope, which restricted us to stimulating one eye, with the cat’s head rotated around to face the ceiling. To record we used the advancer I had made for chronic recording, slightly adapted for the acute work. We were recording cells within a week or so ofmy arrival. I remember coming home one night and saying to Ruth that this collaboration with Torsten was going marvelously well. Our senses of humor and scientific styles seemed to match (or be complementary), and Torsten had wonderful scientific taste, a rock-like solidity and a determination to work on regardless of any roadblocks.

The major breakthrough (to use that hackneyed term) came in our third or fourth experiment. We had isolated a big stable cell which for some hours was unresponsive to anything we did. But as we worked on we began to get vague and inconsistent responses in one region of retina. The ophthalmoscope had been designed for retinal stimulation and recording and was wonderful at generating spots of light of calibrated intensity or dark spots against a light background—but for cortical work it was a horror: it was hard to keep track of where you were in the retina, relative to fovea or disc, and you could only work with one eye. Spots of light were produced by a set of thin wafers the size of microscope slides, made either of brass with holes of various sizes to pass the light or, for black spots, glass slides to which thin metal circles of various sizes had been glued. These wafers, glass or brass, were inserted into a slot in the ophthalmoscope. Stimulus duration was electronically controlled and varied in intensity by a wedge. We struggled, and seemed to be getting nowhere, when suddenly we started to evoke brisk discharges. We finally realized that the discharges had nothing to do with the dark or light spots but were evoked by the action of inserting the glass slide into the slot. The cell was responding to the faint shadow of the edge of the glass moving across the retina, and it soon became clear that the responses occurred only over a limited range of orientations of the edge, with a sharply determined optimum and no response to orientations more than 30 degrees or so from the optimum. We had worked with the cell for about nine hours when we finally stopped for a rest.

This event has sometimes been held up as an example of the importance of “accident” in science. We have never felt that it was an accident. If there is something there to discover one has to take the time to find it, and one has to be relaxed enough about the way one works so as not to foreclose the unexpected. Two other groups failed to discover orientation selectivity because they were too scientific, in a simplistic sense of that word: one group built a device to generate horizontal bright bars, the other group, vertical, in both cases so that they could explore the retina more efficiently than with a roving spot. In a certain early phase of science a degree of sloppiness can be a huge advantage. We put our care into the electrode advancer, the closed chamber and the electrode itself. We soon replaced the ophthalmoscope, which had been designed for quantitative retinal work, with a screen which the cat could face with both eyes, and a slide projector, and we did not quantify anything about stimulus duration, rate of movement or intensity; we turned the stimulus on and off by putting our hand in front of the projector, and moved the projector by hand. We concentrated on stimulus geometry, which we varied systematically using cardboard, scissors and tape. All these things could have been done electronically or mechanically but at enormous expense in time and money, and with sacrifice in flexibility.

At one early stage, having no proper head holder, we used the headholder part of Kuffler’s ophthalmoscope—the part that had the head facing upwards. Putting a screen on the ceiling seemed awkward, so one day we brought in from home a set of bedsheets which we strung from one to the next of the many pipes that decorated the Wilmer basement ceiling (our lab was about 15 feet square and served also as my office; Torsten had a tiny booth in the next room). One day we were mapping out receptive fields for a three-unit recording, a set of parallel, partly overlapping rectangles which we reached by standing on chairs to get at the sheets; these were cells 3004, 3006 and 3007 in our series, which we began at 3000 to give us a flying start to compete with Vernon Mountcastle, who had just published a paper based on 900 units—when in walked Vernon himself. He was visiting Steve, whose office was just across the hall. We were embarrassed by our slapdash set-up and Vernon must have been horrified. But he was suitably impressed by our three cells, and the implication of the parallel receptive fields of these three neighboring cells for columnar organization of visual cortex cannot have been lost on him. Nor on us! Vernon’s discovery of somatosensory columns a few years before was the biggest event in cortical organization since topography, and the possibility that other cortical areas might contain columns was very much on our minds. As he left, Vernon exclaimed to us, “What a great system! You will have your work cut out for you for the next five years”. We thought he was being pessimistic. In five years we hoped to have gone on to the auditory system.

Time is strange. Five years in the future can seem like a century, and five years in the past like yesterday. In 1958 neither Torsten nor I could have imagined that 37 years later we would still be working on the same old area 17.

It took a few months before we had enough material to write our first abstract, for Federation Proceedings (the Society for Neuroscience was still years in the future). We were both almost paralyzed when it came to writing, and we found that first abstract a real struggle. We gave our first version to Steve to look over, and I will never forget coming in the next morning and seeing ‘lbrsten’s face. “I guess Steve didn’t think much of our abstract,” he said ruefully. Steve’s way of criticizing a paper (Figure 2) was like Miss Bradshaw’s. He had a passion for clarity and simplicity and a hatred for pompousness.

Figure 2. First draft of my first abstract, with Torsten Wiesel, written in the fall of 1958, showing comments by Stephen Kuffler.

From that time on all three of us made a fetish of improving our writing, reading every book we could find on the subject, especially Fowler, Gowers, and Strunk and White. Our entire Wilmer-basement group—Steve Kuffler, Torsten Wiesel, Ed Furshpan, David Potter and later Ed Kravitz-always handed around its manuscripts for everyone to read and tear apart. ‘lbrsten’s and my first full-length paper, on simple receptive fields, published in 1959 in the Journal of Physiology, went through 11 drafts, each a complete overhaul. The acceptance letter, which could only have been written by William Rushton, began “Congratulations upon a very fine paper”, and offered no criticisms whatsoever. One has to have known William to realize what a compliment that was.

Shortly after I got to Baltimore, in the early summer of 1958, Furshpan and Potter arrived, having just published their work on the electrical synapse. With ‘Torsten, Steve and I, the five of us formed the nucleus of the group that a few years later became the first department of neurobiology at Harvard. The idea of moving to Boston was concealed from me until very late. Torsten would often say that we had to hurry up with our work because our time was limited, but I could never understand why: my moving to a lab two blocks away should hardly preclude our continuing to collaborate. One day while driving me home, Steve casually asked how deeply committed I was to going over to physiology. Would I consider moving to Boston with him, Torsten, Ed and David? I had had no inkling that any exodus was in the air until that moment. It didn’t take long to decide; our work was going too well to break it off at that point, and though Boston was a complete unknown, the move sounded like an adventure. Ruth and I had come to like Baltimore, and had even made an offer on a house. Luckily that fell through, or we might never have left.

That spring nine families made the migration. Our family, then four (Carl was born at Walter Reed, Eric in Baltimore), rented an apartment for the first year in Newtonville. Harvard, especially the senior faculty, seemed ponderous compared with Hopkins which had been informal and friendly; at Harvard only full professors dared to speak at faculty meetings and the speeches were more like orations. For the first few years our group was lodged within the department of pharmacology, and we grew steadily. Torsten and I had no great security: we had been made assistant professors at Hopkins, but were demoted to the curious rank of associate when we went to Harvard. On the other hand this was just the beginning of NIH extramural support for medical research, and we immediately got grants of about $10,000 a year—a lavish amount in those days. In any case, proposals took about two days to write. One feels not at all envious of young people starting out today, with support so much harder to get and keep, grant writing consuming months, and our field so much more crowded. In 1960 it could not have been less crowded; we virtually had the visual cortex to ourselves. If we had doubts about a paper, its contents, language or its excitement, we could put it in a drawer and think about it for a while.

In the early 1960s we began a pilot project on visual deprivation by sewing closed one eye of a few kittens. Torsten recalls our standing in the hall discussing what we should do. He suggested bringing up the animals from birth in the dark. I said that that sounded like a real bore; why not simply sew closed one eye and have the other one as a control (this is his version; I don’t remember the discussion at all)? We went ahead, sewed the lids, and a few months later were astounded at the magnitude of the changes in responsiveness of cortical cells to stimulating the closed eye. We were lucky; had the fall-off in responses been subtle, requiring, for example, quantification, we surely would not have gone on with the study. But it took off and led to years of work. It was years before we wrote a grant request for this work, which was done strictly on the side, and cost nothing, because the kittens were all bred from lab cats. Cats, in any case, cost only a few dollars each, compared to about $400 today. Animal rights groups were then only a vague cloud on the horizon.

Our work continued to develop, extending to the lateral geniculate, to visual area II, to what we called area 19 in the cat and to the Clare-Bishop (lateral suprasylvian) area; to color, stereopsis and to monkeys. One day Jim Sprague wrote from Philadelphia to say that one of his technicians, Jane Chen, had for personal reasons to move to Boston. Jane was expert in the Nauta method for staining degenerating fibers. Could we use her? We debated. We had a small histology lab which we used to cut and stain sections to identify electrode tracks and to look at geniculates of deprived animals, but we were not anatomists, and we didn’t want to make fools of ourselves. But the chance seemed too good to be missed, and Jane became part of our enterprise. Anatomy and physiology were very much separated then. Housed in separate departments, anatomists almost never did physiology, and we, as physiologists, were unusual in even looking for our electrode tracks (the big exception was the Hopkins group, where the two fields were far more allied: I have already mentioned Rose’s urging me to do anatomy).

In our recordings we had just caught on to the existence of ocular dominance columns, first in cats and then in monkeys, and we thought it would be exciting to identify these anatomically. Our first anatomical foray was to use our electrodes to make tiny lesions in regions the locations of which we could identify by recording. We tried this first in single geniculate layers, and it led immediately to a huge payoff: we could stain the degenerating fibers with the Nauta method, reconstruct the columns in serial cortical sections (in area 17 of monkeys), and show that geniculate afferents ended not in the Line of Gennari, as had been supposed, but mainly in what came to be known as layer 4C, just below the Gennari Line. More than that, the input was tripartite, with magnocellular layers projecting to the upper half of 4C and the parvocellular to the lower half and to 4A. All this seemed like a gift from the gods. We had no credentials for doing anatomy, much less for working in one of the most formidably difficult techniques of that era. Of course, we just made the lesions and looked at the slides: Jane was the expert.

Later we came to use radioactive tracers to answer the same questions. Bernice Grafstein had shown that when injected into an eye a tracer could be shown by scintillation counting to have reached the cortex, having somehow traversed the geniculate. It occurred to us that if we could demonstrate this autoradiographically we would be able to see the entire system of columns. We tried, but with no success. Luckily, at about that time I went to Madison, Wisconsin, to give a seminar in Ray Guillery’s lab, and noticed that they were looking at all their autoradiographs under dark field. I returned to Boston, told Torsten, we put a slide under dark field, and there were the columns in all their glory. I decided that sometimes trips are not a waste of time.

Our science seemed not to conform to the science that we are taught in high school, with its laws, hypotheses, experimental verification, generalizations and so on. We felt like 15th century explorers, like Columbus sailing West to see what he might find. If we had any “hypothesis” it was the simpleminded idea that the brain, in particular the cerebral cortex, with all its ordered complexity, must be doing something biologically meaningful with the information that comes into it—that what came out must be more elaborate (for want of a better word) than what went in. So we recorded cells to see what we could find. I suspect that much of science, especially biological science, is primarily exploratory in this sense. Those who think that “Science is Measurement” should search Darwin’s works for numbers and equations.

The freedom that the system of science administration offered in the 1960s and 1970s was marvelous. One could change one’s program of experiments at a day’s notice without informing (much less getting permission from) a department head or funding agency or animal committee; no one seemed to care about close correspondence between what you said you would do in a grant proposal and what you actually did. You did not eed to have the work practically completed to get it funded. Numbers of papers were presumably counted by deans, but we largely ignored any pressure that might have existed to publish. We felt gratified if we wrote a paper about once a year, and we often combined two or three papers into one big paper if it seemed to make esthetic sense. We were not alone in this. Ed Furshpan could easily take the prize for substance-to-quantity-of-papers ratio, for some years, averaging one totally new synapse per paper.

We had similar feelings about numbers of students and postdocs in our labs. First, it seemed to us that in an entire career, if one contributed to the training of three or four first-rate scientists, one was doing well. Luckily for us, experiments in integrative neuroscience are generally done by the scientists, not by armies of technicians or graduate students, as is the case in molecular biology, so students, though fun and intellectually stimulating, were not a necessity for our own work. Second, we felt that independence is crucially important for training in science—that when you hand young people a problem to work on you may be depriving them of the most important learning experience, namely that of choosing a problem. It seems far better to flounder around for a while, trying one thing after another and finding out what kinds of science suit you, than to be presented with something someone else thought up. Graduate students or postdocs in our group certainly felt neglected, and they complained—Jim Hudspeth, one of the very best, complained the loudest- but I think the policy paid off in the quality of the people we trained (if “trained” is the right word). We learned as much from them as they did from us.

Our attitude toward training was probably to some extent copied from Steve, who never urged us to do or not to do something. At most, he would look bewildered when an idea or result of ours made no sense, or was not clearly described. He did, at the start, urge us strongly to measure and specify such things as the brightness of our stimuli and backgrounds, saying that no one would believe our results unless we put in a few numbers. We put them in, but looked on it as politics more than science. Steve’s main influence on Torsten and me was by example. He did an experiment roughly every day, and he did virtually everything himself-dissections, recordings, writing the papers. When he collaborated, he and his co-worker took turns at the various jobs: dissections, writing papers and so on. This was our style too; for a short time we had a technician tidy up our lab but we discovered that it took her two hours compared to our 10 minutes, and then we could never find anything.

So we had technicians cut and stain histological sections, which we were never tempted to learn how to do. Above all we discovered that in an experiment three is a crowd, and we almost always worked by ourselves. The exception was a most productive collaboration with Simon LeVay in which the work was rather cleanly divided into anatomy and physiology. Obviously in these things one’s style has to be fitted to the science, and I assume that there are good reasons for the 46 collaborators and coauthors in a high-energy physics paper. One can understand, but not envy.

There was a slack period of a few years, in the 1970s, when we attempted an exploration of the region of pre-striate cortex that is bounded by and includes that horror of complexity, the lunate gyrus. We recorded from a few hundred cells from each of two areas, which are now termed 3A and MT. But at that time everything north of 18 was called “19” and we thought (wrongly) that the first area might be area 18 (visual II), and (rightly) that the second might be the analog of the cat Clare-Bishop area. The first (3A) was packed with stereoscopic-depth sensitive cells, but we backed away from writing up the results because we did not know what to call the area. The second (MT) we thought was boring (again, wrongly!) because it was so similar to the Clare-Bishop. We were premature in this undertaking, since what was needed at the time was a working out of the topography of pre-striate areas, as Allman, Kaas, Zeki and Van Essen subsequently did. We had no patience for this, gave the whole thing up and obeyed our inclinations by returning to our old familiar area 17, concentrating on the orientation and ocular dominance columns, hypercolumns and magnification and modules. Now, 25 years later, one has what are possibly reliable topographic maps of one or two dozen pre-striate areas the physiology of which is ripe for exploration. To work out the striate cortex has taken decades, and these various pre-striate areas are already turning out to be just as complicated and interesting. I find today’s rate of progress disappointing, however. Monkeys cost a fortune, and the present popular mode of working with awake behaving animals, fertile as it is, seems ill-suited for the anatomically oriented physiology that is needed, grueling though that sometimes is.

One of the most pleasing advances came to us not during an experiment, but in the course of writing a paper. We had found, in the first year or so of work, that the cells in the visual cortex differ in the complexity of their behavior, forming a hierarchical sequence. Its members we termed “simple”, “complex” and “hypercomplex”. Cells at each level were presumed to receive their input from cells at the preceding level. These cell types were first found in the cat, and later, with some differences, in monkeys. The idea that the orientation columns must have the function of housing together sets of cells that the physiology—the circuits subserving the hierarchy—has shown must be interconnected, seemed to us to be one of the most deeply and aesthetically pleasing ideas of a lifetime.

We of course expected to be able to extend this hierarchy to cells of higher and higher order, and I suppose that was largely why we took on the prestriate areas. To our surprise the quest was not very successful. Today it seems likely that our failure to find more and more complexity related to form perception has to do with the presence of other complicating dimensions of vision that also have to be dealt with by the brain. In plowing ahead we stumbled on two such areas, one concerned (at least partly) with stereopsis, the other with motion, and neither perhaps primarily concerned with shape. The advantage of working in the striate cortex, and also in V-2, was that at these early levels all the submodalities (form, color, movement, depth) are represented, in different layers or as mosaics of stripes or blobs. In the pre-striate areas we were probably not lucky enough to look in the right places. For form analysis, the best place to look would have been area V-4, or the temporal lobe.

It sometimes seems to me that the sedulous nature of our work has been exaggerated, perhaps with intent to flatter, with adjectives like tedious, painstaking, careful, even plodding. But there must be few fields in science in which at the end of a day (perhaps a long day!), you can say that you have really found something new and unexpected. That may not happen every day, but it has not been rare. Examples, in no special order, are the discovery of color cells in blobs, end-stopping, the way geniculate cells enhance the antagonism of receptive field surrounds, color-spatial relationships in geniculate cells, orientation columns, direction selectivity, the scrambled topography of cortex in Siamese cats, the scrambled order of fibers in the optic nerve, the midline representation of the corpus callosum, the absence of sharply defined ocular dominance columns in newborn monkeys, the milder effects of binocular deprivation compared with monocular and the splitting up of binocular inputs as a result of strabismus. Most of these things became evident in the course of a day, more or less, and the sheer excitement is hard to convey. There were of course tough days too, in which nothing seemed to work. I can hear Torsten exclaiming, “Why is everything so difficult?” There were late nights when I knew we should quit when Torsten began to talk in Swedish.

When in 1981 Torsten and I won the Nobel Prize for all this work, the immense pleasure of the award (and the week-long party in Stockholm) was tempered (only slightly) by the worry that we might never be able to work again, at least not at the same pace. Mail, administration and invitations to give talks or receive honorary degrees would consume us. By and large that has not been so, at least not to the extent that I had feared. It had already become harder for us to collaborate by the late 1970s because of increased pressures of many kinds, and finally we had to split, Torsten beginning a collaboration with Charles Gilbert and I with Marge Livingstone. For two 60-year-old guys to continue to work at the pace of postdoctoral fellows and answer the mail and write letters of recommendation and be on committees was to expect too much.

The work with Marge has continued to be exciting. The first two years we spent recording from the cytochrome oxidase blobs and showing their involvement in color mechanisms, and in examining the physiology of the three kinds of stripes into which area 18 (now called V-2) is divided. We became increasingly intrigued by the separation of pathways into branches involved in form, stereopsis, movement and color, and in the striking tendency for these submodalities of vision to be independent of one another perceptually. We got into deep trouble over this foray into psychophysics, a field that has been late in integrating with the rest of neurobiology. But it is understandable that experts in a field that is hundreds of years old and rather sophisticated should object to the methods and ideas of those whom they must have looked on as bulls in a china shop. It was fun, instructive, and gratifying (in a way) to go through a period in which half the papers in neurobiology (it seemed) were aimed at proving our results wrong.

Marge and I have now gone over completely to working in awake behaving monkeys, in my case because after 35 years of mapping receptive fields until well beyond the Late Night with David Letterman Show, I was ready for a change. But I do regret abandoning the struggle to work out cortical organization, which requires a combined anatomy-physiology approach and accurate reconstruction of electrode tracks that is hard to do in animals that are kept around for many months.

Neurobiology did not exist when I started. It was great fun seeing it spring up at the time the departmental barriers separating its components—anatomy, physiology, chemistry and experimental psychology—were broken down. Scientifically we are in a far stronger, healthier state, threatened only by the possible failure of society to keep up the expensive business of supporting us. I hope that does not happen!

Selected Publications

(with Wiesel TN) Receptive fields of single neurones in the cat’s striate cortex. J Physiol 1959;148:574–591.

(with Wiesel TN) Receptive fields, binocular interaction and functional architecture in the cat’s visual cortex. J Physiol 1962;160:106–154.

(with Wiesel TN) Receptive fields and functional architecture of monkey striate cortex. J Physiol 1968;195:215–243.

Evolution of ideas on the primary visual cortex, 1955–1978: A biased historical account. (Nobel lecture.) Biosci Rep 1982;2:435–469.

Eye, brain and vision. Scientific American Library, No. 22. New York: WH Freeman, 1987.

(with Livingstone MS) Connections between layer 4B of area 17 and the thick cytochrome oxidase stripes of area 18 in the squirrel monkey. J Neurosci 1987;7:3371–3377.

(with Livingstone MS) Segregation of form, color and stereopsis in primate area 18. J Neurosci 1987;7:3378–3415.

(with Livingstone MS) Psychophysical evidence for separate channels for the perception of form, color, movement and depth. J Neurosci 1987;7:3416–3468.

Eye, brain and vision. Scientific American Library, No. 22. New York: WH Freeman, 1995.

Herbert H. Jasper

BORN:

La Grande, Oregon

July 27, 1906

EDUCATION:

Willamette University (Philosophy and Psychology, 1923)

Reed College, B.A. (Psychology, 1927)

University of Oregon, M.A. (Psychology, 1929)

University of Iowa, Ph.D. (Psychology, 1931)

University of Paris, D.és.Sci.de l’état (Neurophysiology and Biophysics, 1935)

McGill University, M.D.C.M. (Medicine, 1943)

HONORS AND AWARDS (SELECTED):

Fellow, Royal Society of Canada (1964)

The William G. Lennox Award for Research in Epilepsy (1969)

Officer of the Order of Canada, O.C. (1972)

Ralph W. Gerard Prize, Society for Neuroscience (1981)

Karl Spencer Lashley Award, American Philosophical Society (1982)

McLaughlin Medal and Prize, Royal Society of Canada (1985)

The Milken Family Medical Foundation and the American Epilepsy Society “Most distinguished prize and award for basic research in epilepsy” (1993)

F.N.G. Starr Prize, Canadian Medical Association (1994)

Member of the Canadian Medical Association Hall of Fame (elected 1995)

The Albert Einstein World Science Award of the World Cultural Council (Mexico City, 1995)

Herbert Henri Jasper dedicated his life to studies of the brain in relation to the mind and behavior. He pioneered the establishment of the electroencephalogram (EEG) for the study of the electrical activity of the brain in relation to states of consciousness, learning, and epileptic discharge. He proceeded to use microelectrodes to record from single brain cells and synapses combined with studies of neurochemical mechanisms involved in the control of brain activity.

Herbert H. Jasper*

Dedication to Brain Research, Willamette University, 1924–1926

I was born in La Grande, Oregon in 1906. Through my father, who was a Protestant minister and religious scholar, I became interested in world religions and social problems. I was in uniform during the first world war as a messenger boy in the Army camp where my father was in charge of social services for the troops. I then went to Willamette University in Salem, Oregon, from which my father had graduated in the school of theology and social studies. I majored in philosophy and experimental psychology and decided to devote my life to studies of brain-mindbehavioral problems.

I delved deeply into the history of philosophy, led by Professor Charles L. Sherman. I was fascinated by the Greek philosophers, Socrates, Plato, and their idealistic point of view. This was tempered, however, by the work of Plato’s pupil, Aristotle, and his research in biology and botany that led him to collect species of plants and animals and to speculate about their origin and development, which led him close to the views later expressed by Charles Darwin. My view of Greek philosophy also was tempered by the atomic materialism of Democritus and the Epicurean pleasure principles. I found the origin of medicine in the works of Hippocrates and Galen.

After my initiation into Greek philosophy I proceeded to study the great philosophers of the 17th and 18th centuries—Descartes, Bacon, Kant, Hegel, Spinoza, Berkeley, Locke, Spencer, Hume, and Bergson. I was very interested in Kant’s Critique of Reason for it seemed that his view of metaphysics and epistemology and his psychological analyses of human behavior and mental processes in relation to brain activity was quite reasonable. The extreme subjectivism of Berkeley impressed me little, because it seemed to me a game of logic rather than an attempt to understand the world we live in.

My favorite of the 17th and 18th century philosophers was Bergson with his view of “creative evolution,” continual change and development of truth and the mind. His introduction of the importance of time, with the emergence of new forms and ideas in time, was reminiscent of Einstein’s treatment of time as a fourth dimension. Bergson, however, did not agree with Darwin’s view of natural selection by chance mutations in heredity as the mechanism of creative evolution. His careful studies of the remarkable development of animal organs, such as the brain and the eye, convinced him of a creative design in nature.

Professor Sherman, however, was more interested in the modern philosophers, particularly the pragmatists like Charles Pierce and John Dewey. We spent much time on the work of William James in Principles of Psychology, a truly great work of pragmatic philosophy as well as a comprehensive treatment of his views of the “stream of consciousness” and its relation to the continuous flow of sensations modified by instincts, attitudes, and emotions.

I was introduced to psychology through studies of the functional anatomy of the brain. Professor Sherman gave us a good review of what was then known about the sensory receiving areas of the cerebral cortex; the motor cortex; and the frontal, parietal, and temporal association areas. It seemed that many of the philosophical problems that had been bothering me, and the mechanisms of the mind and behavior as described in psychological terms, might well be understood if we knew more about the brain mechanisms involved.

I met an attractive young lady in our psychology class. Her father was the superintendent of the Oregon State Mental Hospital, located not far from the university, on the outskirts of Salem. I walked her home a few times and then she invited me to tea with her parents in their home, which was a splendid house on the beautiful grounds of the hospital. I was pleased to accept her invitation not only because I was becoming fond of her but also because I was curious about what went on in a state mental hospital.

I arrived on a Sunday afternoon and, walking through the grounds of the hospital, we met several patients who seemed to be roaming around quite freely. One of them spoke to my young lady in a friendly manner. I did not recognize him as a patient and asked the young lady who he was. She replied that he wasone of many patients who had the liberty to walk freely on the grounds while being supervised from a distance.

I found the superintendent to be a charming fellow, willing to discuss the activities of the hospital. He invited me to join in some of the regular patient conferences and ward rounds. I did this on many occasions and was astounded by the strange distortions in thought and behavior we encountered in patients for whom there seemed to be little or no treatment, only good custodial care.

In some patients only a thin line separated them from what might pass as normal or only slightly odd. What disturbances in brain function could underlay such tragic derangements in mental activity and behavior, was a question that has haunted me all my life.

These are only a few of the influences that led me to make a firm commitment at about 20 years of age to devote my life to brain research in all of its aspects. As it happened, the late 1920s and the early 1930s proved to be a most exciting period in the development of neuroscience:

Joseph Erlanger and Herbert Gasser at Washington University in St. Louis, Missouri, had just developed the use of the cathode ray oscilloscope to visualize for the first time the precise form of nerve action potentials and their differences, depending on the diameter and myelination of nerve fibers.

Hans Berger had just begun publication of his studies, Das Elektrenkephalogram bei Menschen, which, when confirmed by Edgar Adrian of Cambridge, England, and many others, launched the use of the electroencephalogram (EEG) for the study of normal and abnormal human brain activity.

Sir Henry Dale in England and Otto Loewi in Germany had begun to establish the chemical transmission of the nerve impulse at synapses and neuromuscular junctions. The dispute between the “Dale School” (soup) and the electrical school (sparks) led by J.C. Eccles, then of Oxford, enlivened meetings of the British Physiological Society in the early 1930s until Eccles himself, with the aid of Arthur Feldberg and Martha Vogt, became a proponent of chemical transmission at synapses throughout the nervous system.

Alan Hodgkin and Thomas Huxley had demonstrated the ionic mechanisms of the transmission of impulses in nerve fibers, with the help of J.Z. Young and K.C. Cole, at the Marine Biological Laboratories in Woods Hole, Massachusetts.

Francis Schmitt with his brother Otto, at Washington University, had begun their studies of the molecular structure of nerve membranes. Frank had also been brought up in a strongly religious background and thought that many of the answers to understanding the function of the nervous system would come from studies of the molecular structure of nerve membranes. This became known as “from molecules to mind” or the “from bottom up” point of view, in contrast with the “from mind to molecules, from top down” point of view, where I started in my thinking about this old problem.

With these and other exciting developments in neuroscience at that time, there is little wonder that I chose to devote my life to brain research. My father was somewhat dismayed for he wondered how I was going to make a living, because I was neither interested in studying medicine to become a doctor, nor in becoming a university professor!

Reed College and Postgraduate Studies at the University of Oregon, 1928–1929 and the University of Iowa, 1930–1931

I had been saturated at Willamette University with studies in philosophy, psychology, physics, and chemistry. I had been shocked by the suicide of a close friend and classmate, and by exposure to a hospital full of mental patients. I was ready to move on after three years of study and work on the side to pay my way.

I had become a unionized meat cutter working after school and during summer vacations. I also had organized a landscape gardening company, employing students to take care of properties in Salem, all of which did well to pay for my living and tuition expenses.

My father moved to a parish in Eastmoreland, adjacent to the campus of Reed College, an outstanding small college in Portland, Oregon. To my surprise I was admitted to Reed in 1926 soon after I applied, even though it was only for my final year of college. I was thus able to live with my parents close to campus and to join the graduating class of 1927.

I studied psychology under the excellent tutelage of Professor William “Monty” Griffith, a large friendly practical professor, who was interested in all aspects of behavioral psychology. I took a minor in philosophy under an equally outstanding philosopher, Professor Edward Sisson. Classes were small, there being only about 300 students and 45 faculty in the entire college. We met frequently in our professors’ homes.

There were few intercollegiate athletics to distract the students, but there was plenty of physical exercise through intramural sports programs. Students received no grades, so that we would not be distracted from our studies. This caused some anxiety on the part of my father who wrote the president toward the end of the year to inquire about my grades and if I would graduate. The president answered by letter telling him that I would graduate with “sufficient extra space to be able to drive out with a four horse team.”

I was required to write a thesis, which was equivalent to a master’s thesis in the graduate schools of most universities. My thesis involved questionnaire studies of students from most of the universities and colleges in Oregon. It was published in part in the American Journal of Sociology in 1929. Titled “Optimism and Pessimism in College Environments,” it was my first publication.

My experiences at Reed made indelible impressions on my future life, even today, 70 years later. The faculty and student environment was delightful. I wrote for QUEST, the college paper, and conducted an experiment with other students which had a lasting impression on my future in neuroscience. Professor Monty Griffith had been describing the effects of certain psychotropic drugs on the mind. A few students in the dormitory invited me to join them in an experiment with one of the drugs mentioned in class, mescaline. I was interested but afraid of what I might be getting into. I tried the drug and was astounded by the profound effects of a few drops of injected mescaline. The whole world changed. I was disorientated completely, had hallucinations and delusions, and sensations of floating in air. It was a most disturbing and frightening experience, with some rather pleasant and exhilarating feelings as well.

We discussed our experiments afterward, and Monty Griffith warned us severely about addictive properties and ever trying such experiments again. I have never forgotten the dramatic effect of such a small amount of a chemical substance upon the mind. I was determined to include brain chemistry in my future program of brain research.

Graduate Studies, University of Oregon, M.A., 1929 and the University of Iowa

In 1929 I enrolled in a Master’s degree program in experimental psychology at the University of Oregon in Eugene. I found an apartment for graduate students, managed by a kindly middle-aged lady, Celia Hager, who mothered us all.

I had two roommates, one a completely blind assistant professor in charge of the laboratories of experimental psychology, Tom Cutsforth. He had lost sight in both his eyes by an accidental injury when he was a very young child. Tom became a close friend and companion, both in fishing and hunting trips in the mountains around Eugene, as well as in the laboratories, helping me to construct the apparatus necessary for my thesis work. My other roommate was a graduate student in psychology by the name of David Turtletaub.

In a cottage next to ours were two sisters, Constance (Connie) and Eleanor (Cindy) Cleaver. Connie was a lively, attractive young lady who was studying art. By coincidence her parents were friends of my parents in LaGrande, Oregon. I found myself spending more and more time with her as time went on, with delightful consequences at the end of the first year.

Professor Edmund S. Conklin was head of the department of Psychology. He specialized in abnormal psychology and was the author of a popular textbook on the subject. Associate professors included Harold Crossland and Robert Seashore, the son of Dean Carl Seashore, head of the Psychology department and the Graduate School at the University of Iowa in Iowa City.

Professor Conklin’s lectures in abnormal psychology were outstanding. I did my thesis under his direction, and with assistance from Robert Seashore and Tom Cutsforth, we designed and constructed some of the apparatus I needed in my studies of perseveration. My thesis was titled “Perseveration and its Relation to Depression and Introversion.” It was published in the Journal of Social Psychology (Jasper, 1931). Because our results were rather negative, we were anxious to get on with more promising experimental work.

In the meantime, Connie Cleaver and I had fallen in love and her interest and work in art opened up new worlds for me. With the agreement and encouragement of our parents, and the urging of our friends, Celia Hager, Tom Cutsforth, Bob Seashore, and others in the psychology department, we were married on Christmas day, 1928 in LaGrande, Oregon—my birthplace and the home of Connie’s father and mother. Connie’s sister, Cindy, was the bridesmaid.

For the first year we lived in Connie’s apartment when her sister kindly moved elsewhere. We both graduated in June 1929. Connie earned her masters degree in art and I was awarded a master’s in psychology.

With the help of Bob Seashore I applied to graduate fellowships at Ohio State, Northwestern, and the University of Iowa, each of which had a very good department of psychology. I was very surprised to have my application accepted in all three universities, presenting quite a problem of choice.

Bob Seashore advised me to take the position that offered the least salary. I objected that I would need more money now that I was a married man, but he reasoned that the department offering the least salary must be the best because it was able get many good students for less. Bob’s father was head of the psychology department as well as dean of the Graduate School at the University of Iowa. The lower stipends made our choice an easy one.

Bob also suggested that Connie should apply for a fellowship in the art department. This seemed to be an excellent arrangement and Connie was awarded a fellowship. The art department had close relationships with the psychology department because of Dean Seashore’s interest in the psychology of music and art.

We packed up and set out for Iowa City together during the summer of 1929. Bob Seashore was there to meet us, having returned to Iowa to visit his parents, who helped us find an apartment upstairs in an old house near the center of town. They also invited us to dinner at their home with Bob and his wife. We had a delightful evening with this friendly family, and received much good advice about living in the small university town of Iowa City.

I am unable to describe in this short autobiography the many important experiences I had during my two years in Iowa. My thesis, under the direction of Professor Lee Edward Travis, head of the department of speech pathology, was based on studies of the effects of hemispheric cerebral dominance on the bilateral coordination of movements in normal patients and those with severe stuttering. My thesis was published in the Psychological Monographs (Jasper, 1932). There were several other studies published separately. Professor Travis, with his electronic engineer, had developed an electrical recording apparatus for muscle and nerve action potentials, but with which we could not record the slower waves of the electrical activity of the brain, which would come later. I used the apparatus to study the time characteristics of electrical stimulation of nerve and muscle known as “chronaxie” as developed by Lapicque and Bourguinon in France.

More important, perhaps, were the studies carried out with other faculty members in the departments of medicine, physiology, and psychiatry. It was at Iowa, under Dr. Travis, that John Knott and Donald Lindsley got their start in electrophysiology after I left.

Important also were the contacts I had with the group at Washington University in St. Louis, including Herbert Gasser, Joseph Erlanger, George Bishop, Howard Bartley, Francis 0. Schmitt, Lorente de No, and James O’Leary.

Bartley and Bishop were studying the electrical activity of the brain in experimental animals. Gasser and Erlanger were developing the use of the cathode ray oscilloscope for the analysis of compound action potentials from peripheral nerves and their relationship to the diameter and myelination of single nerve fibres.

During the winter of 1929 to 1930 we attended a meeting of the American Physiological Society in Chicago, despite a severe snow storm. Many of the St. Louis group were there and we managed to meet them after their papers were presented. Herbert Gasser then introduced us to a charming young couple from the Sorbonne in Paris by the name of Alexandre (Ali) and Andrée Monnier who were studying in St. Louis on a Rockefeller Fellowship. They were returning to Paris with their cathode ray oscilloscope apparatus they had been building. They asked if I would like to come to Paris to work with them for a couple of years. I agreed, after consultation with Connie, who was delighted at the possibility of continuing her art studies in Paris. With the help of Dean Seashore, Allan Gregg of the Rockefeller Foundation, and Ali Monnier, I obtained the support of the Rockefeller Foundation. We sailed from Oregon on a passenger freighter through the Panama Canal in the summer of 1931. It was a long and delightful trip and we arrived in Paris in time to start the year at the Sorbonne in the fall of 1931. It was a most important turning point in my career.

Enlarged Horizons, Rockefeller Fellowship in Europe, 1931–1933

We were greeted warmly by the Monniers and soon were treated like members of their family. We were also greeted warmly by Professor Louis Lapicque, who was head of the physiology department and worked daily in the laboratories with Madame Lapicque and other members of the staff and students. Everyone seemed to be working on chronaxie in one way or another, which was Lapicque’s principal interest. I found it an intriguing theory of excitabilite en fonction du temps in the transmission of impulses across synapses and neuromuscular junctions in the nervous system, isochronism being a sort of tuning process.

I soon found that Lapicque had another great interest, that of sailing his ocean-going yacht, the “Axon,” from his country home near Paimpol in Brittany.

Ali Monnier was a distinguished biophysicist before becoming a neurophysiologist. He was developing a mathematical theory of nerve excitability similar to that being developed by A.V. Hill in London. In addition to our work together with the cathode ray oscilloscope, I was to learn much about the mathematics of nerve excitability and to have experience with chronaxie measurements.

I found that Ali was also a keen sailor and together we sailed his small boat up and down the Seine on summer weekends. I also soon learned to speak fluent French so that I could present some of our work before the French biological society and at other scientific meetings in Paris.

I became acquainted with Alfred Fessard who was also setting up a cathode ray oscilloscope in his laboratories in the College de France. I met Henri Piéron, head of the department of psychology, and visited many other laboratories throughout France and Europe, including many of Ali’s friends in Great Britain. I also met neuroscientists from other parts of the world by attending international meetings in Europe and England during my two-year fellowship at the Sorbonne, at the Marine Biological Laboratories in Roscoff, Brittany, where I spent two summers, and at the Marine Biological Laboratories in Naples, Italy, where I met J.Z. Young.

My work at the Marine Biological Station in Brittany was particularly important. I met many leading molecular biologists there and made lasting personal friendships, such as that of Jacques Monod who later received a Nobel Prize for his work on Messenger RNA, and was able to help me in the establishment of The International Brain Research Organization (IBRO) with UNESCO (he too was a keen sailor).

Also important were the lifelong friendships formed during my postdoctoral fellowship, including E.D. Adrian of Cambridge, Frederic Bremer of Belgium, Ragnar Granit of Stockholm, John Fulton of Yale, and Charles Sherrington and John Eccles of Oxford.

Brown University, 1932–1938

In 1932, I returned to the U.S. at the invitation of Drs. Arthur Ruggles and Leonard Carmichael of the departments of psychiatry and psychology of Brown University in Providence, Rhode Island, to establish a research laboratory at the Bradley Hospital in East Providence, adjacent to the Brown campus.

In the meantime, Connie had gone to Oregon to be with her parents for the birth of our daughter, Marilyn. When they arrived in Rhode Island we were put up in an elegant apartment in the hospital. Dr. Bradley, superintendent of the hospital, and his wife and daughter of about the same age, lived next door. Connie was very happy to have the company of Mrs. Bradley and her young daughter upstairs. They were both assisted by a kindly housekeeper.

For my studies, I was given a suite of rooms in the basement which were originally intended for an x-ray department. The walls were lined with lead which would serve as electrical insulation for our recording equipment.

I was soon able to acquire a good electronics engineer, Howard Andrews, from the department of physics. We were soon joined by Margaret Rheinberger, a neurophysiologist who had trained with Dr. John Fulton of Yale. She had experience in electrical recording and in operating on experimental animals. We soon had graduate students and a few colleagues to add to our staff, including Dr. Carmichael himself, who joined us in some of the experimental programs.

I learned from Dr. William Malamud, a German psychiatrist who had moved from the University of Iowa to Harvard, that he had been following the publications of Hans Berger on Das Elektrenkephalogram in German and thought that I should consider trying to repeat some of his work. I went to Boston to discuss this with him and to have him translate Berger’s publications.

Howard Andrews started immediately to build an apparatus that would be suitable for recording the EEG. We then heard that Adrian had been invited by the American Neurological Association to speak at their next meeting in Atlantic City. I went to the meeting and was pleased to see Adrian again and to discuss his findings and those of Brian Matthews. Dr. Carmichael decided to join us in trying to record EEGs during the summer months of the same year, giving up our vacations for the purpose.

We were successful in obtaining very good records with the splendid apparatus that Howard had created. Howard himself was the first subject, along with other good subjects among the graduate students and staff of the hospital, but his brain waves were difficult to read. We found that Carmichael and I had excellent alpha rhythms which made it possible to confirm many of Berger’s findings. We published the first United States paper on the EEG (Jasper and Carmichael, 1935).

We were in close competition with Hallowell Davis and his wife Pauline, and Alexander Forbes from the Harvard laboratories in Boston. They were soon joined by Erna and Fred Gibbs, William Lennox, Donald Lindsley, and Bill Derbyshire. Albert Grass joined them a little later as their electronics engineer. I kept in close touch with their work in Boston by attending many weekly seminars in the physiology department and meetings of the Boston Society of Neurology, where I became acquainted with Houston Merritt, Tracey Putnam, Raymond Adams, and Stanley Cobb.

It was obvious that we had discovered a method of recording the continuous electrical activity of the brain, which was very sensitive to states of mind and consciousness, sleep and waking, relaxation or anxiety, and arousal and attention, with both local and generalized responses to external and internal sensory stimulation of all kinds.

Dr. Adrian had shown that when the alpha rhythm was blocked, the eyes would open even in a completely dark room. We had shown that after-images when the eyes were closed would also cause blocking of the alpha rhythm, even in a completely dark room.

By implanting recording electrodes in cats, we soon observed the generalized slow waves of sleep. When we observed a change to rapid waves we had learned it to be a sign of waking. This proved to forewarn us of the cat needing to use the litter box. We also discovered that students whom we used as normal subjects would often fail to show an alpha rhythm just before a difficult examination, which proved to be a reliable indication of anxiety.

Alfred Loomis, a wealthy stock broker, had established important research laboratories in Tuxedo Park, New York. He became interested in electroencephalography and invited us to join him from time to time. On one such occasion he also invited Newton Harvey from Princeton, who brought Albert Einstein with him so that they could study Loomis’ brain waves. They put him to sleep, and at first he showed the typical slow waves of sleep. Then the EEG changed to the rapid waves of arousal. He awoke suddenly, asking for a telephone. He called his laboratories in Princeton to tell his colleagues there that he had been reviewing his calculations of the day before and discovered an error which should be corrected. This done, he was able to go back to sleep again. We thus had a dramatic demonstration of the sensitivity of the EEG to mental activity.

The EEG was also sensitive to anesthetic agents and chemical agents, such as benzedrine. Furthermore, it was sensitive to brain metabolism, oxygen tension, pH, brain temperature, local or generalized blood flow, brain lesions such as tumor or trauma, and brain diseases, as in the epilepsies and encephalopathies.

I had been accustomed to using cathode ray oscilloscopes in my work with Ali Monnier in Paris, and I was not about to use any of the ink writers available at the time for fear of missing the more rapid components of the EEG. The precise amplifiers built by Howard Andrews, with direct current amplifiers, Westinghouse mirror oscillographs and photographic recording, assured us of accurate and complete records despite the trouble of getting them.

Woods Hole, Summers of 1932 and 1933

I had completed my research on crustacean neuromuscular systems for my doctoral thesis in Paris by spending the summers of 1932 and 1933 at the Woods Hole Marine Biological Laboratories. At the same time I was able to meet many leading neuroscientists from the United States and other countries who were then working at Woods Hole: Ralph Gerard, J.Z. Young, K.C. Cole, Harry Grundfest, Alan Hodgkin, Herbert Gasser, Francis O. Schmitt and his brother Otto, H.J. Curtis, Ladd Prosser, and a few others whose names I have forgotten. My many discussions with them were important for my future in neuroscience.

Defending My Doctoral Thesis, Paris, 1935

I sent my thesis in English to Negro Monnier in Paris for translation into French, and defended it in Paris in the spring of 1935. My doctoral thesis was composed of two parts: “recherches sur l’excitabilité et les caracteres de la reponse dans le system musculaires des crustacés. Influences des centres ganglionaires” and “electroencephalographie chez l’homme.”

I defended my thesis before a distinguished panel of examiners chaired by Professor Lapicque. The room was full of visitors, including Alfred Fessard, Ali and Andreé Monnier, and many other members of the staff and students. The examining committee seemed satisfied with the principle thesis on the crustacean neuromuscular system, though Lapicque was somewhat dismayed about the work I did with Monnier on “pseudochronaxies.” All were enthusiastic about my second thesis on “electroencephalographie chez l’homme.” I had to treat everyone to a champagne reception afterward as is the custom.

I stayed in Europe for most of the summer of 1935 in order to visit electroencephalographic laboratories which had sprung up in Europe following the publications by Hans Berger and Edgar Adrian with Brian Matthews. This stay included visits with Alfred Fessard and his co-workers, and Hans Berger and his charming family in Germany, where he was suffering from the advance of the Nazis. Berger was deprived of his position in the university and hospital and put under house arrest for his refusal to ask his students to stand and salute Hitler at every lecture. There was a large picture of Hitler placed on the wall behind his lectern. A few years later Berger went into a deep depression at seeing what was happening to his beloved country and committed suicide.

I also visited the Brain Research Institute of Oscar and Cecile Vogt in “Buch bei Berlin,” where Toennies and Kornmuller had developed a very good apparatus for recording electrical activity from the brain in experimental animals. They thought that the pattern of brain waves from different areas of the cerebral cortex in monkeys corresponded to the cytoarchitectonic areas that had been described by the Vogts from their anatomical studies.

We had also documented differences in patterns from different sensory, motor, and association areas of the cortex, although not corresponding so precisely to the cytoarchitectonic areas that the Vogts had described.

In a sound-proofed office, well isolated from the rest of the institute, the Vogts told me that they and the Toennies were far more concerned about persecution by the Nazis than they were about the EEG. Their daughter, Marthe Vogt, asked me what she should do to further develop her interest in brain research. I suggested that she move to England as soon as possible and concentrate on brain chemistry. She followed my advice, leaving immediately for England to escape the Nazis who were about to close their institute. We were able to get her a good fellowship in England where she made important contributions to the development of chemical transmission of the nerve impulses at synapses throughout the CNS in conjunction with the work of Sir Henry Dale and Arthur Feldberg.

I returned to Paris where I accompanied Ali and Andrée Monnier for a trip to England in their little Citroen car. We visited their friends and attended the annual meeting of the Physiological Society in Oxford, where we stayed with John Fulton and a few of his special friends in his rented manor. It was a remarkable meeting. Ivan Pavlov from Russia and Santiago Ramon y Cajal from Spain were given honorary degrees. Pavlov gave a principle address, primarily in Russian with simultaneous English interpretation, on the theme of conditioned reflexes in the higher cognitive functions of the brain.

The most memorable lecture, however, was given by Sir Charles Sherrington. It was his “swan song” because he was retiring immediately after the meeting. It was a brilliant discourse, mostly on higher level functions of the brain, the cerebellum which “molded body posture by inhibition,” and continuous synaptic activity in the cerebrum like “flashing of fireflies on a summer evening.” As usual, he gave credit to his students and colleagues for his remarkable contributions to neurophysiology.

We picnicked with Jack Eccles and his family on the Seine and met many British and foreign physiologists at the meeting. We also had a short visit with Pavlov.

We then visited A.V. Hill in London and visiting scientists Ralph Gerard from Chicago and Professor J.P. Fenn from China, who became a life-long friend who came to meet me and Hank McIntosh several times in Montreal.

We then went to the Maudsley Hospital where we met Dr. Golla and W.G. Grey-Walter, a former student of Adrian’s who had started a most interesting EEG department. We also met Denis Hill and a young fellow by the name of William Cobb, who later established the EEG department at the National Hospital of Queen Square.

We completed our visits by going to Cambridge to visit Adrian and Matthews, who showed us their pioneering work on electroencephalography and what they called “The Berger Rhythm.” Adrian had demonstrated his own excellent Berger Rhythm before the Royal Society in London.

I heard from John Fulton about the meeting of the World Neurology Association at which he was chairing a symposium on the frontal lobes. Carlyle Jacobsen presented his classical work on the frontal lobes of chimpanzees which gave Walter Freeman, a neuropathologist from Washington and Egas Moniz from Portugal, the idea of starting to treat mental diseases by prefrontal lobotomy. I reviewed this sad but interesting story recently in a book on “Epilepsy and the Functional Anatomy of the Frontal Lobe” (Jasper, 1995).

Montreal, 1937–1965

My colleagues and I had heard of Penfield’s observations on the exposed cortex of patients who were being treated for focal epilepsy. We invited him to Brown to give a seminar in the psychology department. We were all impressed by his research on electrical stimulation of local cortical areas in conscious patients during surgery for the treatment of focal epilepsy.

Penfield visited our laboratories at the Bradley Hospital to see our work on electroencephalography for the localization of focii in patients with focal epilepsy. He was skeptical of our work with the EEG, having heard nothing about the EEG before. He agreed, however, to operate on a couple of my patients.

I sent two patients to Montreal whom he considered suitable for operation. I then drove to Montreal on weekends with EEG recording equipment in the back seat of my car in order to be able to record from the exposed cortex on our patients during the operative procedures. Fortunately, Penfield found objective focal lesions in each patient just beneath our EEG localization. He then agreed to take a few more patients, and we continued our commuting collaboration for the rest of the year with satisfactory enough results that he was willing to consider my joining his team in Montreal. However, there was neither money to pay for me and my staff, nor space for our laboratories.

Penfield was able to have my Rockefeller grant moved to Montreal. He then managed to build an addition to the institute, providing good space for our clinical examinations with some room for experimental laboratories. Our electronic laboratories were housed in a storage room in the basement.

I moved to Montreal in 1938. We opened our EEG department with a symposium in February 1939. Most of the leading EEG workers from the United States and Canada were present for the opening ceremonies. After visiting the institute and observing an operation by Dr. Penfield on an epileptic patient with direct electrical recording from the exposed cortex, we held a short symposium before taking off for the Laurentian mountains to spend the weekend in a ski resort. There, at Domaine d’Esterel near St. Marguerite, we continued our scientific meeting and took time out for skiing. We also had a downhill race in which most participated, including Dr. Penfield. This proved to be the first of annual ski meetings by the Eastern EEG Association which have continued ever since.

My time with Wilder Penfield and his family, in which I became an adopted member, working with his splendid enthusiastic staff and hundreds of colleagues and students from all over the world who worked with us, was certainly the most pleasant and productive 27 years of my life.

I began with ward rounds each Monday morning, which were attended by all members of the staff and students, with active participation of all departments of the institute. It was Penfield’s dream to create a multidisciplinary neuroscience institute in which the basic sciences worked closely with the clinicians and the laboratories of radiology, neuropathology, neurochemistry, neuroanatomy, neuropsychology, and, of course, with electroencephalography and neurophysiology, in a fusion of clinical and basic research. This was a forerunner of what soon became what we now know as neuroscience.

I was delighted to take part in the realization of Penfield’s dream, which soon became my own as well; it became for me an international as well as an interdisciplinary dream.

I had two excellent assistants for setting up and starting work in the EEG department. The electronics engineer, André Cipriani, was extraordinarily competent. He was able to make all the recording equipment himself with the aid of a well-equipped electronics and machine shop. He made three sets of four-channel ink writing oscillographs with their appropriate, well-designed amplifiers. André had honors degrees from Jamaica in physics and electronics and a medical degree from McGill. He was also a delightful, good humored fellow.

I was also able to get Dr. Penfield’s chief scrub nurse from the operating room, Mary Roach, to take over the management of our neurophysiological laboratories so that our experimental operating rooms would meet the standards to which she was accustomed. She left during World War II to take charge of Army hospitals, going with the front line troops during the invasion of Italy. She returned from the war with some Italian assistants who worked with her in our neurophysiological laboratories.

Dr. John Kershman, an accomplished neurologist and neuropathologist from London, England, also joined me in the EEG laboratories, conducting detailed studies of more than 1,000 epileptic patients whom we reviewed in gathering material for our paper (Jasper and Kershman, 1945).

Our review included a clinical history and examination, together with radiographic studies, on over 1,000 epileptic patients, quite a few of whom had been operated on by Dr. Penfield.

It was in 1941 that I also published my first comprehensive treatment of “electroencephalography” as a chapter in a book by Penfield and Erickson (Jasper, 1941). Ted Erickson was chief resident in neurosurgery at the time. In that same year I published another paper with him on (Jasper and Erickson, 1941) using apparatus made by Andy Cipriani some time before (Jasper and Cipriani, 1940). This was the first of a long series of neurophysiological experiments we conducted with neurosurgical residents as part of their graduate training. They were all excellent workers. In 1941 I also published a review on “Electrical Activity of the Brain” (Jasper, 1941).

During my first two years in Montreal we were examining 2,000 to 3,000 patients in the EEG department, in addition to having weekly epileptic conferences and several operations with Dr. Penfield. I worked with so many patients that I felt I needed more medical training, and so I started medical school in 1940 as a regular student, while also being on the faculty teaching some of the courses myself. World War II had begun and the medical course had been reduced to three years, but we had begun some war research as well.

I fell in love with one of the nurses, Margaret Goldie, who was a formidable opponent on the tennis court (Connie and I had divorced). Goldie and I were married in 1940 in her hometown of Guelph, Ontario, with Robert Pudenz as my best man and Montreal Neurological Institute (MNI) fellows as ushers at the wedding. Goldie, as she was known, settled into a new house and helped me with my medical studies. She continued to work in the EEG and neurophysiology departments and to perform clinical and operative work with Dr. Penfield and his staff. Goldie and I have two fine children, Stephen and Joan.

With Goldie’s help and that of several fellow students I was able to pass most of the examinations in medical school, even though I was not able to attend all the classes. However, after a couple of years of maintaining such a hectic schedule, I came down with lymphocytic choreomeningitus, a form of nonparalytic polio, and was hospitalized for several weeks. I missed graduation with my class of 1943a and had to join 1943b for my final year. I then went immediately to Army camp to train to be a captain in the Canadian Army Medical Corps, while Goldie became a Red Cross nurse, both of us in uniform.

Through the remainder of the war I conducted war research for the Army (air transport of the wounded and antibiotics for treatment of wounds, electromyography of nerve injuries), the Navy (development of antiseasickness pills), and the Air Force (studies in the physiology of pilot blackout during battle maneuvers and their protection with a blackout suit). We were also engaged in the use of electroencephalography for the selection of pilots for the Air Force.

Dr. William Cone, who had been involved in our studies of the action of antibiotics on the brains of experimental animals, organized a neurological hospital in Basingstoke, England. John Kershman joined the Air Force and Andy Cipriani was appointed chief of the Atomic Research Laboratories near Ottawa.

We recruited K.A.C. (Allan) Elliott, a distinguished South African brain chemist trained in England, who was working at the University of Pennsylvania. Allan joined us to help improve our treatment of brain swelling and edema in the many casualties who were returning from combat with severe head injuries.

Allan established the Donner Laboratories of neurochemistry adjacent to the neurophysiology laboratories. We were soon in close collaboration which enabled me after the war to branch into brain chemistry. We were joined by Donald Tower, Niko Van Gelder, Hannia Pappius, Leon Wolfe, Hugh McLennan, and others. Allan also became a close personal friend; we took many ski trips in the mountains and we sailed on Lake Memphramagog together.

The Post-War Surge of Research Fellows, 1945–1955

We had more than 100 research fellows during the 10 years following the war. The first was Jan Droogleever Fortuyn, a distinguished neuroanatomist from The Netherlands. He had received a Rockefeller Fellowship before the war, but had been interned by the German occupation. He and his wife had suffered terrible hardships and persecution and the loss of so many of their Jewish friends during the Holocaust. His wife was a psychiatrist and well-known poet, and had helped the government to solve labor and bilingual problems between the Flemish and Dutch cultures in Holland. After a period of readjustment, Jan and his wife made a big contribution to our research program at the institute. Also of particular importance was the arrival of Cosimo Ajmone-Marsan from Italy, Jerzey Olszewski from Poland, and many others.

Space does not permit me to mention many of the publications done with these colleagues in this brief review. I will include a few in the references at the end of this chapter. I would like to mention two highlights which occurred in 1954 which gives a summary of some of this work: book published with Wilder Penfield on Epilepsy and the Functional Anatomy of the Human Brain (Penfield and Jasper, 1954, Boston, Little Brown & Co. pp 1-896) and Brain Mechanisms and Consciousness by Adrian E.D., Bremer F., Jasper H.H. and Delasfresnaye J.F., 1954, Oxford, Blackwell Sci. Pub. pp:vii-556.

The International Congress of Physiological Sciences was held in Montreal in 1954. Dr. Penfield and I had just completed our book summarizing much of our work together (Penfield W.G. and Jasper, 1954) with a summary of some of my work with other colleagues. I met many of the leading neuroscientists from around the world, including many from the Soviet Union.

Another event of great importance in 1954 was the Congress of Physiological Sciences, where I had the pleasure of being associated again with many neuroscientists in a satellite symposium. The Congress was held in the Laurentian Mountains near Montreal and our symposium was titled “Brain Mechanisms and Consciousness” (Adrian, E.D., et al., 1954). It has also become a classic in the literature. I served as chairman and principal organizer of the Congress, with papers and discussion provided by H.W. Magoun, J. Olszewski, W.J.H. Nauta, D.G. Whitlock, W.R. Hess, F. Bremer, M.A.B. Brazier, A.E. Fessard, E.D. Adrian, H. Gastaut, W. Penfield, R. Jung, W.G Grey-Walter, D.O. Hebb, K.S. Lashley, L.S. Kubie, and D. McK. Rioch. I also presented my own paper, “Functional Properties of the Thalamic Reticular System.”

The papers, and especially the discussion, of this international symposium on consciousness were most exciting and certainly provided a landmark in the development of neuroscience research into basic mechanisms of consciousness, with many more to follow.

Brain mechanisms of consciousness and unconsciousness have been a central theme of my life in neuroscience research. Studies of the “basic mechanisms of the epilepsies,” which we have made the subject of a series of international symposia with the help of the National Institutes of Health (NIH), have dealt with this subject in the context of epileptic seizures beginning with loss of consciousness. These have been called “centrencephalic” or “cortico-reticular seizures,” with reference to hypothetical brain mechanisms involved. I discussed this question in some detail in a 1991 guest editorial in the EEG Journal.

Neurochemical and Microelectrode Studies

After studying thousands of human EEG records, hundreds of electrocorticograms from the exposed human cortex during operations with Dr. Penfield, and extensive research on the electrical activity of different brain regions from implanted electrodes in experimental animals, I became dissatisfied with the limitations of these techniques. I was convinced that we needed to know far more about the firing of individual brain cells in various cortical and subcortical regions in waking animals and humans. I was also convinced that we needed to know much more about the neurochemical basis of neuronal excitability and the transmission of impulses at synapses.

Neurochemical Studies

With the help of Allan Elliott, an outstanding neurochemist, we were able to tackle some of these neurochemical problems. We wanted to make use of the samples of epileptic cortical tissue from epileptic patients that had been extracted during operations. Dr. Elliot and Donald Tower first sought excitatory substances such as acetylcholine (ACH), but they were unable to find consistent changes in ACH metabolism in focal epileptic tissue.

We then wondered if a lack of an inhibitory substance controlled the excitability of the brain. We invited Dr. Ernst Flory and his wife Elizabeth from the California Institute of Technology to join us because he had discovered, in a brain extract, a substance with strong inhibitory effects on the crustacean stretch receptor, which he called Factor I (for inhibition). We worked together with Allan Elliott on the analysis of Factor I.

We had heard of children who had seizures because of a lack of some substance in their commercially prepared milk. It proved to be vitamin B6, which is essential for the production of an amino acid known as GABA (gamma amino butyric acid). Injection of this vitamin would control the seizures. We then thought that Ernst Flory’s Factor I might be GABA.

We had great trouble isolating GABA from the inhibitory factor in brain extracts, but with the aid of an analytical chemist from the Merck Company, we succeeded in purifying a crystalline substance that proved to be GABA. Confirmation of its inhibitory action on cortical tissue in animals was then carried out with success (Jasper, 1984).

We began systematic studies of all the amino acids that were released or extracted from the cortex in experimental animals during sleep and waking. Following experimental epilepsy, we performed chemical analysis on cortical tissue and on the fluids extracted from the cortex by a superfusion technique using a specially designed perfusion chamber that we installed in the skull, resting upon the cortical surface after removing the dura and penetrating the piarachnoid covering with microelectrodes. This made it possible to sample the local fluid in the cortex in animals without general anesthesia, during sleep and waking, during learning experiments, and following local experimental epileptogenic lesions.

We performed the analysis with the help of Leon Wolfe and a superb analytical chemist from Japan, Ikuko Koyama. We began these studies at MNI and continued them after I moved to the University of Montreal, where Ikuko worked closely with me and with Nico Van Gelder. We also collaborated with Dr. Tomas Reader, a postdoctoral fellow from Buenos Aires, Argentina.

We performed an analysis for the presence of ACH, all of the amino acids, and finally for the monoamines noradrenaline, serotonin, and dopamine.

We also conducted ACH determinations with an Italian postdoctoral fellow, Gaston Celesia, who later became editor of the EEG Journal. With Celesia we found that the liberation of ACH was increased three to four times in concentration when the cats were awakened from natural sleep, or during electrical stimulation of the brain stem reticular formation to awaken or arouse the animals (Celesia and Jasper, 1966). Arousal consistently produced a marked increase in ACH liberation as compared to slow wave sleep.

We also found local epileptiform spikes produced from cortex treated with eserine or physostigmine when the animal was aroused by stimulation of the brain stem reticular formation.

Later, with another fellow at the University of Montreal, J. Tessier, we found that there was an increase in the liberation of ACH during rapid eye movement (REM) sleep as compared to that in slow wave sleep (Jasper and Tessier, 1971). We discovered with J.H. Ferguson that ACH, when applied to the cortical surface, after preventing its hydrolysis with eserine, resulted in a very large sustained epileptic discharge which could be triggered by weak sensory stimulation in the cat. We concluded that ACH was a powerful convulsant agent when applied under certain conditions (Ferguson and Jasper, 1971).

In summary, we found that changes in the concentration of glutamic and aspartic acids, with sometimes an increase in taurine, and with a decrease in GABA, were characteristic of epileptogenic cortical tissue. Arousal caused an increase in glutamic acid as well as ACH, with a decrease in GABA. Sensory stimulation seemed to decrease the liberation of the monoamines. Microiontophoretic studies showed important interactions between ACH and the liberation of monoamines, suggesting a presynaptic effect of ACH on monoamine terminals.

For my 80th birthday celebration in 1986, and to my great pleasure, my colleagues at the University of Montreal, Tom Reader and Bob Dykes, and Massimo Avoli and Peter Gloor at the MNI of McGill University, organized a remarkably fine comprehensive symposium titled “Neurotransmitters and Cortical Function: From Molecules to Mind.” I collaborated with them in writing an overview of this splendid symposium with the title “Molecular Controls and Communication in Cerebral Cortex,” (Jasper et al., 1988) from which I will quote a few excerpts:

Significance of cortical neurotransmitters

The contributors to the present symposium have provided many fascinating and important highlights of recent research on the many neurotransmitters or modulators which have played a leading role in the remarkable advances being made during recent years in our understanding of chemical and molecular mechanisms involved in the organization of cortical function. In this final chapter we shall attempt to present some of our impressions of the overall importance of these developments with an emphasis on the subtitle of this book, “From Molecules to Mind.”

Amino Acids

It would seem that the only good candidates for the chemical synaptic mediation of the rapid transient transmission of excitatory and inhibitory actions on specific information processing, cognitive, and specific motor functions of cerebral cortex are amino acids (glutamic and aspartic acids), which are universally excitatory, while GABA is the major, if not the only, generally active inhibitory substance in cerebral cortex. All of the other neuroactive substances found in cerebral cortex have slower and longer lasting effects, modulating excitability and the action of other neurotransmitters. Some may be “cotransmitters” as shown by Jones in this volume with his immunocytochemical studies of glutamic acid decarboxylase (GAD, the enzyme for GABA synthesis from glutamate) and certain peptides.

It would seem to be of considerable importance that the metabolism of glutamate and GABA are so closely interrelated, GABA being produced by the decarboxylation of glutamate by means of a specific enzyme GAD, together with the coenzyme pyridoxine phosphate (vitamin B6). Rate limiting steps in the synthesis of both GABA and glutamate are also closely related as shown by Szerb in this volume.

The fact that the most important excitatory substance can be the immediate precursor of the most important inhibitory substance suggests that these interrelationships may be relevant to the maintenance of a balance in excitatory and inhibitory controls in synaptic mechanisms involved both in information processing as well as in integrative motor control. Defects in GABA mediated inhibitory controls may lead to epileptic discharge as described by Avoli, and may abolish pattern discrimination in cells of visual cortex, as shown by Sillito and Murphy. Dykes et al. have shown that blocking of GABA action by bicuculline enlarges and blurs receptive fields of single cells in somato-sensory cortex.

Thus, GABA may play a leading role in all higher integrative functions of cerebral cortex in which patterns of excitation are being molded by inhibition.

The specific ionic channels mediating the excitatory properties of glutamate and aspartate have not been clearly elucidated, but they probably involve both Na and Ca conductances. The ionic mechanism of inhibition by GABA involves Cl channels. GABA receptors are very closely related and coupled to benzodiazepine receptor sites as described by Lambert et al. The barbiturates may also act, in part, via the GABA system, further increasing the importance of GABA in such physiological phenomena and pointing to its importance in neuropharmacology.

Kris Krnjevic described microelectrode studies of the excitatory action of Acetylcholine on cortical cells. He concluded that ACH does not act like a classical neurotransmitter at cortical synapses. Cellular impedance is increased instead of decreased with excitation, and the resulting excitation has a slow onset and prolonged duration. The effect is thought to be due to blocking of K⁺ channels, thus prolonging the action of other transmitters. A second messenger such as cyclic GMP might be involved acting via some form of protein phosphorylation.

ACH plays a most important role in regulating the state of reactivity of cortical cells, as in sleep and waking and attention, as well as in the reinforcement and prolongation of cortical and hippocampal synaptic activity important in mechanisms of memory, as suggested by its deficiency in Alzheimer’s disease.

Peptides

The discovery and localization of over 60 neuropeptides, together with their specific receptor proteins in the brain has presented us with complex problems of understanding their functional significance, since such significance has been determined in only a few of them (e.g., substance P, enkephalin, somatostatin, and endorphin).

Microelectrode Studies

I had already begun microelectrode studies of single neuronal cell firing in various depths of cerebral cortex and, with stereotaxic techniques, from subcortical structures in basal ganglia, thalamus, and brain stem (Li and Jasper, 1953), but we needed to develop techniques for single cell recording in conscious behaving animals and humans.

With the help of a former student, David Hubel, who was then working at the Walter Reed Army Medical Research Laboratories in Washington, D.C., I learned how to make tungsten microelectrodes for single cell recording, which I developed further in Montreal with recording chambers and micrometer controls that enabled not only the recording of the electrical activity from single cells in waking experimental animals and humans, but also the collection of fluid from local areas of cerebral cortex, and from subcortical regions, for biochemical analysis.

In collaboration with Dr. Gilles Bertrand, we were able to perfect a stereotaxic microelectrode technique for recording from single cells in the human thalamus and basal ganglia during operations for the treatment of Parkinson’s disease (Jasper and Bertrand, 1966a, b, and c).

I also carried out intracellular microelectrode studies in collaboration with Costa Stefanis, a postdoctoral fellow from Athens, Greece, who eventually became professor of psychiatry at the University of Athens, and president of the mental health division of the World Health Organization (Stefanis and Jasper, 1964; Jasper and Stefanis, 1965).

The use of microelectrode techniques to study states of sleep and waking, epileptic discharges, attention, conditioning, and other states served to open many new vistas of neuroscience research that were to occupy me for the rest of my professional life.

With the help of two excellent postdoctoral fellows, Gianfranco Ricci from Rome and Ben Doane from Hebb’s department of psychology at McGill, we studied unit firing from many areas of the cerebral cortex in monkeys during avoidance condition to specific frequencies of photic stimulation (Jasper, et al., 1960). We presented our results at the Moscow Colloquium in 1958 (Jasper and Smirnov, 1960).

There were 49 official members of this colloquium hosted most generously by the Academy of Science. There were also many nonparticipating guests who came mostly from the Soviet Union. Participants were seated around a large oblong table. We heard the presentation of many exciting papers and had animated discussions. I was privileged to share with Academician L.S. Beritashvili from Tiflis, Georgia, the position of honorary president. Acting presidents were Professors H. Gastaut and V.S. Rusinov.

I quote from the welcoming remarks of Academician A.V. Topchiev, the vice president of the Academy of Science of the USSR, as follows:

We hope that this colloquium will not only be an important landmark in the further development of the scientific problems you are elaborating, but that it will consolidate the friendly ties between the participants of the colloquium, based on reciprocal contacts and exchange of experience. This will, in turn, further the noble task of establishing mutual understanding and friendship among the nations of the world.

At the close of the sessions we passed a unanimous motion to continue and enlarge the international collaboration we had so much enjoyed by sending a delegation to UNESCO to form a permanent international interdisciplinary brain research organization to promote continued international and interdisciplinary collaboration throughout the world. Professor Alfred Fessard and I headed this delegation.

With the help of UNESCO and the Council for the International Organization of Medical Sciences (CIOMS), together with an interdisciplinary organizing committee, we were successful in establishing a truly international and interdisciplinary brain research organization known as the International Brain Research Organization (IBRO) in 1960, which was officially incorporated by the Parliament of Canada as an independent international body with headquarters in Paris.

I moved to Paris with my family for one year and then spent four years, almost full time, getting IBRO established. We undertook many successful projects, with UNESCO publishing bulletins telling of our activities: fellowships, symposia, workshops, etc., and an important survey of neuroscience in many countries. These national surveys resulted in the establishment of many national and regional organizations for brain research or neuroscience.

The survey in the United States was aided by the National Academy of Sciences and the National Institutes of Health following a special visit by Dr. V.G. Longo of Italy and me to Washington, D.C. This visit resulted in the formation of the Brain Research Commission and, eventually, of the Society for Neuroscience (SFN) 10 years later, in 1970.

Celebration of the 25th anniversary of the Society for Neuroscience in San Diego in 1995 was preceded by a celebration of the 35th anniversary of IBRO, which had become the world federation of neuroscience, with about 35,000 members.

I gave an opening address at this Fourth International Congress of IBRO, held in Kyoto, Japan, under the presidency of Professor Masao Ito. This was another outstanding experience of my life, which I enjoyed with my wife, Mary Lou, and with the excellent hospitality of our Japanese colleagues.

In my opening address I recalled the Moscow Colloquium, the birthplace of IBRO, and the resolution that we would try to make IBRO not only a medium for the international and interdisciplinary collaboration of neuroscientists, but that we should use our personal contacts with neuroscientists worldwide to improve friendly relations among nations. After the close of the Moscow Colloquium in 1958, I had had a private conference with the president of the Soviet Academy of Science which resulted in his agreement to cooperate with our international efforts in this direction.

I suggested that brain research might be an excellent channel for the promotion of better international relations because so many of these problems are based on malignant mental attitudes that might respond to scientific studies of brain function as a determinant of social behavior. I feel strongly that modern neuroscience, with all of its advances during recent years, should be used to apply knowledge and techniques to the understanding and prevention of such malignant mental attitudes that form the basis for so much conflict.

Time and space do not permit continued elaboration of the rapidly growing field of neuroscience research. Such discussion does not belong in my autobiography anyway, since I have been struggling to follow the rapid advances in this field as shown in a recent publication titled “Early efforts to find neurochemical mechanisms in epilepsy” (Jasper, 1992) in which I described these developments as “a new ball game.”

Acknowledgments

I would like to acknowledge the many friends, colleagues, and students I have had over these many years who have contributed largely to the success of my research endeavors and to the pleasure of my career in neuroscience. I am especially indebted to the hundreds of staff members and students who collaborated with me for 27 years at the MNI and to the staff members and students who collaborated with me over the past 30 years at the University of Montreal, a collaboration which is still continuing today.

I also would like to pay tribute to the work of Francis O. Schmitt who organized the Neuroscience Research Program (NRP) in which I took an active part for many years (1962–1975). Of particular importance in relation to the present The History of Neuroscience in Autobiography is the first such history organized to celebrate Frank Schmitt’s 70th birthday at the Massachusetts Institute of Technology in October 1973 (Worden et al., 1975). ‘Twenty nine of the leading neuroscientists contributed chapters to the book. My own chapter was titled “Philosophy of Physics—Mind or Molecules.”

I was particularly involved in the final NRP Colloquium on “The Organization of the Cerebral Cortex,” held at Woods Hole, Massachusetts in 1979 (Schmitt et al., eds., 1981). I was a contributing editor in the section on “The Role of the Cerebral Cortex in Higher Brain Function.” My chapter was titled “Problems of Relating Cellular and Modular Specificity to Cognitive Functions: Importance of State Dependent Reactions.”

Prizes and Awards

I have recently received numerous prizes and awards, which manifest the support I have had from many sources. I will mention only a few: the Ralph Gerard Prize of the Society for Neuroscience; officer of the Order of Canada; the McLaughlin Medal of the Royal Society of Canada; the F.N.G. Starr Award of the Canadian Medical Association; election into the Canadian Medical Hall of Fame; the Albert Einstein World Science Award of the World Cultural Council, received in Mexico City, December 1995; and Le Grand Officier de l’Ordre National du Quebec, June 1996.

I would like to share these prizes with my father, who was my original inspiration, and with the hundreds of colleagues with whom I have lived and worked for more than 70 years of dedication to research on the brain and its relation to the mind and behavior.

Finally, I would like to express my most sincere appreciation to the Society for Neuroscience which, for 25 years, has been a constant source of inspiration and information about progress in all branches of neuroscience. I would particularly like to thank the Society’s executive director, Nancy Beang, for her personal friendship and her remarkable organization of annual meetings and other activities of the Society, together with a dedicated series of presidents, councilors, and committee members.

I also thank Larry Squire and the SFN Publications Committee for this opportunity to contribute to the first volume in this series, The History of Neuroscience in Autobiography, with such a distinguished group of colleagues.

I also express great appreciation to my wife, Mary Lou McDougall Jasper, for her constant support in these strenuous endeavors and for her help in the preparation of this manuscript.

Selected Publications

Adrian ED, Bremer F, Jasper HH, Delafresnaye JF. Brain mechanisms and consciousness. Oxford: Blackwell Scientific Publications, 1954;v–556. (Published simultaneously by Charles C. Thomas, Springfield, IL, and Ryerson Press, W. Toronto, Canada.)

Avoli M, Reader TA, Dykes RR, Gloor P. Neurotransmitters and cortical function: from molecules to mind. New York: Plenum, 1988;v–619.

Celesia GG, Jasper HH. Acetylcholine released from cerebral cortex in relation to state of activation. Neurology 1966;16:1053–1064.

Ferguson JH, Jasper HH. Laminar DC studies of acetylcholine activated epileptic discharge in cerebral cortex. Electroencephalogr Clin Neurophysiol 1971;30:377–390.

Jasper HH. Cortical excitatory state and synchronism in the control of bioelectric autonomous rhythms. Cold Spring Harb Symp Quant Biol 1936;4:320–338.

Jasper HH, Cipriani A. A method for the simultaneous recording of focal cerebral blood flow, pH, electrical activity, and blood pressure. Am J Physiol 1940;128:485–492.

Jasper HH, Kershman J. Electroencephalographic classification of the epilepsies. Arch Neurol Psychiatr 1941;45:903–943.

Jasper HH, Droogleever-Fortuyn J. Experimental studies of the functional anatomy of Petit Mal Epilepsy. Res Publ Ass Nerv Ment Dis 1947;26:272–298.

Jasper HH. Charting the sea of brain waves. Science 1948;108:343–347.

Jasper HH. Diffuse projection systems; the integrative action of the thalamic reticular system. Electroencephalogr Clin Neurophysiol 1949;1:405–420.

Jasper HH, Ajmone-Marsan C. Thalamocortical integrating mechanisms. Res Pub! Ass Nerv Ment Dis 1952;30:493–512.

Jasper HH. Unspecific thalamocortical relations. In: Field J, Magoun HW, Hall VE. Handbook of Physiology; Neurophysiology II. Washington, D.C.: Am Physiol Soc, 1960;1307–1321.

Jasper HH, Ricci G, Doane B. Microelectrode analysis of cortical cell discharge during avoidance conditioning in the monkey. In: Jasper HH, Smirnov GD, eds. The Moscow colloquium on electroencephalography of higher nervous activity. Electroencephalogr Clin Neurophysiol 1960;Suppl 13:137–155.

Jasper HH, Smirnov GD, eds. The Moscow colloquium on electroencephalography of higher nervous activity. Electroencephalogr Clin Neurophysiol Suppl 1960;13.

Jasper HH, Stefanis C. Intracellular oscillatory rhythms in pyramidal tract neurones in the cat. Electroencephalogr Clin Neurophysiol 1965;18:541–553.

Jasper HH, Bertrand G. Recording from microelectrodes in stereotaxic surgery for Parkinson’s disease. J Neurosurg 1966a;24:219–221.

Jasper HH, Bertrand G. Stereotaxic microelectrode studies of single thalamic cells and fibers in patients with dyskinesia. Trans Am Neurol Assoc 1966b;79–82.

Jasper HH, Bertrand G. Thalamic units involved in somatic sensation and voluntary and involuntary movements in man. In: Purpura DF, Yahr MD, eds. The thalamus. New York: Columbia University Press, 1966c;365–390.

Jasper HH, Tessier J. Acetylcholine liberation from cerebral cortex during paradoxical (REM) sleep. Science 1971;172:601–602.

Jasper HH. Philosophy or physics—mind or molecules. In: Worden FG, Swazey JP, Adelman G, eds. The neurosciences: paths of discovery. Cambridge: MIT Press, 1975;401–422.

Jasper HH. The problem of relating cellular or modular specificity to cognitive functions: importance of state dependent reactions. In: Schmitt FO, Worden FG, Adelman G, Dennis SG, eds. The organization of cerebral cortex. Cambridge: MIT Press, 1981;375–393.

Jasper HH. Margaret Goldie Jasper, a tribute. Electroencephalogr Clin Neurophysiol 1983;56:534–535.

Jasper HH. The SAGA of K.A.C. Elliott and GABA. Neurochem Res 1984;9:449–460.

Jasper HH, Reader TA, Avoli M, Dykes RW, Gloor P. Molecular controls and communication in cerebral cortex: an overview. In: Avoli M, Reader TA, Dykes RW, Gloor P. Neurotransmitters and cortical function: from molecules to mind. New York: Plenum, 1988;593–605.

Jasper HH. Current evaluation of the concepts of centrencephalic and corticoreticular seizures. Electroencephalogr Clin Neurophysiol 1991;78:2–11.

Jasper HH. Early efforts to find neurochemical mechanisms in epilepsy. In: Avanzini G, Engel J Jr, Fariello RG, Henemann G, eds. Neurotransmitters in epilepsy. Amsterdam: Elsevier, 1992;(Epilepsy Res Suppl No 8)1–8.

Jasper HH, Riggio S, Goldman-Rakic PS. Epilepsy and functional anatomy of the frontal lobe. Advances in neurology, Vol. 66. Philadelphia: Lippincott Raven Press, 1995.

Levi-Montalcini R. NGF: an uncharted route. In: Worden FG, Swazey JP, Adelman G, eds. The neurosciences: paths of discovery. Cambridge: MIT Press, 1975;244–265.

Li CL, Jasper HH. Microelectrode studies of the electrical activity of the cerebral cortex in the cat. J Physiol 1953;121:117–140.

Magoun HW. The ascending reticular activating system. Res Publ Assoc Nerv Ment Dis 1952;30:480–492.

Morison R, Dempsey EW. A study of thalamo-cortical relations. Am J Physiol 1942;135:281–292.

Mountcastle VB. An organizing principle for cerebral function: the unit module and the distributed system. In: Edelman GM, Mountcastle VB, eds. The mindful brain. Cambridge: MIT Press, 1978;7–50.

Mountcastle VB, Edelman GM, eds. The mindful brain: cortical organization and the group selection theory of higher brain function. Cambridge: MIT Press, 1978.

Penfield WG. Epileptic automatism and the centrencephalic integrating system. Res Publ Assoc Neru Ment Dis 1952;30:513–528.

Penfield WG, Jasper HH. Epilepsy and the functional anatomy of the human brain. Boston: Little Brown, 1954;1–896.

Schmitt FO, Worden FG, Adelman G, Dennis SG, eds. The organization of the cerebral cortex. Cambridge: MIT Press, 1981;v–592.

Schmitt FO, ed. Macromolecular specificity and biological memory. Cambridge: MIT Press, 1962.

Sharpless S, Jasper HH. Habituation of the arousal reaction. Brain 1956;79:655–680.

Stefanis C, Jasper HH. Intracellular microelectrode studies of antidromic responses in cortical pyramidal tract neurones. J Neurophysiol 1964;27:828–854.

Worden FG, Swazey JP, Adelman G, eds. The neurosciences: paths of discovery. Cambridge: MIT Press, 1975.

Young JZ. Sources of discovery in neuroscience. In: Worden FG, Swazey JP, Adelman G, eds. The neurosciences: paths of discovery. Cambridge: MIT Press, 1975; 15–46.

*Some highlights of 70 years in neuroscience research.

Sir Bernard Katz

BORN:

Leipzig, Germany

March 26, 1911

EDUCATION:

University of Leipzig, M.D., 1934

University College of London, Ph.D. (Physiology, with A.V. Hill, 1939)

APPOINTMENTS:

Sydney Hospital, Australia (1939)

University College of London (1946)

Professor of Biophysics Emeritus, University College of London (1978)

HONORS AND AWARDS:

Fellow, Royal Society of London (1952)

Copley Medal, Royal Society (1967)

Fellow, Royal Society of Physicians (1968)

Foreign Associate, American Academy of Arts and Sciences (1961)

Nobel Prize for Physiology or Medicine (1970)

Foreign Associate, National Academy of Sciences USA (1976)

Ralph W. Gerard Prize, Society for Neuroscience (1990)

Sir Bernard Katz carried out fundamental studies of the neuromuscular junction. He established the quantal nature of neurotransmitter release, and described the mechanism of synaptic transmission.

Sir Bernard Katz

To tell you the truth, sir, we do it because it’s amusing!

In October 1924 my great friend and teacher, A.V. Hill, made his first visit to America. He was known among his colleagues as one of the leading physiologists. Around that time, at the age of 37, he had received a Nobel Prize for his work on energy production in living muscle, which had led to invitations to visit the United States and lecture on this subject. The first evening after his arrival (one traveled by sea, and jet lag was unknown), he gave a public lecture to a scientific society in Philadelphia on “The Mechanism of the Muscle.” At the end of his talk, a serious-looking elderly member of the audience got up and asked disapprovingly what practical use the speaker thought there was in his research. Professor Hill considered for a moment whether he should enumerate the many cases in which immense and obvious benefit to humankind had come from discoveries and experiments that were made purely to satisfy the intellectual curiosity of the investigator, but now I let him tell his own story:

To prove to an indignant questioner on the spur of the moment that the work I do was useful seemed a thankless task and I gave it up. I turned to him with a smile and finished, “To tell you the truth we don’t do it because it is useful but because it’s amusing.” The answer was thought of and given in a moment: it came from deep down in my soul, and the results were as admirable from my point of view as unexpected.

My audience was clearly on my side. Prolonged and hearty applause greeted my confession. My questioner retired shaking his head over my wickedness and the newspapers next day, with obvious approval, came out with headlines “Scientist Does It Because It’s Amusing!” And if that is not the best reason why a scientist should do his work, I want to know what is. Would it be any good to ask a mother what practical use her baby is? That, as I say, was the first evening I ever spent in the United States and from that moment I felt at home. I realized that all talk about science purely for its practical and wealth-producing results is as idle in this country as in England. Practical results will follow right enough. No real knowledge is sterile. The most useless investigation may prove to have the most startling practical importance: Wireless telegraphy might not yet have come if Clerk Maxwell had been drawn away from his obviously “useless” equations to do something of more practical importance. Large branches of chemistry would have remained obscure had Willard Gibbs not spent his time at mathematical calculations which only about two men of his generation could understand. With this faith in the ultimate usefulness of all real knowledge a man may proceed to devote himself to a study of first causes without apology, and without hope of immediate return.

It was more than 10 years later that I came to London to join A.V. Hill’s laboratory to serve my apprenticeship with him. That time, 1935 to 1939, was the most inspiring period of my life. Hill’s personality had a profound influence on me; this influence is neatly summed up in the words that he addressed to his disapproving critic in Philadelphia. My own experience has taught me and has fully confirmed the truth of Hill’s provocative statement. We are, in fact, “professional amateurs,” lucky enough to maintain our amateur status throughout our professional scientific career. And if you think this is self-contradictory, I would remind you that a straight and simple definition of an “amateur” is someone who loves his work and finds great entertainment in what he is doing.

Nowadays such sentiments may be called arrogant, immoral, socially unacceptable, or elitist. I will not defend myself against such nonsense. I know that scientific research has become much more expensive during the last 50 years, and that scientists’ intentions have therefore become subject to more intense public scrutiny. It is true that the type of work that Hill and many of his contemporaries were doing in the 1920s and 1930s was done on a shoestring budget, costing practically nothing, and the public therefore was more tolerant of those eccentric researchers who did it just to amuse themselves. Today it would be more difficult to get away with a remark of such apparent flippancy. But I am convinced that Hill’s response still truthfully reflects the primary motivation of many of the most productive investigators in basic science. For those who have to decide whom to support in science, let them recognize that much of the best scientific work will continue to be done because of the thrill and excitement of ending up, after a hard struggle, with a successful experiment, with a discovery shedding new light on a problem—it will be done because it is interesting and amusing.

Growing up a “Stateless Alien”

I was born in March 1911 in the town of Leipzig in the middle of Germany. Although I was also brought up there, I never acquired German nationality. For the first six and a half years of my life, though quite unaware of it, I was in fact a subject of the Russian Tsar. My father, who was born in Russia in the town of Mogilev on Dnjepr, had left the country in 1904 at the time of the Russo—Japanese War and the internal unrest it caused, and a little later settled in Leipzig. He had never bothered to apply for naturalization in Germany. Doing so was not a simple formality, and he most likely considered it a far too complicated and unnecessary procedure.

My father was engaged in the family business of the fur trade, of which Leipzig was an important international center. His business obligations and social contacts did not require him to travel outside the German borders, and even though we were officially regarded as “enemy aliens” during World War I (1914–1918), this did not seriously interfere with his activities. After the Russian Revolutions of 1917, our family members—like other Russian expatriates who did not opt for Soviet citizenship—lost their nationality and became stateless persons. This circumstance had few practical consequences unless we wanted to go on foreign travel, because the strict visa requirements made life quite difficult. I did not realize until I was a teenager that I was growing up as an “alien,” and not as a German citizen. Although I resented this, I accepted it as a fact of life, which I thought I would be able to remedy in due course. I did not foresee that I was going to remain stateless and without a proper passport for the first 30 years of my life.

Although my alien status made it difficult for me to obtain the necessary documentation to travel and to emigrate to England, it made it much easier to tear up my few shallow roots that remained in Germany, the country of my birth, and to strike new roots in England in 1935.

I had a rebirth at the age of 24 when I arrived at the port in Harwich, England, one afternoon in February 1935. I had escaped from Hitler’s Reich and my arrival in England was a terrifying experience. His Britannic Majesty’s Officer of Immigration, though courteous and apparently quite sympathetic, questioned me for a long time. All the other passengers had gone through immigration while I still was being interviewed, and I feared that not only was I going to miss the train to London, but that I was going to be sent back to “Nibelheim” (“Nibelheim” is a grim scene in Wagner’s “Rheingold,” reminiscent of a concentration camp, with the dwarf-like Nibelung race being used as forced laborers, hammering away at the stone wall of a mounain cave. To me, Nibelheim is an apt description of Nazi Germany). But in the end the officer relented and, to my immense relief, allowed me to enter the United Kingdom. My difficulty was that I had no passport, but only a “Nansenpass,” the green identification certificate that was issued to stateless persons by the League of Nations’ Commissioner for Refugees.

The next day, I climbed a long staircase to the top floor of the physiology building of University College of London and presented myself to Professor Hill. He received me as a new member of his scientific family. Having got away from dark and hostile surroundings, the contrast was a tremendous experience for me. I felt a little like David Copperfield when he arrived, bedraggled and penniless, at the home of his aunt and was put into a clean hot bath. This was a new life for me, and Hill’s laboratory became a precious home. I was fortunate in many respects. I had no real scientific credentials to show; Hill took me on “as an experiment” on a simple hunch. Even as a physiologist, the day of my acceptance in his laboratory marked my transition from an embryonic to a postnatal stage.

Not until much later did I realize how much I owed my father for his decision not to seek German citizenship, or perhaps for his casual inactivity in this matter. This circumstance proved of inestimable advantage to me after the outbreak of World War II in 1939. This time, being a stateless person of Russian descent, I definitely was not regarded as an enemy alien by Australia or England, and I was able to become a British subject and an Australian citizen and soon after to enlist and to serve with the Australian forces.

Family Ties

I was very attached to my father—a good looking, humorous person who took life easy and was courteous and straight with his friends as well as his colleagues. He was, in fact, well liked by everybody who knew him. Yet like most nice people he lacked drive and was not a particularly successful business man. Any drive or initiative that I have inherited probably came from my mother’s side.

I cannot trace my family back for more than two generations. They were all Jews of Eastern European, Ashkenazi origin. I have faint memories of my maternal grandmother who came from Warsaw and lived in a flat above my parents in Leipzig. I had two uncles whom I knew well, one on each side of the family, and I was on particularly good terms with my mother’s younger brother whom I liked very much. He served as a noncommissioned officer in the German Army during World War I, later trained in the diamond trade, and moved to the business centers in Amsterdam and Antwerp. He traveled a great deal around the world, spoke several languages fluently, and possessed a strong sense of humor which appealed to me.

My father came from a large family. Grandfather David Katz was, judging from his photograph, a tall patriarchal man, which I thought fit his name. The surname Katz is common among Jews of Russian origin. The name has nothing to do with the German word for cat (Katze), but is an abbreviated form of the Hebrew words Cohen Tsedek, signifying a particular section of priests who claim to be descended from Aaron (the brother of Moses) and who have special religious duties and privileges. I, however, was brought up in a completely “unorthodox” and liberal way. My paternal grandfather, David Katz, married twice and had 15 children. He was a well-to-do and respected fur merchant in the town of Mogilev. He barely survived the Russian Revolutions and died in his 90s in 1919. I have little knowledge of, and no contact with, the Russian branch of my family. I had many other relatives, among them several grandchildren of David Katz who had left Russia and gone to Leipzig, London, Milan, and New York, and were mostly engaged in the fur trade. The London branch was very generous and helpful when I arrived in England in 1935.

Dissension among Jewish Society in Germany

Before Adolf Hitler rose to power, there was a fairly sharp class distinction in the Jewish society in Germany, between the indigenous “German Jews,” or more precisely those who regarded themselves as established German citizens of Jewish faith, and the “Ostjuden,” the more recent immigrants from Russia and Poland who tended to be looked on as somewhat of an embarrassment by their brethren and as not fully assimilated to German culture. This distinction sometimes created social friction and mutual resentment between the two classes, which struck me as quite ludicrous. There were, however, antagonisms and recriminations of a more serious, political kind.

German Jews in their central organization (Central—Verein Deutscher Staatsbürger Jüdischen Glaubens) were preoccupied with defending their citizen rights against anti-Semitic propaganda. They felt threatened not only by racial attacks and vituperations from right-wing anti-Jewish groups, but also by the spread of Zionism which was prevalent among the the Ostjuden. The latter were critical and even contemptuous of the assimilatory tendencies of the “establishment.” There were in fact no sharp boundaries between the two groups. Indeed, the founding father of modern political Zionism, Theodor Herzl, himself came from a culturally assimilated Viennese background. As later events proved, it was the Zionist doctrine that helped Jews maintain their morale and self-respect in an intensely hostile environment, not just during World War II, but beginning in 1933.

Realizing the irrational nature of racial hatred and particularly of anti-Semitism, it always seemed to me extraordinary that some of the native German Jews should have deluded themselves into believing that the root of all their exposure to hostility was the immigration of undesirable and ill-adapted co-religionists from Eastern Europe, the Ostjuden. This kind of self-indulging fantasy dies hard. After all that the Jews experienced in our lifetime, I was stunned when one of my colleagues—who comes from an established German—Jewish family and now resides in California—recently reasserted this belief to me in the strongest terms, and assured me of its historical accuracy and of his conviction that it is the Ostjuden who should be blamed for the misfortune that had befallen German Jewry. He is a distinguished scientist and his statements made me ponder the peculiar sequestration of the human mind and its limited capacity for critical self-assessment.

School and University

The inter-war years in Germany can be roughly divided into three phases. The first, 1918 to 1924, was a period of revolution, continuing unrest, financial disaster, hyperinflation, and bitterness. The second phase, 1924 to 1929, was one of peaceful stabilization and gradual economic as well as political recovery. The third phase began with a second financial debacle, the Wall Street crash at the end of 1929, which had enormous international repercussions leading to years of mass unemployment, renewed unrest, and extreme political polarization until the takeover of Germany by Hitler and his Nazi thugs. The first two of these periods coincided with my school years and the third covered my life as a medical student at the University of Leipzig.

The immediate aftereffects of World War I and of the treaty obligations imposed at Versailles resulted in Germany’s failure to pay the required war reparations, the occupation of the industrial district of the Ruhr by the French army, and a policy of passive resistance by the German government and people against French policy that could only be financed by hyperinflation (vast printing of increasingly worthless paper money), which led to the impoverishment of the middle class and left a legacy of bitterness and resentment. All these events were punctuated by abortive uprisings by German ultra-right wing groups that were countered by general strike and suppressed by the army.

This phase of revolution and attempted counterrevolution came to a sudden end when the newly appointed president of the Reichsbank, Dr. Hjalmar Schacht, managed to stabilize the currency in 1924 and instill new confidence in the nation’s ability to survive and pay its way. During the next five years life became more quiet and peaceful, both in Germany and on the international political scene. The economy seemed to flourish, the extremist parties lost popular support, and even the anti-Semitic agitation fueled by Hitler and his followers seemed to subside and become latent for a while.

All this changed again after the worldwide financial disaster in 1929. A new wave of political extremism rose and led to violence in the streets. Until the spring of 1932, the German government, led by an able and courageous prime minister, Dr. Heinrich Brüning, managed to resist the onslaught of the rising Nazi party. But suddenly, by an amazing act of betrayal, Brüning was summarily dismissed by the Reichspräsident, the old Field Marshal von Hindenburg, who had owed his recent re-election to Brüning’s personal efforts. From that moment, the takeover by Hitler seemed inevitable. At that time, in the summer of 1932, I began to make plans to emigrate after completing my medical course.

School Days, First Traumatic Shocks

I have only rather faint recollections of primary school, 1917 to 1921. I remember, at age eight or nine, challenging a teacher who had made a vicious and insulting remark about Russian Jews. He probably had not realized there was somebody in the audience who was likely to take offense, and he may have felt rather abashed to be taken to task. But my attack in the presence of witnesses clearly was an impermissible breach of discipline, and I paid for it by having my life made quite miserable during the rest of the term.

The first time the disadvantages of being a foreigner were brought home to me was at age nine. I still remember the occasion quite vividly. I sat for the entrance exam for a fashionable secondary school, the Schiller Real-Gymnasium, a sort of modern grammar school with a good scholastic reputation, situated in an affluent suburb of Leipzig. The written examination took place in the morning, and I thought it had gone rather well. In the afternoon, all the boys assembled with their parents in the big hall and the names of the successful candidates were called out in order of merit. I waited, and waited, to hear my name. Gradually my heart sank. Could I possibly have failed? But how? The others all left and I looked at my father, wondering what could have happened. Eventually he received a letter from the headmaster informing him that I had passed the examination with good marks, but unfortunately, because of the heavy pressure of applications, they could not take a foreigner.

At the time that did not seem too bad, it was only later that I began to wonder why they had let me take the exam in the first place. I was not altogether surprised when an acquaintance who seemed to know what was going on at that school told me that my examination marks had actually been a little too good for the headmaster, who considered it detrimental to the reputation of his school to have the new intake of pupils topped by a Russian Jew.

The headmaster’s decision not to accept me turned out to be a blessing in disguise. On the basis of his letter and of my examination record, I was accepted without further tests by the König Albert Gymnasium, a classical “humanistic” school that specialized in Latin and Greek. The school was regarded as old-fashioned and so presumably had a smaller intake of pupils. I never regretted attending. The school was an easy walking distance from my home—which was not unimportant because we started early, even during the dark and cold winter mornings. But more important, I became fond of the school and still remember some of my teachers with gratitude and affection.

In retrospect I enjoyed the classical curriculum. Now I often wish I had the time and ability to read the works of the great Greek and Latin writers and poets in their original language. I also feel that I should have made an effort to pick up more of the advanced mathematical teaching that was offered at the school, even at the expense of some of the classics.

I remain greatly indebted to some of the language masters, in particular to Hans Leisegang and Hans Lamer. Lamer was the headmaster, a devoted classics scholar with an international reputation, who instilled in me a real appreciation of the great Greek and Roman poets and gave me a feeling for my classical cultural heritage. Leisegang had an even greater influence on me. It was he who made me treat words and phrases with respect and to use the language as a precision tool. I might describe him as an ultraconservative reactionary—a representative of a German military officers’ caste—but he was also a great teacher and scholar, and a man of strong principles. The standard of the school, old-fashioned as it was, can be gauged from the fact that several of its masters received calls to university chairs. Leisegang himself, who was a part-time lecturer in philosophy at the University of Leipzig, went from the school to the chair of philosophy at University of Jena, in 1931. He later was imprisoned for having made derogatory remarks about Hitler (as I recall, he publicly objected to the “corporal” taking up a prominent position at the funeral of Field Marshal Hindenburg). It was Leisegang who gave me a thorough grounding in the development of German literature and philosophy, from the idealistic and romantic schools to dialectic materialism and psychoanalysis, and he did this in a way that struck me as balanced and almost objective.

The normal high school curriculum took nine years. I did well in the academic subjects and, about halfway through the König Albert, was encouraged to skip one year so that I spent just eight years (1921–1929) there. My school reports were very good except in gym and singing, in which my performance was deplorable and from which I tried to extricate myself. This deficiency may have had something to do with the fact that I was growing up without any brothers or sisters. I was never a loner, but I kept away from congregational activities of any kind. I had good friends, but usually only one at a time. My out-of-school activities consisted mainly of reading and walking. I liked swimming, preferably at the seaside, when there was opportunity for it. I joined a football club, but did not make much headway with the game. I enjoyed the theater and became an opera fan, being particularly keen on Wagner’s dramas. After several years I became put off by his medieval romantics, and thereafter I felt more attracted by the beauty and dramatic power of Verdi’s genius.

At age eight my mother tried to make me play the piano; but I soon abandoned it. Seven years later I started again with better tuition and understanding. Although I never became proficient, I enjoy playing and it has given me a welcome diversion from intellectual tasks. Another hobby, which I acquired at the age of 16, and to which I became temporarily addicted, was the game of chess.

During high school I experienced several traumas. They stand out vividly in my memory and they were reinforced and accumulated during my undergraduate years at the university and led to my progressive alienation from Germany. I was shocked at the assassination of Walter Rathenau, the Jewish foreign minister, by anti-Semitic youngsters in the summer of 1922. Rathenau was the first patriotic German Jew who had risen to high ministerial office, and it was unacceptable and intolerable to a large section of the German people.

In the same year, a very unpleasant boy by the name of Rocca joined my form at school. He came from a viciously anti-Semitic family, and I was puzzled and dismayed to find that he tried to make life difficult for me—spreading slanderous insinuations behind my back—though he had no great success and was unpopular among my schoolmates. I could not make out why he used me as a target for his venomous hatred. In retrospect, I suppose he resented the fact that he himself belonged to an ethnic and religious minority in a predominantly Protestant Saxon population, but this hardly explains it. At that time, a large underground exhibition hall had been built below the old market square in Leipzig. One day, after I had been absent from school for a religious festival, Yom Kippur, a friend told me that Rocca had, during my absence, called the boys together and informed them of a marvelous plan that his father had discussed with him at home. The plan was that the Jewish population of Leipzig should be invited to assemble in the underground fair hall, and after closing the doors should be killed off by filling the hall with poison gas. The boy who informed me was aghast and horrified and thought he ought to warn me about that venomous young devil. This episode has never been erased from my mind, and it gives an indication of ideas some people were harboring in their heads for 20 years before they were able to put them into practice.

The effect of these incidents became stronger during the next 10 years, though it was not until the dismissal of Heinrich Brüning by Hindenburg in 1932 that I finally decided there was little future for decent people, and none at all for me, in the Germany of the time. At the age of 11, however, my reaction was different. What impressed me was not so much the threat of violence—the situation was too far from reality at the time. I could not visualize such events actually occurring. What did upset me was the fact that a person with whom I was compelled to be in almost daily contact, should be possessed by such unprovoked venomous hatred toward me. This I found bewildering and hurtful.

In 1926, at the age of 15, I jumped a class and found myself among a group of older boys. I shared a desk with another Jewish scholar, Heinz Wydra, with whom I formed a close association during my remaining school years and who had a considerable influence on me. He was a strong chess player and acquitted himself well in local tournaments and club matches. It was he who taught me the game, and we managed to play games in school during unimportant or boring lessons. I have never advanced to more than average club-player strength, but I can say that I have derived great entertainment and excitement from the occasional good game, to the extent that I usually lose a night’s sleep replaying the moves and their alternatives in my head. My addiction to chess was replaced, for nearly half a century, by a similarly obsessive addiction to physiological experiments. The excitement produced by the occasional successful experiment was similar to that of a good performance at chess. In both cases, the sudden flash of insight after a long struggle in the dark, the intuitive vision of a solution to a seemingly intractable problem, is exhilarating. The trouble with chess is that it becomes a time-consuming occupation and is not compatible with other similarly demanding work, such as scientific research or even, as I soon discovered, with an undergraduate medical university course.

During my last three school years, we had to choose between a continuation of the classical linguistic course, and a mathematically and scientifically oriented curriculum. I chose the former which gave me more free time, and in the afternoons I drifted off to one of the cafes in Leipzig that had been invaded by chess players. How these establishments could manage to exist, catering to chess enthusiasts who sat around for hours consuming one cup of coffee, I have never been able to figure out. I spent quite an undue amount of time in those places, time that could have been better occupied, had I chosen the more difficult option at school. It was not the lack of natural science training that I later came to regret. This deficiency was made up quite satisfactorily by excellent elementary science teaching in the preclinical university course. But the weakness of my grounding in mathematics was something for which I have never been able to compensate. As to the time misspent on chess, this came to an abrupt end when I started my medical course, and I did not seriously resume this hobby until 50 years later, after my retirement from academic office.

My friendship with Heinz Wydra had another and more important consequence in that he succeeded in converting me to active Zionism. He started by persuading me to read the works of Theodor Herzl and introducing me to a Zionist youth club and later to a student organization. Until the age of 16 my contacts with the Zionist organization had been slight. My father was a sympathizer and supported the movement without being actively engaged. My own involvement increased slowly at first, but it became sufficiently strong to give me a powerful moral backing during the rise of the Nazis, which enabled me to treat antisemitic insults with complete contempt. Wydra himself emigrated to Palestine after completing his legal studies, and after the war played an important part in the economic development of Israel.

During my last year at school, I had to make up my mind what line of work to pursue during my lifetime. In those days such a decision carried for most of us a heavy responsibility. We had to commit ourselves irreversibly for all practical purposes. The thought of going along by trial and error, switching from one course or from one profession to another, horrified me and would not have been financially possible for my parents. My father accepted that I was not going to follow in his footsteps and join the next generation of fur traders, and my performance at the Gymnasium pointed to some sort of academic profession. A successful pass of the Abitur, the high school leaving examination, entitled one to enter any German university in any faculty and any subject regardless of previous specialization, or rather lack of specialization at school. There was no numerus clausus, no entrance examination or special interview barrier, with the result that some university courses became heavily and detrimentally oversubscribed.

My high school teaching might have inclined me toward the study of philosophy. I had done no natural science at all and had no high regard for it. But I felt that sooner or later I might have the responsibility of supporting my parents. My father, of whom I was very fond, had been a good companion but not a very successful business man, and I did not feel confident about his financial security. So I had to think of something more practical than philosophy, and it came down to a choice between medicine and the law. I talked to a few people, went to some public lectures at the university, and in the end chose to become a medical doctor and started my course at the University of Leipzig in April 1929. One of the factors that influenced me was an impressive lecture given by Professor Victor von Weizsäcker¹ on the social impact of medicine, which showed me that there was—potentially at least—a great deal of intellectual satisfaction to be derived from the practice of medicine.

Life as a Medical Student, 1929–1934

As soon as I entered the preclinical course at Leipzig, I found my timetable almost fully occupied, starting at 7 a.m. with botany and going on until the late afternoon in the anatomy dissection room. Fortunately students enjoyed a considerable amount of academic freedom and could skip lectures that they found too boring or redundant. Nevertheless, it meant an end to the chess sessions in the cafés.

During my first year I had to make up for my total lack of knowledge in the natural sciences. The medical students joined the scientists in their elementary courses in botany, chemistry, physics, and zoology, in addition to the preclinical subjects of anatomy, physiology, and biochemistry. I found it an advantage not having taken science in high school. All the material I was presented with during my first year at the university was fresh and new, some of it taught by persons of the highest caliber, and there was a good deal that I found absolutely fascinating. I had the benefit of an outstanding physics teacher, the famous Peter Debye (who a few years later received a Nobel Prize in chemistry). He gave his lectures, accompanied by experimental demonstrations, every morning from 8 until 9. Debye was both a great scientist and a great showman who took visible pride in his lectures. He was a marvelous expositor of facts, ideas, and theories. Debye clearly enjoyed teaching as much as research, and he showed his delight in all the successful tricks that he demonstrated in class with a constant smile on his face.

I spent a large portion of my free time in the Institute for the History of Medicine. The institute was directed by Henry Sigerist who, in 1932, followed an invitation by W.H. Welch to found a similar institute in the United States, at Johns Hopkins University. Sigerist was assisted by Owsei Temkin, a great scholar who joined and in due course succeeded Sigerist at Johns Hopkins. I have retained the greatest admiration for Temkin and always think of him as my teacher as well as a good friend, even though in later years we have had only few occasions to communicate. The institute provided a meeting place for the more civilized among the medical students, with opportunities for seminars and discussions on wide-ranging subjects, in the medical as well as the historical and literary fields.

My introduction to the natural sciences had a tremendous effect on my general outlook on life and human activities. I suddenly realized the power and depth of scientific ideas and their continuous subjection to criticism and further trials by experiment. I felt almost revulsion against my previous preoccupation with what I now regarded as presumptuous philosophical speculations and with a genre of verbose literature that seemed to make a virtue out of obscurities. I was influenced strongly by the superb collection of Helmholtz’s public lectures. In these, Helmholtz—one of the greatest experimental scientists of all time—explained difficult subjects with exemplary clarity.

During my undergraduate days I succeeded gradually in extending my social contacts, and I formed some new friendships which survived beyond World War II up to the present day. During my first semester I encountered Rudolf Bachmann, a most congenial colleague with whom I established close and enduring rapport. He became an accomplished histologist and in the postwar years occupied the chair of anatomy at the University of Munich. After my emigration from Germany we lost direct contact for some 30 years, but we resumed our friendship in the late 1960s and I have been visiting him and his family frequently since then. We share an appreciation of the classics and of music, and we closely converge in our sense of humor and our detestation of pretentiousness and pomposity.

I made some good friends when I joined student camps on the Baltic coast in the summers of 1931 and 1932. These camps had been organized by members of the German youth movement and were attended by about 50 undergraduates (males and females), as well as a few university dons. I still remember the occasion when I had gone with a small group to a nearby railway station to pick up the famous physicist, Professor Friedrich Hund, and escort him to our holiday campus. There was general applause and hilarity when we introduced ourselves, bowing to each other in the formal German manner and solemnly announcing: “Katz”—“Hund”!²

The vacation camps were interesting. There were plenty of seminars and discussions among students of all faculties who argued about social and political problems and about the philosophical foundations of science and the humanities. These events were interspersed with music, swimming, sailing, and even a sea journey to the Hanseatic city of Danzig. One outcome of those holiday activities was that I fell hopelessly in love with an attractive German girl. When I finally brought the matter to a head, she wisely, and not unexpectedly, turned me down. My ensuing state of depression did not last long, because it soon was superseded by the advent of Hitler’s regime and I was forced to think hard and make a new decision about my future.

What helped me was that I had joined a Zionist students’ association which brought me into contact with the local leaders of the Zionist movement. For about a year I was employed on a part-time basis to run public appeals and manage the Jewish National Fund. The purpose of this organization was the acquisition of land for new settlers in Palestine. This job was, in fact, only one of the various part-time jobs that I held as a medical undergraduate.

During my first year at the university I found employment as an assistant to two medical practitioners who ran a joint practice in one of the suburbs of Leipzig. These practitioners specialized in a combination of subjects: ear-nose-and-throat as well as eye diseases. My colleagues were amazed to hear that, as a green preclinical student I was allowed, and even able, to learn the diagnostic techniques of otoscopy, laryngoscopy, and ophthalmoscopy, that I was dispensing routine treatment and even performing minor operations (some of the patients actually preferred me), and that I was earning useful pocket money on the side. During my later clinical years my timetable did not allow me to continue this “surgery practice.” Instead, I formed an association with a scientific journalist and publisher who asked me to supply him with suitable popular articles on medical and scientific subjects for distribution to the lay press. This arrangement enabled me, at the cost of late-night work, to earn not only pocket money, but also to maintain financial independence at home, during a time of considerable political upheaval.

I took my preclinical exams in six subjects (anatomy, botany, chemistry, physics, zoology, and physiology/biochemistry) in the summer of 1931. The examination system consisted exclusively of “vivas.” The students were expected to form up in groups of four and present themselves to the examiner. Somehow it seemed the right thing for four Jewish students to get together and make up one such group. I do not think it ever occurred to me to approach non-Jewish colleagues for this purpose; this would have been far too embarrassing and was simply “not on.” In 1931 there was no difficulty in making up a Jewish foursome. But for our clinical examination in 1934, we only managed to get three of us together, and this was not quite the correct thing. I remember the reaction of our revered professor of anatomy, Hans Held (a famous neurohistologist and, as leader of the neural continuity theory, a lifelong antagonist of the even more famous Nobel Prize winner, Ramón y Cajal). Held sadly shook his head when he found there were only three candidates presenting themselves for the examination in topographical (clinical) anatomy. He evidently could not work out the reason and asked us where the fourth member of the group was. There was a moment of embarrassed silence. I only just restrained myself from replying that, while we were numerically incomplete, we made up for it by being 100 percent non-Aryan!

The “viva voce” type of exam had its pluses and minuses, its efficiency depending very much on the idiosyncrasies and general intelligence of the examiner. During our preclinical tests, the assistant examiner in physics allowed one of my colleagues to bluff him with fictitious quotations from the literature. I did rather well in zoology, being able to recite the Latin names of various exotic animals, but when Professor Johannes Meisenheimer asked me what the common German name for “echidna” was, I could not tell him. He kindly overlooked it.

Two other incidents from my preclinical exams stand out in my memory. Professor Held tested us by confronting us with a hessian-covered formalin-soaked bundle of stuff, lifting one small bit of tissue with a forceps through a gap in the hessian cover and asking: “Was ist das?” When he had heard the answer, he would say every now and then: “Meinen Sie?” (“Do you think so?”), the meaning of which was somewhat difficult to interpret. Professor Martin Gildemeister in physiology had a very different technique. In our session, he took a wooden ruler, drew it sharply across the back of his hand and asked us: “What happens?” This question did not permit one to push a preset mental button and deliver an answer to a well rehearsed question from a book. It was rather disconcerting, but it gave us the opportunity to discuss why the skin would turn first white then red, the mechanism of the hyperemic response, the possible involvement of local chemical agents or of a nervous reflex, etc. Each of us answered brief questions in turn and, by the end of the conversation, Gildemeister had assessed the four of us and allotted marks which, on that occasion, varied between top grade and failure.

One of the highlights in the physiology course was the annual demonstration of an experiment that had been performed in the 1860s by Carl Ludwig (the most distinguished head of the school) and his Russian assistant, E. Cyon. The experiment showed the existence and the function of a sensory nerve—the depressor nerve of the heart—the impulses of which originate in the region of the heart, travel to the central nervous system, and elicit a reflex discharge of centrifugal impulses slowing and depressing the heartbeat. Ludwig was one of the great founders of the study of physiology, and many of his pupils established famous schools all over the world.

Ludwig’s assistant, E. Cyon, was a very strange character whose peculiar career has been described in a fascinating article by George F. Kennan in The American Scholar (autumn 1986). Having previously read some anecdotes about Cyon—he had the reputation of being an accomplished swordsman and an occasional duelist—and knowing that he often was quoted in the scientific literature as “von Cyon,” I imagined that he was a somewhat eccentric aristocratic Russian who amused himself by taking up physiological research. From Kennan’s article I learned that he was, like myself, of Russian—Jewish descent, had studied medicine, and had become a physiologist. Cyon later was appointed to a prestigious chair of physiology at the Medical/Surgical Academy in St. Petersburg, but after falling out with most of the students as well as the staff, he had to leave. He emigrated to France where he dropped out of physiology and became a political agent, continuing to make few friends and numerous enemies. He clearly was an able scientist and had been acclaimed as an inspiring teacher by the young I.P. Pavlov. But Cyon was a difficult and resentful character, and probably his own worst enemy. I was fascinated and rather shocked by Cyon’s story. It struck me that to some extent we had a similar background and we even walked the same floors, and perhaps worked in the same rooms, in the old Physiological Institute in the Liebigstrasse in Leipzig. Fortunately, our paths diverged completely after we left Leipzig, and any possible resemblance ended there!

I was attracted to neurophysiology at an early stage, from about 1930 onward. In those days, the establishment of the laws of electric excitation of nerve, and their precise mathematical formulation were regarded as a great thing. In retrospect it seems a somewhat naive approach, reminiscent a little of the attitude of Sinclair Lewis’ Dr. Martin Arrowsmith, a novel that was fashionable at the time and describes a rather naive young scientist who takes special pride in mathematical formulations. The exact fitting of strength—duration curves to electric stimuli of various shapes and intensities was considered a wonderful achievement, even though it was only a formal exercise which shed little light on the physical mechanism of excitation. Nevertheless, I felt it was fascinating that one could make accurate and repeatable measurements of electric excitability on living tissues and express the results by a simple mathematical equation. To do the experiments all one needed were some calibrated boxes of simple electrical gear, resistances, condensers, etc., and an isolated nerve—muscle preparation of a frog.

Now there’s the rub. In our elementary physiology class, the first thing we were taught was to overcome our repugnance to the killing of frogs. Much of our basic knowledge of the normal function of living tissues and their cells has come from experiments on the isolated organs of cold-blooded animals, which survive for long periods when kept at room temperature and in a simple salt solution. I have no doubt that this kind of experiment will be indispensable for solving many remaining important problems. Whether this justifies the killing of animals is an entirely different matter and depends on one’s personal religious belief and on what is regarded as acceptable by the society in which one lives. I have killed a very large number of frogs in my lifetime to use their nerves and muscles for my experiments and to find out how they work. I have never been able to overcome my utter dislike for the act of killing, although it was done as humanely as I was taught to do. I do not know whether one can produce any valid moral justification for such action. But I do not think that it is any more reprehensible to kill an animal for the advancement of natural knowledge than to do so for the consumption of food.

Immediately after my preclinical exam I went to see Professor Gildemeister and asked for an opportunity to do some experimental research in the Physiological Institute which might also form the basis of my medical doctor’s thesis. Passing the final medical examination (Staatsexamen) at a German university was a separate thing: it did not entitle a person to call oneself Doctor of Medicine. For this, one had to submit a printed thesis and undergo a separate viva, though the standards required for the Dr.Med. degree were generally quite low and the degree could be attained without experimental work—for instance by the description of a few clinical observations. Again, while the prescribed timetable of my clinical curriculum was almost fully occupied, there were periods when I could absent myself from the formal lectures and clinical demonstrations, and in any case I was used to working late hours. What is more, I felt increasingly revolted by the behavior of the majority of my fellow students who no longer bothered to conceal their Nazi sympathies and anti-Semitic vulgarities. So, I welcomed, and made use of, every opportunity I could find of withdrawing into the solitary atmosphere of my laboratory.

With Gildemeister’s permission I was able to spend much time in the physiology department, learning some relatively advanced experimental techniques and doing some rather juvenile and inconsequential research on muscle permeability, under the direction of J.D. Achelis. Achelis was an intelligent person and an able experimenter, and I retained a high respect for his character despite his unfortunate later involvement with the Hitler regime. I regarded Achelis as an honest, upright person, but he belonged to a group of people who considered the rise of Hitler indispensable for the rebuilding of a strong Germany and who in the end joined the Nazi party, ready to overlook its violence and vulgarity, or perhaps fancying that their personal participation might have a civilizing effect. I knew that Achelis’ interests and activities were spread over a wide field, covering not just physiology, but the history of medicine, philosophy of science, and politics.

With surprise and shock I learned, in the spring of 1933, that Achelis had suddenly vanished from the institute and re-emerged as a high official in the Prussian Ministry of Education in Berlin, charged with responsibilities for the appointment and dismissal of university personnel. I believe, and this was also Gildemeister’s opinion, that Achelis had romantic ideas and deluded himself into believing he would have enough authority to exert a moderating influence in the Nazi governmental machine. Hisservice did not last very long. After 18 months when he had become disillusioned, he dropped back into academic life, taking the chair of physiology at Heidelberg University, but his short period as a Nazi administrator did him immense harm.

Gildemeister commented to me that although Achelis had tried to soften the blows, he was held responsible for the dismissal of many Jewish academics, and all he had achieved was an international reputation of a man with “blood on his hands.” The most damaging case in which Achelis was involved was the dismissal of Otto Krayer, a young pharmacologist who was one of the few university dons who showed great courage in sticking to their moral principles. Krayer had been offered promotion to a university chair, from which the previous holder, Philipp Ellinger, a Jew, had just been removed. Krayer found it incompatible with his principles to accept such an appointment, and he did not simply refuse the offer, but wrote an eloquent letter explaining his reasons: He considered the dismissal of Jewish scientists to be an injustice, and his ethical beliefs as a scientist and a teacher did not permit him to remain silent. The result was Krayer’s own immediate dismissal. This was not an instance of an internationally famous personage who could easily find a good job elsewhere, it took him some time to emigrate. Eventually, after a period as a professor at the American University in Beirut, he was able to build up a distinguished school of pharmacology at Harvard University. I learned about Krayer and his encounter with the Nazis from A.V. Hill, who never forgave Achelis for his role in that affair.

However, with all Achelis’ faults and mistakes, I retained a personal regard for this man; he had been my teacher, and I was obliged to him for that. What is more, after he moved to the Berlin ministry in 1933, he did not immediately break off relations with me. When he realized that I was ready to throw up my medical course and emigrate to Palestine, he suggested that I visit him in Berlin and discuss my plans for the future. This action must have involved for him some risk, and I gave him high marks for it. After the war, he paid the price for his activity as a Nazi official and was himself removed from his university chair. He found satisfactory employment in the pharmaceutical industry, but this hardly made up for dishonorable discharge from academic life. Many years later, his successor at Heidelberg University, Professor Hans Schaefer, visited me in London and we talked about Achelis. I told Schaefer that I regarded Achelis as an honest man who had been unwise and made serious mistakes, and had compromised himself by his association with the Nazi regime, but that I never considered him capable of a villainous act. I was glad to hear from Schaefer later on that he had reported our conversation to the senate of Heidelberg University and, as a result, Achelis had been formally rehabilitated, meaning that he had his formal academic title reinstated. This must have given him some pleasure during the last years of his life.

My part-time research at the Physiological Institute at Leipzig led to the publication of a couple of papers in Pflüger’s Archiv, and I used these papers for my M.D. thesis in November 1934. What is more, I had entered the work in manuscript form in 1933 for a university competition and won the Siegfried Garten Prize of the medical faculty. Siegfried Garten had been the predecessor of Martin Gildemeister in the chair of physiology. After Garten’s death his family had made a bequest to fund this prize which was open to medical students who were engaged in physiological research. For a non-Aryan to obtain a faculty prize in Nazi Germany was a somewhat less than straightforward matter. Fortunately, the custom required one to submit one’s prize essay under a pseudonym. So Bernhard Katz became, for a time, Johannes Müller (the father of 19th century German physiology and teacher of Helmholtz). The judgment and, in fact, the management of the prize fund was left entirely to the discretion of the professor of physiology, Martin Gildemeister. There were only two candidates and Gildemeister knew, of course, who they were. It would have been much safer for him not to let the prize go to me. Nevertheless, he decided to award it to Müller, alias Katz. When Gildemeister “discovered” that the winner was a non-Aryan, he announced publicly that, under these circumstances, the prize money could of course not be handed out—and a little later gave it to me under the counter. I thoroughly appreciated this, as it happened to me at a time of domestic and financial difficulties.

The Garten Prize and the papers in Pflüger’s Archiv may seem like a considerable achievement for a medical student, but I cannot say that I am proud of my first publications. In fact, I regard my work published during my Leipzig period as a prenatal effort, and my status as a physiologist, before my arrival in London, as purely embryonic. Nevertheless, my work in Leipzig had some slender but interesting connections with what was going on in Hill’s laboratory at that time. The only reprint request I remember receiving in 1934 came from Ulf von Euler who happened to be working with A.V. Hill on a related subject. I reminded von Euler of this in 1970 (when we had just heard that we were to share a Nobel Prize in physiology for very different work), but he had quite forgotten the earlier episode. What I had found in 1933 was a curious reaction of frog muscle to stretching, a response that proceeded slowly and could be followed by measuring the electric impedance of the tissue. A year before, a stimulating effect of stretching on the muscle’s metabolism, quite similar in time course, had been discovered by T.P. Feng, a young Chinese physiologist who was doing postgraduate work in Hill’s laboratory, and with whom I was privileged to form a close friendship many years later when at long last we were able to meet.

When the Nazis took over early in 1933, I still had some 20 months to go before completing my medical course, and it was not at all clear whether I would be able to do so. For me the only practical alternative was to join the exodus to Palestine and try to make myself useful on a kibbutz. I thought very carefully about it, had long discussions with my friends in the Zionist movement, and made a day trip to Berlin where I consulted first my former teacher, J.D. Achelis, and then Enzo Sereni, an Italian Jew who played a prominent part in the Zionist labor movement and, at that time, was in charge of migration.³ Achelis advised me not to break off my clinical studies, but to complete the course if at all possible and then decide where I wanted to go. Sereni urged the opposite, namely to emigrate to Eretz Israel (“the land of Israel”) immediately, suggesting that anything else was a waste of time. All this was not very reassuring, but I felt more confidence in the advice given by my ex-teacher who at least knew something about me. I returned from Berlin somewhat deflated, the only moral boost being that I was able to use my student’s day return ticket to fly back to Leipzig without extra charge, my first experience of air travel.

For the next year, I just carried on. Toward the end of 1933, when I received the Garten Prize, my friends in the Zionist organization were so impressed that they themselves dissuaded me from any lingering thought of discontinuing my clinical course and encouraged me to complete it, with the idea of my ultimately going to Jerusalem and joining the Hebrew University.

Preparing for Emigration, 1934–1935

In 1934 it was still possible to obtain the British magazine Nature and read it in unexpurgated form in the university library. I found in it an article by A.V. Hill which had a great influence on my future. The article was a condensed version of his Thomas Huxley Memorial Lecture given at Birmingham on November 16, 1933. I knew of Hill’s reputation as one of the great physiologists of the time, and I had heard of the warm friendship he had extended to his German colleagues at the end of World War I. I was all the more impressed by Hill’s forthright condemnation of the treatment of his colleagues during the Nazi regime, and I much enjoyed the ensuing correspondence in Nature between the scientific Nazi boss, Professor Johannes Stark, and A.V. Hill. Stark was a well known physicist and had received a Nobel Prize in 1919. After that he had ceased to be active scientifically, but became a strong supporter of the Nazi party, and in 1933 emerged as head of the Physikalisch-Technische Reichsanstalt in Berlin. This institution had been headed by people of the caliber of Helmholtz and Nernst, and in 1933 its director Friedrich Paschen, who was an old friend of A.V. Hill and a person of liberal views, was dismissed to make way for Stark who became a kind of scientific Gauleiter in the Third Reich.

When A.V. Hill denounced the Hitler regime and its persecution of Jewish and dissident scientists, Stark promptly took him to task and stated, in letters to Nature, that there was no factual basis for Hill’s critical remarks, the German government had been obliged to protect itself against the influence of disloyal persons and was only taking lawful actions as any respectable government would do in similar circumstances. A.V. Hill terminated the correspondence with a brief note saying that gifts of money had been received in response to his appeal for assistance to help colleagues who had been driven out of Germany. He added that he was uncertain whether these donations were the result of his own eloquence, or rather should be attributed to Professor Stark’s arguments, and he felt sure some thanks were due to Professor Stark on this account. It was characteristic of A.V. to dismiss and poke fun at even the most vicious absurdities with an elegant and humorous touch. “Laughter,” he said, “is the best detergent for nonsense.” Hill’s Thomas Huxley Lecture and the correspondence in Nature gave me the first glimpse of A.V. Hill’s personality, and I found it so attractive that I made every effort to go and work with him as soon as I could.

I discussed my plan with my superiors in the Zionist organization, and they were very helpful and arranged for me to meet Dr. Chaim Weizmann, the well-known Zionist leader, and put my case to him. I also approached Professor Gildemeister who agreed to write a letter of recommendation to A.V. Hill. And I wrote to my relatives in London who promised to help me in getting my British visa, and who did much more than that when I arrived in England. Without their support, I would not have been able even to cross the English Channel.

My interview with Chaim Weizmann stands out clearly in my mind, and I have also kept detailed minutes of our conversation. Weizmann had gone to spend a holiday at Karlsbad, a spa in Czechoslovakia, in July 1934. My friends in the Zionist office knew about his movements and were in touch with him through their London contacts. My friend, Dr. Fritz Loebenstein, who headed the local (Leipzig) branch of the Zionist organization said, “Why don’t you just hop across the border and see what he can do for you?” and handed me an appropriate letter of introduction. This task was not quite so simple for a stateless person without proper travel documents. However, I managed to obtain a 24-hour tourist’s permit from the guard at the Saxon border, went to Karlsbad where I booked myself in for one night, and then presented myself at Weizmann’s hotel. We had a long talk at the end of which he promised to try and get some financial support for me when I went to London (this resulted in a grant of £50 per annum for two years, that only lasted but actually sufficed for several months!). The final arrangement was that I should correspond with Weizmann’s personal assistant, Dr. Josef Cohn, to fix the dates and details of my planned emigration. I found Chaim Weizmann a most impressive person. To me he is not only the outstanding political leader of the Zionist movement, later to become the first president of the Jewish state, but I regard him as one of the outstanding men of this century, and I feel privileged to have been able to meet him.

I felt elated when I left Karlsbad the next day, slipped back across the border without the guard noticing that I had overstayed my permit, and entered the coach going back to Leipzig. During the trip I settled down to pleasant meditations about my future, but was interrupted by a Sudeten German girl, who had joined the coach and seemed to regard me as one of her Nazi saviors, telling me how they were longing to be liberated by us. She was evidently puzzled by my coolness and total lack of response.

In the autumn of 1934 I took my clinical finals and in November obtained my M.D. Thereafter I worked for a few months as an unpaid intern in the Jewish Hospital in Leipzig, doing both medical and surgical rounds.⁴ I liked working with patients, and I think I should have enjoyed practicing as a physician, had I not been taken on by A.V. Hill and become addicted to experimental physiology. At the beginning of February 1935, I packed my bags and, equipped with travel tickets, a Nansen certificate with a temporary British visa, and the princely sum of £4, I took the train (wooden seats, third class) to Holland. There I transferred to the English Channel ferry at Flushing and arrived in Harwich, England, the next day.

University College of London, 1935–1939⁵

On the day after my arrival in London, I climbed the staircase in the physiology building of University College right up to the top floor, and there I found A.V. Hill, an impressive figure of a man, tall, good-looking, of youthful appearance with contrasting gray hair. He was talking to Donald Solandt about some experiment that was in progress. He took me into his tiny office where we started a bilingual conversation. I had very carefully rehearsed one sentence in English, namely, “Would he allow me to speak in German as this was easier for me?” To which A.V. replied, all right, but it was easier for him to speak in English, and so we continued bilingually for a while. At the end of our conversation, he said he would take me on “as an experiment,” with which I felt very satisfied.

He then showed me around the laboratory and introduced me to the people. I met J.L. Parkinson, A.V.’s incomparable laboratory manager and general scientific assistant. Parkinson soon took me in hand, saw that I was provided with the necessary equipment, frogs, dissecting instruments, Ringer solution, etc.; instructed me in the English language; and generally saw to it that I was kept going and happy. “Parky” was very quick in improvising, putting simple bits of apparatus together and helping the research workers to get started and to overcome irksome difficulties. He also made it his job to protect A.V. Hill from unwanted cranks, uninvited journalists, and in general from visitors whom Parky regarded as undesirable characters. In those days, the anatomy front door on Gower Street was kept closed with a Yale lock at all times, and you needed a key to let yourself in from outside. If somebody whom Parkinson diagnosed as a crank came to see A.V., the hapless caller would be led through a labyrinth of corridors, then into a lift, and finally—after a devious passage through more corridors—would suddenly find himself being ushered through a large impressive door onto Gower Street with the door banging irreversibly shut behind him. One day, A.V. Hill saw Parkinson escorting Sir Charles Sherrington in the direction of the anatomy front door and had just time to stop them with the shout: “Hello Sherry, it looks like Parkinson is going to throw you out!”

After meeting Parky, A.V. took me into A.C. Downing’s workshop. Downing was a skillful instrument maker who had built the highly sensitive moving-coil galvanometers and constructed all the thermopiles and most other delicate instruments that A.V. Hill had designed for his experiments on the heat production of nerve and muscle. To complete the introduction to A.V.’s small research laboratory I met Donald Solandt, from Toronto, who had come to join A.V. in his work on electric excitation theory, and Miss Barbara Garrard (later Mrs. Solandt), who was using tiny thermocouples for measuring the osmotic pressure of minute volumes of blood and tissue fluids. Finally, I met Mrs. Melville, who was half-time personal secretary to Hill, the other half looking after the editorial correspondence connected with the Journal of Physiology, and I shook hands with Arthur Treadwell, who was the junior laboratory assistant. This completed the outfit in biophysics, which for administrative purposes formed a subdivision of the department of physiology.

I saw all that during my first hour at University College. Before I left the laboratory, A.V. showed me some items on display which had been imported from Germany. Among them was a toy figure of Hitler, in brownshirt uniform and swastika, with a movable saluting arm, mounted on a plasticine pedestal stuck against the wall. This was to make people like me “feel at home,” though later I heard A.V. explain to an official type of visitor from Germany that he was really keeping the miniature statue in his laboratory as a sign of gratitude for the scientific workers Hitler had thrown out and sent him. In successive years the number of these symbols gradually increased, and some of them were distinctly vulgar and caused varying degrees of amusement and occasionally embarrassment to casual visitors.

So that was my first day’s experience at University College of London. I left the laboratory feeling on top of the world. Having been accepted by A.V. Hill was a tremendous boost. His personality was extraordinary, it lifted my morale, and nothing would have deflected me from going to work with him despite an income of a £50 per year and despite the advice of other colleagues that I should get a medical diploma and then see where I wanted to go. I did in fact consider this, but I became so absorbed by the work in Hill’s department that I could not face re-immersing myself in textbooks of pathology again.

It was an outstanding piece of good luck to have been taken on as an apprentice by A.V. Hill; it was the decisive influence on my life and career. I still harbor the hope that a first-class biographer will undertake the job of writing a full life of A.V. Hill. I have tried, in the Biographical Memoirs of the Royal Society, to describe how he managed to combine a life’s devoted work in the laboratory with public service: defending science against what he termed “the enemies of knowledge;” helping refugees from Nazi Germany; directing antiaircraft defense in World War I and initiating and organizing radar in the 1930s; working as a member of the British parliament and advising the government of India on postwar reconstruction during World War II; and many other instances of public service. He was the person from whom I have learned more than from anybody else, about science and about human conduct. A.V. Hill was the most naturally upright man I have known. Without ever being rude, he always said precisely what he meant, and you were never in any doubt exactly where you stood with him. In later years, I often found it helpful, when I was confronted with an awkward decision, to sit back and ask myself: “Now, what would A.V. have done in this situation?” To be associated with a man of his stature at a formative period of one’s life is indeed a great gift of fortune.

I retain vivid memories of the spring and summer of 1935, especially of meeting and at times seeing in action, some famous physiologists whose achievements I had heard about as a student, but whom I had not dreamt of encountering in person. Shortly after my arrival at University College, I listened to a lecture on brain waves which E.D. Adrian gave to the students’ physiological society and I recall Henry Barcroft, who was a lecturer in our physiology department, eloquently introducing Adrian’s talk. A.V. himself made a special point of introducing me to visiting colleagues. I was thrilled to shake hands with Joseph Barcroft, whom I had also admired, and getting to know William Rushton who, although already a well-established scientist, had to prepare himself—at Joseph Barcroft’s behest—for medical finals across the road. In his spare time, Rushton came over to do the odd experiment with me. I was well aware of William Rushton’s formidable onslaught and demolition of Professor Louis Lapicque’s theory of neuromuscular isochronism, and I was amazed to learn that this accomplished neurophysiologist from Cambridge University had to work hard to remember things for his medical exam which 1 was in the happy process of forgetting.

In May 1935 I got my first glimpse of Cambridge when I went up for a day to attend the meeting of the Physiological Society. To my great astonishment I witnessed what seemed almost a stand-up fight between J.C. Eccles and H.H. Dale, with the chairman E.D. Adrian acting as a most uncomfortable and reluctant referee. Eccles had presented a paper in which he disputed the role of acetylcholine as a transmitter in the sympathetic ganglion, on the grounds that eserine, a cholinesterase inhibitor, did not produce the predicted potentiating effect. I had some difficulty in following the argument as I was not fully acquainted with the terminology: The word transmitter conveyed to me something to do with radiocommunication, and as this did not make sense, the matter was a bit confusing. When Eccles had given his talk, he was counterattacked in succession by Brown, Feldberg, and Dale, all persons whom I saw on that occasion for the first time, but whose work was to have a very important influence on my own activities in later years. At that meeting, however, what impressed me most was Dale’s rebuttal of Eccles’ criticism. Eccles had used a somewhat unfortunate form of words, I think it was “pace Dale” (meaning “with due respect” or possibly the opposite), which Dale interpreted as peremptory and considered more appropriate for a Hyde Park oration than for a scientific argument at a meeting of the Physiological Society. It did not take me long to discover that this form of banter led to no resentment between the contenders, it was in fact a prelude to much fruitful discussion over the years and indeed to growing mutual admiration between Dale and Eccles.

In the summer of 1935, I went to the Marine Biological Laboratory at Plymouth, England, where I learned something about the crustacean nerve—muscle system from Carl Pantin. A.V. Hill had gone to attend the International Physiological Congress in Leningrad and Moscow. He returned to his cottage at Ivybridge, some 10 miles from the Plymouth laboratory, and I remember visiting him and his family at their pleasant little house, “Three Corners.” It was during that Plymouth period, 50 years ago, that I first met another person from whom I was to learn a great deal about neurophysiology, a younger man by the name of Alan Hodgkin.

I have the most pleasant memories of my first summer in Plymouth, not on account of any scientific achievements, but because of the beautiful countryside, the magnificent view from the laboratory window on Plymouth Hoe, the welcome relaxation through swimming, cycling, and walking through Devonshire lanes and along the Cornish coast. I remember walking through Cawsand one day and arriving at a little public house in Whitsands Bay where I ordered a simple lunch in my recently acquired, imperfect English. I shall always recall with great pride the publican addressing me with the question: “Are you from the north of England?”

In 1935 to 1936 the experiments in Hill’s laboratory centered around a theory of electric excitation and accommodation which he had developed and which was capable of coordinating a vast range of observations and putting them on an easily calculable basis. The fundamental assumptions were very simple: An electric current causes excitation if it displaces the membrane potential (in the depolarizing direction) by a critical amount (the threshold); this is opposed by two processes of different relaxation times: (a) the potential change itself tends to decay with a brief time constant, (b) the threshold rises slowly so that the effect of a steady potential change maintained by a constant current is gradually neutralized. Although these were oversimplified assumptions, they were sufficient to give an excellent quantitative description of a great variety of stimulation phenomena. These assumptions also fit most of the classical strength-duration curves obtained with constant-current pulses and condenser discharges, the characteristic relation between intensity and frequency of sinusoidal alternating currents (with an optimum frequency the value of which is determined by the two relaxation times), the reduced effect of slowly rising currents, etc. Hill’s theory was not the only one of its kind, nor did it explain the physicochemical mechanism of excitation, but its great success in coordinating all kinds of stimulation data on very simple premises probably helped to put an end to half a century of similar, but less successful attempts.

Having myself been involved in the experimental tests, I can say that I found the work attractive and indeed fascinating for two quite different reasons. In the first place the work enabled one to make reproducible measurements of quite extraordinary accuracy with simple equipment. Secondly, although the verification of the theoretical equations was not by itself very fruitful, a number of discrepancies from the predictions of the simple theory gradually emerged which did have important consequences. Such discrepancies led to the recognition of the nonlinear characteristic of the nerve membrane, and of the occurrence of a regenerative voltage change even in the subthreshold range of membrane potentials (the local response), which in turn provided a clue to the mechanism whereby an impulse is initiated.

My association with Hill’s work on excitation theory had a peculiar sequel. In 1938, A.V. was approached by Professor Asher of Bern, who was then the editor of the Ergebnisse der Physiologie, with the request for a lengthy review article on this subject. Hill’s interests had changed, he said he did not have enough time, and suggested me as a possible author; so the request was passed down to me. I felt honored, of course, produced a long manuscript, and sent it off in good time. The next thing was a letter from Professor Asher addressed to A.V. Hill informing him that the article could not be published without an Aryan co-author! Somebody suggested to A.V. Hill that perhaps Mr. Winston Churchill might be approached for this purpose (all this happened some time before the outbreak of war). I decided, however, to ask for the immediate return of the manuscript, and it was published in September 1939 as a monograph by Oxford University Press, whose generosity in taking on such a loss-making proposition I have never ceased to admire.

In some respects it could be said that Hill’s efforts in 1935, devoted to establishing a descriptive formal theory of electric excitation, were a retrograde step. In previous years he had been much concerned with the mechanism of the nerve impulse, and his famous lecture in 1932 on “Chemical Wave Transmission in Nerve” was full of stimulating ideas and speculations about the physical chemistry of the nerve impulse, only to be deliberately set aside and ignored in his 1935 theory. It was, however, a not entirely unfashionable attitude at the time. It is sometimes difficult to realize that even the basic concept of the membrane potential being directly involved in the process of electric excitation was not accepted by some of the most eminent neurophysiologists in the 1930s. One only has to look at the monograph by Erlanger and Gasser to see that this is not an exaggerated statement. And although the idea had been circulating for several decades, it became firmly accepted only during the single cell/intracellular recording era which followed soon after.

After a year or two, A.V. Hill recovered from his temporary diversion into theoretical excitation laws and returned with great vigor to his first love, the energy exchanges and heat production in muscle. In 1938 he produced his classical paper on “The Heat of Shortening and the Dynamic Constants of Muscle,” a remarkable single-handed effort made at a time when he was busy with organizing air defense, aiding refugee scholars, and attending to his job as secretary of the Royal Society. My own research activities went in a different direction. Although A.V.’s personal influence remained as powerful as ever, I was not greatly attracted by the myothermic work, the interpretation of which seemed too difficult to me. The events that influenced my own experimental plans came from several other directions: the single axon approach which I learned from Alan Hodgkin, the rather advanced electronic and oscillograph techniques introduced into our laboratory by Otto Schmitt, and the discovery by Dale and his colleagues of chemical transmission at the neuromuscular junction. Certainly, the work I was doing in 1938 to 1939, before I joined Eccles in Australia, was in line with these tendencies and had little connection with Hill’s personal research.

In March 1938, A.V. took me in his old open-air Humber car to Cambridge. We went to E.D. Adrian’s house on Grange Road so that Hill and Adrian could examine me for a Ph.D. I remember Adrian stipulating at the beginning of the procedure that I was not to test their knowledge of the contents of my thesis, which contained a lot about electric excitation and the evidence for a local response to subthreshold stimuli. The examination was uneventful; what I remember best is the pleasant lunch with the Adrians that followed it. For me the importance of obtaining a Ph.D. was that it allowed me to apply for, and to obtain, a Beit Memorial Fellowship, which at that time was the preeminent junior research award in the biomedical sciences in the United Kingdom. I held the Beit Fellowship for less than one year and at the beginning of August 1939, one month before the start of World War II, departed for Australia, together with my parents whom I fortunately was able to extricate from Germany in March of that year.

I left A.V. Hill and University College with very great regret and much reluctance, but there was one compelling reason why I regarded Eccles’ invitation to join him in his Sydney laboratory as an offer I could not refuse. The reason was not the better salary—the Beit paid £400 per year and that was perfectly adequate to keep the three of us—financial improvement alone would not have induced me to go. But I felt it would have been a poor show and would have looked very bad, if a person like myself who still had to regard himself as a guest in a foreign country, were to decline a call from a colleague far away in an isolated position. So, with a heavy heart I packed my few things, said goodbye to University College, and with my parents sailed from Southampton, England, on a Dutch liner. We were supposed to transfer to another boat in Colombo, Ceylon, and one day before we reached Colombo we heard that the German foreign minister, Herr von Ribbentrop, had gone to Moscow to sign a nonaggression pact with the Soviets. I knew the game was up and that war was imminent—indeed the ship that was to take us on from Colombo to Australia was commandeered and we got stuck in Colombo for a few unpleasant weeks.

I did not relish the idea of going on to Sydney and had the quite unrealistic idea of trying to obtain a passage back to England, thinking somewhat naively that I would be of more use during the war in England than in Australia. After a few weeks of haggling with local shipping agents and persuading some of the local authorities that it would be unwise to keep me in Colombo without a job and with the prospect of our becoming destitute and a burden to them, we eventually managed to continue our journey and arrived in Sydney in October. I remember that while we were marooned in Colombo, the University of Ceylon happened to advertise a vacant professorship in physiology. What deterred me from applying was the requirement, which was explicitly stated in the advertisement, that the applicant had to be able to repair the broken string galvanometer in the department.

Australia, 1939–1945

When I arrived in Sydney, I was welcomed by Jack Eccles who himself had returned to Australia in 1937 and had built up a small research laboratory on the top floor of the Kanematsu Institute of Pathology at Sydney Hospital. It took me several months to settle down to experiments because the events in Europe, even during the so called “phony,” inactive period of the war, had absorbed my interests, and the neuromuscular junction seemed to be of second-rate importance at the time. I was greatly helped in the settling-down process by young Stephen Kuffler who had arrived on the scene the year before, having left Vienna as a newly hatched M.D., about as raw as I was when I first joined A.V. Hill at University College. Stephen and I took to each other. We liked making the same sort of jokes and had an uncanny capacity for generating identical puns almost simultaneously at the slightest provocation.

When I first met Stephen, he was still somewhat bewildered by the interpretation of and the involved terminology adorning the electrical traces from muscles and motor endplates which he and Eccles were recording. Each bump had a different name, and there were also special names such as detonator responses for things which one could not see. It took a few years before Stephen took off under his own steam and showed his great powers as an experimenter. Once he had started on his single nerve-muscle fiber preparation, Eccles and I felt he had clearly outrun us. But every now and then he used to joke about his pretended total ignorance and scientific limitations. I remember one of his prize remarks: “They say, if the threshold goes up, the excitability goes down. Isn’t it funny: It’s fifty-fifty, and I always seem to get it wrong!” thus betraying his apparent contempt for terminology and also for statistics. Another characteristic comment of his came after a lecture that I had given to the junior medicals at Sydney University. I noticed that the students had been reasonably quiet and had not talked too much during the lecture, which suggested that they may have been paying some attention. Nevertheless I was surprised to have seen quite a number of the female students busily getting on with their knitting during the lecture. Stephen commented: “That’s all right; it gives them something to think about, while they are talking.” Stephen told me that the real reason why Eccles had taken him on in the first place was that he was looking for a suitable tennis partner and he had tested him on his nice grass court. I am afraid my own proficiency as a tennis player was negligible, but I can tell you a little anecdote about my experience with Eccles’ grass court.

It took Eccles many years, until 1947 to 1948, before he accepted without reservation the idea of chemical transmission at the neuromuscular junction. We had plenty of arguments about it in those days in Sydney. But I think I can claim to have converted him, temporarily at least, in 1939 shortly after I joined him. I vividly remember visiting him in his pleasant house with its fine tennis court and beautiful view of Sydney harbor. One day he asked me to cut the grass for him. I had never used a mowing machine before and I did not think it required much intellectual effort or preparation. He had an electric lawn mower operated from the 240 V mains. I rapidly cut down one lane and on the first turn about managed to cut through the mower’s electric cable, and there I was, in a state of incomplete tetanus for several seconds, unable to release my hands from the machine, to the great horror of the onlookers. Jack Eccles was very nice and sympathetic about it; he never asked me to replace the machine or pay for the repairs, in fact he was so concerned that he threw the electric mower away and bought a petrol-driven machine instead. And I believe that was the precise moment when I converted Professor Eccles from electrical to chemical transmission. Of course, his reply is that even the petrol mower needs an electric spark, a detonator, to make it work!

I spent about two years working full time at the Kanematsu Institute in Sydney. When I got there, Eccles and Kuffler had been doing their experiments entirely on the whole cat, recording in situ from innervated zones of the soleus muscle. Having been trained as a “frogman” in A.V. Hill’s laboratory, I did not much like this type of experiment, nor was I much good in setting it up. I ganged up with Stephen Kuffler, and I was pleased when we succeeded in getting hold of some nice Australian tree frogs, the sartorius muscles of which proved to be very suitable for the experiments we wanted to do, and this kept me busy and moderately happy for two years.

In 1941 I obtained my British naturalization papers in Sydney and shortly afterwards managed to enlist with the Royal Australian Air Force (RAAF), first as a rookie, then graduating as a radar officer. Otto Schmitt had taught me some fairly advanced tricks that one could play with thermionic valves, and that helped me a great deal during my period as a radar trainee. But my four years in the RAAF taught me a great many more useful things, about electronics as well as about human beings. I spent a good deal of time tramping around New Guinea together with an Australian radar mechanic, Norman Smith. He was an excellent companion, one of those men who can put his hands to everything, from farming to house building, from catching snakes in the bush to constructing electronic apparatus. He is, in fact, a schoolteacher now in retirement living in Murwillumbah, New South Wales, and I am proud to say that we still keep up a friendly correspondence. My service in the RAAF had a very important effect on my life: it greatly increased my self-confidence and I felt that no longer would I need consider myself a guest when I returned to England after the war.

My enlistment in the Australian forces greatly boosted my morale, and somehow I felt that now I had bought my ticket to return home to England when the war was over. But in no way did my enlistment diminish my feeling of gratitude and indebtedness to the friends in England who had offered me a home and a refuge in 1935, who had made it possible for me and my parents to escape from the indignities and humiliations of Hitler’s Reich, and who had given me my education as a scientist.

During the last year of the war I was posted back to Sydney as a liaison officer at the Radiophysics Laboratory. This was quite an interesting place, housed within the University of Sydney and harboring a number of young physicists who later became Fellows of the Royal Society. I believe I may have been at the Radiophysics laboratory during a time when among the female typists in the office there was one young lady by the name of Joan Sutherland, who subsequently became one of the world’s greatest operatic stars. During that year I found I had plenty of spare time on my hands, and I used it most diligently, partly to do some more experiments together with Stephen Kuffler on crustacean nerve—muscle junctions, and—more importantly—to pursue and eventually marry Miss Marguerite Penly, who, I am glad to report is still putting up with me even though she still is not fully acclimated to the English weather. A month before the wedding I received a telegram from London, which was in fact A.V. Hill’s wedding present, inviting me to return to University College of London as Henry Head Fellow of the Royal Society and assistant director of research in biophysics. A.V.’s wedding present caused a great deal of consternation to some members of my wife’s family, but fortunately did not prevent the marriage from taking place at the appointed date. My marriage to Marguerite Penly was undoubtedly my most important achievement during my period in Australia. I am convinced that my marriage greatly enhanced my reputation among friends and colleagues who were probably no less astonished than I was that a young lady of such outstanding charm and attraction should have accepted me as a husband.

Back in London, 1946–Onward

My wife and I had some difficulties in arranging our sea voyage from Sydney to Southampton. It was a time when ocean liners had not yet been taken out of war service and refurbished. The ships were used to send troops home from various parts of the globe, and once I had got myself demobilized from the RAAF, I found myself at the end of the queue—one of those odd civilians who was regarded not only as the lowest form of animal life but who had to pay a first-class fare and be thankful for not being thrown into the ship’s hold. Actually, we had to spend our two months’ sea passage in the style of returning convicts, being confined to separate dormitories, and pretty squalid ones at that. But I did not mind that very much; I felt I was going home, and as it turned out that journey did conclude my wanderings over the globe.

When we arrived in London early in 1946, my wife and I were fortunate in being offered accommodation at the top of the Hill’s very pleasant house in Highgate, and this tided us over for the first two postwar years. University College was still recovering from war damage and various kinds of civil-service occupation. I remember spending a week painting the walls in the biophysics laboratories and ending up with a rather vicious dose of painter’s colic. With J.L. Parkinson’s help, we soon managed to put Otto Schmitt’s oscillograph and amplifiers back into working order. In addition, Parky conspired to collect a lot of Royal Air Force surplus radar gear, and we converted a nice CHL Mark V receiver and display unit into a large demonstration oscilloscope for the physiology lecture theater. Once we had got the equipment functioning, I quickly picked up the threads from previous work and did some more experiments on the local response. I then spent over a year trying to sort out the electrical membrane properties of muscle fibers, and I came across an odd phenomenon that still arouses some interest and goes under the name of anomalous or inward rectification.

In the summer of 1947 our first son was born. A little later I joined Alan Hodgkin in Plymouth where I participated in the work on the squid axon, and continued to do so during several successive summer vacations.

For a couple of years at the college I became interested in the local generator potentials elicited by stretch in the muscle spindle of the frog. After that, practically all my experimental work had to do with neuromuscular and synaptic transmission. When I became head of the newly created biophysics department in January 1952 I was lucky in having excellent friends to support me. I want to pay special tribute to an outstanding provost of University College, Ifor Evans, and to my colleagues in my neighboring departments, John Young, Andrew Huxley, Heinz Schild, and above all, Lindor Brown, with whom I developed a close personal rapport of the kind I used to enjoy with Stephen Kuffler. In the laboratory I was equally blessed in having admirable friends to collaborate with, Paul Fatt, José del Castillo, Stephen Thesleff, and, for some 25 years, Ricardo Miledi. We worked on miniature endplate potentials, on quantal release of transmitter substances, on the role of calcium in transmitter release, on the postsynaptic action of acetylcholine, on acetylcholine noise and the statistical derivation of the molecular transmitter action, and on various related problems that cropped up from time to time. Perhaps the most exciting discovery among these was the realization that nerve cells talk to each other by secreting droplets of transmitter, discrete packets containing thousands of active molecules at a time. Together with ultrastructural evidence, this discovery led to the theory of vesicular exocytosis which, after 40 years, retains a focal position in synaptic research.

I have had the good fortune not only of deriving much first-class entertainment and excitement from my work, but also of seeing some beautiful experiments come out of the laboratories of my younger friends and colleagues: the observations on vesicular exocytosis by John Heuser and Tom Reese and their co-workers; the direct demonstration of single ion channels in chemosensitive membranes by Erwin Neher and Bert Sakmann; and more recently, the experimental induction of neuroreceptors and ion channels in amphibian oocytes by Ricardo Miledi and his colleagues. Needless to say, it is most gratifying to see outstanding advances being made by the next generation of scientists and to witness the important part played in it by colleagues who at one time were actually members of our own group.

Selected Publications

Erlanger J, Gasser HS. Electrical signs of nervous activity. Philadelphia: University of Pennsylvania Press, 1937;x, 221.

Hill AV. Chemical wave transmission in nerve. Cambridge: Cambridge University Press, 1932;ix, 74.

Hill AV. The international status and obligation of science. Nature 1933;132:952–954 (see also Nature 1934;133:614–615).

Hill AV. Excitation and accommodation in nerve. Proc R Soc Lond B Biol Sci 1936;119:305:–355.

Hill AV. The heat of shortening and the dynamic constants of muscle. Proc R Soc Lond B Biol Sci 1938;126:136:–195.

Katz B. Electric excitation of nerve. Oxford: Oxford University Press, 1939;ix, 145.

Katz B. Nerve, muscle and synapse. New York: McGraw-Hill, 1966; ix, 193.

Katz B. The release of neural transmitter substances. Liverpool: University Press, 1969; ix, 60.

Katz B. Archibald Vivian Hill 1886–1977. Biographical Memoirs of the Royal Society 1978;24:71:–149.

Katz B. Planning and Following the Unexpected in Scientific Research. Creativity Research Journal 1994;7:225:–238.

¹Victor von Weizsiicker (1886–1957) was a distinguished clinical neurologist, and as a moral and social philosopher, he was widely known and respected for his freely expressed liberal views. He was the uncle of the former president of the Federal Republic of Germany. In 1935, after I joined A.V. Hill’s laboratory, I discovered that Victor von Weizsiicker had earlier in his life done some important physiological research and had preceded me, by some 21 years, as a pupil and collaborator of A.V. Hill.

²In German, it sounds as though the two natural enemies (cat and dog) are meeting for a hostile encounter.

³Sereni had a tragic end. During the later part of the war he was parachuted into Nazioccupied Italy and fell into the hands of the S.S. who tortured and killed him.

⁴The Jewish Hospital in Leipzig had been founded and named after Chaim Eitingon, the head of a wealthy family of fur merchants who, like my father, had emigrated from Russia at the beginning of the century. Eitingon’s family had succeeded in building a large business with important international connections and were known, well beyond the Jewish community, as benefactors to the town of Leipzig and its university. I knew them slightly through my father who had been on friendly terms with the Eitingon family from the early days. I was quite appalled to read of vicious attacks by some political writers on the family’s good name, accusing them of undercover activities and complicity in the Stalin purges during the 1930s! Fortunately, a full discussion of the case has subsequently been published in the New York Times Book Review (16 June 1988), which reveals the baselessness and absurdity of those claims.

⁵Reprinted with permission from Bernard Katz’s Bayliss-Starling Memorial Lecture published in J. Physiol. (1986), Vol. 370, pp. 1-12.

Seymour S. Kety

BORN:

Philadelphia, Pennsylvania

August 25, 1915

EDUCATION:

University of Pennsylvania, A.B., 1936

University of Pennsylvania, M.D., 1940

Philadelphia General Hospital, Internship, 1940

APPOINTMENTS:

University of Pennsylvania (1943)

National Institute of Mental Health and Neurological Diseases (Scientific Director, 1951)

Laboratory of Clinical Science, NIMH (Chief, 1956)

Harvard Medical School (1967)

Professor Emeritus, Harvard Medical School; Senior Scientist Emeritus, NIMH (1983)

HONORS AND AWARDS (SELECTED):

American Academy of Arts and Sciences (1960)

National Academy of Sciences USA (1962)

National Academy of Sciences Kovalenko Award (1973)

American Philosophical Society (1977)

Passano Award (1980)

Ralph W. Gerard Prize, Society for Neuroscience (1986)

The Georg Charles de Hevesy Nuclear Medice Pioneer Award (1988)

National Academy of Sciences Award in Neuroscience (1988)

Karl Lashley Award, American Philosophical Society (1992)

Lifetime Achievement Award, International Society for Psychiatric Genetics (1993)

Seymour Kety is best known for his pioneering studies of global and regional cerebral blood flow and oxygen consumption in the human brain. He conducted this work in normal subjects at various stages of the sleep-wake cycle and in patients with a wide variety of diseases. He also initiated the best controlled studies to date showing a strong genetic component in the etiology of schizophrenia.

Seymour S. Kety

I was born on August 25, 1915 and reared and educated in Philadelphia. By the time I reached adolescence, I had experienced a number of environmental influences that Anne Roe found with unusual frequency in her classical studies of the lives of biological and natural scientists. I was the first born and, for my first 10 years, the only child. My father died when I was 12 and my mother’s brother and four sisters generously shared their home with us. It was a traditional Jewish home, not particularly observant religiously, but steeped in American Jewish culture. Although financial problems were present, so were books, great music, and lively discussion. Our name was Kitei in Russia but when my grandfather came to America, an immigration officer anglicized it to Kety. In Russian Kitei means “Chinese” and there are several humorous and romantic attempts to explain the origin.

At the age of seven, I was run down by an automobile which struck my face and fractured a leg. I must have clamped down on my tongue and almost completely severed it. I was taken to a hospital and I remember the surgeon putting a needle through my tongue and sewing it together again. I was hospitalized for a long time with a fractured leg which ended up shorter than the other, and because of some scarring of the muscles and tendons, I developed an equinus, so called because I was forced to walk on the toes. For several years I wore a special kind of shoe that was conspicuous and embarrassing. It wasn’t until I was 13 or 14 that I was taken to an orthopedic surgeon who cut and lengthened the Achilles tendon in a simple operation. After several weeks of being in a cast, my foot was flat and I could wear ordinary shoes.

In that earlier long period of hospitalization and home care with my leg in traction, I developed a great interest in reading. My family had bought me the Book of Knowledge, a series of volumes that described in a very engaging way the contents of a large panorama of disciplines: physics, chemistry, astronomy, biology, history, philosophy, and literature. I must have read practically all of those volumes in the period during which I was confined to my home. That gave me a fantastic background that substituted for athletics and other interests I might have had. I never really appreciated baseball or football. Eventually, I played some tennis.

When I was about 10-years-old, one of my aunts gave me a chemistry set; and after playing magic with that for a while, I became interested in the science and developed a laboratory in the basement. When I was in high school I would save my lunch money and instead of lunching on shepherd’s pie, I’d eat a couple of soft pretzels for which Philadelphia was famous, and go to the chemical supply house near the school and buy more interesting chemicals and supplies than came with chemistry sets. Eventually, I built quite a formidable laboratory which strengthened my interest in chemistry. In fact, I wrote a book called The Boys’ Book of Chemistry in which I described for a young boy the principles of chemistry and led through various historic or exciting experiments. The book, of course, was never published; it was written in a series of notebooks and I was never satisfied with it sufficiently to want to see it published. By the time I got to high school I was quite proficient in chemistry.

I went to an unusual high school, Central High, in Philadelphia which, I think, was second only to Boston Latin in terms of its age and distinction. Central High began as a city college and it still retained many of the collegiate amenities. For example, we received a baccalaureate degree when we graduated and we had professors, not teachers, who all liked to teach, and many were interesting characters. I took the classical course which included Latin and Greek. The professor of classical languages, Professor Howes, was erudite and rather liberal politically. In addition to having us recite Xenophon and Caesar and Horace and Homer, he would give us discourses on politics and living. We would select someone in the class to get Howes started by asking him a provocative question as soon as we entered his class and sat down. If we were fortunate, he would discourse on that topic and we would never have to reveal how poorly prepared we were. One day he surprised us by saying, “Well, gentlemen, who’s the starter today?”

I had a number of professors there who were very important as models for me. The greatest was Bradner MacPherson, a charismatic professor of English literature and a sincere friend. I remember how terribly upset I was when I learned that he had died of pneumococcic meningitis just before the advent of the sulfonamides and penicillin. The disorder, when he contracted it, was 100 percent fatal. Today it would be a simple matter to cure.

Another important influence was Edwin Landis who was the professor of physics. Edwin Landis, incidentally, was the uncle of Eugene Landis, a distinguished physiologist who did the classical work on capillary fluid exchange at the University of Pennsylvania and became a professor of physiology at Harvard. Edwin Landis inspired a number of us. He started a science and philosophy club in which we tangled with important problems like vitalism and materialism, consciousness, and the nature of consciousness for a very illuminating and exciting experience. We found a sentence in Virgil, “Felix qui potuit rerum cognoscere causas,” “Happy is he who is able to understand the causes of things.” It was there that I developed a long-lasting interest in the unique experience of consciousness and how it is derived from the brain, a problem to which I still have not found a satisfactory answer, although others appear to have, at least for them.

We also learned about the General and Special Theories of Relativity in the course of which I asked a question that Professor Landis could not answer. He suggested that I write to Albert Einstein which I did. To our intense gratification the great man sent back a splendid letter in reply, which answered the question in considerable detail. What a great scientist was he who was not too busy or important to answer the question of a high school student in another country.

My maternal uncle, Harry Snyderman, who took the place of my father during my adolescence, had a great influence on me. He was extremely scholarly, read incessantly, and built up the largest collection of books that I’ve ever seen in a private home. He knew more about literature than anyone I’ve ever met since. He was an excellent critic and an accomplished grammarian. He was also a self-taught pianist. He never learned to read music but he could always play things by ear and he was remarkable in the way he would sit down and play most anything that he heard. He had a profound influence on me even though I never developed his grasp of literature or music.

I was very successful at Central High, graduating with high honors and winning a number of awards. It was said that no one had won as many in the history of the school. Because this was not my mother’s claim but came from one of the older teachers, I had no basis for denying it. I went to the University of Pennsylvania on scholarship. Some of my mentors in high school wanted me to apply to Princeton or to Harvard but I didn’t see the point because even if I were able to get a scholarship to those places, I would not have been able to muster living expenses. So I chose the university in the city where I lived. My education at Central High was so full and rich that college was quite a let down. I found that there was really not much of a challenge to me. Even in chemistry, I breezed through most of it and it wasn’t until we got to physical chemistry that I reached the point where I had to study.

In college I had a job with a toxicologist who was interested in lead and was a consultant to a number of lead companies. He had me do lead analyses on the urine of the workers there. I used the standard procedure, part of which was to precipitate the lead as an insoluble salt and then to redissolve it with sodium citrate, in which the citrate formed a complex ion, which is called a chelate, with lead. That was important to me because I thought that perhaps it would be possible to treat lead poisoning with citrate. That disorder is associated with the deposition of lead in the bones, which perhaps citrate could extract and permit to be excreted. I was able to test that hypothesis a few years later.

I was planning to go to graduate school for a degree in chemistry, but was persuaded instead to apply to medical school, which turned out to be a wise choice. The preclinical years in medical school gave me a much broader education in the biological sciences, especially those of the brain which no single department of the graduate school could have provided. Neuroscience was not a course or even a discipline in 1935; was it even a word?

During a research elective at medical school, I had an opportunity to test my hypothesis of the mobilization and excretion of lead through chelation with citrate. I added lead to the diet of some rats until they became chronically intoxicated, then measured the excretion of lead after feeding them sodium citrate. The citrate profoundly increased the excretion of lead. I suppose you could call this the first scientific discovery that I made. Previously, the experiments that I did were just reproducing what others had done and described, but this time it was very exciting to see a hypothesis come true right in front of my eyes.

When I completed medical school in 1940 I married Josephine Gross who was in her last year of medical school. In all the years of our marriage she has shared my work and decisions, graciously and selflessly adapting her career to mine in the moves we decided to make. I took an internship at the Philadelphia General Hospital, the descendent of Blockley which had been the oldest hospital in the country. When Josephine was ready for an internship she chose the same hospital, not only because I was there, but because her father took his internship there in 1912. The director called me into his office to inform me that a fine female physician, who was probably my wife, was coming as an intern. Unfortunately, however, the hospital had no facilities for married couples, so I would remain in the men’s quarters while my wife stayed with the female interns. Because the hospital was providing our room and board in lieu of a salary, it would have been ungrateful of me to have objected. We did manage to live together eventually. Josephine went on to residency in pediatrics and in 1990 we celebrated our 50th anniversary.

During my busy internship I spent my spare time at a laboratory studying the nature of the lead citrate ion and measuring its degree of association. I demonstrated that lead did form a very tight complex with citrate. I then calculated that there was enough citrate circulating in the blood normally to carry a significant amount of lead in the soluble complex form. This was true in chronic lead poisoning and perhaps the mechanism by which the body slowly excretes the metal. One could facilitate that process by increasing the citrate in the blood through administration of sodium citrate and thus increase the excretion of lead. I wrote this up and sent it to the Journal of Biological Chemistry and was very fortunate to have my first scientific paper (Kety, 1942) accepted in so prestigious a journal.

Then I administered sodium citrate to workers with lead poisoning and was fortunate to find a chemist in the hospital laboratories who was interested in lead poisoning and willing to carry out the blood and urine assays. He was able to show that citrate treatment increased the excretion of lead significantly and led to a progressive fall of lead in the blood levels (Kety and Letonoff, 1943).

That was the forerunner of the chelate treatment that became the standard treatment for lead poisoning. This uses more complex organic molecules that form a much tighter complex lead.

After I completed my internship, I applied for a National Research Council fellowship. I wanted to go to Boston to work with Dr. Joseph Aub who was the world authority on lead poisoning. I was still interested in lead poisoning and, as a matter of fact, it was the work that I had done on citrate and lead poisoning that won the fellowship. I wrote to Dr. Aub and asked about coming to join him.

Shortly after joining Dr. Aub, World War II broke out. I applied for a commission in the Army, but was rejected because of residua from my accident 20 years earlier. Dr. Aub had replied with a strong welcome but with a warning that he wasn’t working on lead. Instead, due to the war, he had turned his laboratory to the study of traumatic shock.

Dr. Aub was a warm and charming scientist. Besides his work on lead poisoning, his major contributions were in metabolism and, more recently, in cancer research. Working in his laboratory introduced me to Paul Zamecnik, who had just returned after a fellowship at the Carlsberg Laboratories in Copenhagen with Lindestrom-Lang, and to Alfred Pope, a contemporary, the same age as mine, but a Harvard man.

Alfred Pope and I became good friends and have remained so ever since. We were the two junior members of that laboratory, who stayed up late watching the dogs in shock, taking their blood pressure, and doing any biochemistry that had to be done. We became interested in shock and developed a recognition of the homeostatic reflexes that were operating in shock whose purpose, obviously, was to preserve the circulation of the brain and the myocardium at the expense of the circulation in other organs. Blood vessels of the brain and the heart are specially adapted so that they are not constricted by sympathetic activity. Stimulation of the sympathetic nervous system would cut down the blood flow to the kidneys and to the skin and to the viscera; but it would not cut down the blood flow to the coronaries and the brain for obvious teleological reasons.

Al and I wrote a paper that we published in the American Heart Journal (Kety and Pope, 1944) on the homeostatic reflexes that operate in shock and how they preserved the cerebral circulation. I also came across a paper published in the same year in the American Journal of Physiology by Dumke and Carl Schmidt from the University of Pennsylvania. This paper measured the circulation of the brain of the rhesus monkey with a bubble flow meter inserted into the internal carotid artery. This was the first time that anyone had been able to measure quantitatively the blood flow through the mammalian brain. I decided that when I finished my fellowship with Dr. Aub I would seek a position with Carl Schmidt and go back to Philadelphia. I was successful in doing that even though Dr. Aub urged me to stay. Neither of us knew that I would return to Harvard 25 years later.

Shortly after I arrived at Carl Schmidt’s laboratory, he invited me to assist him in the studies of oxygen consumption in the brain of the monkey. Besides obtaining values for that function in the mammalian brain under light anesthesia, that study also demonstrated a striking increase in metabolism during convulsions and a decrease under anesthesia (Schmidt, Kety, Pennes, 1945). Less extreme states, of course, were not readily examined. What challenged me, however, was the human cerebral circulation because the human brain was so different from that of the monkey even though they were very close approximations, but different as opposed to the liver or to the kidneys. The animal kidney is a very good model of the human organ, the detailed function of which can be studied and understood, one from the other. I felt that just as the brain is unique among organs for its complexity, so is the human brain unique among that of other creatures in its capacity, its versatility and plasticity, its ability to conceptualize and create, to experience ecstasy and deep grief, and to describe to outside observers the results of its inner processes. It is also the human brain that falls prey to serious disorders of these functions, for which no comparable animal models exist. It was apparent that the study of the circulation and metabolism of the human brain while it was engaged in these functions and experiences might teach us something about these processes, and its study in disease might be of benefit to those suffering from neurological or mental disorders. It was thoughts such as these that moved me to seek a means of studying the circulation of the human brain.

Measurement of the Human Cerebral Circulation

While in Boston, I had heard an inspiring lecture by Andre Cournand, describing his early work on the output of the human heart in health and disease, and I was impressed with the possibility that clinical studies could be more physiological, relevant, and fundamental, under certain circumstances, than studies in animals. Cournand had used the classical Fick principle, calculating cardiac output (equal to blood flow through the lungs) from the oxygen taken up by the lung and the oxygen content in blood entering and leaving, all of which he could measure independently. The crucial sample was the pulmonary arterial blood which he could obtain from the right atrium by catheterization.

Much earlier, in 1927, the Boston psychiatrist Abraham Meyerson had described a simple technique for obtaining cerebral venous blood in man from the superior bulb of the internal jugular, making it possible to measure the arteriovenous difference across the brain for substances utilized or produced in significant amounts by that organ. That approach was then used by a group in Boston to infer cerebral circulation from the arteriovenous oxygen difference, assuming that cerebral oxygen consumption, which could not be measured, was constant. But the arteriovenous oxygen difference was also used in Albany to infer metabolic rate of the brain with the assumption that blood flow was constant. What had limited the validity and acceptance of both these approaches was that the arteriovenous oxygen difference, being a function of both blood flow and oxygen consumption, was not a valid measure of either alone. The oxygen consumption of the brain could not be measured independently and certainly could not be assumed to be constant under a wide variety of functional states, because it would be expected to vary with the state of activity or disease that was the object of investigation.

By 1943, the Fick principle had been applied by Homer Smith to the kidney, and two years later by Stanley Bradley to the measurement of hepatic blood flow. In each case they took advantage of the ability of these organs specifically to excrete a foreign substance at a rate that could be independently measured. Unlike the kidney and liver, however, the brain was not known to remove selectively and specifically a foreign substance from the blood and excrete it for accurate measurement.

I realized, however, that the brain would absorb by physical solution an inert gas, which reached it by way of the arterial blood. The accumulation of such a gas in the brain should be independent of the metabolism, determined instead by the rate of perfusion and relatively simple physical principles such as diffusion and solubility which should be quite constant in the brain whether the subject was asleep or awake, working out a complex mathematical problem or suffering from schizophrenia.

In the brain of a monkey I found that a cerebral arteriovenous difference did exist for the non-metabolized gas, nitrous oxide, as it was breathed, and that this difference went from wide to narrow over a period of 10 minutes. The Fick equation would have to be converted to differential form to deal with the nonsteady state of equilibration with a metabolically inert tracer like nitrous oxide. To solve the resulting equation for cerebral blood flow it would be necessary to measure the concentrations of the gas in arterial and mixed cerebral venous blood as the arterial blood and brain came toward equilibrium, and to integrate the difference over time.

Arterial and cerebral venous blood were obtainable but I would also need to know the amount taken up by the brain as a whole during that time. One could, of course, do this by external counting of a radioactive inert gas, but a simpler approach presented itself. The arteriovenous difference became progressively narrow with time because the brain was coming to equilibrium with the blood passing through it. If that was the case, there would be a time in which the venous blood draining the brain would be in virtual equilibrium with the brain itself and could be used as a measure of the partial pressure of gas in the brain. At that time, the cerebral venous concentration would yield the concentration of nitrous oxide in the brain, if corrected for the differential solubilities of the gas in brain and blood. With both the numerator and the denominator measurable, cerebral blood flow in unit weight of brain (F/W) could be determined.

I could not find a flaw in this reasoning and I was now in position to explain it to Carl Schmidt. He was impressed and offered to set up some monkeys with bubble flow meters to compare my results with the meter’s results in the same monkeys. He did this and the correlation between the two measures was excellent.

The equilibration between blood and brain could be studied in animals and was found to be sufficiently complete at the end of 10 minutes (Kety, Harmel, et al., 1948). It was also possible to obtain a more accurate measure of the partition coefficient of nitrous oxide between brain and blood and of the remarkably constant solubility of the gas in human brain in a variety of disorders. Later, studies with radioactive krypton indicated that in man, 10 minutes was also sufficient for nearly complete equilibrium. Two other series of studies indicated that the venous blood was well mixed by the time it emerged and that contamination from the distribution of the external carotid was minor (Shenkin, Harmel, Kety, 1948). Once cerebral blood flow could be measured, cerebral oxygen consumption could be calculated from that and the arteriovenous oxygen difference across the brain.

The first systematic study in man was carried out on 14 healthy young men who volunteered to serve as subjects (Kety and Schmidt, 1948). The values for blood flow and oxygen consumption were in the same range as those we had previously found in the monkey when both were reduced to unit weight of brain. I am still impressed, however, with how large a share of the body’s economy is used in supporting the brain—about a fifth of the cardiac output and of the oxygen consumption at rest—but how small the utilization of energy by the human brain—a mere 20 watts—in comparison with what man-made giant computers required. In the 50 years that have elapsed since then, the energy requirements of computers have come down closer to that figure.

The number of problems to which the new technique could be applied were legion but I tried to select those that might contribute to fundamental knowledge about the brain, its physiological functions, or in the case of disease, where there was reason to think that an alteration in cerebral circulation or metabolism would be crucially involved. Among the very first studies was the one on schizophrenia (Kety, Woodford, et al., 1948) which was begun because it had been proposed that a deficit in oxygen supply and utilization occurred in the brain, but there was an equally cogent reason. The development of the nitrous oxide technique was supported in part by a small grant from the Scottish Rite Schizophrenia Program. Although the directors had never asked about the relevance of cerebral circulation to schizophrenia, when an application to that problem was possible we were eager to make it. This involved long trips to the Delaware State Psychiatric Hospital with collaborators Rachel Woodford and Merel Harmel, where Fritz Freyhan, an excellent psychiatrist and investigator, had selected a series of chronic schizophrenic patients willing to participate in the studies. The results, however, were not illuminating. The brain of the schizophrenic patient had the same blood flow and utilized oxygen at the same rate as that of normal individuals. That did not dissuade me from the belief that we were dealing with a disease of the brain—the remarkable dissipation of the psychosis often produced by a chemical substance, amytal, convinced me that chemical processes were involved. It appeared quite likely that the mental changes in schizophrenia depended on chemical and neural processes too localized and differentiated to be revealed in the circulation and metabolism of the whole brain. My summary of the findings–“…a generalized change in circulation or oxygen utilization by the brain of schizophrenics may safely be ruled out, although there remains the possibility that local disturbances confined to small but important regions may still occur since the method used yields only mean values for the entire brain.“–recognized the most serious limitation of the nitrous oxide technique and the need to examine the circulation and metabolism within the brain’s unexplored complexities which I then proposed to address.

In respect of medical disorders, the finding that cerebral circulation was normal in essential hypertension despite a perfusing pressure that was twice normal, was important (Kety, Hafkenschie, et al., 1948). This was found without intervention by the known sympathetic supply to the brain (Harmel et al., 1948), suggesting a humoral vasoconstriction or a homeostatic autoregulation, both of which are now known to occur. Other medical or neuropsychiatric problems to which the technique was applied shortly after its development were diabetic acidosis, epilepsy, increased intracranial pressure, surgical anesthesia, and senile dementia (Kety, Polis, et al., 1950). The technique was also applied successfully to the complex problem of measuring coronary blood flow and myocardial metabolism (Bing et al., 1949).

We were not alone for long in applying this technique, in spite of its limitations, to other clinical problems. Scheinberg and Stead were the first to apply it in America, while Professor Aizawa, chairman of neurology at Keio University, introduced the nitrous oxide method in Japan, followed by Niels Lassen and his colleagues in Denmark, Cesare Fieschi and Agnoli in Italy, and several others in Europe.

In 1948, I moved to the Graduate School of Medicine, joining Julius Comroe’s department of physiology, and began working on a grant I was fortunate enough to receive from the new National Heart Institute in Bethesda for studies on the theory of inert gas exchange, prompted largely by my feeling that in the exchange of inert tracers between capillaries and tissue would be found the means of measuring local blood flow in the brain. I had moved empirically in that direction in the measurement of muscle blood flow from the clearance of ²⁴Na ions (Kety, 1949). Now, having chosen as my next objective the measurement and study of regional blood flow, the most promising approach appeared to lie in a more exhaustive study of the physical processes on which the nitrous oxide technique was based, that is the exchange of diffusible, nonmetabolized molecules between capillary and tissue. Louis Goodman, the editor of Pharmacological Reviews had invited me to write a review on the distribution of anesthetic gases and I responded by offering to review the theory of the exchange of inert gases at the lungs and tissues.

In the development of the nitrous oxide technique, the familiar Fick Principle was converted to differential form and made applicable to the accumulation of an exogenous nonmetabolized substance in the brain, rather than to the absorption of oxygen at the lungs. To solve the resulting expression for cerebral flow it was necessary to evaluate concentrations of the tracer in arterial and mixed cerebral venous blood, both of which were obtainable, but also the amount taken up by the brain as a whole, which, it was possible to show, could be obtained from the cerebral venous blood.

In the case of an individual small region, on the other hand, I saw no way of measuring the concentration of tracer in its effluent blood under physiological conditions. It would be possible, however, to measure the concentration of a radioactive tracer in the individual small regions throughout the brain by means of autoradiography in animals and external detectors in man. From the tissue concentration at a particular locus, it should be possible to derive the concentration of tracer in the venous blood from that site on the basis of physical principles. Where diffusion is not limiting, a tracer in the entering capillary blood will achieve practical equilibrium with the surrounding tissue at the time of its exit. This permitted the derivation of an expression for the concentration of tracer in a small tissue region at a specific time in terms of blood flow through the region, partition coefficient of the tracer between the tissue and blood, the diffusion constant for the tracer in tissue, the geometrical relations of the capillaries there, and the past history of the tracer in the arterial blood from the time of its introduction (Kety, 1951). In 1951, when that expression was derived, I did not foresee the many applications it would have as the technology of tracer detection and localization moved forward over the next 30 years.

There would be some diffusion limitation in the case of many possible tracers, however, and it was desirable to elucidate the physical and biological factors on which capillary:tissue equilibrium depends and to develop an expression to take them into account. Some 30 years before, Christian Bohr and August Krogh had described the exchange of oxygen at the capillaries of lung and tissue. In a steady state, oxygen gradients would be constant, but in the case of an unmetabolized tracer the gradients would change with time and introduce another level of complexity. By building on the derivations of Bohr and Krogh it was possible to derive an expression for the exchange of an inert but diffusible tracer between flowing capillary blood and the surrounding tissue in terms of perfusion rate, the capillary diffusing surface, and the diffusion coefficient of the tracer through the capillary membrane (Kety, 1951). That derivation was a first approximation because it made two simplifying assumptions: first, that after diffusing through the capillary wall the tracer was instantly dispersed throughout the external phase, and second, that its concentration did not change there appreciably in the time of a single passage of blood through the capillary. Because the capillary volume in the brain is less than 5 percent of the parenchyma, the latter assumption would introduce a negligible error, and because the capillaries of the brain are arranged in baskets around the cellular elements rather than in parallel, the first assumption is supported by the more rapid radial diffusion.

Louis Sokoloff joined me in Julius Comroe’s department as a postdoctoral fellow and in short order undertook the study of cerebral metabolism in hyperthyroid disease. We were unprepared for his finding (Sokoloff et al., 1953) that the brain did not share in the generalized increase in metabolism that occurs in hyperthyroidism. In order to explain this unprecedented result he hypothesized, and eventually demonstrated, that the important action of thyroxin was on protein rather than carbohydrate metabolism. He pursued this observation to discover the role of thyroxin on protein synthesis, explaining its effects on metamorphosis and dendritic proliferation.

We knew that in diabetic coma the cerebral oxygen consumption was reduced by 50 percent (Kety, Polis, et al., 1948), so we were not surprised to find that in deep anesthesia a similar depression in energy metabolism occurred (Wechsler et al., 1951). Our study on sleep, however, produced some surprising results (Mangold et al., 1955). Although it was not unusual for some of our subjects to fall asleep and have to be awakened during our previous studies, it was not easy to get them to sleep when we wished. I was a subject in the sleep study and although I was quite comfortable, the effort of trying to sleep kept me awake. In the course of numerous unsuccessful trials we did have six subjects sleep for the 10 minutes necessary to make a measurement. The results were unexpected. Except for one subject in which it was increased, the utilization of oxygen by the brain was mildly depressed (about 15 percent, compared to coma or anesthesia at 50 percent), in spite of the prevailing belief, which stemmed from Pavlov and Sherrington, that sleep was characterized by a suppression of neuronal activity. It was not until Edward Evarts succeeded in recording from individual cortical neurons of sleeping animals, and the confirmation provided by our later studies of regional circulation that the observations in man showing sleep to be an active process became credible.

The Intramural Basic Research Program of NIMH

In 1950 my research was interrupted for a while by an unexpected visitor from Bethesda. The studies of cerebral blood flow in schizophrenia had come to the attention of Robert Felix, director of the newly founded National Institute of Mental Health (NIMH) in Bethesda, and in that year visited me at my office at Penn to invite me to join NIMH as its first scientific director. It was then that my commitment to psychiatric research began.

I was very happy in Comroe’s department and had no desire to work for the federal government. Yet, I was challenged by the problem of mental illness, and recognized that the magnitude of the problem was matched by our ignorance about it. What greater challenge and better opportunity existed than to plan and develop a research program broad enough to examine the problem of mental illness in all of its complexities.

After thinking about it for two months, visiting Bethesda, seeing the 200 laboratories being constructed for the new institute, meeting its small but dedicated staff, and conferring with James Shannon and Harry Eagle, the scientific directors of the Heart and Cancer Institutes, I accepted the challenge and spent most of my research career there.

Dr. Felix was the ideal director for NIMH. He appreciated the need for substantially increased research and defended it valiantly. He did not presume to know in what directions our research program should go, or if he did, he did not permit that to influence me. For my part, these mysterious illnesses that had baffled the human race for centuries had not revealed any of their secrets to me.

We would need research at the clinical level, of course, but for that to be meaningful there was the greater need for considerably more fundamental knowledge in the sciences of brain and behavior to provide the foundation for rational and plausible clinical research. I could think of no better investment of the new and unprecedented resources placed at my disposal than using them to establish a broad program of basic research that represented all of the disciplines on which psychiatry depends.

Perhaps because my background was more deficient in the social sciences than in any of the others, I decided to establish the Laboratory of Socio-Environmental Studies with John Clausen as its chief. Shortly thereafter, Wade Marshall became head of neurophysiology. Alexander Rich, who appointed David Davies, represented physical chemistry—soon to become molecular biology—and Giulio Cantoni, soon joined by Seymour Kaufman, developed comparative biochemistry. When the Clinical Center was completed Robert Cohen was asked to be director of Clinical Research and together, we recruited David Shakow to direct a large laboratory of psychology, representing a wide spectrum of experimental, developmental, and clinical psychology.

I was also charged with organizing the Basic Research Program of the National Institute of Neurological Diseases and recruited several additional neuroscientists: William Windle, joined by Sanford Palay in neuroanatomy, Roscoe Brady in neurochemistry, Kenneth Cole in biophysics, Ichiji Tasaki in neurobiology, Karl Frank in neurophysiology, and Roger Sperry in developmental neurobiology, until he was wooed away by Cal Tech. One concern that some had expressed was rapidly put to rest. A government institution with the proper philosophy could attract a faculty as distinguished as that of any university (of the initial group that joined me, eight became members of the National Academy of Sciences and of the larger number we recruited and helped to train, more than 20 achieved that distinction). The research programs of the two institutes were organized in parallel and merged into a single basic research program as they should have been, since the neurosciences have as much pertinence to mental illness as to neurological disease. It is unfortunate that they were separated some years later for parochial reasons. The neurosciences, unfortunately, have continued to suffer unnecessary splits since they were recognized as a single discipline.

In 1953, I was invited to join a group of distinguished neurochemists from England (Derek Richter, Henry McIlwain, Geoffrey Harris, and Joel Elkes) and America (Jordi Folch-Pi, Heinrich Waelsch, and Louis Flexner) to initiate a series of International Neurochemical Symposia to recognize that newly articulated discipline. I had thought of myself as a physiologist rather than a biochemist, but the work on the oxygen and glucose metabolism of the human brain in vivo had apparently turned a new leaf in neurochemistry and made me a bona fide member. We organized a series of stimulating conferences on the cutting edges of neurochemistry, cerebral metabolism, neuropathology, and regional function, in Oxford, Aarhus, Strasbourg, and Varenna, which I am sure contributed immensely to the development of the field and led directly to the establishment of both the American and International Neurochemical Societies.

Before moving in that direction, however, several of us, but particularly Heinrich Waelsch, began talking to our counterparts in Europe, especially Albert Fessard, with the aim of forming an international brain research organization, IBRO. The nascent organization was adopted in utero at an International Colloquium on Electroencephalography and Clinical Neurophysiology in Marseilles in 1955. IBRO was formally organized in Moscow at another EEG and Clinical Neurophysiology Colloquium in 1958. IBRO was by no means exclusive; its first executive committee consisted of Anokhin (USSR), Fessard (France), Harris (U.K.), Magoun (U.S.), Moruzzi (Italy), and Waelsch (U.S.), with Jasper (Canada) as Executive Secretary and Waelsch as Treasurer.

The Society for Neuroscience had its roots in IBRO. A national organization of brain sciences was required to represent the United States in IBRO and Waelsch took the initiative in setting one up. He introduced Ralph Gerard and me to the idea of establishing a Committee on Brain Sciences under the National Research Council which became our corporate member in IBRO. But the work became more than that, initiating a survey of Brain Research Resources and sponsoring historical studies of the role of basic research in important clinical advances. It was quickly realized that this committee was fulfilling a much more important need in this country than as an affiliate of a rather bureaucratic international association. The committee sponsored the new Society for Neuroscience and elected Ralph Gerard unanimously as Honorary President.

Autoradiograms of Regional Blood Flow and Neuronal Activity

The first application of my theory and mathematical derivations of inert gas exchange at the capillary was published in 1955 with our measurement of blood flow in small regions throughout the brain of the cat (Landau, Freygang, Rowland, Sokoloff, and Kety, 1955). Shortly after I arrived in Bethesda as scientific director of the newly established Mental Health and Neurological Diseases Institutes of the National Institutes of Health (NIH), I was delighted to have a young postdoctoral fellow, William Landau, ask to work with me to examine the regional circulation of the brain. As the first and simplest approach, we selected tissue clearance, an idea that had worked very well for me in studying muscle circulation (Kety, 1949), but that was not successful in the highly heterogeneous brain. I turned to autoradiography as the technique of choice for observing and measuring the concentrations of a radioactive tracer all over the brain, which would permit us to use the equations from 1951 to compute blood flow in the various regions. We were fortunate to recruit two additional collaborators, Lewis Rowland, and Walter Freygang, from the Neurology Institute, and Louis Sokoloff who had joined me from the University of Pennsylvania. Landau and Rowland were to become two of the most distinguished professors of neurology in the United States and Sokoloff would be celebrated for developing the deoxy-glucose technique for regional cerebral metabolism.

A radioactive inert gas was used (¹³¹I-trifluormethane) and I proposed a method for measuring its concentrations throughout the brain by means of calibrated autoradiograms from which the regional blood flow values were calculated. Because our tracer was a gas, sections were made from brains frozen in liquid nitrogen and then exposed to film at -40°. A microtome that would cut sections from frozen brain was not immediately available and my colleagues showed me that an ordinary band-saw could make excellent sections that would produce very satisfactory autoradiograms. In 1955 we published our first report of the blood perfusion in 28 structures of the living brain (although the measurements were made on sections of the cat brain, the perfusion-determined accumulation of tracer took place in the living state). We were not surprised to find that blood flow in the cerebral cortex was four to five times as high as that in white matter, but the extremely high values in the medial geniculate and the inferior olivary nucleus challenged us. At first we hypothesized that the clicking of the radioactivity counters were activating these auditory nuclei, but when Landau completely deafened the animals the flow was not reduced. There is little doubt that the high perfusion rate reflects a high rate of functional activity in these nuclei since various respiratory enzymes have their highest concentrations there.

Among the most significant experimental observations made with the use of this technique were those on the effects of thiopental and of photic stimulation reported by Sokoloff at the International Neurochemical Symposium on Regional Neurochemistry (Kety and Elkes, 1961). Thiopental anesthesia differentially reduced blood flow in cortical regions and sub-cortical structures subserving sensory functions, while photic stimulation was associated with marked increases in perfusion of the striate cortex, lateral geniculate ganglia, and superior colliculi. Although there had been a few reports suggesting an increase in perfusion accompanying increased functional activity, Sokoloff’s was the first clear demonstration of that important homeostatic relationship, and of the perceptive inference by Roy and Sherrington nearly 100 years ago that local neuronal activity, metabolic rate, and perfusion were closely coupled.

In 1961, Ingvar and Lassen were the first to apply these principles of capillary:tissue exchange of an inert gas and the derived equations to measurement of regional blood flow in man, using ⁸⁵Kr, and later, ¹³³Xe. Ingvar and Franzen were the first to study regional cerebral blood flow in schizophrenia and discovered the diminished perfusion of the frontal lobe. Weinberger has related this specifically to a deficit in cognitive function. Thus, the questions that impelled me to develop a local blood flow technique were answered in the very disorder that prompted them.

Measurement of cerebral blood flow and cerebral metabolism had usually gone hand in hand, and in 1977 Sokoloff and associates published the theory and technique for the measurement of regional glucose metabolism, using the non-oxidizable congener, 2-deoxyglucose, radioactively labeled so that its accumulation in the various regions of the brain, determined by the rate of glucose utilization, could be captured by autoradiography. The accumulation of tracer in Sokoloff’s highly original technique depends not on diffusion but on chemical processes involved in transport and the spatial resolution in the autoradiograms was fine enough to delineate the ocular dominance columns of Hubel and Wiesel. The introduction of positron emission tomography (PET) which fully exploited the possibilities presented by the distribution of appropriately labeled tracers in the brain, offered an advanced and theoretically sound approach to the non-invasive measurement of regional cerebral blood flow and metabolism in man. Background problems were minimal and the resolution was higher than that obtainable with earlier methods of external counting. Deoxyglucose, labeled with fluorine-18 made possible the measurement of glucose metabolism by PET in a large number of neurological and psychiatric disorders. Water labeled with the positron emitting isotope of oxygen (¹⁵O) has been the tracer most used for blood flow although lipid soluble tracers show less diffusion limitation at high flow rates. In fruitful collaboration with Michael Posner, Marcus Raichle, using ¹⁵O labeled water, has applied the equations and techniques for regional cerebral blood flow to human subjects performing a number of cognitive tasks. It is in the studies now possible of the neural pathways and processes involved in human thought that my early hopes regarding the measurement of human cerebral blood flow are now being realized.

Shortly after my appointment at the NIH, Seymour Vestermark, director of training at NIMH, asked whether I would like to have some experience with psychoanalysis which he thought would be only reasonable for the scientific director of a mental health institute. He indicated that his program would pay for it and that he would find the most distinguished analyst in the Washington, D.C. area. When I told this to Josephine she said, “If they offered to remove your appendix for nothing, would you let them do it?” I turned down the generous offer then but took him up on it a few years later, perhaps because my appendix was finally acting up. Dr. Edith Weigert, probably the senior psychoanalyst in the Washington area, agreed to be my analyst and I spent more than a year in a classical analysis four mornings a week. I found it very pleasant, lying relaxed and talking about myself; I remember dipping into the unconscious very sparingly, but enough to make me aware of its existence.

The Laboratory of Clinical Science

By 1956, several investigators had joined the Intramural Research Program of the NIMH whose interests were in the interface between the basic neurobiological sciences and clinical psychiatric problems, and a new grouping designated the Laboratory of Clinical Science was established with Ed Evarts as its reluctant chief. By that time, the Basic Research Program was fully staffed. I was eager to involve myself more in research and less in administration, and the implications of the new neurobiological knowledge to psychiatry attracted me. I asked to be allowed to step down from the scientific directorship to join the new laboratory as its nominal chief.

The initial group consisted of Edward Evarts, Julius Axelrod, Louis Sokoloff, Marian Kies, Roger McDonald, who was succeeded by Irwin Kopin, Philippe Cardon, and Seymour Perlin, who was succeeded by William Pollin. Although quite diverse in their scientific interests, they shared a commonality of motivation and a mutuality of spirit, which made the 11 years I spent in that laboratory one of the most exciting and rewarding periods of my life.

What were these new and promising implications that attracted many of us? It was not the numerous enthusiastic claims that were being made regarding abnormal proteins, metabolites, or toxic factors in the blood or urine of schizophrenic patients, which lacked plausibility and did not survive replication. Rather, it was a number of less spectacular but more credible observations with more remote relevance—observations that suggested that the synapses of the brain, like those in the periphery, were chemically mediated switches rather than electrical junctions. Acetylcholine by that time had achieved the status of a putative neurotransmitter in the brain, but there were other substances like serotonin, noradrenalin, and dopamine, that could conceivably serve in such a role, and which had only recently been identified in the brain. Lysergic acid diethylamide, a drug which had attracted wide attention because of its hallucinogenic properties, had also been found to block some of the pharmacological actions of serotonin. Three other psychotomimetic drugs, dimethyltryptamine, mescaline, and amphetamine were substituted forms of serotonin or dopamine.

Only a few years before, chlorpromazine had been found to be remarkably effective in the alleviation of psychotic behavior and reserpine was being used as a major tranquilizer. Although it was to take 10 years for the action of chlorpromazine on dopamine synapses to be discovered and substantiated, knowledge of the remarkable ability of reserpine to deplete the brain of serotonin was literally around the corner—in Bernard Brodie’s laboratory at the Heart Institute. If the synapses involved in the mental states and behaviors produced or ameliorated by such drugs were chemically mediated, those observations would offer plausible sites at which these drugs could act.

Moreover, if central synapses in general were chemical switches, then a biochemistry of behavior was conceivable, and at the synapse, not only drugs, but genetic factors, dietary constituents, hormones, metabolic, immune, and infectious processes, could all be seen to act, altering the patterns of transsynaptic interaction and affecting behavior and mental processes. For the first time, plausible and heuristic approaches could now be opened and explored that might some day explain the biological disturbances of mental illness and the symptoms that depend on them.

The most productive way of exploring these new approaches was not by way of a crash program. The gap between the knowledge we had and the clinical problems was still too wide to be spanned all at once by any concerted effort. What was needed was to narrow the gap by an increase in knowledge on both sides, which is best done by relying on the creativity and judgment of individual scientists who know better than anyone else what their next step should be. The members of the laboratory pursued their own research goals, some studying the clinical problems in greater detail and in the light of new knowledge, most expanding the base of fundamental knowledge in areas that they perceived to be relevant. Where appropriate, collaborative efforts developed within the laboratory, and quite as often, outside of it. I believe that subsequent events have justified this approach.

Among the claims that were being made at that time was one postulating the formation of a toxic, hallucinogenic metabolite of circulating epinephrine in schizophrenia, which was sufficiently provocative that some of us decided to examine it further. The difficulty was that in 1956 we knew little enough about the normal metabolism of epinephrine, let alone its metabolism in disease. One strategy would be to administer labeled epinephrine in pharmacologically insignificant amounts and compare the urinary chromatographic profiles of radioactivity. The carbon-14 labeled material that was available would not provide sufficient specific activity. It was possible that a tritium-labeled epinephrine could be prepared with the requisite stability and activity, and I made arrangements to have tritium-labeled epinephrine of high specific activity synthesized. By the time the labeled compound arrived, however, that strategy was no longer necessary.

In the year that had elapsed, Axelrod, taking off from a brief report in the literature, had demonstrated the enzymatic O-methylation of catecholamines in vitro, characterized the enzyme responsible, predicted the major catecholamine metabolites, and then went on to extract and identify them in the urine of animals. When the radioactive epinephrine became available, it was a simple matter to examine its metabolism in normal subjects (LaBrosse et al., 1961) and in schizophrenics. No evidence was found for an abnormal metabolism of circulating epinephrine in that disorder. There is not the space nor the necessity of indicating Axelrod’s contributions to our present knowledge of catecholamine metabolism and inactivation at the synapse. They have not solved a major psychiatric problem as yet, but when the final chapter to our understanding of mental illness is written, his work will occupy a prominent place in it.

Evidence from many quarters produced a general agreement that the biogenic amines were important as neurotransmitters in the brain. Electron microscopy and fluorescence histology were the most direct and compelling, but these were reinforced by microinjection and electrophysiological studies, and by the demonstration in vitro of specific receptors for several of the transmitters.

The list of neurotransmitters and synaptic modulators has gotten longer, extending from the biogenic amines to include amino acids and polypeptides. The involvement of specific members of the list in the pharmacological action of most of the psychoactive drugs has been reasonably well established. It is also clear that neurotransmitters and modulators play important roles in the mediation of certain mental states and types of behavior, although their precise action and interactions remain to be elucidated. It is not possible to state, at present, how they are involved in mediating the symptoms of mental illness or whether they play an etiological role.

In 1961, after struggling with the decision for several months, I persuaded myself that it was not inappropriate for a biologist to serve as chairman of a department of psychiatry and accepted the Henry Phipps Professorship of Psychiatry at Johns Hopkins. Believing as I did that the biological sciences were moving into psychiatry to enrich it and feeling that the search committee at Hopkins had taken a courageous step toward such a rapprochement, I could hardly decline. Despite a plea from a prominent psychoanalyst not to drive another nail into the coffin of psychiatry, but with the encouragement of Aubrey Lewis, whose breadth of understanding and far-sightedness I admired greatly, I assumed the post that Adolf Meyer had made famous. It was not long, however, before I realized that being chairman of a department of psychiatry and psychiatrist-in-chief of an important university hospital entailed more administrative responsibilities far beyond the field of research with which I was comfortable. I resigned after a year with considerable regret.

The Study of Schizophrenic Adoptees and Their Two Families

In 1959, I reviewed the large number of claims being made of chemical or biological disturbances responsible for the syndrome of schizophrenia (Kety, 1959). Few of these reports survived replication and most could be rejected on the basis of simple scientific design. It was only in the area of genetics that the evidence available seemed a bit more convincing. Of course, the evidence had been available for some time but most psychiatrists had dismissed it because at that time it was not popular to think favorably about genetic factors. Most psychiatrists believed, and few were prepared to contradict the dictum, that schizophrenia was not necessarily a mental disorder, but a way of thinking that one learned from one’s parents, which could be treated by education and by psychological and social manipulation. The actual evidence was that schizophrenia ran in families and had a higher concordance in monozygotic (MZ) twins than in dizygotic (DZ) twins. That certainly was compatible with the operation of genetic factors, but fell short of proving it because in each proposition there were alternative explanations, usually invoking environmental influences. So for the clustering of schizophrenia in families: “a lot of things run in families and that doesn’t mean they’re all genetic.” Wealth runs in families. Pellagra and kuru ran in families and were thought to be genetic and genetic models were developed for the transmission of these disorders. It was eventually discovered that these were dietary diseases and that they ran in families because families shared the same diet. Either a diet poor in vitamin B3 for pellagra, or dietary in the case of kuru because the wife and the children ate the brains of their departed husbands and fathers who were suffering from the slow, viral disease.

In the case of twins, the two most extensive studies by Franz Kallmann in America and Elliot Slater in London were very compelling. Kallmann reported an 85 percent concordance of schizophrenia in monozygotic twins, Slater a 75 percent concordance—which even when conservatively corrected was still about 50 percent. These findings were rejected, however, aside from matters of age correction, for failure to minimize ascertainment and selection bias.

Furthermore, twin studies operate on the assumption that the environmental similarities are the same for monozygotic and dizygotic twins—which isn’t true. Monozygotic twins share much more of their environment than do dizygotic twins. They look alike, their parents treat them alike, they parade them in a double perambulator, they dress them alike, they have the same bedroom, and they often sleep in the same bed. They are usually in the same class and they have the same friends. Dizygotic twins have a much greater variance in their environment. It was difficult to tell how much of the high concordance for schizophrenia in MZ twins was the result of the genes or the environment they shared.

Obviously, concordance rates in MZ and DZ twins separated at birth and reared in different environments could produce less ambiguous evidence but there were only single or few case reports and no controlled, systematic studies.

I tried to think of a way to separate genetic from environmental factors in family studies and suddenly realized that adoption did just that: an adoptee shares his genetic endowment with his biological family but his environment with another family. If schizophrenia runs in families because of shared genes, it should be found in the biological family of a schizophrenic adoptee but found in the adoptive family if caused by rearing or other components of the family environment. It seemed reasonable that with appropriate controls to remove ascertainment and selective bias, and with sufficient numbers, adoption could indeed untangle genetic from environmental influences in the family. I suggested this in an article in Science (Kety, 1959). “A means of better controlling the environmental variables would be to make a careful study of schizophrenic adopted children with comparison of the incidence in blood relatives and in foster relatives. Perhaps only a survey on a national scale would provide the required numbers of cases.”

When I occupied the Henry Phipps chair at Hopkins I was still living in Bethesda and commuting daily between Bethesda and Baltimore. In the course of the hour’s drive, I had plenty of time to think about research and psychiatry, and this question had a high priority. I planned a major study involving a large population, preferably, a national population. Such a study could best be done at the NIMH and without the administrative distractions of a large department. This recurrent and insistent refrain had much to do with my decision to return. When I returned in 1962, I looked forward to undertaking the study I had described earlier by looking in the population of adopted individuals for those who had become schizophrenic, finding their biological and adoptive relatives, then asking the question, “If schizophrenia is familial, in which family of an adopted schizophrenic does the disorder occur, in the biological or the adoptive family, or in both families, or in neither?”

Back at the NIMH I talked to my colleague, David Rosenthal, who had succeeded David Shakow as chief of the psychology laboratory. I found that he was interested in an adoption strategy that would examine the separate effects of family rearing and genetics on adoptees. We recognized that we were dealing with two sides of the same coin. David could use the total sample of adoptees I was planning to acquire, looking for biological parents who became schizophrenic, while I was seeking schizophrenia in the adoptees.

Then we learned that Paul Wender who was a research associate working at St. Elizabeth’s Hospital was pulling together a sample of adoptive parents of schizophrenics because he was interested in their characteristics. Are these characteristics different from those of the biological parents? If Ted Lidz is right, the adoptive parents of schizophrenics ought to be just as sick as their biological parents or at least just as schizophrenogenic. We invited Paul to join us in a collaborative effort employing three different adoption strategies. He was beginning to seek adoptive parents of schizophrenics through local adoption agencies, but we realized that this would not be suitable for the studies we were planning. There were about 20 different adoption agencies, each with its own rules and attitudes about research, invasion of privacy, and record keeping. Even if we could get an adequate sample of adoptees, how were we ever going to identify and trace their biological and adoptive relatives in the United States where people are moving around a great deal? Then how would we learn which of the adoptees or their relatives had became mentally ill 25 years later?

Then we learned from Sarnoff Mednick of the remarkable population and psychiatric records in Denmark. They seemed to be just what we needed for the studies we had in mind. I flew over to Copenhagen in 1962 and met with Fini Schulsinger, head of psychiatry at the Kommunhospitalet, who showed me some of the records, introduced me to some of the people, and persuaded the authorities to give us access to their records with our assurances of complete confidentiality. With Schulsinger as a collaborator, we specified the records and the information we would need.

There was no adoption register so it was necessary to develop one. This was possible from the court records required in every legal adoption in the Department of Justice, which also gave us the names of the biological and adoptive parents. Other registers identified siblings and half-siblings. To ascertain the feasibility of the enterprise, we did a small pilot study and were encouraged to go ahead. With funds from the NIMH Intramural Research Program and a staff recruited by Schulsinger, we undertook my study of the biological and adoptive families of adoptees in the Copenhagen sample who had become schizophrenic, and Rosenthal’s study of the adopted away offspring of a schizophrenic parent. We found a total of nearly 5,500 legal adoptions by adoptive parents not biologically related to the adoptee. The results were presented in 1967 at a conference on the transmission of schizophrenia and published in 1968 (Kety et al., 1968; Rosenthal et al., 1968). At the same meeting, Wender presented his study of the adoptive parents of schizophrenic adoptees conducted at the NIH Clinical Center (Wender et al., 1968), the first well controlled test of the “schizophrenogenic parent hypothesis” of which I am aware.

The first findings in the study of the biological and adoptive relatives of adoptees who had become schizophrenic were based entirely on hospital records. They were later augmented by comprehensive psychiatric interviews with the relatives (Kety, Rosenthal, Wender, et al., 1975). A new study of adoptees and relatives in the rest of Denmark (The Provincial Study) provided a replication of the Copenhagen study which doubled the number of subjects, confirmed the previous results, and increased their significance (Kety, Wender, et al., 1994). In all of Denmark, 47 adoptees were found who had developed chronic schizophrenia; their biological relatives—parents, siblings, half-siblings—showed a prevalence for that disorder of 5 percent compared with 0.4 percent in the biological relatives of 47 normal adoptees. No schizophrenia was found in the adoptive relatives of the schizophrenic or control adoptees.

These studies were highly consistent in finding schizophrenic illness significantly concentrated in the biological siblings, parents, and offspring of schizophrenic patients even when separated by adoption. Adoptive parents who had reared a schizophrenic adoptee in Wender’s study (Wender et al., 1968) had none of the characteristics attributed to schizophrenogenic parents.

These studies had an impact on the field because of the unique and rigorous design (case-matched controls, blind diagnoses, lack of ascertainment, selective, and subjective bias), and because they strengthened the argument for genetic factors in the earlier family and twin studies by ruling out alternative possibilities and failed to support schizophrenogenic rearing in the etiology of schizophrenia.

NIMH Turns Away from the Brain and Mental Illness

In circumstances prevailing in other branches of medicine, the demonstration of the chemical nature of synaptic transmission, the development of drugs capable of alleviating the symptoms of mental illness quite specifically, and the elucidation of their synaptic actions– as well as the new evidence for genetic factors in the etiology of the major psychoses—would have ushered in an era of widespread public and professional support for the exploitation of the new research opportunities that were then presented. But it was not to be as simple as that. The NIMH became dominated by quite a different philosophy in which the kind of research that I had espoused lost its high priority, and basic research, biomedical research, and even research on schizophrenia and mental illness was disparaged.

Support of research requires a recognition of ignorance and the community psychiatry movement in the United States brooked no doubts regarding its convictions on the social etiology of mental illness and the types of social engineering required in order to treat and prevent it. The NIMH broke away from the NIH, much to the frustration of James Shannon, the great director of the NIH. He did insist, and was successful, however, in keeping the Intramural Research Program intact within the NIH and under the judicious and courageous leadership of John Eberhart.

The remainder of the NIMH was reorganized, in the course of which the Division of Extramural Research was fragmented and parochialized. Research in the fundamental neurosciences was unsupported on the premise that these had little relevance to psychiatry. I shall never forget the meeting I attended at which psychiatry as a branch of medicine and rigorous science was gutted and exorcised from the Grants Program. Stanley Yolles, Bob Felix’ successor as director of NIMH, had called the senior staff together for a weekend retreat, presumably to help formulate the objectives and structure of the new NIMH. We amused ourselves individually while the director was closeted with his two or three henchmen until Sunday afternoon when we were called together to see and possibly to discuss the new table of organization and structure of the institute. I was shocked. The branches and study sections responsible for evaluating research proposals and allocating funds, traditionally designated to span a wide spectrum of basic disciplines and clinical areas, were all reduced to a repetitious melange of community cliches: metropolitan problems, adolescent problems, minority problems, and social problems, to mention a few. There were surprisingly few comments from the floor. I confessed to being disappointed, pointing out that there was no place in the table for basic research, for biomedical research, or even for research on schizophrenia. There was no logic and no justification for organizing the national program on mental health and illness on such an arbitrary and narrow pedestal. Yolles commented that it didn’t have to be logical if it was what the Congress wanted. There was no evidence that this had been mandated or even emphasized by Congress and no recognition of the responsibility for scientific leadership that resided with institute directors.

I readily accepted an invitation from Harvard to organize a program of psychiatric research at the Massachusetts General Hospital and later at the McLean Hospital. I did not feel that I was fleeing a sinking ship since the Intramural Research Program was in excellent hands with its future assured. I was concerned with the Extramural Program and recognized an opportunity of broadening it from the outside. Fortunately, I was able to recruit or co-opt an excellent consortium of young scientists, and a few senior scientists like Walle Nauta, Alfred Pope, and Philip Holzman who were willing to participate in a research program like that of the Laboratory of Clinical Science at NIMH. We put together a compelling and broad program justifying a substantial budget and submitted it to the Research Grants Division of the NIMH without seeking the advice of the extramural staff who expected to be consulted on any substantial application. The proposal received very fair treatment; reviewed by an outstanding ad hoc group for a priority of 1.0, we were awarded the grant. I had hoped that this might initiate the establishment of a branch devoted to multidisciplinary research in mental illness. It did stimulate the submission of a similarly successful proposal from Yale but no branch.

Some years later, I asked Axelrod to join me in a visit to Bertram Brown, who had succeeded Yolles but retained a similar agenda as director of the NIMH. I knew that Brown was taking gratuitous pride in Axelrod’s Nobel Prize and we had a simple request to make. Would he consider establishing a Neuroscience Branch or Study Section in his Extramural Program? I was not expecting to be turned down, but we were, flatly. The reason generated a déjà vu-he had no constituency requesting it. No matter that the best scientists are more interested in their research than in polishing their political clout, or that the director’s responsibility was to plan and advocate a competent research program rather than to cater to self-serving pressure. Thus, for more than a decade, the NIMH turned its back on neuroscience, leaving it mainly to the National Institute of Neurological Disorders and several of the other institutes to sponsor, support, and take pride in the burgeoning development of an exciting field which continues to hold great promise for an understanding of mental illness.

I may have been more successful turning the People’s Republic of China around (Kety, 1976). I was asked to join the first official biomedical delegation from the National Academy of Sciences and the Institute of Medicine to the PRC in 1973, to represent neuroscience, neurology, and psychiatry. I met the professors of neurology and neurophysiology (many will recognize the name of Professor Chang in Shanghai) but no psychiatrists. I was told there were no departments of psychiatry at the medical schools and in hospitals we visited because there was no mental illness. In Beijing I asked to meet Professor Wu Chen Yi whom I knew from the literature but to no avail. At the state banquet in our honor I made a toast “to the psychiatrists of China, wherever they may be.”

Toward the end of our stay in Beijing we met with Dr. She Hua, minister of health, who told us about the progress his country was making in eradicating various epidemic diseases. When we were invited to ask questions, I ventured:

We have all been impressed with the accomplishments you have enumerated, but you have omitted the.topic of mental illness which we in the West regard as a major public health problem. We have been told that there is no mental illness in China and if that is the case that is the greatest accomplishment of all. We would like to know how you have done this; in fact, there is a group of psychiatrists eager to visit who will want to talk to me when I return. Shall I encourage them or tell them that this is not the right time?

She Hua smiled warmly and responded: “We have our share of mental illness, but we treat it differently now than previously. We don’t put such patients in dungeons but in mental hospitals where they talk to doctors and nurses and among themselves to learn more about their problems. We also use drugs, Western drugs. Your colleagues from America are welcome to come here at any time to exchange knowledge with our psychiatrists.” There were numerous officials present at this meeting who must have taken She Hua’s statement as a change of policy. It was certainly followed by a remarkable change in whom I could meet.

The next day we visited the Great Wall, each in the company of a counterpart. I rode with the editor of the China Medical Journal and held forth on what has recently become our concept of mental illness—disorders representing an interaction of genetic and environmental influences. I contrasted that with the official attitudes I have observed in most communist countries where genetic differences are denied since all are created equal and, since the environment has been cleansed of all untoward influences, there remains little opportunity for mental illness to develop. At a reception back in Beijing I was happy to meet Professor Wu Chen Yi who invited me to give a lecture in his department at Beijing University.

When our plane landed at the Shanghai airport, I was greeted by Professor Yen, who invited me to visit his large mental hospital where I saw schizophrenic patients treated with acupuncture and with chlorpromazine.

It was most gratifying to visit China with my wife a few years ago at the invitation of the China Medical Society to receive an Honorary Professorship at Shantu University where Professor Wu Chen Yi directed a beautiful psychiatric Institute after his retirement at Beijing and Professor Yen was the psychiatrist-in-chief at a large and modern Mental Health Center in Shanghai.

Our own NIMH to which I have returned after retiring at Harvard, had also experienced a major renaissance. Bertram Brown was succeeded by Herbert Pardes who recognized the importance of rigorous basic and clinical research, the excitement of the neurosciences, and began a major transformation of the Extramural Program which each of his successors—Shervert Frazier, Lewis Jude), and Fred Goodwin—has continued. The institute has rejoined its Intramural Program and shares the scientific traditions of the NIH to which it has returned.

Selected Publications

Kety SS. The lead citrate complex ion and its role in the physiology and therapy of lead poisoning. J Bio Chem 1942;142:181–192.

Kety SS, Letonoff TV. The treatment of lead poisoning by sodium citrate. Am J Med Sci 1943;205:406–414.

Kety SS, Pope A. The cardiovascular system in traumatic shock. Am Heart J 1944;27:601–609.

Kety SS, Nathanson IT, Nutt AL, Pope A, Zamecnik PC, Aub JC, Brues AM. The toxic factors in experimental traumatic shock III. Shock accompanying muscle ischemia and loss of vascular fluid. J Clin Invest 1945;24:839–844.

Schmidt CF, Kety SS, Pennes HH. The gaseous metabolism of the brain of the monkey. Am J Physiol 1945;143:33–52.

Kety SS, Schmidt CF. The determination of cerebral blood flow in man by use of nitrous oxide in low concentrations. Am J Physiol 1945;143:53–66.

Kety SS, Schmidt CF. The effects of active and passive hyperventilation on cerebral blood flow, cerebral oxygen consumption, cardiac output, and blood pressure of normal young men. J Clin Invest 1946;25:107–119.

Schmidt CF, Kety SS. Recent studies of cerebral blood flow and cerebral metabolism. Trans Am Neural Assoc 1947;72:52–58.

Kety SS, Harmel MH, Broomell HT, Rhode CB. The solubility of nitrous oxide in blood and brain. J Biol Chem 1948;173:487–496.

Shenkin HA, Harrnel MH, Kety SS. Dynamic anatomy of the cerebral circulation. Arch Neural Psych (Chicago) 1948;60:240–252.

Kety SS, Schmidt CF. The nitrous oxide method for the quantitative determination of cerebral blood flow in man: theory, procedure, and normal values. J Clin Invest 1948;27:476–483.

Kety SS, Schmidt CF. Effects of altered arterial tensions of carbon dioxide and oxygen on ce, rebral blood flow and cerebral oxygen consumption of normal young men. J Clin Invest 1948;27:484–492.

Kety SS, Shenkin HA, Schmidt CF. Effects of increased intracranial pressure on cerebral circulatory functions in man. J Clin Invest 1948;27:493–499.

Kety SS, Polis BD, Nadler CS, Schmidt CF. Blood flow and oxygen consumption of the human brain in diabetic acidosis and coma. J Clin Invest 1948;27:500–510.

Kety SS, Hafkenschiel JH, et al. Blood flow, vascular resistance and oxygen consumption of the brain in essential hypertension. J Clin Invest 1948;27:511–514.

Kety SS, Woodford RB, et al. Cerebral blood flow and metabolism in schizophrenia. The effects of barbiturate semi-narcosis, insulin coma, and electroshock. Am J Psych 1948;104:765–770.

Bing RJ, et al. The measurement of coronary blood flow, oxygen consumption, and efficiency of the left ventricle in man. Am Heart J 1949;38:1–24.

Kety SS. The measurement of regional circulation by local clearance of radioactive sodium. Am Heart J 1949;38:321–328.

Harmel MH, et al. The effects of bilateral stellate ganglion block on the cerebral circulation in normotensive and hypertensive patients. J Clin Invest 1949;28:415–418.

Kety SS. Gas-blood diffusion I. Pulmonary diffusion coefficient. In: Comroe JH, ed. Methods of Medical Research, Vol. II. Chicago: Year Book Publishers, 1950;234–243.

Kety SS. Circulation and metabolism of the human brain in health and disease. Am J Med 1950;8:205–217.

Kety SS. The theory and applications of the exchange of inert gas at the lungs and tissues. Pharmol Rev 1951;3:1–41.

Freyhan FA, Woodford RB, Kety SS. Cerebral blood flow and metabolism in psychoses of senility. J Nerv Ment Dis 1951;113:449–456.

Wechsler RL, Dripps RD, Kety SS. Blood flow and oxygen consumption of the human brain during anesthesia produced by thiopental. Anesthesiology 1951;12:308–314.

Sokoloff L, et al. Cerebral blood flow and oxygen consumption in hyperthyroidism before and after treatment. J Clin Invest 1953;32:202–208.

Kety SS. Blood flow and metabolism of the human brain in health and disease. In: Elliott KAC, Page IH, Quastel JH, eds. Neurochemistry. Springfield, Charles C. Thomas, 1955;294–310.

Mangold R, et al. The effects of sleep and lack of sleep on the cerebral circulation and metabolism of normal young men. J Clin Invest 1955;34:1092–1100.

Sokoloff L, et al. The effect of mental arithmetic on cerebral circulation and metabolism. J Clin Invest 1955;34:1101–1108.

Kety SS, Landau WM, Freygang WH. Measurement of regional circulation in the brain by the uptake of an inert gas. Proc XIX Internat Physiol Cong 1953;511.

Landau WM, Freygang, WH, Rowland LP, Sokoloff L, Kety SS. The local circulation of the living brain; values in the unanesthetized and anesthetized cat. Trans Am Neuro Assoc 1955;80:125–1239.

Kety SS. The general metabolism of the brain in vivo. In: Richter D, ed. Metabolism of the Nervous System. London: Pergamon Press, 1957;221-237.

Kety SS. Determinants of tissue oxygen tension. Federation Proc 1957;16:666–670.

LaBrosse EH, Axelrod J, Kety SS. O-methylation, the principal route of metabolism of epinephrine in man. Science 1958;128:593–594.

Kety SS. Biochemical theories of schizophrenia. A two-part critical review of current theories and of the evidence used to support them. Science 1959;129:1528–1532, 1590–1596.

Kety SS. Theory of blood tissue exchange and its application to measurement of blood flow. In: Bruner HD, ed. Methods in Medical Research, Vol. VIII. Chicago: Year Book Publishers, 1960;223–227.

Kety SS. Measurement of local blood flow by the exchange of an inert, diffusible substance. In: Bruner HD, ed. Methods in Medical Research, Vol. VIII. Chicago: Year Book Publishers, 1960;228–236.

Sokoloff L, Kety SS. Regulation of cerebral circulation. Physiol Rev 1960;40(Suppl 4):38–44.

Kety SS. A biologist examines the mind and behavior. Many disciplines contribute to understanding human behavior, each with peculiar virtues and limitations. Science 1960;132:1861–1870.

Pollin W, Cardon PV, Kety SS. Effects of amino acid feedings in schizophrenic patients treated with iproniazid. Science 1961;133:104–105.

La Brosse EH, Axelrod J, Kopin IJ, Kety SS. Metabolism of 7-H-epinephrine-dbitartrate in normal young men. J Clin Invest 1961;40:253–260.

LaBrosse EH, Mann JD, Kety SS. The physiological and psychological effects of intravenously administered epinephrine and its metabolism in normal and schizophrenic men III. Metabolism of 7-H3-epinephrine as determined in studies on blood and urine. J Psych Res 1961;1:68–75.

Kety SS, Elkes J, eds. Regional Neurochemistry. Oxford: Pergamon Press, 1961;540.

Kety SS. The Academic Lecture: The heuristic aspects of psychiatry. Am J Psych 1961;118:385–397.

Kety SS. The cerebral circulation. In: Fishman AP, Richards DW, eds. Circulation of the Blood: Men and Ideas. New York: Oxford University Press, 1964;703–742.

Kety SS. Current biochemical approaches to schizophrenia. New Eng J Med 1967;276:325–331.

Kety SS, Javoy F, Thierry AM, Julou L, Glowinski J. A sustained effect of electroconvulsive shock on the turnover of norepinephrine in the central nervous system of the rat. Proc Nat Acad Sci USA 1967;58:1249–1254.

Rosenthal D, Kety SS, eds. The Transmission of Schizophrenia. Oxford: Pergamon Press, 1968.

Kety SS, Rosenthal D, Wender PH, Schulsinger F. The types and prevalence of mental illness in the biological and adoptive families of adopted schizophrenics. In: Rosenthal D, Kety SS, eds. The Transmission of Schizophrenia. Oxford: Pergamon Press, 1968;345-362 (see also: J Psych Res 1968;6(Suppl): 345–362).

Wender PH, Rosenthal D, Kety SS. A psychiatric assessment of the adoptive parents of schizophrenics. In: Rosenthal D, Kety SS, eds. The Transmission of Schizophrenia. Oxford: Pergamon Press, 1968;235–250.

Rosenthal D, et al. Schizophrenic’s offspring reared in adoptive homes. In: Rosenthal D, Kety SS, eds. The Transmission of Schizophrenia. Oxford: Pergamon Press, 1968;377–391.

Reivich M, Isaacs G, Evarts E, Kety SS. The effect of slow wave sleep and REM sleep on regional cerebral blood flow in cats. J Neurochem 1968;15:301–306.

Kety SS. The precursor-load strategy in psychochemical research. Mandel A, ed. Methods and Theory in Psychochemical Research in Man. New York: Academic Press, 1969;127–131.

Kety SS. The biogenic amines in the central nervous system: their possible roles in arousal, emotion, and learning. In Schmitt FO, ed. The Neurosciences: Second Study Program. New York: The Rockefeller University Press, 1971;324–336.

Musacchio JM, Julou L, Kety SS, Glowinski J. Increase in rat brain tyrosine hydroxylase activity produced by electroconvulsive shock. Proc Nat Acad Sci USA 1969;63:1117–1119.

Kety SS. Julius Axelrod: A triumph for creative research. In: Snyder SH, ed. Perspectives in Neuropharmacology. New York: Oxford University Press, 1972;3–7.

Kety SS. Prospects for research on schizophrenia—an overview. Neurosci Res Prog Bull 1972;10(4):456–467.

Kety SS, Rosenthal D, Wender PH, Schulsinger F, Jacobsen B. Mental illness in the biological and adoptive families of adopted individuals who have become schizophrenic: a preliminary report based upon psychiatric interviews. In: Fieve R, Rosenthal D, Brill H, eds. Genetic Research in Psychiatry. Baltimore: The Johns Hopkins University Press, 1975;147–165.

Kety SS. The Paul H. Hoch Award Lecture. Progress toward an understanding of the biological substrates of schizophrenia. In: Fieve D, Rosenthal D, Brill H, eds. Genetic Research in Psychiatry. Baltimore: The Johns Hopkins University Press, 1975;147–165.

Kety SS. Foreword. In: Swazey JP, ed. Chlorpromazine in Psychiatry: A study of Therapeutic Innovation. Cambridge: MIT Press, 1974.

Kety SS. From rationalization to reason. Am J Psych 1974;131(9):957–963.

Wender PH, Rosenthal D, Kety SS, Schulsinger F, Welner J. Crossfostering: a research strategy for clarifying the role of genetic and experimental factors in the etiology of schizophrenia. Arch Gen Psych 1974;30:121–128.

Kety SS. Psychiatric concepts and treatment in China. China Quarterly 1976;315–323.

Kety SS, Rosenthal D, Wender PH, Schulsinger F, Jacobsen B. Mental illness in the biological and adoptive families of adopted individuals who have become schizophrenic. Behav Gen 1976;6(3):219–225.

Kety SS. Biological concomitants of affective states and their possible role in memory processes. In: Rosenzweig MR, Bennett EL, eds. Neural Mechanisms of Learning and Memory. Cambridge: MIT Press, 1976;321–326.

Kety SS, Rosenthal D, Wender PH, Schulsinger F. Studies based on a total sample of adopted individuals and their relatives: Why they were necessary, what they demonstrated and failed to demonstrate. Schizophrenia Bull 1976;2(3):413–428.

Kety SS. The biological roots of mental illness: Their ramifications through cerebral metabolism, synaptic activity, genetics and the environment, Harvey Lectures Series 71. New York: Academic Press, Inc., 1978;1–22.

Kety SS. The 52nd Maudsley Lecture. The syndrome of schizophrenia: unresolved problems and opportunities for research. British J Psych 1980;136:421–436.

Schulsinger F, Kety SS, Rosenthal D, Wender PH. A family study of suicide. In Schou M, Strongren E, eds. Origin, Prevention, and Treatment of Affective Disorders. New York: Academic Press, 1979;277–287.

Kety SS. Mental illness in the biological and adoptive relatives of schizophrenic adoptees: Findings relevant to genetic and environmental factors. Am J Psych 1983;140(6):720–27.

Kety SS. Basic principles for the quantitative estimation ofregional cerebral blood flow. In: Sokoloff L, ed. Brain Imaging and Brain Function. Association for Research in Nervous and Mental Disease Research publications, Vol. 63, New York: Raven Press, 1982;1–7.

Kety SS. Regional cerebral blood flow: Estimation by means of nonmetabolized diffusible tracers-an overview. Seminars in Nuclear Med 1985;15:324–328.

Wender PH, et al. Psychiatric disorders in the biological and adoptive families of adopted individuals with affective disorders. Arch Gen Psych 1986;43:923–929.

Kety SS. Citation Classic: Visualization of circulation and functional activity throughout the brain. Curr Contents / Life Sci 1989;27:12; based on Kety SS. The theory and application of the exchange of inert gas at the lungs and tissues. Pharmol Rev 1951;3:l–41.

Kety SS. The early history of the coupling between cerebral blood flow, metabolism, and function. In: Lassen NA, Ingvar DH, Raichle ME, Friberg L, eds. Brain Work and Mental Activity. Munksgaard, Copenhagen, 1991;19–29.

Kety SS, Ingraham LJ. Genetic transmission and improved diagnosis of schizophrenia from pedigrees of adoptees. J Psych Res 1992;26:247–255.

Kety SS. Genetic and environmental factors in the etiology of schizophrenia. In: Matthysse S, Levy DL, Benes FM, Kagan J, eds. Psychopathology: The Evolving Science of Mental Disorders. Cambridge: Cambridge University Press, 1996.

Kety SS, et al. Mental illness in the biological and adoptive relatives of schizophrenic adoptees: Replication of the Copenhagen Study in the rest of Denmark. Arch Gen Psych 1994;51:442–455.

Benjamin Libet

BORN:

Chicago, Illinois

April 12, 1916

EDUCATION:

University of Chicago, B.Sc., 1936

University of Chicago, Ph.D. (Physiology, with Ralph Gerard, 1939)

APPOINTMENTS:

Albany Medical College (1939)

Institute of Pennsylvania Hospital (1940)

University of Pennsylvania School of Medicine (1943)

University of Chicago (1945)

University of California, San Francisco (1949)

Professor of Physiology Emeritus, University of California, San Francisco (1984)

Benjamin Libet was trained in physiology and initially studied cerebral electrical and metabolic activities, and synaptic and nonsynaptic interactions in vertebrates and invertebrates. Later, he carried out a series of novel studies in neurosurgical patients, investigating the physiological bases of conscious sensation, volition, and experience.

Benjamin Libet

How did it all happen—that the first-generation American child of Ukrainian Jewish immigrants, raised during the Great Depression in near poverty in Chicago, developed into a neuroscientist who carried out fundamental experimental research on brain processing in conscious experience (among many other types of research)? Perhaps the adage “only in America” provides the answer, at least for that time period.

My paternal grandfather came to America—Chicago—in 1905 from a town called Brusilov in the Ukraine, not far from Kiev. He came at least in part to avoid being impressed into the czar’s army to fight in the Russo-Japanese war of 1905. Grandpa Harry Libitsky was a highly skilled tailor who sewed men’s suits entirely by hand. I have sometimes thought that I may have inherited my microsurgical skills from his abilities in needlework.

On his return to the United States after a brief visit to Brusilov in about 1909, my grandfather brought my father, then 13 or 14 years old, back with him. My grandfather left behind his wife and three younger children, with my grandmother expecting another child. World War I intervened before he could arrange for the rest of the family to come to Chicago, and they did not arrive until 1921. My grandmother never forgave him for not getting them out earlier. She suffered greatly during the interval, both from lack of funds and from the terrorizing activities of various gentile gangs, including raids by the cossacks. At one point she came down with an illness that she thought was fatal and fell back on an old superstition that one might mislead and avert the Angel of Death by adopting a different name. She dropped her name of “Bobtsy,” vowed to be identified henceforth as “Genia,” and would not tolerate my grandfather calling her by her original name later in America.

My father, Morris, had had only the standard Jewish-Hebrew school education back in Brusilov. He wanted to attend a public school after arriving in Chicago, but grandfather Harry would not let him. My father was forced to seek work and become self-sufficient; he became a machine-operating tailor in men’s clothing factories. I believe that my father had excellent innate intelligence and that the frustration of being unable to pursue more intellectual activities led to serious personal difficulties for the rest of his life. However, he remained on good terms with my grandfather. Although grandpa Harry was tough about my father’s development, he was a doting gentle grandfather to my siblings and me. In fact, he was an important and early source of familial love for me. “Zaydeh” (the Yiddish term for grandfather) could not understand the importance of my academic work in neurophysiology because I was not becoming a practicing M.D. He was later mollified when he heard that I was teaching doctors.

My mother, Anna Charovsky, emmigrated from Kiev in 1913, just one year before the outbreak of World War I in Europe. Had her departure from Kiev been delayed for a year, I, Ben Libet, would not have appeared. Anna’s father, Mayer, was a small-time cattle dealer. Her mother, Devorah, died during the birth of Anna’s younger sister, Chavah. Anna was unusual among Jewish girls in having attended a state school and the Gymnasium (equivalent to high school and junior college here) and having had some experience as a school teacher before emigrating. Her older brother, Avram, who had himself become an engineer, promoted Anna’s academic pursuits. Anna emigrated with a married older sister, Pearl; they all headed for Chicago where another older brother, Louis Charous, had already settled.

Anna and Morris first met in Chicago. They were married in 1915, and somewhat over nine months later I was born, on April 12, 1916. My brother, Meyer, came along a year and a half later, and then my sister Dorothy in July of 1921. At home, my parents spoke Yiddish, and that was my first language until I picked up English playing with other kids in the street. Both my parents soon became proficient in English without studying it formally.

From the start I liked learning at school and found most subjects relatively easy. My mother strongly supported my academic work, perhaps seeing it as an achievement that she (and my father) did not have the opportunity to pursue. Mother seemed to have full confidence that I could and would do well in academic work as well as in most other activities. She was, of course, overly sanguine in that confidence; but I am sure her confidence in me contributed greatly to my ability to face academic and other problems during most of my life. Much later, when J.C. Eccles was awarded the Nobel Prize in 1963, both mother and my sister Dorothy knew I had worked with him in 1956 to 1957. When Dorothy asked mother, “Guess who won the Nobel Prize?” mother promptly answered, “Ben!”

I was also musical and at an early age began singing in a lusty alto voice songs that I heard on records played on our crank-up Victrola phonograph. In 1925 the world-renowned Hebrew-Orthodox cantor, Josef Rosenblatt, was coming to Chicago to sing the High Holy Day services. Mother took me to audition for the a cappella choir that was to accompany Rosenblatt. When the choir director asked me to sing, I boomed out “My Country Tis of Thee” and was promptly taken on. With my $25 earnings mother bought a piano for me. I also earned two $10 tickets (tickets were $10 to $100 each) to the Rosenblatt-conducted services. That enabled my father and grandfather to attend; both loved to listen to a great cantor even though my father, at least, almost never entered a synagogue otherwise. Every year thereafter until I left Chicago in 1939—except for my fourteenth year with my voice changing to a baritone—I sang in professional choirs in synagogues, earning helpful fees.

I graduated from a public elementary school at age 12 and from the John Marshall High School at 16. In those years the University of Chicago offered scholarships to students who did well in a three-hour competitive examination in one subject of their choice. I took the exam in chemistry (we had an exceptionally good chemistry teacher in high school), and I did well enough to be offered a half-tuition scholarship ($150 in 1932!). My high school provided the other $150 in the form of the “Mary Zimmerman Scholarship” (named for the noble-mannered teacher of Latin, a subject I had studied for four years). Having graduated from high school during the Great Depression, I could not have gone to the University of Chicago without those scholarships. I continued to get scholarships through the undergraduate years and received paid assistantships and a university fellowship as a graduate student (there were no student loans or predoctoral stipends from the government in those times).

Even so, I had to live at home with my parents throughout my university education, commuting every day for seven years (four for the B.S. plus three for the Ph.D.), mostly by way of the Chicago trolley cars that took an hour each way. I was not alone in that; several other graduates from my high school had a similar history. Some became nationally known professors of chemistry (Irving Klotz, Arthur Jaffey, Theodore Puck), one a zoologist-ecologist and physician (Asher Finkel), and one (my closest friend, Louis Yesnick) a physician-internist. Another (Jacob Mosak) became an eminent economist at the United Nations. My future wife, Fay (Fannie Evans), also commuted from her home to the University of Chicago for three years before our marriage. I wonder whether students today would put up with those kinds of hardships to attend the university, especially at the graduate level.

For some of those years (approximately 1930 to 1936) my whole family (my parents and their three teenage children) lived in one large room directly to the rear of our small candy store. My mother had realized that such a source of income was essential if we were to ride out the Depression without asking for welfare. In the summer of 1932 I worked in delicatessen stores, 12 hours a day, six to seven days a week, for $10 to $12 a week. In 1933, I was lucky to land a job at the Chicago World’s Fair at $17 a week. I am not citing all this as a complaint, though I wished it had been easier; I accepted these conditions as a matter of course so I could go to the University of Chicago and work toward my academic goals.

Undergraduate Studies: University of Chicago

My entry into the University of Chicago, at age 16, opened up a whole new vista of intellectual and social experiences. The tone was set at the start when Robert M. Hutchins, the youthful president of the University of Chicago, greeted the freshman class. He was a tall, handsome, elegant man who talked to us as if we were adults, kidded us with his wry humor, and spoke to us about his “New Plan for the College.” In that plan, initiated one or two years earlier, students were given their own responsibility for learning, attendance at classes was not mandatory, all students took four general year-long courses (biological sciences, social sciences, humanities, and physical sciences) in their first two years (plus some electives), and grading in the general courses was based completely on six-hour comprehensive examinations in each course at year’s end. These “comp exams” were devised by a professional board of examiners separate from the course instructors; that feature shifted the teaching and learning processes toward longer-range achievements and encouraged questioning and argumentation by students without fear of retribution in the grading.

What an enormous change from high school. The students had initial anxieties about how to cope with such responsibility, but soon relished it. Classroom attendance was close to 100 percent. The university induced its greatest, internationally famous professors to lecture in the general courses; their lectures were so stimulating that we had no thought of skipping them. The University of Chicago had an atmosphere of openness, rationality, and imaginativeness that I have not encountered in other universities. Additional benefits came from associating with other able students.

Although I liked chemistry, I had an affinity for studying living things. In a summer boys’ camp, when I was 12 years old, I joined a biology group. In one demonstration the counselor pithed a frog (that is, destroyed its brain) and, after exposing the living viscera, showed us that various organs could still respond and function in the absence of the brain. When he finally excised the heart and it continued to beat in isolation, I was startled and fascinated. Had I just been told that the heart can beat in isolation, or seen it modeled on a computer, I would not have experienced the stimulating impression that the real thing provoked (I also credit a high school biology teacher with further fostering my fascination with the nature of living things).

I first met Ralph Gerard in my freshman general biological science course at the University of Chicago. He was the instructor for the twiceweekly discussion section of about 25 students in the quarter term for physiology. Gerard was an associate professor, 32 years old, and already completely bald. His large, penetrating blue eyes, bald head, and brilliance as a speaker made him a striking figure. Gerard was recognized nationally and internationally for his work on nerve metabolism and for the classical review he had published that year (Gerard, 1932). But he was also interested in educational issues, especially in methods of teaching science. He conducted the section by asking for questions which he then turned back to the students. He treated every student response seriously and with respect, stimulating some of us to make imaginative inquiries and suggestions. The biological sciences II course in my second year included student lab exercises. Louis Yesnick and I requested that Gerard allow us to repeat von Helmholtz’s experiment to measure conduction velocity in the motor nerve of the frog using the sciatic nerve-gastrocnemius preparation. We did the experiment successfully, and I was thrilled to find we could indeed reproduce the values of the elegant experiment Helmholtz had done before the days of amplifiers and oscilloscopes.

Yesnick and I decided to major in physiology for the bachelor’s degree. In our senior year we were both assigned to do an undergraduate research project with Professor Arno B. Luckhardt, who told us to test how an increase in intracranial pressure may affect the production of urine. I think that question stemmed from some clinical experiences or reports. Luckhardt was a warm-hearted, gentle man. He had become especially recognized for his discovery of the excellent general anesthetic qualities of ethylene. He reputedly turned down the then immense sum of a million dollars for the patent rights because he wanted the public to benefit from the finding in the most accessible manner. Unfortunately, ethylene was quickly found to be easily ignited and explosive in the operating room.

Graduate Research with Gerard

I had completed the requirements for the B.S. degree in the second of the three quarters in my senior year, and so, deficient in funds, I graduated in March 1936 with an election to Phi Beta Kappa. I applied and was accepted for entry in the fall of 1936 into both the University of Illinois Medical School and the University of Chicago Medical School. I accepted the former because of the much lower costs. But I wavered about entering medical school until the actual day for registration, when I realized more firmly that I wanted to do research in physiology. I found the prospect of the prescribed four years of medical school courses a much less appealing option, and looking beyond that, I did not at the time feel inclined to practice medicine. The long-range prospect of a university research and teaching career seemed more attractive, although much less certain of achievement. On registration day, I also realized that the University of Illinois had my $50 registration deposit, a significant sum in 1936. So I went to cancel my registration by lying shamelessly to the dean that my father was ill and saying truthfully that I would be financially strapped. The dean graciously had my $50 returned and urged me to re-apply the next year if conditions improved.

I was then promptly admitted to the graduate division of the University of Chicago and went to see Gerard about joining his research activities. I admired Gerard and the activities of his research group, and was strongly attracted to neurophysiological issues. Four or five bright graduate students were working with Gerard on problems of neural metabolism (Frieda Panimon), sleep (Helen Blake), oxygen and circulatory requirements of brain (Oscar Sugar), and so on. The brilliant biophysicist Franklin (Frank) Offner, had just produced a crystal-type pen-writer for recording changes in bioelectric potentials with frequencies up to about 100 Hz or more. Frank also constructed and maintained the amplifiers for research in the lab, including a “push-pull” amplifier that he invented to provide ungrounded bipolar recording with less external electrical interference. Among those who had already finished and departed from the University of Chicago were Robert Cohen and Mabel Blake-Cohen (electroencephalography, EEG), Herman Serota (local changes in cerebral blood flow with a heated thermocouple), and Wade and Louise Marshall (electrophysiology of the brain). Gerard was in the forefront of studies of the nature of “brain waves,” which Hans Berger had recently discovered in humans and reported in 1929. Among those who came to Gerard’s lab for experience in that field were Horace Magoun and J.Z. Young.

Young and Gerard had, the year before my arrival, demonstrated that the brain of the frog not only showed spontaneous EEG activities but that it continued to do so after being removed from the frog’s skull and being placed in a dish. For my entry into research Gerard suggested that I find out about the nature of the EEG activity in the isolated frog brain. Fundamental arguments were going on about the neuronal basis of the EEG. Gerard left the issue wide open for me to develop leads on my own, and he did not give me any special training in electrophysiological recording methods. Frank Offner helped to introduce me to the equipment in the lab.

I was unable to get the isolated frog brain to show any activity in almost daily trials for about four weeks. Then suddenly the brain exhibited a beautifully regular six-per-second rhythm at and near the olfactory bulbs. I later decided that the earlier attempts had failed because of the way the decapitation scissors were angled. The blades had to be positioned at a sharply oblique or flat angle, so as to be almost horizontal to (in the same plane as) the antero-posterior axis. Apparently with angles more perpendicular to this axis the intracranial space experienced some crushing during the quick cut. The brain did not “like” being squeezed or pulled, and precautions also had to be observed when pulling off the top of the cranium and transferring the brain to the dish of Ringers solution.

Use of the isolated frog brain allowed the possibility of modifying the extracellular environment by simply changing substances or adding them to the bath fluids. Electrophysiological studies, including intracellular ones, are also easier to do when the brain is not in situ. These possibilities were achieved later for mammalian brain by the use of thin slices, presumably done first by Henry Mcllwain. But the isolated frog brain, in contrast to slices, provides intact neural circuitry and exhibits fine EEG rhythms. I have wondered why this frog brain preparation has not come into more general use. I myself became extremely allergic to frog’s blood during my three years working with it; I would get almost intolerable bronchial asthma after each study period with the frog. The asthma prevented me from continuing to study the isolated frog brain.

Gerard and I found that various changes in ionic composition of the bath could convert the almost sinusoidal six-per-second rhythm to a variety of different frequencies and wave configurations (Libet and Gerard, 1939). That finding lent strong support to the view that the normal EEG represented potentials with a similar frequency and wave shape in the individual neurons, with a large number of these “beating” in relative synchrony. This view is still current, based on further evidence with intracellular recordings. The alternative view, held at that time by Herbert Gasser and others, regarded the relatively long-duration EEG waves (the roughly 100 msec waves in the Berger rhythm of human brain) as each reflecting a proper composite of short-lasting “spikes” (with about 1 msec durations) or possibly of their after-potentials, as seen for nerve impulses. Our finding in the frog brain made it almost impossible to imagine how that alternative view could account for the radical changes that we could produce in the recorded EEG. Additionally, we found that even a tiny bit cut from the olfactory bulb could still exhibit a regular rhythm; that finding argued against the requirement of elaborate networks for the EEG.

Because the results were so interesting, Gerard asked me to give a paper at the April 1938 meeting of the American Physiological Society, in Baltimore, Maryland. At that time the neurophysiology presentations were few enough to require only a single session for each time slot. And so this 22-year-old beginner presented the paper in a room full of luminaries such as Herbert Gasser, George Bishop, Lorente de N6, Francis Schmitt, and Hallowell Davis. My talk was received well. In another session I heard the young Alan Hodgkin, from England, present one of his first landmark findings—he proved that conduction of the action potential involved passive electrotonic spread from the active site.

I should also tell a story about the trip to Baltimore. Gerard decided to drive his car from Chicago, taking me along with Helen Blake. On the way we stopped in Cincinnati to visit an experimental psychiatrist, a Dr. Tietz as I recall. Gerard had induced Dr. Tietz to try administering methylene blue to patients with catatonic schizophrenia, on the basis (I suppose) that this hydrogen acceptor molecule would facilitate oxidative brain metabolism (a hot topic at the time). Dr. Tietz brought in a catatonic woman who displayed the usual nonresponsiveness to questions. Dr. Tietz then gave the patient an intravenous injection of 50 ml of a methylene blue solution. The patient turned the sickly color of green cheese, and I almost fainted with nausea. However, the patient became remarkably responsive and rational for about 30 minutes. But she reverted to the catatonic state as the color wore off. That striking effect should merit a follow-up study.

Gerard had the idea that the presumed synchronization of the electrical waves in a large number of neurons was achieved by intercellular currents, initially started by some “pacemaker” cells. A high concentration of nicotine altered the EEG wave shape but did not stop the rhythm. As that procedure should block all cholinergic synapses, we thought the result supported the intercellular field idea. Of course, we now know that cerebral synapses are not simply cholinergic or even all nicotinic when they are cholinergic. I think it would still be of considerable interest to test the synchrony mechanism by at least blocking all nerve conduction, which could be done by applying both tetrodotoxin (TTX) and a calcium-channel blocker (to stop both the Na⁺-type and ca⁺⁺-type nerve impulses), agents not available at that time.

Gerard and I produced another startling finding that supported the transmission of neural actions via intercellular field currents. At the end of an experiment that left the brain still showing activity, I added caffeine to the bath, because that substance was known to affect brain function. The caffeine converted the normal EEG waves to very large seizure-type waves that appeared in intermittent bursts; this finding clearly presented a model for an epileptic condition. I also established that these “caffeine waves” first appeared at the anterior pole of a cerebral hemisphere and traveled to the posterior end at the rather slow speed of about 5 cm per second.

In a discussion with Gerard, we considered the possibility that transmission of the caffeine wave was mediated by the large intercellular currents that were reflected in the surface-recorded potential changes. To test this hypothesis we hit on the bold idea of seeing whether the caffeine waves would be transmitted across a complete transection of the brain. I transected the brain completely at a level about halfway between the anterior and posterior cerebral poles and allowed the cut halves to come back in closely normal apposition (Gerard and Libet, 1940; Libet and Gerard, 1941). We were astonished to find that a distinct fraction of the traveling caffeine wave appeared in the cerebral portion posterior to the transection.

Twenty-five years later (in 1964) I was in Paris at a dinner party given by Alfred Fessard and Denise Albe-Fessard for my wife Fay and me and the Marshalls (Wade and Louise). Wade told me that he, like some others, had not believed my report of caffeine-wave transmission across a cut. Wade liked to repeat experiments by others when he had serious doubts about them; he did that for the “suppressor strip” proposal by McCulloch and Dusser de Barenne and showed that their findings were almost certainly due to artificially induced “spreading depression” (SD) rather than to an inhibitory motor cortex mechanism. Wade told me he had repeated my caffeine-wave experiment and obtained a similar result. I told him he should have published that confirmation; had he found an opposite result, he would no doubt have published it! I suggest that the caffeine-wave transmission experiment merits attention and perhaps a reinvestigation with modern technical capabilities.

The final product of those wonderfully productive three years of graduate work with Gerard was the discovery and analysis of slow, so-called “steady potentials” (SPs) in the frog brain (Libet and Gerard, 1941). Bipolar recording of the pia-ventricular potentials (with one electrode inserted into the cerebral ventricle so as to lie directly below another electrode on the pial surface) indicated that the recorded SP might reflect a resting steady potential gradient along the long axis of neurons in the pallium. Shifts in that SP could be made by applying currents from an external source; shifts in a given direction produced changes in the magnitude and even the polarity of endogenous EEG components, seen especially well with the caffeine waves. Subsequently, others (e.g., James O’Leary and Sidney Goldring) carried out investigations of SPs in the mammalian brain.

When my first publication with Gerard was to appear in 1938, I had to decide whether to keep my family name of Libitsky. Both Gerard and our department chairman, the great Anton J. Carlson, told me that, with few job opportunities in 1939, the Libitsky name might turn off prospective employers in an era of fairly common anti-Jewish bias, even in universities. Additionally, I felt inclined to adopt a more Americanized name; I felt that the Ukrainian source of the “sky” ending did not deserve any loyalty in view of the history of anti-Semitism and pogroms there. I think I also desired to adopt a symbolic indicator of my forging a career outside the confines of the conditions from which I had come. That wish definitely did not include an intention to disavow any of my family or my Jewish background, to which I have remained proudly committed. Instead of just dropping the “sky,” I also changed the second “i” to an “e,” winding up with Libet. I liked that partly because it sounded more French, like Gerard’s name. That got me into embarrassing moments later when my French colleagues assumed I was indeed French—my ability to speak French was almost zero. My brother Meyer also adopted the name Libet, although a number of cousins on my father’s side changed their names to Libit. At times I have regretted changing my name, but mostly I have been satisfied with the decision.

Postdoctoral Activities, 1939–1945

I achieved my Ph.D. from the University of Chicago in June 1939, and Fay and I were married on July 1. We had met in 1936 and “gone steady” for three years. When I received the Ph.D. hood at the convocation in Rockefeller Chapel, President Robert M. Hutchins (who was over six feet tall) seemed to be a bit surprised to see this five-foot-eight-inch, slightly built youngster of 23 (who looked like he was not yet 20). There had been, of course, other young Ph.D. recipients; in fact, Ralph Gerard got his Ph.D. at 21, also from the University of Chicago, and served as a professor in a Midwest college the following year.

I was fortunate in that period of job scarcity to have been offered an instructorship in physiology at the Albany Medical College in Albany, New York, at a salary of $1,800 a year. After spending the summer of 1939 continuing the study of slow potentials in Gerard’s lab (he had dug up a private donation of $100 to help support me for that time), Fay and I headed for Albany by bus in September. The chairman of the department in Albany was Harold Himwich, whose interests centered on brain metabolism and its functional implications in normal brain and in human psychiatry.

I carried out one or two worthwhile experiments on the cat brain. In one of these, together with Joseph Fazekas and Himwich, I studied the sensitivities of brain electrical activities to a sudden and complete stoppage of cerebral blood flow. We showed that an auditory-evoked potential—recorded simply with an electrode on the exposed surface of the auditory cortex—in response to a simple clap of hands, could continue to be elicited for up to 50 seconds, long after the resting EEG was gone (Libet et al., 1941). The response consisted of the “primary” initial EP (cortical evoked potential); the later EP components (which we did not understand well at the time) had been largely eliminated by the general anesthetic. The relative persistence of the primary EP could have interesting relevance to reports of near-death experiences by patients who survive a period of cardiac arrest. While in Albany, I also lectured extensively to the medical class, in which a fair number of the students were my age or older.

In April 1940, my wife and I took the train, coach seats, from New York City to New Orleans for the American Physiological Society meeting. In the same coach were Birdsey Renshaw and Donald Barron, who were engrossed in discussions of the latest spinal cord physiology during the two-day trip. My talk at the meeting dealt with work done in Chicago on SPs and on the transmission of the caffeine waves across a transection. The New York Times gave feature treatment to my report, with the headline “Brain Lightning.”

Back in Albany, I found Himwich a well-intentioned and likable person. However, the style of his research and the expectations he had for me did not appeal to me. On Gerard’s recommendation, I was taken on by K.A.C. (Allen) Elliott in June 1940. Elliott’s lab was in the Institute of the Pennsylvania Hospital for Nervous and Mental Disorders in Philadelphia. The scientific experience with Elliott was very valuable, even though my long-range research interest did not lie in his neurochemistry field. Elliott’s desk was in the large lab room itself, so he was always accessible and was involved with each day’s experimental runs. I learned much about rigorous controls and quantitative results, as well as some neurochemistry.

Elliott and I measured O₂ uptake with Barcroft manometers and matched that with biochemical analyses (done mostly by Dwight B. McNair Scott). We established some fundamental points about carbohydrate metabolism of brain tissue: (1) We found that homogenized suspensions of rat brain had an O₂ uptake similar to that of brain slices for the initial few hours at 37°C. When we used homogenized preparations, the biochemical measurements were easier to quantify (Elliott and Libet, 1942). (2) We found that homogenizing the brain in hypotonic solutions (NaCl omitted from the Kreb-Ringers solution) resulted in a severe loss in O₂ uptake, even when we measured the latter with normal Ringers restored. That result indicated that some cellular structures were necessary for normal O₂ metabolism and were disrupted by the hypotonic treatment. Had we then pursued the question of which cell structures were affected by the hypotonic treatment, we might have discovered the crucial role of mitochondria some years before Lehninger did. Ah, well, that is another example of a missed discovery. (3) We found that O₂ uptake of isotonic homogenates was almost completely accounted for by the amount of glucose metabolized, including some of the increases in lactate and pyruvate (Elliott et al., 1942). (4) When we omitted glucose from the medium, we found that O₂ uptake was reduced to about 60 percent of that with glucose. Most of that O₂ uptake was due to combustion of noncarbohydrate material. Such “internal combustion” of cell constituents does not occur when glucose is available. The possibility that nonglucose combustion might affect neuron structure was of considerable interest to the psychiatrist who was using insulin-hypoglycemic shock treatment for schizophrenia at that time. The discovery could also be relevant to electroconvulsive shock therapy and to epileptic seizures. It seems likely that neuronal energy metabolism rises to such high levels during cerebral seizures that the glucose available from the circulating blood is temporarily insufficient to sustain these levels, and that neurons resort to some noncarbohydrate energy sources during such functional hypoglycemic periods.

Elliott and I (1944) also made an interesting discovery that ferrous compounds, together with ascorbic acid, could considerably enhance O₂ uptake by brain tissue, probably with phospholipid as substrate. We then partially isolated an iron protein from liver, one that could replace inorganic iron, and named it “ferrin” (Libet and Elliott, 1944). Ferrin was different from iron-carrier ferritin. We did not pursue ferrin further, but it would seem to merit more interest.

World War II Activities

On December 7, 1941, we heard the announcement of the Japanese attack on Pearl Harbor on the radio in our small apartment in Philadelphia. And our first child, Julian, was born January 31, 1942. The engagement of the United States in World War II led to speeded-up medical school curricula and to war-related research. The department of physiology at the University of Pennsylvania, chaired by H.C. Bazett, took me on as an instructor in 1943. That terminated my three-year stint with Elliott, with his acquiescence. Elliott later moved to McGill University in Montreal as chairman of biochemistry and as neurochemist in the Montreal Neurological Institute, with Wilder Penfield, Herbert Jasper, and others. At the University of Pennsylvania I lectured to the medical students on endocrinology and gastrointestinal physiology. Grayson McCouch was the resident neurophysiologist, and I had a solid background in endocrinology from my studies at the University of Chicago. Merkel Jacobs, the distinguished general physiologist at the University of Pennsylvania, attended all the medical lectures and told me he liked the style and content of my lectures. One of the students in those classes, Robert Fishman, identified himself to me many years later after he took up the chair of neurology at the University of California, San Francisco (UCSF).

For research I joined Bazett in his studies of body temperature and principles of clothing insulation as related to military requirements. We also assembled a small portable O₂ cylinder fitted to a face mask with an intervening demand-only valve for the O₂. The device was to give aviators who might be shot down over the North Sea a few minutes of breathing during which to escape from the airplane underwater (this development was before scuba gear). The Canadian Air Force asked us to demonstrate the mask in Toronto. I walked about in a pool of deep water with this device (and without my glasses, so I could barely see where I was going). Bill Gibson, then a Canadian Air Force officer, told me he has a film of that demonstration.

In August 1944, I had a stressful time when my father suffered a skull fracture in an accident and died after a week in a coma. He was 48 years old and had been in good health. Shortly thereafter the Personal Equipment Lab at the Army-Air Forces Wright Field near Dayton, Ohio, needed a physiologist, and Bazett suggested me for the job. My family and I moved into a pre-fab housing structure in “Harshman Homes,” situated just outside the western edge of Wright Field. The B-17 “Flying Fortresses” flew in over our heads for their landing, rattling the house and our teeth. The walls between us and our neighbors in the duplex allowed us to hear much of their talking, and vice versa. The house was heated with a little coal-burning stove. In all this, our second child, Moreen, was born on November 7, 1944. We did not complain much; we were making our contribution to a war effort we were keenly in favor of.

I was in a clothing section of the survival-and-rescue operations as a “materials engineer.” We helped design and test clothing for fliers in the Air Force—antigravity suits for fighter pilots and waterproof coveralls for use by fliers who might fall into the icy waters of the North Sea. Among other things, our civilian head of the section (a fine person, Richard Goldthwait) assigned me to deal with the “General Gerow boot.” Although the problem of trench foot, or immersion foot, was not prevalent in the Air Force, an Air Force general named Gerow devised a boot that he thought would solve the problem (we felt his motivation may have been to show that the Air Force could solve an Army problem and thus to help the push for the Air Force to become a separate military branch). To start that study, I demanded to see what the Navy was doing about immersion foot. A combat-experienced major and a lieutenant were assigned to fly me to Washington, D.C. to visit the Naval Medical Research Institute. I had never flown before, and I requested a parachute for the trip in the two-engine military plane. When we landed in Washington it was too late in the evening for business. My pilots, both from the same town in Georgia, decided to fly home for an overnight visit and invited me along. Because they did not have authorization for this, the major flew the plane close to the ground most of the way to Georgia to avoid detection, freezing me with anxiety. He landed the plane at night on a simple concrete strip near his home town in Georgia; the strip was illuminated by the headlights from his relatives’ cars!

We returned to Washington the next day and at the Naval Medical Research Institute I found that the Navy had solved the problem of immersion foot. Damage from immersing feet in cold water was due primarily to heat loss and the resulting poor circulation. The Navy came up with closed cell-sponge rubber, a material now used by divers in their wet suits, and had devised a boot insert of rubber that retains its insulating quality even when wet. General Gerow mistakenly thought that immersion/trench foot was simply due to long exposure of feet to the water in wet socks. His boot had a rubber tube going down to the foot; the upper end of the tube was attached to a rubber bulb which the wearer could pump by hand to force air down around the foot. Because I could not lightly dismiss a general’s product I set up a test of the Gerow boot, the Navy boot, and another ordinary hip-length rubber boot offered by one of the military officers in the lab. A group of about five soldiers had thermocouples affixed to their feet and, wearing the boots in question, were asked by their sergeant to slog into the cold muddy banks of the nearby river. After some extensive time with cold mud in their boots, I measured their foot temperatures with a portable potentiometer. The non-Navy boots, including Gerow’s, failed badly. When I left Wright Field in September 1945 I was given an “Award of Merit.”

University of Chicago and the Woods Hole Marine Biological Laboratory, 1945–1949

I returned to the University of Chicago in September 1945, again on Gerard’s recommendation. As an instructor in biological science, I taught in the general course that I myself had taken as a freshman in 1932. I enjoyed that teaching experience much more than my other teaching in professional schools. The students were generally bright and eager to learn the subject for its own interest and relevance to human life rather than in the mode of what-do-I-have-to-know-for-clinical-practice often encountered in professional students. The topics covered all of biology, from botany through psychology, and so I learned much myself.

In research I was involved in the studies of functional neurochemistry carried out by some of the graduate students (including Lou Boyarsky and later, Sidney Ochs). But I also got back to the issue of SPs in the brain. Looking about for some cerebral process likely to exhibit distinct slow potentials, I hit on looking at the spreading depression (SD) that had been described by Aristides Leão (1947).

Amplifiers with sufficiently long time constants were not available to me. I simply set up a sufficiently sensitive galvanometer in a Wheatstone bridge circuit, recorded the deflections beamed to a large semicircular scale, and plotted the SP changes on ordinary graph paper. Julius Kahn, then a graduate student in neuropharmacology, worked with me. We indeed found a large SP shift when SD, initiated by a brief but strong stimulus to a spot on the rabbit’s cerebral cortex, progressed through the area on which sat our Ag-AgCl recording electrodes.

Hiss Ferreira (from Brazil) was then at the University of Chicago for some research experience with K.S. Cole. When I described these results to Ferreira, he said he thought his compatriot Leão was working along the same line. On writing to Leão, then in Robert Morison’s lab at Harvard, I found that Leão had carried out the same experiments a few months before I did, and was about to send off a paper for publication. He graciously acknowledged our activity in a postscript of that paper (Leão, 1951). Somehow, I was demoralized by being “scooped” on this story, and I felt any paper by me would be passe. And so I did not write up those results until some 15 years later (Libet and Gerard, 1962).

Gerard brought Stephen Kuffler to the University of Chicago on a research fellowship in 1947. Steve picked up on the small motor nerve system that Lars Leksell had described for mammalian muscle spindles, and proceeded to analyze the actions in frog muscles.

Also, in that period of 1945 to 1948 in Gerard’s group, Gilbert Ling developed the technique of making the glass microelectrode for intracellular studies. Judith Graham Pool had begun this use of a glass microelectrode earlier, when Gerard had her develop such an electrode to deliver acetylcholine (ACh) intracellularly; that research served as a test in his debate with David Nachmansohn about the role of ACh in conduction of the impulse. Gilbert was able to reduce the electrode tip to a 0.5 μm level by a suitably quick pull of the molten glass capillary tube. That smaller size tip gave recordings of consistently high membrane potentials in frog muscle (Ling and Gerard, 1949), and it opened the way for the breakthrough research by way of intracellular recordings in the nervous system. Among the visitors who came to see Ling’s technique was Alan Hodgkin in, I believe, late 1947. Hodgkin then designed the cathode-follower pre-amp, which permitted recordings of rapid changes in membrane potential (like action potentials), with these electrodes, rather than being suitable only for resting membrane potentials.

In the summers of 1947 and 1948, I had a marvelous experience at the Marine Biological Laboratory (MBL) in Woods Hole, Massachusetts, made possible by fellowships from the Lalor Foundation. Going to the MBL had the dual benefit of allowing me to pursue an interesting problem with the squid’s giant axon and of getting my family out of the Chicago summer into the refreshing coastal, academic, and social environment at Woods Hole. An additional achievement was my role in introducing Stephen Kuffler to Woods Hole. When I wrote to him back in Chicago about the great qualities of the MBU/Woods Hole environment, Kuffler promptly came there with his family. He quickly became a permanent summertime leader at MBL.

I had for some time thought that the increase in membrane conductance during a nerve impulse might be due to conformational changes in molecules related to the actomyosin system in muscle. As a partial test of the hypothesis, one should expect that ATPase, closely associated with muscle actomyosin, would also be associated with the axon membrane. To test that hypothesis, I homogenized the axoplasm and the cleaned sheath of the giant axons of the squid separately and tested each for ATPase activity. I indeed found a substantial ATPase activity that was about 100 times as concentrated in the sheath as compared with the axoplasm; ATPase in sheath was even greater than in muscle. In my second summer (1948) at Woods Hole, I tried to pin down the localization of the enzyme within the sheath. I found that muscle-free connective tissue, like that making up most of the sheath, had ATPase activity about one-third that of the axon sheath. That finding indicated that the axolemma itself would have ATPase activity many times greater than that of the whole axon sheath. One reason for describing those results here is that I never wrote a full paper on them; at that time I was in the midst of moving to California (in September 1948) and also having to deal with new jobs in 1948 and again in 1949. Actually, these results were fully summarized in two abstracts (Libet, 1948a and b). Skou noticed these and credited that work for the first cytochemical localization of membrane ATPase when he later reviewed the evidence relating enzymatic ATPase activity to the Na-K pump (the enzymatic mediation of Na-K transport was not known in 1948) (Skou, 1965).

There is an interesting footnote to the ATPase story: I presented my findings at the summer’s-end conference at the MBL in 1947. I added that ATPase was not more concentrated in optic ganglion than in axon sheath, unlike cholinesterase, and that this finding supported a role for ATPase in nerve conduction rather than in synaptic transmission. David Nachmansohn thought this threatened his view that ACh and cholinesterase somehow mediated the nerve impulse. He gave a vigorous defense of his view, suggesting that the lack of a higher ATPase concentration in the ganglion argued against my proposal, as there were likely more small-axon membrane lengths in ganglion than in the giant axon, per unit weight. With a calm style that surprised myself, I pointed out (1) that my values were for axon sheath, a small fraction of the whole axon, not for the tissue in bulk; and (2) that I could turn his own argument around and suggest that his much higher cholinesterase findings for the ganglion could more readily fit with a role in synaptic transmission than in nerve conduction, as there were no synapses in the nerve. That generated a laugh from the audience. K.S. (Casey) Cole later complimented me for picking up the other end of a double-ended argument; and old Otto Loewi told me in his charming way that he did not follow the discussion too well but that he thought I had the better of it. On the other hand, George Wald later berated me for attacking such an important scientist; Wald surprised me, as he generally gave the impression of being a liberal and on the side of truth, not of authority. In any case, Nachmansohn himself did not harbor any antagonism, and we became good friends.

My allergic asthma was becoming intolerable in the Chicago winters, and so I reluctantly left the University of Chicago and Gerard’s lab in the fall of 1948. I accepted my only offer from California, to be director of research in the Kabat-Kaiser Institute for Neuromuscular Rehabilitation in Vallejo. (I almost wound up in marine biology when the institute in Coral Gables, Florida expressed an interest in me. However, the institute backed off after receiving my application form, in which I gave my religion as one of Jewish descent. In retrospect, I have silently thanked the institute, as I would never have gotten into the research on brain and conscious experience had I gone to Coral Gables instead of San Francisco.) Herman Kabat was applying an interesting reflexology approach to enhancing motor behavior in patients with multiple sclerosis, etc. However, I felt the program in Vallejo did not meet my goals in science. And so I was happy and fortunate to be taken on as an assistant professor to fill a teaching opening at UCSF, starting in July 1949.

The stress of looking for a position in California more suitable than the one in Vallejo and then moving to San Francisco enhanced a chronic duodenal ulcer. On the day in September 1949 that I had taken my wife to the University of California Hospital to deliver our third child, Ralph, my ulcer eroded into a small artery and I almost bled to death. I was rescued by the skillful surgery of a young but up-and-coming surgeon, Orville Grimes, with the aid of 14 pints of blood. Fortunately, AIDS had not yet arrived.

Early Years in San Francisco, 1949–1956

At UCSF, I taught the full course in human physiology single-handedly to the classes in dentistry, pharmacy, and dental hygiene. The medical class was still receiving the first two preclinical years of study on the U.C. Berkeley campus, and so I gave lectures in neurophysiology to them in Berkeley, especially after the retirement of the chairman, J.M.D. Olmsted, in 1952. Olmsted was succeeded by Leslie L. Bennett, a kindly and scholarly endocrinologist. The University of California, Berkeley faculty invited the school of medicine to move completely from San Francisco; that was something I and others were in favor of. But it was rumored that it was the powerful clinical faculty in San Francisco that prevailed on the University of California regents to move the basic medical science departments from Berkeley to San Francisco (some of the surgeons and cardiologists were the personal doctors for some of the University of California regents and for high state officials). Vigorous new building then took over on the UCSF campus. The medical school departments in Berkeley moved to San Francisco in 1958 to 1959.

In San Francisco I had joined the “Biomechanics Laboratory” on my arrival in July 1949. This group was engaged in a massive team effort to measure the mechanics, muscle physiology, and energy demands in human locomotion in normal and amputee subjects. The effort was led by Verne Inman, a professor of orthopedic surgery, and Howard Eberhart, a professor of engineering at the University of California, Berkeley, and it produced some extraordinary quantitative reports. I teamed up with Bertram Feinstein, then a neurologist, to study the human electromyogram in the context of the group’s interest. In that work we established a role for tendon organ inhibition in strong muscle actions (Libet et al., 1959). That study involved locally anesthetizing the entire tendon of the anterior tibial muscle. I realized that we might improve the spread of the injected procaine, as well as eliminate the painful sting produced by the acid in the procaine-HCl, by bringing the pH up to about 7.4 before the injections. We did this by mixing in an appropriate amount of sterilized NaHCO3, which also converted most of the procaine into the more tissue-diffusible un-ionized free alkaloid. That procedure indeed produced the desired effects; I do not know why it has not been adopted widely to eliminate the painful sting from injections of cocaine derivatives in their acid forms.

With Henry J. Ralston II (father of Henry [Pete] Ralston III, chair of our anatomy department since the 1980s) we also studied the effect of stretch on frog muscle. After getting some coaching on the recording of end-plate-potentials (EPP) from Steve Kuffler at Woods Hole in 1951, I showed that modest stretch of the rectus muscle produced a substantial increase in EPP amplitude (Libet and Wright, 1952). Kuffler picked up on that finding, and later an elaborate analysis of that effect was carried out in his lab. In 1952 I was promoted to associate professor with tenure.

In 1950 to 1951, faculty members were required to sign a “loyalty oath.” This was promulgated by the Truman administration during the prevailing McCarthyite atmosphere of a witch hunt for alleged “reds” in government. The oath included items like “I have not belonged to any organization listed as subversive by the Attorney General.” I would have been happy to give a simple denial of being a Communist, but the requested statement was a serious affront to freedom of assembly and expression. As a young assistant professor I could not afford to face possible dismissal, so I signed the oath “under protest,” and accompanied it by a letter that expressed my feelings. At the time I periodically gave a brief series of lectures for residents at the Letterman Army Hospital in the Presidio of San Francisco. I refused to sign the loyalty oath connected to that small job. That refusal prompted a visit by two officers from Army Intelligence. After some tricky questioning they went away apparently satisfied about my political status; even so, I was not again asked to give lectures at Letterman.

Research on Synaptic and Postsynaptic Responses

In 1954 or 1955, John Eccles stopped in San Francisco on his way back to Australia from a conference in the United States. When I expressed an interest in getting back into research on the CNS, Eccles invited me to come to his lab in Canberra. In 1956, I obtained a fellowship grant from the Commonwealth Fund and took off for a sabbatical year with my whole family (four children then, with Gayla having arrived in 1952). On the trip to Canberra, we had a few hours’ stopover in Sydney and were roaming about in a small park. A tall stranger approached us to ask if we were the Libets! This turned out to be Anders Lundberg, whose wife Ingeline correctly guessed our American identity from the children’s clothing and behavior. In Canberra, the Lundbergs occupied a house adjacent to ours, and we became good friends. The friendship was later cemented when we visited them in Göteborg, Sweden. I have spent some wonderful times with Anders at his country place in Flaton, an island in the archipelago west of Göteborg.

Eccles’ department was in the forefront of research on synaptic mechanisms and spinal cord functions, and it was an exciting and informative experience for me. Being exposed to the newer ideas and techniques there helped to reset my research outlook and provided a crucial turning point for my future work. Among the stimulating people there were David Curtis (just getting his Ph.D.), William Liley, Anders Lundberg, Ricardo Miledi, Kris Krnjevic, and of course Rose Eccles and Jack Coombs (who had produced our electronic gear) and Jerry Winsbury (the mechanical engineer who designed and constructed our special research hardware and vertical microelectrode puller). Eccles had about five fully equipped lab rooms, each with a shielded recording room, all served by a capable and congenial “diener” (laboratory assistant), Arthur Chapman.

I had begun to acquire the habit of morning and afternoon tea back in Philadelphia with Elliott, and that became a fixed pattern with me in Canberra. My family and I also had to learn how to make an adequate fire in the large fireplace of the pleasant house assigned to us, and to tuck hotwater bags into our beds on cold nights.

Eccles suggested that Bob Young and I work with him on a problem to test for “plasticity” of function in the CNS (Bob was then a graduate student from Harvard and is presently professor of neurology at the University of California, Irvine). Working directly with the master was just what I wanted. The experiment involved cutting some lumbar ventral roots to see whether the resulting chromatolysis of motoneurons would produce a reconfiguration of their synaptic inputs. On the day of experiment, Eccles himself isolated and set up most of the muscle nerves related to the affected spinal segments. By the time Bob and I exposed the spinal cord with all the proper fixations and set the cat in the recording room, the testing did not begin until after dinner. I recall the thrill when we first achieved a solid intracellular penetration of a motoneuron and saw as well as heard the large antidromic action potential with its “overshoot” of the resting potential. We worked well into the night, until 2 or 3 a.m. Eccles did this with unflagging energy and enthusiasm, while I sagged. It was then that I decided to orient my future research so as not to require that kind of effort.

We found no evidence of alterations in the input-motoneuron pattern, but we hit on a different important discovery (Eccles et al., 1958). The strange form of the motoneuron action potentials led us to postulate that these had a dendritic firing origin in these chromatolyzed neurons. Eccles designed experimental tests that confirmed that hypothesis. We had thus demonstrated for the first time that CNS neurons could fire dendritic action potentials. The design of our tests was subsequently employed by others, e.g., in the Kandel, Spencer, and Brinley work (1961) on dendritic spikes in the brain.

My subsequent work in Canberra on synaptic responses in sympathetic ganglia was conditioned by my coming down with infectious hepatitis A in January 1957. The disease apparently resulted from my eating the delicious whipped cream scones served by Mrs. Rene Eccles on Sunday afternoon gatherings at the Eccles’ home. She obtained the cream without pasteurization from a neighbor who, it turned out, was himself down with hepatitis at the time. The others were given gamma globulin injections, and no one else got the disease.

During my month of recovery at home I read Rose Eccles’ Ph.D. thesis with leisurely thoroughness. I became excited by the possibility that the slow ganglionic potentials she had recorded at the surface of the rabbit superior cervical ganglion (SCG) might represent genuine postsynaptic responses with extraordinary durations in seconds. My early experience with slow potentials in the brain (when I was with Gerard in Chicago) had sensitized me to look for slow synaptic responses that might provide the neural basis for SPs in brain. An earlier report by Laporte and Lorente de Nó (1950) had indicated the likelihood of a slow inhibitory postsynaptic potential (IPSP) in turtle ganglia and was also a stimulating factor.

When I returned to work, I explained to John Eccles what I had in mind and, with his approval, I induced Rose Eccles to introduce me to her methods for studying the rabbit SCG. Her methods involved making surface recordings, with one Ag-AgCl electrode on the ganglion and a second electrode on the crushed end of the internal carotid branch of the postganglionic nerve, with stimulating electrodes on the preganglionic nerve. Most studies were carried out on the excised preparation, cleaned and mounted in a neatly designed chamber that permitted dipping the preparation into the oxygenated bath medium when it was not up in the air for recording. Rose had reported (Eccles, 1952) that the curarized ganglion exhibited a depressed initial N wave (the well-known excitatory postsynaptic potential [EPSP]), so that it did not fire an action potential; this was followed by a P wave (surface positive, duration about 0.5–1 second) and an LN wave (late-negative, lasting some seconds). Repetition of preganglionic volleys rapidly built up the P and LN waves but not N.

We first applied botulinum toxin to test whether preganglionic release of ACh was necessary for producing the slow P and LN waves. The toxin slowly abolished all of the ganglionic responses. This result indicated that P and LN (as well as N) were dependent on a release of ACh. Because P and LN potentials were not abolished even by strong cholinergic-nicotinic blockers (like curare) that wiped out the N wave, I decided to test a muscarinic blocker like atropine. The “doctrine” at that time was that the sympathetic ganglion response was a purely nicotinic one, as in striate muscle. We were delighted to find that a weak concentration of atropine could wipe out the P and LN components while leaving the N wave alone. That result indicated that the slow P and LN components were also postsynaptic responses mediated, at some step, by ACh acting on muscarinic receptors.

Those findings set me off on a series of studies that dominated my laboratory experimentation for about 25 years. My other line of research, on the cerebral basis for conscious experience, began about that same time and has continued even after my retirement in 1984. I would like to organize most of the remaining history around each of these research programs separately.

I shall digress briefly to note my small role in the founding of the Society for Neuroscience. Gerard invited me to join an initiating committee for the Society that met during the meetings of the International Physiology Congress in 1968 in Washington, D.C. I was appointed a coordinator for the northern California region. Actually, I had, in the early 1950s, started and conducted a monthly discussion group for neuroscientists in the San Francisco Bay area that became known as BANG (Bay Area Neuro-Group). BANG went on fruitfully until the mid-1960s. It was a kind of forerunner of a chapter of the Society for Neuroscience.

I would also note my shock and depression after my mother’s death in 1967. While on corticosteroid treatment for a nasty skin disease, pemphigus, she developed an uncontrollable infection. I did not learn how serious this was until it was too late for me to come from San Francisco to Chicago to spend some time with her in her last days. She deserved a better fate.

Slow Synaptic Actions

I concluded the series of experiments begun with Rose Eccles after returning to San Francisco. I first had to set up my own lab (patterned after those in Canberra) in the newly constructed building into which the department of physiology moved from Berkeley in 1958. In the first paper (R.M. Eccles and Libet, 1961), I proposed a diagram for the intraganglionic pathways in which, on the basis of our evidence, the existence of a functional interneuron was postulated to mediate the P wave (presumed to be an IPSP). Monoaminergic small intensely fluorescent (SIF) cells had just recently been described histologically (see Eränkö and Eränkö, 1971). I proposed that the SIF cell received preganglionic ACh input that excited the cell by a muscarinic action, and that it then delivered a catecholamine that elicited a hyperpolarizing response of the ganglion cell. (In a quantitative study of changes in monoamine fluorescence of the SIF cells, done with Christer Owman in Lund, Sweden, we showed that depletion and restoration of DA content in the SIF cells were causally related to the loss and restoration of slow IPSP (sIPSP) responses, respectively (Libet and Owman, 1974).) That proposal elicited considerable interest and pro and con arguments (see Libet, 1992). The electron microscopists soon demonstrated preganglionic endings on SIF cells (Elfvin, 1963; Williams, 1967) as well as some close synaptic-like contacts by SIF cells with ganglion cells. I went on to show that the P and LN waves should be regarded as slow IPSPs and slow EPSPs, respectively (Libet, 1964); and that the synaptic latencies for these responses were also extraordinarily long (about 10 and 300 msec, respectively) (Libet, 1967).

Those long durations and long latencies indicated one was dealing with novel kinds of PSPs, strikingly different from the well-established fast PSPs, whether the latter were in autonomic ganglia, skeletal neuromuscular junctions, or in the CNS. When I began to report these findings and views in the early 1960s, I met with disbelief from some neuroscientists. Admittedly, the experiments employed surface field recordings. But the arrangement of neurons with their axons bundled into the extended postganglionic nerve made the interpretations convincing; there was perhaps the unlikely possibility that some specially arranged glial cells could be responsible for the slow potentials. However, with intracellular recordings, we laid these doubts to rest.

With the first of a series of capable Japanese visitors (Shiko Chichibu, later professor in Kinki University in Osaka; and Tsuneo Tosaka, professor at Tokyo Medical College), we made the initial intracellular studies on frog ganglia. Tosaka reported these findings at the International Physiological Congress in 1965. I presented them at the FASEB meetings in the United States (Libet, 1966). Nishi and Koketsu (1968) then quickly entered the field with their talents for microelectrode studies and produced a full paper in 1968 that confirmed our reports while adding further findings. In my usual style of being slow to write up full papers, we got ours out just in time to appear in the same issue of the Journal of Neurophysiology (Libet et al., 1968; Tosaka et al., 1968).

In a return visit by Tosaka in 1968, we managed to make intracellular studies on the mammalian (rabbit) SCG (Libet and Tosaka, 1969). Good intracellular penetrations of neurons in mammalian ganglia are difficult to make. These ganglia are full of elastic connective tissues and behave like sponge rubber balls. Attempts to soften the ganglia with elastase and collagenase result in a loss of synaptic responses; presumably the synaptic contacts are loosened away from the ganglion cells.

The intracellular studies conclusively established the neuronal, postsynaptic nature of these slow responses. The studies also proved that more than one type of receptor was present on the same ganglion cell. Both the nicotinic and muscarinic receptors for ACh were present, as well as one for catecholamines. That finding was a relatively novel proposition. Of course, various slow PSPs have since become widely recognized and studied in many different types of neurons.

An even slower EPSP (“LLN,” or late-late negative) was discovered in the frog ganglion by Nishi and Koketsu (1968). This PSP had a duration of up to 30 minutes, after a brief repetitive preganglionic input. This lateslow EPSP was not mediated cholinergically or adrenergically. Jan et al., 1979 later showed that the transmitter was the polypeptide known as LHRH (the releasing hormone for the luteinizing hormone in the pituitary gland)! Lily and Y.N. Jan (1982) went on to show that LH-RH was released only by preganglionic C fibers. But the LLN response was also elicited in the B neurons that received no innervation by C fibers at all. This finding provided a proven example of a synaptic transmitter diffusing for at least some micrometers to elicit a response. We had earlier proposed such “loose” synapses for the slow EPSP.

Some years later we demonstrated a similar late-slow EPSP in the rabbit SCG in the presence of complete cholinergic and adrenergic blockade (Ashe and Libet, 1981a). This response also lasted about 30 minutes after a brief repetitive train of preganglionic volleys, even when these were at low frequencies of three per second. This late-slow PSP in rabbit SCG had a synaptic delay of about one second and an amplitude greater than that of a maximal fast EPSP.

Electrogenic Mechanisms

With my third Japanese collaborator, Haruo Kobayashi in 1966 to 1968, we found that the slow EPSP was produced with no increase in membrane conductance (Kobayashi and Libet, 1968). That was probably the first example of a chemically transmitted PSP that was not generated by the well-known increases in ionic conductance. In frog ganglia the slow EPSP was actually related to a decrease in membrane conductance. We dismissed the possibility that this finding represented a decrease in K⁺ conductance because the slow EPSP did not show a reversal of polarity at EK⁺ (about –80 to –90 mV in those cells). However, these peculiar characteristics led Brown and Adams (1980) to discover a new K⁺ conductance; the ionic channels for this K⁺ conductance were open only in the depolarized range of membrane potentials below –60 mV, and these channels opened or closed slowly, with time constants in seconds. These K⁺ channels, when open, could be closed by a muscarinic ACh action which thereby results in a slow depolarization; they were thus named the “M” channels. This M-channel mechanism appears to account fully for the slow EPSP in frog ganglia; it is in accord with our finding that this PSP was absent in cells with normal resting potentials of –70 mV (Libet et al., 1968; Kobayashi and Libet, 1968; Tosaka et al., 1983). That was not the case for the mammalian ganglia, which exhibit a large slow EPSP in normal cells at –70 mV. The slow EPSP in rabbit SCG is therefore not equivalent to that in frog ganglia; indeed it was an early example of a “metabotropic” synaptic action; its generation appears largely to be mediated intracellularly via cyclic GMP, produced by the muscarinic activation of guanyl-cyclase (Libet et al., 1975; Hashiguchi et al., 1978, 1982).

Long-Term-Enhancement (LTE) of Slow PSPs

When Tosaka and I were experimenting with the possible role of dopamine (DA) as the transmitter for the sIPSP (in 1969 to 1970) we serendipitously made an extraordinary discovery (Libet and Tosaka, 1970). Temporary exposure of the rabbit SCG to DA was followed by a prolonged enhancement of the slow depolarizing response to a muscarinic action (by ACh, or by methacholine, etc.). This LTE persisted for at least as long as the ganglion remained in functional condition (three to four hours in the chamber). Amines other than DA did not produce LTE. Later, Ashe and I showed a similar effect of DA on the slow IPSP and slow EPSP, but not on the nicotinic fast EPSP (Ashe and Libet, 1981b).

Finally, Sumiko Mochida and I demonstrated that such an LTE could be obtained simply with a brief train of preganglionic volleys, even at relatively low frequencies of repetition (Mochida and Libet, 1985; Libet and Mochida, 1988). That finding was in accord with our earlier demonstration that intraganglionic DA in the SIF cells could be released by preganglionic stimulation. Also, the LTE could be blocked by D₁, but not by D₂ antagonists; and the application of cyclic AMP, whether extra- or intracellularly, could substitute for DA to give LTE (Libet et al., 1975; Kobayashi et al., 1978; Libet, 1979). The latter results indicated that DA acted by stimulating adenyl-cyclase (a property already established by others) and that the resulting increase in cyclic AMP mediated the long-lasting increase in the effectiveness of the muscarinic receptor for the slow EPSP (and for the sIPSP, whether on SIF cell or ganglion cell).

Our reports of LTE, starting with Libet and Tosaka (1970) provided, perhaps, the first example of the modulation of a postsynaptic response to one synaptic transmitter (ACh, acting muscarinically) by another transmitter, DA. After a seminar I gave in Stockholm in 1971, Ragnar Granit commented that it was the first time he had heard of an example of a “synaptic amplifier.” The modulating action is not only specific for DA but is produced by DA (or cyclic AMP) without any change in membrane potential or conductance (Kobayashi et al., 1978).

LTE modulation by DA was discovered some eight years before long-term potentiation (LTP) (Bliss, 1978). There are similarities but also important differences between the two. Both last many hours after a brief, repetitive input; they are sensitive to reduction in extracellular Ca⁺⁺ and to the specific inhibitor of Ca-calmodulin, calmidazolium; the inhibitor of protein synthesis anisomycin has no effect on the first several hours of LTE and LTP. They are different as follows: (1) in the specific postsynaptic response that is enhanced; (2) in the frequency of the effective neural inputs (3 to 10 per second for LTE, usually a high frequency for LTP); (3) in the requirement of a second transmitter, DA, for LTE, rather than a large depolarization of whatever origin for LTP; and (4) in that LTE does not require a conjunction or near-synchrony between DA input and the ACh response that is subsequently enhanced, whereas LTP does require such a conjunction between a depolarizing input and a weaker synaptic (glutaminergic) input. The last difference makes LTP a better model for mediating classical learning. But LTE could provide a basis for enduring changes in synaptic reactivity that may underlie the shifts in vigilance and mood thought to be controlled, in part, by DA systems (see Libet, 1986, 1988).

Another remarkable feature of LTE deserves attention: Cyclic GMP, the putative intracellular mediator of the slow EPSP, was found to disrupt or block the production of LTE but only if applied within the first 5 to 10 minutes after the exposure to DA; it had no effect on the test-expressions of LTE once that has been produced (Libet et al., 1975). That temporal discrimination in the effectiveness of cyclic GMP distinguishes between the processes that produce or consolidate an enduring plastic change and those involved in expressing the change.

I would suggest that the LTE phenomenon deserves more attention, for it may have a potentially important role in brain functions.

Brain Processes in Conscious Experience

The question of how the brain produces conscious experience had been lurking in my mind since my time as a graduate student. I am sure that question has been and is on the minds of many neuroscientists, but excruciatingly little direct experimental research has appeared. Neurosurgeons like Harvey Cushing, Otto Foerster, and especially Wilder Penfield, have produced valuable studies mapping the conscious responses that could be elicited by electrical stimulation of the cerebral cortex, but they did not go into the physiological questions of the neural dynamics—of how rather than where neuronal activities specifically resulted in conscious experience, an awareness of something.

My entry into this field was made possible by my good fortune in having the neurosurgeon Bertram Feinstein as a colleague and friend. Feinstein was one of the relatively small group of neurosurgeons who had an interest in using the opportunities (set up by therapeutic procedures) to study experimental questions of both fundamental and clinical importance. He had the additional, uniquely humble quality of allowing someone more expert in a given research matter to take the leadership in the design and conduct of an experiment. When Bert invited me to study some important physiological questions that would benefit from access to intracranial electrodes, I jumped at the chance of studying conscious experience in awake human subjects. Feinstein’s new operating room (at the Mt. Zion Hospital in San Francisco) was designed to foster electrophysiological studies and was completed in 1958 to 1959. I was also fortunate in the composition of the research team (including W. Watson Alberts and E.W. (Bob) Wright at that time); the team also worked with Feinstein on the stereotactic technology for therapeutic purposes.

I should note that my decision to commit a major research effort to this question was a risky one, in terms of my career. In such difficult and relatively unknown terrain there was every possibility of a complete failure to find out anything worthwhile. I would be working on an issue that was not popular at the time. Indeed, there was a fair amount of antagonism, especially by many positivists, psychologists, and philosophers, who held that studying subjective, introspective experience was not a fit scientific activity. That attitude has mellowed in recent years with the development of cognitive science and with demonstrations that subjective experience can be studied quantitatively and reliably.

As late as 1977, when we already had made some intriguing discoveries, a leading neurophysiologist urged me, as a good friend, to give up this brain research and concentrate fully on my studies of slow synaptic actions in ganglia. Fortunately, I had achieved tenure as an associate professor in 1952 and the chairman of my physiology department, Leslie Bennett, a scholar with broad interests, approved of my spending a large fraction of my research time with Feinstein at the Mt. Zion Hospital. With our first report of results in 1964 (Libet et al., 1964; Libet, 1966), I received interest and approval from a number of great neuroscientists (including John Eccles, Ragnar Granit, Frederic Bremer, Lord Edgar Adrian, Charles Phillips, Wilder Penfield, Herbert Jasper, Ralph Gerard, Anders Lundberg, and Robert Doty) and that helped to bolster my courage to carry on in this field.

I was confronted with the difficult question of how to begin such an investigation. I decided that the subjective side of the brain-mind study must be kept to the simplest possible so that my brain research group could concentrate on the physiology. Because we were given access to electrodes in the cerebral somatosensory system, we adopted as our criterion of a conscious subjective experience the introspective report of a simple somatic sensation. Report of such a “raw feel” would be fairly immune to possible emotional distortions, and reliability of the reports could be established by the investigator’s ability to manipulate production of this sensory experience, by changing stimulus intensities, etc. That ability also allowed us to design tests of causative, rather than merely correlative, factors in the relationship between brain processes and a conscious experience. The other principle was that we should study the differences in cerebral processes for the transition between unconscious (nonconscious) responses and just threshold conscious responses. That procedure would avoid having to deal with all the brain features that are necessary for, but not uniquely causative of, conscious experience.

Given these circumstances, we adopted a classical physiological approach. We started with the question, What kinds of activations of cortical somatosensory (SI) neurons lead to production of a conscious sensory experience? More specifically, what are the changes in electrical stimuli that are needed to go from below threshold to a just-threshold sensory experience? This formulation also opened the possibility for characterizing neuronal activities that may mediate unconscious mental functions, when these activities are insufficient to elicit awareness. Also, stimulating the SI cortex directly got us closer to the cerebral requirement for awareness than is the case for a peripheral sensory input; the latter can give rise to a multiplicity of ascending parallel actions at the cortex, actions that are difficult to specify or manipulate experimentally. Finally, the operational criterion for a conscious experience had to be an introspective report of it by the subject. Purely behavioral responses that did not directly represent the subject’s introspective experience could not be valid criteria. To study the physiology of subjective experience, I thought it obvious that we must study the subject’s report of it. I soon discovered that such a definition met with considerable opposition, but that has faded in recent years.

Delay in Awareness

The most interesting requirement for producing a just-threshold sensory experience turned out to be the duration of the train of repetitive stimulus pulses (Libet et al., 1964). With minimum effective stimulus intensity, a minimum train duration of around 0.5 seconds was required. My colleagues and I went on to show a similar requirement for stimulation of subcortical cerebral sites in the somatosensory pathway, e.g., in ventrobasal thalamus and medial lemniscus. Although stimuli to skin or sensory nerve can be effective even with one pulse, we developed several lines of evidence that strongly supported the view that cerebral responses to the single skin pulse also had to persist for 0.5 seconds or more to give a threshold sensation (Libet et al., 1967; Libet et al., 1971; Libet, 1973; Libet et al., 1992; Libet, 1993a,b). All of the evidence, then, indicated that our awareness of the sensory world is delayed by about 0.5 seconds (or more) and is not synchronous with the actual events sensed.

Subjective Referral Backwards in Time; Antedating of Sensory Experience

If awareness is delayed, my research group and many others were concerned about how to account for the fact that sensory experiences seem subjectively to appear with no delay from the real time of the events. It took us a while to realize we must distinguish subjective timing from neural timing, the latter being the time at which neuronal activations became sufficient or adequate for eliciting the awareness. That distinction led us to the hypothesis that, after the actually delayed appearance of the experience, subjective timing is automatically antedated; and that the primary evoked response (of the SI cortex to the earliest signal arriving, within 10 to 20 msec of a peripheral stimulus) serves as a timing signal to which the experience is subjectively referred. Fortunately, we were able to devise and carry out a convincing, crucial experimental test of the hypothesis (Libet et al., 1979). One of my thrills in research occurred when I observed the astonishing confirmatory results of that test as they came out of the subjects’ reports during the experiment.

Subjective referral in the spatial dimension was already well known. The simplest example of that is seen when the subject reports feeling something in a hand and not in the contralateral SI cortex that is stimulated to produce the sensation. But spatial referral is evident also in all peripheral sensory inputs, in which the pattern of neuronal responses in the cortex are spatially quite distorted in relation to the original sensory configuration. We had now discovered that there is also subjective referral in the temporal dimension. Both forms of subjective referral serve to “correct” the sensory experience so that it appears to coincide with the actual sensory event despite spatial and temporal distortions imposed by the way the brain represents it. There is no known neural mechanism that could have predicted such subjective referrals. The question of why such subjective referrals appear may be in the same metaphysical category as one that asks why or how certain cerebral activities give rise to any conscious subjective experience at all. What we can do, scientifically, is study how the neural and subjective events are related, especially if we can discover causative relationships.

Cerebral Initiation of a Voluntary Act vs. Conscious Will

Kornhuber and Deecke (1965) had reported that a slowly rising negative potential was recordable at the scalp preceding a “self-paced” act by a human subject. The “Bereitshaft Potential” or “readiness potential” (RP) began about 0.8 seconds or more before the act. However, the authors made no attempt to relate this interesting finding to the operation of conscious will. In a symposium discussion some years later, I heard Eccles say that, in view of the RP finding, the conscious will to act must obviously be appearing almost a second before the act. I realized that Eccles had no direct evidence for making that assertion, and such an alleged advance appearance of conscious will seemed to me to be unlikely. However, to devise an experimental test of the question seemed impossible, as one would have to find a way to measure the time of appearance of the subject’s conscious intention to act, in conjunction with recording the RP in a voluntary act.

It was during my stay as a Scholar in Residence in the Bellagio Center for Advanced Study, on Lake Como in Italy, that a seemingly simple way of determining the time of a subjective intention to act occurred to me. This was in the fall of 1977, and I was there working on the paper on antedating (Libet et al., 1979), and so the question about voluntary action was floating about in a mostly subconscious fashion. The method, in principle, was simply to have the subject observe the equivalent of a “clock-time” at which he/she first became aware of an intention to “act now,” and then to report that “clock-time” later to the observer. We tried this out in 1978 and found, to our surprise, that subjects could report these timings with a reliability of ±20 msec (S.E.). We also addressed a number of other issues, especially that of validity.

In the experimental series, RPs were recorded for the same voluntary acts for which subjects reported the times of the first awareness of intending to act (Libet et al., 1983). In studies of self-paced movements, by Kornhuber and Deecke and by others, there were some limitations on volition, but we eliminated those. The resulting freely volitional self-initiated acts showed RPs beginning an average of –550 msec (before the act), well before the –200 msec for the appearance of the reported conscious intention to act. The 350 msec difference between these values had a strong statistical significance. I discussed this finding and important implications of it for free will and individual responsibility in a paper in Behavioral and Brain Sciences, accompanied by 25 critical commentaries (Libet, 1985). Our basic experiment (Libet et al., 1983) has been repeated and the results confirmed by several groups (e.g., Keller and Heckhausen, 1990). On the other hand, our experimental studies of conscious sensory experience employed intracranial electrodes, and that radically restricts opportunities for others to repeat them. There have, however, been at least several confirmations of the requirement of repetition of inputs to somatosensory cortex (e.g., Amassian et al., 1991).

I must add a note about my stay in Bellagio. My wife Fay and I were given a large airy room plus a study in the villa, formerly a ducal palace. This was the first and only time we experienced the aristocratic lifestyle. For the roughly 12 resident scholars and their spouses there was a butler and about 10 assistants, and a chef with several assistants. The servants told Fay and me that our room had been occupied by President John Kennedy during a trip to Italy. One of the servants was named Amilcar, a name associated with Hannibal’s march through northern Italy some 2,000 years earlier. Amilcar could make remarkably accurate weather forecasts by simply looking at the sky and putting up a wet finger. That ability fascinated one of the other resident scholars who happened to be a world renowned meteorologist. The opportunity to interact with the other scholars, who were all eminent in their fields (sciences, humanities, literature, etc.), was a great benefit. On one Saturday evening gathering, I sang classical lieder (by Schubert and Scarlatti), accompanied very capably on the piano by the wife of a scholar from England.

Cerebral Transition Between Unconscious Detection and the Conscious Awareness of a Signal

Even when stimulations of the somatosensory system were too brief to elicit a conscious sensation, substantial neural activities were recordable. I proposed that these shorter-lasting activations may mediate unconscious mental functions, whereas longer-lasting similar activations produce awareness; I called this proposal the “time-on” hypothesis. My brain research team was able to carry out an experimental series that directly tested this hypothesis (Libet et al., 1991). This research study (during 1987 to 1990) was made possible by the availability of patients with stimulating electrodes permanently implanted in ventrobasal thalamus (by UCSF neurosurgeons Yoshio Hosobuchi and Nicholas Barbaro, for treatment of intractable pain). Also, a room and computer facility were loaned to me at UCSF by my colleague and good friend, Michael Merzenich; I had already achieved emeritus status and had no facility of my own for this work. My good friend and colleague, neurosurgeon Bert Feinstein, had unfortunately died prematurely in 1978. Subsequently we lost not only his supply of research subjects and collaborative efforts, but also the splendid research facility and research team that had functioned so fruitfully at the Mt. Zion Hospital. I had been intending, on my retirement from the University of California, and after giving up my animal lab and the work on sympathetic ganglia, to move to the Mt. Zion facility and continue with the brain research. That plan fell through with Feinstein’s death.

The experimental test of the “time-on” hypothesis for explaining the cerebral difference between unconscious and conscious functions involved the following: Stimuli of varying train durations (0 to 750 msec) to ventrobasal thalamus were delivered in different trials, and the subjects were asked (1) to report on the presence or absence of a stimulus, even when nothing was felt (a forced choice) and (2) to report whether they felt any sensation or even anything different, in each trial. Stimuli in a given series were all at the same near-threshold intensity that was required for eliciting a conscious sensation when such pretested stimuli had a train duration of 400 msec. The results, from hundreds of trials with each subject, showed (1) that subjects detected the presence of a stimulus even when they felt nothing and were guessing, with accuracies well above the 50 percent expected on pure chance; and (2) to go from detection-without-awareness to detection-with-awareness (even of the most minimal and uncertain level) required an additional almost 400 msec of stimulus duration.

The transition between an unconscious mental function and a conscious one could thus be controlled by or be a function of the duration of the appropriate neuronal activations. Such a relationship raised the possibility that unconscious mental functions in general may be mediated by neuronal activities too brief to elicit awareness; and that awareness may arise from those same kinds of neuronal activities if they simply persist long enough.

More recently, I proposed the existence of a hypothetical “conscious mental field” that would have the attributes of a unified subjective experience and the ability to effectuate conscious will by modulating appropriate neuronal activities (Libet, 1993b, 1994). I had, by design, previously not proposed any hypotheses or theories of mind-brain relationships without subjecting them first to some experimental testing. That was also my intention for this field theory; the hypothesis and an experimental design to test it had occurred to me more than 30 years earlier, but I was not able to muster the appropriate patients suitable for the test or the collaboration of the few neurosurgeons who did have access to such subjects. The saving grace in my present proposal is, at least, that it is accompanied by a description of an experimental design to test it. The experiment is a difficult one and would benefit from preliminary testing with monkeys before going to the human subject, but it is in principle workable. I suspect this proposal is getting a cool reception from my neuroscience peers. I found it interesting, however, that the young people (graduate students and young postdocs) generally have found the proposal not only an acceptable idea but even an attractive one. I was recently pleased to find that Karl Popper was proposing existence of a “conscious force field” that has much in common with my proposal (Popper et al., 1993; Lindahl and Arhem, 1994).

Some Concluding Remarks

My approach to research has been predominantly one of seeking for or being attuned to fundamental questions of broad significance and staying with an experimental program to answer these questions. Of course, the questions and hypotheses to answer them had to be formulated in ways that permitted experimental designs that were practicable and potentially fruitful; as we know, that skill is an essential ingredient for experimental research. On the other hand, if such experimental qualifications were met by me, I was ready to commit my efforts to them, even if the research topics were not in the mainstream of neuroscience research. Indeed, I liked working on issues that were not being pursued competitively, giving me the opportunity to explore such issues patiently without external pressures (except for those from the granting agencies).

That style of research was begun with my initial efforts as Gerard’s pupil, as it also characterized much of Gerard’s pioneering research activities. The style is clearly evident in my two major lines of research during the last 35 years, especially so in the one on brain processes in conscious experience. I was told a number of times, in the responses from granting agencies (the National Institutes of Health and the National Science Foundation) and by some leading neuroscientists, especially by behavioristic psychologists, that I was not working on a properly fruitful subject. On the other hand, a large number of the internationally prominent figures in neuroscience expressed strong interest in and approval of my work on the physiology of subjective experience. I also received antagonism from some philosophers; but, again, the interest and appreciation from others (including Stephen Pepper, Karl Popper, Thomas Nagel, and Martin Edman) served as a comforting counterbalance. Actually, I was surprised at the degree and nature of the opposition to this experimental plunge into the fundamental problem of mind-brain interaction. Happily, there has been in recent years a growing and widespread interest in the nature of consciousness. This interest has been accompanied by a wider recognition that our work provided one of the few direct and fruitful experimental attacks on the problem.

I am delighted with the growth of interest in the issues of brain and conscious experience. I would still like to continue with some experimental research in this fascinating area, but that will be contingent on my own energy levels and on the availability of facilities, collaborators, and suitable subjects. I had indeed begun, in 1992 to 1993, to try for a study that might provide a rigorous test of my hypothesis that unconscious and conscious functions can be mediated in the same cerebral areas. That effort was abruptly stopped by my having to undergo major surgery in late 1993, but I hope to get back to that experimental program. I am, however, currently attempting to write a book that will be addressed to a general audience about my work on conscious experience.

Of course, research, writing, and lecturing are not all there is to living. I have been fortunate to have a loving interaction with my family and warm relations with friends, both scientific and other. Music has been important in my family and continues to be a major source of pleasure. My four children play stringed instruments, with a high level of musicality. We have a cellist (Julian), violist (Moreen), and two violinists (Ralph and Gayla). My wife Fay is an accomplished pianist, and I have been a singer. Indeed, it was through her piano and my singing that we first met, in 1936. When we were in Australia in 1957 with Eccles, our cellist son Julian (then 15), my wife, and I entered an audition by the Australian Broadcasting Commission. We were selected to perform on the national radio network; I appeared in three programs, Julian in two of these, and Fay also in the third, billed as a Libet family recital. My wife Fay has, by her example, helped to expand my appreciation of the artistry in music to that in paintings, sculpture, and ceramics. I have always felt that my scientific research involved a strong element of artistic creativity, especially in the intuitive nature of the hypotheses and experimental designs; such feelings have also been expressed by some other scientists about their work.

Selected Publications

Slow Synaptic Actions

Ashe JH, Libet B. Orthodromic production of non-cholinergic slow depolarizing response in superior cervical ganglion of rabbit. J Physiol 1981a;320:333–346. (E)

Ashe H, Libet B. Modulation of slow postsynaptic potentials by dopamine in rabbit sympathetic ganglion. Brain Res 1981b;217:93–106. (E)

Ashe JH, Libet B. Pharmacological properties and monoaminergic mediation of the slow IPSP, in mammalian sympathetic ganglion. Brain Res 1982;242:345–349. (E)

Ashe JH, Libet B. Effect of inhibitors of protein synthesis on dopamine modulation of the slow-EPSP, in rabbit superior cervical ganglion. Brain Res 1984;290:170–173. (E)

Eccles RM, Libet B. Origin and blockade of the synaptic responses of curarized sympathetic ganglia. J Physiol 1961;157:484–503. (E)

Hashiguchi T, Ushiyama N, Kobayashi H, Libet B. Does cyclic GMP mediate the slow excitatory postsynaptic potential: comparison of changes in membrane potential and conductance. Nature 1978;271:267–268. (E)

Hashiguchi T, Kobayashi H, Tosaka T, Libet B. Two muscarinic depolarizing mechanisms in mammalian sympathetic neurons. Brain Res 1982;24:378–383. (E)

Kobayashi H, Libet B. Generation of slow postsynaptic potentials without increases in ionic conductance. Proc Natl Acad Sci USA 1968;60:1304–1311. (E/T)

Kobayashi H, Libet B. Actions of noradrenaline and acetylcholine on sympathetic ganglion cells. J Physiol 1970;208:353–372. (E)

Kobayashi H, Libet B. Is inactivation of potassium conductance involved in slow postsynaptic excitation of sympathetic ganglion cells? Effects of nicotine. Life Sci 1974;14:1871–1883. (E/T)

Libet B. Slow synaptic responses and excitatory changes in sympathetic ganglia. J Physiol 1964;174:1–25. (E)

Libet B. Long latent periods and further analysis of slow synaptic responses in sympathetic ganglia. J Neurophysiol 1967;30:494–514. (E)

Libet B, Tosaka T. Slow postsynaptic potentials recorded intracellularly in sympathetic ganglia. Federation Proc 1966;25(2):270. (E)

Libet B, Chichibu S, Tosaka T. Slow synaptic responses and excitability in sympathetic ganglia of the bullfrog. J Neurophysiol 1968;31:383–395. (E)

Libet B, Tosaka T. Slow inhibitory and excitatory postsynaptic responses in single cells of mammalian sympathetic ganglia. J Neurophysiol 1969;32:43–50. (E)

Libet B, Kobayashi H. Generation of adrenergic and cholinergic potentials in sympathetic ganglion cells. Science 1969;164:1530–1532. (E)

Libet B, Tosaka T. Dopamine as a synaptic transmitter and modulator in sympathetic ganglia; a different mode of synaptic action. Proc Natl Acad Sci USA 1970;87:667–673. (E/T)

Libet B. Generation of slow inhibitory and excitatory postsynaptic potentials. Federation Proc 1970;29:1945–1956. (T/R)

Libet B, Owman C. Concomitant changes in formaldehyde-induced fluorescence of dopamine interneurones and in slow inhibitory post-synaptic potentials of rabbit superior cervical ganglion, induced by stimulation of preganglionic nerve or by a muscarinic agent. J Physiol (Lond) 1974;237:635–662. (E)

Libet B, Kobayashi H. Adrenergic mediation of the slow inhibitory postsynaptic potential in sympathetic ganglia of the frog. J Neurophysiol 1974;37:805–814. (E)

Libet B, Kobayashi H, Tanaka T. Synaptic coupling into the production and storage of a neuronal memory trace. Nature 1975;258(5531):155–157. (E/T)

Libet B. Slow postsynaptic responses in sympathetic ganglion cells, as models for the slow potential changes in the brain. In: Otto D, ed. Multidisciplinary perspectives in event-related brain potential research. Washington, D.C.: U.S. Environmental Protection Agency 600/9-77-043, Superintendent of Documents, 1978;12–18. (T)

Libet B. Dopaminergic synaptic processes in the superior cervical ganglion: models for synaptic actions. In: Horn A, Korf J, Westerink BHC, eds. The neurobiology of dopamine. London: Academic Press, 1979;453–474. (T/R)

Libet B. Which postsynaptic action of dopamine is mediated by cyclic AMP? Life Sci 1979;24:1043–1058. (T/R)

Libet B. Slow synaptic actions in ganglionic functions. In: Brooks CM, Koizumi K, Sato A, eds. Integrative functions of the autonomic nervous system. Tokyo and Amsterdam: Elsevier/North Holland Biomedical Press, 1979;197–222. (R/T)

Libet B. Functional roles of SIF cells in slow synaptic actions. In: Eränkö S, Soinila S, Paivarinta H, eds. Histochemistry and cell biology of autonomic neurons, SIF cells, and paraneurons. New York: Raven Press, 1980;111–118. (R/T)

Libet B. Heterosynaptic interaction at a sympathetic neurone as a model for induction and storage of a postsynaptic memory trace. In: Lynch G, McGaugh JL, Weinberger NM, eds. Neurobiology of learning and memory. New York: Guilford Press, 1984;405–430. (T/R)

Libet B. Mediation of slow-inhibitory postsynaptic potentials. Nature 1985;313:161–162. (T)

Libet B. Nonclassical synaptic functions of transmitters. Federation Proc 1986;45:2678–2686. (T)

Libet B. Mediation of non-classical postsynaptic responses by cyclic nucleotides. In: Avoli M, Reader TA, Dykes RW, Gloor P, eds. Neurotransmitters and cortical function. From molecules to mind. New York: Plenum Press, 1988; 453–470. (T/R)

Libet B, Mochida S. Long-term-enhancement (LTE) of post-synaptic potentials following neural conditioning, in mammalian sympathetic ganglia. Brain Res 1988;473(2):271–282. (E)

Libet B. Introduction to slow synaptic potentials and their neuromodulation by dopamine. Can J Physiol Pharmacol 1992;70(suppl):S3–Sll. (R/T)

Mochida S, Libet B. Synaptic long-term-enhancement (LTE) induced by heterosynaptic neural input. Brain Res 1985;329:360–363. (E)

Mochida S, Kobayashi H, Libet B. Stimulation of adenylate cyclase in relation to dopamine-induced long-term-enhancement (LTE) of muscarinic depolarization, in rabbit superior cervical ganglion. J Neurosci 1987;7:311–318. (E)

Mochida S, Libet B. Postsynaptic long-term-enhancement (LTE) by dopamine may be mediated by Ca²⁺ and calmodulin. Brain Res 1990;513:144–148. (E)

Tosaka T, Chichibu S, Libet B. Intracellular analysis of slow inhibitory and excitatory postsynaptic potentials in sympathetic ganglia of the frog. J Neurophysiol 1968;31:396–409. (E)

Tosaka T, Tasaka J, Miyazaki T, Libet B. Hyperpolarization following the activation of K⁺ (M) channels by excitatory postsynaptic potentials. Nature 1983;305(5930):148–150. (E)

Brain and Conscious Experience

Libet B, Alberts W, Wright E, Delattre L, Levin G, Feinstein B. Production of threshold levels of conscious sensation by electrical stimulation of human somatosensory cortex. J Neurophysiol 1964;27:546–578. (E)

Libet B. Cortical activation in conscious and unconscious experience. Perspect Biol Med 1965;9:77–86. (T)

Libet B. Brain stimulation and the threshold of conscious experience. In: Eccles JC, ed. Brain and conscious experience. New York: Springer-Verlag, 1966; 165–181. (T/R)

Libet B, Alberts WW, Wright EW, Feinstein B. Responses of human somatosensory cortex to stimuli below threshold for conscious sensation. Science 1967;158:1597–1600. (E)

Libet B, Alberts WW, Wright EW, Feinstein B. Cortical and thalamic activation in conscious sensory experience. In: Somjen GG, ed. Neurophysiology studied in man. Amsterdam: Excerpta Medica, 1972;157–168. (T)

Libet B. Electrical stimulation of cortex in human subjects and conscious sensory aspects. In: Iggo A, ed. Handbook of sensory physiology. Berlin: SpringerVerlag, 1973;743–790. (T/R)

Libet B, Alberts WW, Wright EW, Lewis M, Feinstein B. Cortical representation of evoked potentials relative to conscious sensory responses and of somatosensory qualities—in man. In: Kornhuber HH. The somatosensory system. Stuttgart: Thieme, 1975;291–308. (E/T/R)

Libet B. Neuronal vs. subjective timing, for a conscious sensory experience. In: Buser PA, Rougeul-Buser A, eds. Cerebral correlates of conscious experience. Amsterdam: Elsevier/North Holland Biomedical Press, 1978;69–82. (T)

Libet B, Wright EW Jr, Feinstein B, Pearl DK. Subjective referral of the timing for a conscious sensory experience: a functional role for the somatosensory specific projection system in man. Brain 1979;102:191–222. (E)

Libet B. The experimental evidence for subjective referral of a sensory experience backwards in time: reply to P.S. Churchland. Philos Sci 1981;48:182–197. (T)

Libet B. Brain stimulation in the study of neuronal functions for conscious sensory experiences. Hum Neurobiol 1982;1:235–242. (T)

Libet B, Wright EW, Gleason C. Readiness-potentials preceding unrestricted “spontaneous” vs. pre-planned voluntary acts. Electroencephalogr Clin Neurophysiol 1982;54:322–335. (E)

Libet B, Wright EW Jr, Gleason CA. Preparation-or-intention-to-act, in relation to pre-event potentials recorded at the vertex. Electroencephalogr Clin Neurophysiol 1983;56:367–372. (E)

Libet B, Gleason CA, Wright EW, Pearl DK. Time of conscious intention to act in relation to onset of cerebral activities (readiness-potential): the unconscious initiation of a freely voluntary act. Brain 1983;106:623–642. (E)

Libet B. Unconscious cerebral initiative and the role of conscious will in voluntary action. Behav Brain Sci 1985;89:567–615. (T)

Libet B. Consciousness: conscious, subjective experience. In: Adelman G, ed. Encyclopedia of neuroscience. Boston: Birkhauser, 1987;271–275. (R)

Libet B. Are the mental experiences of will and self-control significant to performance of a voluntary act? Response to commentaries by L. Deecke “The natural explanation for the two components of the readiness potential” and by R.E. Hoffman and R.E. Kravitz “Feedforward action regulation and the experience of will.” Behav Brain Sci 1987;10(4):781–786.

Libet B. Conscious subjective experience and unconscious mental functions: a theory of the cerebral processes involved. In: Cotterill RMJ, ed. Models of brain function. Cambridge: Cambridge University Press, 1989;35–49. (T)

Libet B, Pearl DK, Morledge DM, Gleason CA, Hosobuchi Y, Barbaro NM. Control of the transition from sensory detection to sensory awareness in man by duration of a thalamic stimulus. Brain 1991;114:1731–1757. (E)

Libet B, Wright EW, Feinstein B, Pearl DK. Retroactive enhancement of a skin sensation by a delayed cortical stimulus in man: evidence for delay of a conscious sensory experience. Consc Cognition 1992;1:367–375. (E)

Libet B. The neural time-factor in perception, volition, and free will. Rev de Metaphysique et de Morale 1992a;97:255–272. (T)

Libet B. Voluntary acts and readiness potentials. Electroencephalogr Clin Neurophysiol 1992b;82:85–86.

Libet B. The neural time-factor in conscious and unconscious events. In: Experimental and theoretical studies of consciousness, Ciba Foundation Symposium #174. 1993a;123–146. (T/R)

Libet B. Neurophysiology of consciousness. Selected papers and new essays by Benjamin Libet. Boston: Birkhauser, 1993b. (E/T/R)

Libet B. A testable field theory of mind-brain interaction. J Consciousness Stud 1994;1(1):119–126. (T)

Libet B. Neural time factors in conscious and unconscious mental functions. In: Hameroff SR, Kaszniak AW, Scott AC, ed. Toward a scientific basis for consciousness. Cambridge: MIT Press (in press), 1996. (T/R)

Libet B. Neural processes in the production of conscious experience. In: Velmans M, ed. The science of consciousness. London: Routledge (in press), 1996. (T/R)

Additional Topics

Eccles JC, Libet B, Young RR. The behavior of chromatolyzed motoneurones studied by intracellular recording. J Physiol 1958;143:11–40. (E)

Elliott KAC, Libet B. Studies on the metabolism of brain suspensions I. Oxygen uptake. J Biol Chem 1942;143:227–246. (E)

Elliott KAC, Scott DBM, Libet B. Studies on the metabolism of brain suspensions II. Carbohydrate utilization. J Biol Chem 1942;146:251–269. (E)

Elliott KAC, Libet B. Oxidation of phospholipid catalyzed by iron compounds with ascorbic acid. J Biol Chem 1944;152:617–626. (E)

Feinstein B, Gleason CA, Libet B. Stimulation of locus coeruleus in man. Preliminary trials for spasticity and epilepsy. Stereotact Funct Neurosurg 1989;52(1):26–41. (E)

Gerard RW, Libet B. On the unison of neurone beats. Livro de Homenagem aos Prof Alvaro e Miguel de Almeida. Rio de Janeiro, 1939;288–294. (T)

Gerard RW, Libet B. The control of normal and “convulsive” brain potentials. Am J Psychiatry 1940;129:404–405. (E/T)

Gerard RW, Libet B, Cavenaugh D. Cholinesterase activity of intact nerve; DFP inhibition. Federation Proc 1949;8:55–56. (E/T)

Kaitin KI, Bliwise DL, Gleason C, Nino-Murcia G, Dement WC, Libet B. Sleep disturbance produced by electrical stimulation of the locus coeruleus in a human subject. Biol Psychiatry 1986;21:710–716. (E)

Libet B, Gerard RW. Automaticity of central neurons after nicotine block of synapses. Proc Soc Exp Biol Med 1938;38:886–888. (E/T)

Libet B, Gerard RW. Control of the potential rhythm of the isolated frog brain. J Neurophysiol 1939;2:153–169. (E)

Libet B, Gerard RW. Steady potential fields and neurone activity. J Neurophysiol 1941;4:438–455. (E)

Libet B, Fazekas JF, Himwich HE. The electrical response of the kitten and adult cat brain to cerebral anemia and analeptics. Am J Physiol 1941;132:232–238. (E)

Libet B, Elliott KAC. An iron-protein complex obtained from liver. J Biol Chem 1944;152:613–615. (E)

Libet B. Enzyme localization in the giant nerve fiber of the squid. Biol Bull 1948a;95:277–278. (E/T)

Libet B. Adenosinetriphosphatase (ATP-ase) in nerve. Federation Proc 1948b;7:72. (E/T)

Libet B, Wright EW. Facilitation at neuromuscular junctions by stretch of muscle. Federation Proc 1952;11:94. (E)

Libet B, Feinstein B, Wright EW Jr. Tendon afferents in autogenic inhibition in man. Electroencephalogr Clin Neurophysiol 1959;11:129–140. (E)

Libet B, Gerard RW. An analysis of some correlates of steady potentials in mammalian cerebral cortex. Electroencephalogr Clin Neurophysiol 1962;14:445–452. (E)

Libet B, Siegel BV. Response of a virus-induced leukemia in mice to high oxygen tension. Cancer Res 1962;22:737–742. (E)

Libet B, Gleason C, Wright EW Jr, Feinstein B. Suppression of an epileptiform type of electro-cortical activity by stimulation in the vicinity of locus coeruleus. Epilepsia 1977;18:451–461. (E)

Libet B, Gleason CA. The human locus coeruleus and anxiogenesis. Brain Res 1994;634:178–180. (E/T)

Ralston HJ, Libet B. The question of tonus in skeletal muscle. Am J Physical Med 1953;32:85–92. (T)

Ralston HJ, Libet B. Effect of stretch on action potential of voluntary muscle. Am J Physiol 1953;173:449–455. (E)

Samuels AJ, Boyarsky LL, Gerard RW, Libet B, Brust M. Distribution, exchange and migration of phosphate compounds in the nervous system. Am J Physiol 1951;164:1–15. (E)

(E) = experimental, chiefly

(T) = theoretical, chiefly

(R) = review, chiefly

Additional Publications

Amassian VE, et al. Parasthesias are elicited by single pulse, magnetic coil stimulation of motor cortex in susceptible humans. Brain 1991;114:2505–2520.

Bliss TVP. Synaptic plasticity in the hippocampus. J Physiol (Lond) 1978;280:559–572.

Brown DA, Adams PR. Muscarinic suppression of a novel voltage-sensitive K⁺ current in a vertebrate neurone. Nature (Lond) 1980;283:673–676.

Eccles RM. Responses of isolated curarized sympathetic ganglia. J Physiol (Lond) 1952;117:196–271.

Elfvin L-G. The ultrastructure of the superior cervical sympathetic ganglion of the cat II. The structure of the preganglionic end fibers and the synapses as studied by serial sections. J Ultrastruct Res 1963;8:441–476.

Eränkö O, Eränkö L. Small intensely fluorescent granule containing cells in the sympathetic ganglion of the rat. Progr Brain Res 1971;34:39–52.

Gerard RW. Nerve metabolism. Physiol Rev 1932;12:469–592.

Jan LY, Jan YN. Peptidergic transmission in sympathetic ganglia of the frog. J Physiol (Lond) 1982;327:219–246.

Jan YN, Jan LY, Kuffler SW. A peptide as a possible transmitter in sympathetic ganglia of the frog. Proc Natl Acad Sci USA 1979;76:1501–1505.

Kandel ER, Spencer WA, Brinley FJ. Electrophysiology of hippocampal neurons I. Sequential invasion and synaptic organization. J Neurophysiol 1961;24:225–242.

Keller I, Heckhausen H. Readiness potentials preceding spontaneous motor acts, voluntary and involuntary control. Electroencephalogr Clin Neurophysiol 1990;76:351–361.

Kobayashi H, Hashiguchi T, Ushiyama NS. Postsynaptic modulation of excitatory process in sympathetic ganglia by cyclic AMP. Nature (Land) 1978;271:268–270.

Kornhuber HH, Deecke L. Hirnpotentialänderungen bei Willkürbewegungen und passiven Bewegungen des Menschen: Bereitschaftpotential und reafferente potentiale. Pfiugers Arch 1965;284:1–17.

Laporte Y, Lorente de Nó R. Potential changes evoked in a curarized sympathetic ganglion by presynaptic volleys of impulses. J Cell Comp Physiol 1950;35(2):61–106.

Leão AAP. Further observations on the spreading depression of activity in the cerebral cortex. J Neurophysiol 1947;10:409–414.

Leão AAP. The slow voltage variation of cortical spreading depression of activity. Electroencephalogr Clin Neurophysiol 1951;3:315–321.

Lindahl BIB, Århem P. Mind as a force field: comments on a new interactionist hypothesis. J Theor Biol 1994;171:111–122.

Ling G, Gerard RW. The normal membrane potential of frog sartorius fibers. J Cell Comp Physiol 1949;34:383–396.

Nishi S, Koketsu K. Early and late after-discharges of amphibian sympathetic ganglion cells. J Neurophysiol 1968;31:109–121.

Popper KR, Lindahl BIB, Århem PA. A discussion of the mind-brain problem. Theor Med 1993;14:167–180.

Skou JC. Enzymatic basis for active transport of Na⁺ and K⁺ across cell membrane. Physiol Rev 1965;45:596–617.

Williams THW. Electronmicroscopic evidence for an autonomic interneuron. Nature (Lond) 1967;214:309–310.

Louis Sokoloff

BORN:

Philadelphia, Pennsylvania

October 14, 1921

EDUCATION:

University of Pennsylvania, B.A., 1943

University of Pennsylvania, M.D., 1946

Philadelphia General Hospital, Internship, 1946

APPOINTMENTS:

University of Pennsylvania (1949)

National Institute of Mental Health (1953)

HONORS AND AWARDS (SELECTED):

American Society for Neurochemistry (President, 1977–1979)

National Academy of Sciences USA (1980)

Albert Lasker Clinical Medical Research Award (1981)

American Academy of Arts and Sciences (1982)

Association for Research in Nervous and Mental Disease (President, 1983)

Karl Lashley Award (American Philosophical Society, 1987)

Louis Sokoloff began his scientific career as a student of Seymour Kety, and went on to develop the 2-deoxyglucose technique for measuring quantitatively regional metabolism in the brain. This led directly to the invention of revolutionary noninvasive methods for functional imaging of the human brain.

Louis Sokoloff

It is with some uneasiness that I undertake the preparation of an autobiography. For 45 years, I have been totally immersed in scientific research and have written many scientific articles in the traditional style, which required that a report be impersonal with only its scientific content of consequence. Indeed, I still shrink from the use of personal pronouns and rely heavily on the passive voice. This is the tradition, probably more idealistic than realistic, in which only truth, and not people, is of significance. Rigorous attention to accuracy and proper documentation is paramount. In this autobiographical sketch, I am forced to rely on memory, and I learned at a 1995 meeting of the Association for Research on Nervous and Mental Diseases on learning and memory that recalled memory may be more imaginative than real. Nevertheless, my commitment is made, my task is clear, and I shall do my best to relate those events in my life that are of significance to my career as a neuroscientist with as little distortion of the truth and as much freedom from self-serving bias as I can achieve.

Origins and Early Years

Like almost all my American colleagues of a “certain age,” which I shall not define, I belonged to the generation that President Franklin D. Roosevelt had labeled in his initial inaugural speech as one that had a “rendezvous with destiny.” We were certainly influenced, indeed shaped, by the momentous and historic events that evolved during the most critical periods of our physical and intellectual development. In our childhood and adolescence, we lived through the Great Depression, and then, as we were emerging from that economic crisis and entering young adulthood, we were confronted with the challenges of World War II. I believe that it is a fair statement that nothing in my personal, intellectual, and professional life was not directly or indirectly influenced or derived from the impact of those cataclysmic events.

I was born in Philadelphia, Pennsylvania, the second son of immigrant parents. My father had emmigrated alone as a young man from the Ukraine in 1912. No one else from his family ever came; he left a mother and sister there whom I never met, with whom I never had any contact, and whose fate is unknown to me. He came from a city, perhaps a village, that was then known as Elisavetgrad but, according to my current Russian postdoctoral fellow, is now the city of Kirovograd. My mother, the oldest of six children, had quite independently also arrived in the United States in 1912. She accompanied her father from a town now in Poland that was then just on the Russian side of the border between Russia and Germany; I do not recall its name. Her mother, four sisters, and a baby brother were brought over shortly afterward. All had emmigrated to the United States to escape czarist persecution and the ravages of pogroms, which they were reluctant to describe but to which they occasionally alluded. My parents met in Philadelphia not long after their arrival and married; my brother was born in 1915, and I in 1921. It was about 1924 that my father attained American citizenship; my mother became a citizen some time later.

I was born at home in a row house in South Philadelphia, which we owned and in which we lived until we lost it during the Great Depression when I was about 11 or 12. The physician who delivered me remained our family doctor until I was in medical school. South Philadelphia is notorious as a tough neighborhood. Its residents were largely poor and working class; many were immigrants or first generation Americans, and they represented a variety of national origins: German, Hungarian, Irish, Italian, Polish, and Russian. The residents of our street were mainly, but not exclusively Jews, both native born and of Eastern European origin. I can recall no evidence of tension among the ethnic groups living in the immediate neighborhood, but we did have street gangs that engaged in fights that were more territorial than racial, ethnic, or religious. I belonged to the Third Street Gang, and we had prearranged rumbles with the American Street (the next street) gang. Our weapons were halves of broken paper clips fired from rubber bands. Such street battles were held until one of the participants lost an eye in a battle.

The most prominent influence in my early years was the emphasis my parents placed on education. Neither had had much formal education. My father’s formal education ended when he was about 12 and was forced to work to support his mother and sister after his father’s death. It was then that he learned the tailoring trade that helped us to survive during the depression years. My mother, as the oldest daughter, had learned to keep house, which she did very well; she kept an immaculate home and was an outstanding cook, which, except for her two sons, was the source of her greatest pride. Possibly because of their lack of education, they valued their childrens’ education above all else. They could not help us directly but gently coerced my brother and me to do our homework and to do well in school, and we did. I vividly remember my grandfather asking me what I wanted to be when I grew up. At that age, of about 5 to 10 years, it was probably something that we considered heroic, such as a cowboy, policeman, or sports hero. His response never left me. He advised me to choose a profession, any one, in which all my significant possessions would reside in my mind because, being Jewish, sooner or later I would be persecuted and would lose all my material possessions; what was contained in my mind, however, could never be taken from me and would accompany me everywhere to be used again.

Emphasis on education and Americanization permeated the home atmosphere. Though both my parents spoke Russian, they never did so to my brother and me, something that I strongly regret. I do recall a Russian phrase, which as a child I had heard my father exclaim when he had hit his finger with a hammer while hanging a picture. I have since learned its meaning; it is not repeatable here. That probably explains why I never heard my father use any vulgar or improper expletives in English; he resorted to Russian, which the children did not understand. We did speak some Yiddish at home, which I used mainly to converse with my grandparents, and I also learned to read Yiddish newspapers. To my regret, my knowledge of Yiddish was almost completely erased when I later studied German in college. I became fluent in German and comfortably conversed with my grandfather, but when I later made a serious effort to learn French, it more or less displaced the German. Apparently my brain is capable of retaining only one foreign language at a time.

My earliest memory of gifts given me by my parents is of two used volumes of the Baldwin Reader and a worn faded copy of a book titled First Steps in the History of Our Country, which my father had bought at Leary’s Bookstore, then the oldest bookstore in the United States. The book cover was maroon in color, and on its front was an oval cameo of the head of George Washington in profile. Each chapter of the book was devoted to a historic figure who had contributed in some way to American history; among them were Washington, Jefferson, Lincoln, Jackson, Grant, and Boone. The story that had the longest and strongest affect on me was the one on James Wolfe, the general who led the English army in the capture of Quebec and ended the French and Indian War in 1759. The chapter describes how on the evening before the decisive battle, Wolfe sat on the deck of a boat that went back and forth on the St. Lawrence River ferrying the English troops to Wolfe’s Cove, where they could scale the heights to the Plain of Abraham above. Sitting on the deck surrounded by his staff, Wolfe repeated over and over again the following verse:

The boast of heraldry, the pomp of pow’r,

And all that beauty, all that wealth e’er gave,

Await alike the inevitable hour.

The paths of glory lead but to the grave.

Finally, after the last boatload of troops had disembarked and the first lights of dawn were breaking in the east, Wolfe arose and stated, “Gentlemen, I would rather have written that verse than take Quebec today.” What impressed me most was the final sentence of the chapter, “No one responded because none dared to say that the soldier was greater than the poet.” Obviously, I was taken by the story and the verse, for I still remember it after so many years. Some time later I learned that the verse was from Gray’s “Elegy Written in a Country Churchyard” and was struck by another of its verses,

Full many a gem of purest ray serene

The dark unfathomed caves of ocean bear.

Full many a flower is born to blush unseen

And waste its sweetness on the desert air.

The fatalism in the poem’s message resonated in me. Perhaps because of my genetic make-up, cultural heritage, or early experiences in a difficult time, I developed a pessimism and stoicism that has always led me to hope and work for the best but to expect the worst, and, in the words of Rudyard Kipling, to “meet with triumph and disaster and treat those two impostors just the same.” This may come as a surprise to those who have served in my laboratory because I always tried to exhibit to them a spirit of optimism in the conduct of research. In directing a research project, I always revealed to my co-workers the potential and anticipated obstacles only one at a time because I have seen good ideas too often throttled at conception because of intimidation by anticipated problems to be solved.

As soon as I learned how, I read avidly and broadly, an activity facilitated by proximity to a branch of the Philadelphia Public Library about a block away from our home. William Penn’s original design of the city specified that streets be arranged in checkerboard fashion with each block 0.1 mile in length.

I studied hard and did well at school, but my greatest passion was baseball. I followed the fortunes, or more often the misfortunes, of the Philadelphia Athletics, now in Oakland, and the Philadelphia Phillies. My heros were Al Simmons, Mickey Cochrane, Jimmy Foxx, and Lefty Grove of the A’s and Chuck Klein of the Phillies. Although I was small for my age, I tried to participate in the sport and was a mediocre second baseman or shortstop on a boys’ neighborhood baseball team, the Centennials. We could not afford uniforms and settled instead for blue baseball caps with a white C on them. The name was probably suggested by the sesquicentennial celebration of the Declaration of Independence in Philadelphia in 1926.

The Depression and Secondary School Years

It would have been nearly impossible to grow up in an industrialized area like Philadelphia during the Great Depression without developing serious misgivings about an economic system that created and allowed the severe injustices and hardships inflicted on a major portion of the population. From the age of eight and continuing through my teens, I was witness to large numbers of proud and able-bodied men reduced to begging; masses of people going hungry; professionally trained people selling pencils, shoelaces, apples, anything to earn enough to feed themselves and their families. I will never forget the beggar who rang our doorbell one evening, and when presented with a penny, he returned it and asked for food instead because he was hungry; he then ravenously consumed the food that my mother offered him in our kitchen. Experiences such as these stimulated in me an intense interest in political affairs, economic issues and systems, and history, particularly of modern Europe. I zealously read newspapers, news magazines, any periodicals that I could find in the public library, and followed with trepidation the rise of Nazism in Germany, the invasion of Abyssinia by the fascist forces of Italy, and the twilight of the League of Nations. Many of my school and neighborhood friends and acquaintances became inquisitive about and experimented with economic systems alternative to capitalism. I myself developed an interest in the platforms of the Socialist Party led by Norman Thomas and often argued vociferously but unsuccessfully with my father, a loyal Democrat, that he should vote Socialist. Some of my classmates actually joined the Young Communist League (YCL). Fortuitously in the light of later events, that is, the period of MacCarthyism in the United States when I came to work for the Federal Government at the NIH, I managed to avoid joining any politically active organization. My participation in political affairs was more intellectual than activist. That was probably because I was fervently anti-communist, and on the basis of my own experiences and those of my communist colleagues, I was wary of the danger that organizations with ostensibly respectable and desirable goals, such as the American Youth for Democracy (AYD), the Association of lnterns and Medical Students (AIMS), and the Association of Scientific Workers (ASW), were, in fact, a front for the promulgation of communist ideology and goals, which I believed to be mainly foreign policy objectives of the Soviet Union.

Our family did not escape the ravages of the depression. My father was employed as a finisher of fur coats—one who sewed linings in the coats—in the firm Mawson, DeMany, and Forbes. Luxury items like fur coats were hardly in fashion during the depression. The company was forced out of business, and my father was then unemployed at a time when there was still no social security or unemployment insurance in the United States. As a result, we lost the house because of inability to pay the real estate taxes, and when I was 10 or 11 and in the fifth or sixth grade, we moved to a much smaller rented house. It was only about three or four blocks from the previous home, and I did not have to change schools. The move was, nevertheless, traumatic. It meant leaving old and familiar friends with whom I had grown up, socialized, and played baseball and other games. It meant becoming a stranger in a new milieu where I would have to make new acquaintances and friends, a difficult prospect for me at the time because I was shy and introverted. It was, of course, a trivial experience compared to that of my parents who had to leave members of their family and emigrate to a new country with a new language, but I did not think of that then. It turned out, however, to be a fortunate move for me, for it did eventually have favorable consequences for my future intellectual development.

The new home was located on a small side street where it was easy for the residents to know and associate with one another. The row houses had open front porches, which the residents used to escape the oppressive heat and humidity of summer evenings. They also sat in rocking chairs on the sidewalk to catch the breezes. Air-conditioning was found only in movie houses and department stores. Most of the families, therefore, knew each other quite well, were often friends, and frequently helped one another through financial and other crises that were so frequent during the depression.

Five houses down from us on the same side of the street there lived a man, Israel Abrams, who was in his twenties and taught mathematics first in a junior high school and then in a high school in the Philadelphia public school system. He was one of those who often sat on his front porch, and perhaps because he had learned that I was a serious student, he took an interest in me, my studies, and my ambitions. By the time I met him, my interest in science, particularly biology, had already been more or less fixed, and he guided and advised me in my reading and thinking about science. Abrams was also an avid tennis player, and when I was about 12, he gave me a tennis racquet that he was replacing. That introduced me to a sport that I once passionately pursued and still enjoy. Tennis lessons were unaffordable, but I tried to model my game after those of touring professionals who annually played at the Philadelphia Convention Hall. Among them were Ellsworth Vines, whose service style I imitated, Fred Perry, whose forehand I tried to copy, and Don Budge, whose incredible backhand I tried unsuccessfully to emulate. Unlike my experience in baseball, I did develop some skills in tennis, enough at least to play in the number one singles position on my high school tennis team for three years. However, our team perpetually occupied last place in both the Public High School and Interscholastic Leagues, and I won only three matches in those three years. One of my losses was to Victor Seixas, who was then the National Boys’ Champion and later won championships at Wimbledon and Forest Hills and who, with Tony Trabert, brought the Davis Cup back from Australia to the United States.

My interest in biology began at an early age when my brother set up a balanced aquarium of tropical fish, plants, snails, and so on. I was intrigued by that community of living things and spent hours observing it as well as reading about aquarium animals and plants. I studied the anatomy, classifications, habitats, and diseases of fish and aquatic plants, and I still have a card file on the various species used in aquaria. There was a time when I thought of becoming an ichthyologist but was dissuaded from that by Abrams. My reading then expanded to biology and science as a whole. Like many of my generation, I was greatly influenced by Paul De Kruif’s Microbe Hunters, as well as by Donald C. Peattie’s Green Laurels and Eric Nordenskiöld’s History of Biology. Another book that I spent hours reading was Chemistry in Medicine; it was distributed free by the Chemical Rubber Company by request on a penny post card. Each chapter in the book was devoted to a specific medical or biological problem and described the research that had contributed to its solution, such as discovery of vitamins and the cause and cure of pellagra, the development of germ theory, and the work of Pasteur, Koch, and Metchnikoff. A life spent in biological research then seemed attractive, and that goal was encouraged by Abrams.

The depression was severe during my years in the secondary schools, but it nevertheless had a salutary effect on the quality of my education. Jobs were scarce, but teaching positions in the Philadelphia public schools were among the best and eagerly sought. Consequently, we had excellent and dedicated teachers, a number of whom had doctoral degrees. Some had left university faculty positions because of the better salaries and security in the public school system. From Furness Junior High School I particularly remember Mrs. Micocci, whose enthusiasm and good humor made even the writing of English compositions relatively painless; Mr. Paravacini and Mr. Kappel, who made the study of mathematics fun; Mr. Kaplan’s stimulating classes in history made even more vivid and relevant by the momentous events in Europe precipitated by the antics of the Nazis in Germany and the Fascists in Italy; and the patience, dedication, and innovativeness of Miss Lynn, who taught us General Languages and Latin. I had no skill at all in art, and as hard as he tried, Mr. Koppelman could detect no trace of artistic talent in me. The effectiveness of the teaching was enhanced by the nature of the student body. Most of us were from immigrant families imbued with the virtues and importance of education. There were almost no disciplinary problems; the few that occurred were dealt with quickly, firmly, and decisively.

I later attended the South Philadelphia High School for Boys. There had once been only one high school, but the boys and girls were separated into two schools because of the high incidence of illegitimate pregnancies. It was a tough school in a tough neighborhood and fully consistent with the national reputation of South Philadelphia. The school was located in an area known as “Little Italy” because of its large population of Italian immigrant families, mostly from Sicily and Naples. The student body, however, was multiethnic and multiracial and included Poles, Russians, Irish, Jews, Germans, an occasional black, and sometimes even one of Anglo-Saxon origin. Marian Anderson had gone to the girl’s high school, and Mario Lanza, then known as Alfredo Cocozza, was there two years ahead of me. Despite its reputation for toughness, it was an excellent school, second in academic standing only to Central High School, which was located in central city and was limited to specially qualified students. There were many students in our school, including me, who could have qualified but never applied because they could not afford the trolley fares needed for transportation. School buses were then available only for handicapped children, many of whom went to special schools. Unlike my junior high school, this school required faculty who were not only good teachers but also strict disciplinarians, and they were firm and strict indeed. The principal was Frank Nieweg, which in German means “never away,” and he lived up to his name. He did not hesitate to suspend or even expel students who did not adhere to accepted codes of behavior. Even smoking on school grounds was cause for suspension. Requirements were high, grading was severe, and teachers did not hesitate to fail students who did not meet the standards. George Kimmelman, who taught senior class English, routinely failed about onethird of the class in the first grading period, about a quarter in the second, and as much as 10 percent in the final grades for the term. Failure in a major subject meant repeating not only the course but the entire grade as well. Mr. Feick taught us physics, and he was extremely rigorous and demanding. On one of his examinations, I received a score of 98 with no obvious reason for the deduction of two points. Although I was happy with the grade, I was curious and inquired about the loss of the two points; it was because I had left out two commas in my examination paper. Mr. Wolfe taught us chemistry and constantly admonished us never to believe anything unless we had positive evidence to support it, certainly good advice for a budding scientist. Other more humane teachers were Dr. Eilberg, a geometry teacher, who liked to challenge us by betting us pennies that we would be unable to solve problems in geometry that he selected; I collected a lot of pennies. I particularly enjoyed Mr. Egnal, a history teacher, and, Mr. Gregory, who taught biology, probably because both served in sequential years as the coach of the tennis team of which I was a member. In my senior year, when I was concentrating on my studies to achieve the grades needed to win a Board of Education scholarship to one of the universities, I considered resigning from the tennis team; it was Mr. Gregory who dissuaded me, arguing that he himself had once faced the same dilemma and found that the athletic activities and the diversion they provided actually improved his academic performance.

The depression weighed heavily but not entirely unfavorably on my intellectual development. My father was frequently unemployed or on strike. Fortunately, his tailoring skills were sufficiently diverse so that he could find work in the manufacture of men’s suits or women’s dresses when work in the fur trade was unavailable. Most of our neighbors and school associates were in similar straits. Because we could not afford material things, my friends and I found recreation in sports and intellectual discourse. We spent many of our free hours discussing literature, history, philosophy, science, and political and social issues. We learned to construct or assemble from parts obtained cheaply in junk yards various objects that our families could not afford. For example, we built our own radios, beginning with crystal sets and progressing to short wave sets. We wound our own coils with enamel-coated wire on the cardboard cylinders from rolls of toilet tissues. I can vouch that the sound from one’s own constructed radio is far more pleasing than that from a purchased radio or hi-fi set.

The College Years

It was clear that the family finances would not support college educations for my brother and me; our only recourse was to obtain scholarships. Inasmuch as athletic scholarships were out of the question, we would have to gain them by scholastic achievement. The Philadelphia Board of Education provided two scholarships for each high school graduating class, one to the University of Pennsylvania (Penn) for the top student in the class and the other to Temple University for the second. There were also Mayor’s Scholarships to the University of Pennsylvania, which were granted on the basis of competitive examinations. My brother, who was six years ahead of me, came in third in his class and missed out on either of the Board scholarships, but the following year he won a Mayor’s Scholarship. I was more fortunate; I was first in my class and thus was also able to attend the University of Pennsylvania for the following four years.

When I entered college in September 1939, I had already decided on a career in biology. That decision was fully consistent with my previous leanings, but it was undoubtedly also influenced by the fact that my brother had majored in zoology in college. As we lived at home, I had access to his books, and while still in high school, I eagerly studied his biology textbooks. From his Guyer’s Animal Biology, I learned thoroughly the taxonomy of the animal kingdom and all the phyla and classes and, indeed, much more. I found it all fascinating. At that time, Penn had separate botany and zoology departments and offered majors in either one or the other but not in biology. I was inclined toward zoology. Job opportunities for zoologists, however, were scarce during the depression, and alternatives had to be considered. In high school I had already considered medicine or veterinary medicine as acceptable alternatives. Naively, I thought that medicine was merely applied biology.

Penn then had no specific premedical curriculum. Students interested in medicine matriculated in a liberal arts and sciences curriculum and added to the core curriculum the courses required for admission to medical school. Some of the courses in the first two years were prescribed, that is, English literature and composition, foreign language, mathematics, history or philosophy, and science. In my first two years I chose for my sciences zoology, botany, inorganic and organic chemistry, and qualitative and quantitative analytical chemistry; in subsequent years I added physics, physical chemistry, and various courses in zoology. My foreign language choice was German because before the Nazi period German science was predominant, and it was customary for scientists to spend some time studying in Germany.

Three successive semesters of English composition were required, the first one on narration, the second on description, and the third on exposition. In the first two courses, we generally had to write a composition each week. The course on exposition required us to write feature or special articles that needed more time; for example, I wrote one titled “Unclean! Unclean!” which was a history of leprosy through the ages. The standards were kept high, and the grading was rigorous. Mistakes in grammar were treated seriously. Dangling participles were unacceptable, and a run-on sentence resulted in a failing grade for the composition. This experience is probably responsible for my continued rigid insistence on proper language usage that my fellows and collaborators have known too well. There was one experience in my second semester of English composition that I still vividly recall. One of the students objected to our having to write a composition every week and asked how that would help him earn a better living. The instructor, Mr. Lee, responded, ‘’You don’t go to college to enrich your pocket book; you go to college to enrich your mind.” I fear that this sentiment is now lost in antiquity.

One memorable course was Modern European History, which lasted from September 1940 to May 1941. The first semester covered the period from the Congress of Vienna to the beginning of World War I; the second continued from then right up to the last day of the course. One-hour lectures were given at 9 a.m. every Monday, Wednesday, and Friday by William Lingelbach, an eminent historian who was also dean of the College of Arts and Sciences. A syllabus had been handed out in advance that listed the topics of each of the lectures, and the topic of the last lecture was “Europe—Subject to change without notice.” The ambiguity amused the class, for it was a time during World War II when the Nazi hordes were rampaging throughout Europe, and we were uncertain whether it was Europe or the subject of the lecture that was subject to change without notice. On the morning of the last lecture, the front-page headline of the Philadelphia Record heralded the airborne invasion of Crete by the Germans. The lecture that morning was on the battle of Crete, and it was extraordinarily scholarly and erudite; it gave a brief history of Crete and its strategic importance to both the Germans and the British in the war.

Major fields of study were selected in the second year to begin in the third year, but this choice became a family problem. I was committed to zoology, but my brother convinced my parents that opportunities for zoologists during the depression were limited and that I would have difficulty obtaining employment after graduation unless I were admitted to medical school. Admissions to medical schools, however, were then quite limited for certain minorities, such as Jews. The family recommended that I major in chemistry because prospects for employment were better for chemists than for zoologists. I resisted but agreed to a compromise. Zoology would be my major, but I would in addition choose as electives all chemistry courses required of chemistry majors. This was fortunate, for not only did I enjoy chemistry, but the background in chemistry later proved to be useful and, indeed, played a role in directing my interests toward biochemical and metabolic processes.

It was in my third year at Penn that I was exposed to my first research experience. Lewis V. Heilbrunn in the Department of Zoology taught a mixed graduate-undergraduate course in general physiology, which was essentially cellular physiology with little organ or system physiology represented. Prerequisites for the course, in addition to the basic chemical and biology courses, were physics and physical chemistry, both of which I was also taking in my third year. Because my academic record was quite good, Heilbrunn accepted me even though I had not yet completed all the prerequisite courses. It was an enlightening experience and more than anything, influenced me to choose a career in scientific research. The atmosphere was exciting, indeed exhilarating. Heilbrunn was analytical and critical, sought definitive and rigorous explanations of biological phenomena in terms of physical and chemical mechanisms, and was impatient and even brutal with loose logic. He was readily accessible to the students and seemed to revel in their company. For example, Heilbrunn and his wife, the artist Ellen Donovan, frequently held open house on Saturday nights, and his graduate and undergraduate students often congregated at their home at the end of the evening. Often there were other guests, friends, and associates of the Heilbrunns, who would add to the richness of the company. Those were highly intellectual evenings, with discussions about a variety of subjects in the arts, sciences, and humanities. The culture and life of the academic scientist seemed to be full and rich, and I was attracted to the choice of such a career.

Heilbrunn’s course extended over two semesters. It included two hours of lecture and four hours of laboratory work per week. Heilbrunn’s lectures, like his textbook (Heilbrunn, 1938), strongly espoused his ideas about the role of calcium in biological processes. Earlier work of his colleagues, D. Mazia and J.M. Clark, had stimulated some of those ideas. Heilbrunn had previously recognized the role of calcium in the maintenance of cell membrane integrity and in the regulation of intracellular protoplasmic viscosity. Mazia and Clark (1936) showed that electrical, osmotic, or mechanical stimulation and ultraviolet radiation of Elodea cells caused almost instant formation of calcium oxalate crystals in the vacuoles of the cells that were known to contain high levels of oxalic acid. The only reasonable explanation was that the stimulations were associated with an almost instantaneous rise of intracellular ionic Ca⁺⁺, probably by release from bound sites. From these and many other observations, Heilbrunn hypothesized that release of free Ca⁺⁺ was an essential component of the processes of excitation, conduction, muscular contraction, blood-clotting, secretion, and so on. These are ideas that today are almost taken for granted, but at that time Heilbrunn’s was almost a lone voice in the wilderness. He so forcefully pushed these ideas in his lectures that at the end of the final examination for the first semester of the course, one of the students led the class in a college cheer, “C-a-1-c-i-u-m! Calcium! Calcium! Calcium!”

The laboratory portion of the course consisted of a series of prescribed exercises at the beginning of each semester, followed by an original research project during the remainder of the semester. It was impossible to complete the prescribed experiments, let alone the research projects, in the time allotted to laboratory work in the roster, and students routinely returned during evenings and weekends to complete their work. Heilbrunn and his graduate students and assistants were often there, and much time was spent not only in scientific discussions but also in anecdotes related by Heilbrunn about himself and some of his famous scientific colleagues. He made all of us, even the undergraduate students, enjoy the exhilaration of being involved in the process of scientific inquiry and discovery.

My research project during the first semester was suggested by Heilbrunn. It was to determine if protoplasmic flow in the pseudopod of the amoeba obeys Poiseuille’s Law. I can quickly summarize the results: it does not. My project in the second semester was suggested by Daniel Harris, an instructor who had obtained his Ph.D. with Heilbrunn. The project was to fractionate cells and localize enzymes to the subcellular components. This was several years before the isolation of mitochondria by Hogeboom et al. (1948). The cell I chose for study was the unfertilized frog egg, probably more for economic than scientific reasons. The cells were homogenized and separated by centrifugation into plasmasol (the term used then for cytosol), lipids, yolk, and pigment fractions. We localized lipases to the lipid fraction, dipeptidases to the plasmasol, and a few other enzymes that I no longer remember. The results do not seem interesting now, but that experience in research had an important influence in shaping my goals for the future.

Its immediate effect was to persuade me to choose as an elective in my final year “Zoology 50, Undergraduate Research in Zoology.” That course enabled me to continue research with Heilbrunn. The United States was then in World War II, and Heilbrunn had obtained a grant from the U.S. Army to study effects of heat on biological systems because the British 8th Army had suffered numerous heat-related casualties in the deserts of Egypt and Libya. Most of his group were assigned to various aspects of this problem. I was given the assignment to determine in the rat sciatic nerve-gastrocnemius preparation, which was more sensitive to heat—nerve or muscle. Electrodes were applied to both the nerve and the muscle, and a lever-pen assembly to register contractions was attached to the muscle. Either the muscle, the nerve, or both were immersed in Ringer’s solution at 41°C, and alternately the nerve and the muscle were electrically stimulated until the muscle stopped contracting. When nerve alone was heated, the muscle responded to either nerve or muscle stimulation for prolonged periods. When only the muscle was heated, muscle contractions in response to nerve stimulation ceased in 5 to 10 minutes but continued to be elicited by direct faradic stimulation of the muscle for 15 minutes or longer. We concluded that the myoneural junction was the element of greatest susceptibility to heat. The observation was considered sufficiently interesting to publish, and I reviewed the literature in preparation for the writing of the manuscript. I also sought advice from others in the group. At the time, I shared an office with Paul LeFevre, who was then a graduate student and later became well known for his work on red cells. One day he alerted me to a report by Claude Bernard published in Charles Richet’s Dictionnaire de Physiologie in 1870. Bernard had done essentially the same experiments and come to the same conclusions, except that he had used oil instead of Ringer’s solution as the medium. Because the finding had already been made and reported, it was decided not to proceed with publication. How different this attitude was from those prevailing in biomedical science today; now the use of Ringer’s solution instead of oil might be considered sufficiently different to justify not only publication but the claim of a significant new discovery. Apropos differences in attitudes between then and now, Heilbrunn once remarked that anyone publishing an average of more than two full papers per year was not doing good work or doing his own work. Today, such a publication rate would probably be considered too meager to merit promotion, tenure, or the acquisition of a grant.

The exposure to scientific research with Heilbrunn caused me to reconsider the study of medicine, and I discussed with him the possibility of my applying to graduate school and seeking a Ph.D. with him. He was willing to accept me but strongly advised me to proceed to medical school. Because of the war, his graduate students were being drafted into the armed forces before achieving their degrees, but medical students were being allowed to complete their studies first. Furthermore, he noted sarcastically that an M.D. degree did not necessarily spoil one for scientific research. I took his advice and applied to the medical school at Penn. Heilbrunn sent a letter of recommendation to the Admissions Committee and told me that whenever he had sent a letter as strong as that one, the applicant was accepted. I was, indeed, admitted to the class beginning in the spring of 1943.

Medical School and Internship

To provide physicians more rapidly for the armed forces, medical schools in the United States adopted an accelerated program in which the full four-year curriculum was compressed into approximately three years. The semester system and vacations were abandoned, and courses followed one another in rapid succession. About three months after entry to the school, the military essentially took over the medical, dental, and veterinary schools. Most of us were inducted into one of the military services, most of us, including me, into the Army Specialized Training Program (ASTP) and a lesser number into the V-12 program of the Navy. Those in the Army were given the rank of Private First Class (PFC); the Navy inductees were treated as cadets. The students in the ASTP at Penn were assigned to barracks, several to a room, improvised in fraternity houses and dormitories of the university. We were trained to be soldiers, for example, to salute and to march, and were instructed in map reading, how to stop tanks, and so forth. We assembled for reveille early each morning and then marched in platoon formations to breakfast at the Palestra, the basketball arena of the university that had been renovated into a gigantic mess hall. That is where we ate all our meals or, more precisely, Army rations. The military did, however, keep hands off the educational process; curriculum and matters of medical education remained fully responsibilities of the university.

There were some benefits to the military take-over. First, the military assumed all the expenses of the medical education and even paid us $54 a month. I, almost certainly, would otherwise never have been able to finish medical school because of our limited financial resources. Secondly, it kept us out of combat, at least for a while; ASTP was sometimes said to stand for “All Safe Till Peace.” We were not comfortable with this protected status at a time when our troops were engaged in bloody battles in Europe and the South Pacific, particularly because we were easily recognized by the official shoulder patch of the ASTP that we were required to wear at the top of the left sleeve of our outer garments. The patch was a gold or orange octagon edged by a thin royal blue border. In the middle was a flaming lantern, like Aladdin’s lamp, and a vertically oriented sword, the handle pointing downward. Officially it was supposed to symbolize the sword of valor and the lamp of knowledge; we in the medical ASTP referred to it as the catheter and the flaming urinal.

Our first course in medical school was gross anatomy, followed soon afterward by histology and neuroanatomy. At first, I found the atmosphere in medical school intellectually stifling. Compared with the exciting, thought-provoking, problem-solving, and mature atmosphere of Heilbrunn’s laboratory, the rigidity of the curriculum and the treatment of the students in medical school seemed more like that in grade school. I could not develop much interest, let alone enthusiasm, in subjects that required memorization of huge amounts of descriptive, primarily visual information. My mind did not work that way; I was stimulated more by dynamic processes that could be measured and quantified. Nevertheless, I persisted, studied hard, and survived that dull period until eventually we progressed to physiology, biochemistry, and pharmacology; those were more to my liking. All three of those courses were extremely well taught by excellent teachers who often emphasized the research that unearthed the facts being presented. Unlike the present trend in medical schools, each course included hands-on laboratory experiments carried out by the students themselves. The experiments were designed to illustrate important principles. In the lectures, the methods and results of published experiments that had led to the facts being taught were described, interpreted, and critically analyzed. The enthusiasm of many of the teachers for experimental science was transmitted to the students. In physiology Henry Bazett, chairman of the department and a former student of the great physiologist, John Scott Haldane, presented heavily research-oriented lectures on cardiac physiology. He once confessed that he had done experiments on himself in every branch of physiology, except one; he drew the line at experiments involving female sex hormones. Merkel Jacobs, known for his research on diffusion and red cells, taught peripheral circulation. His clear-minded, analytical, rational approach made physiology seem as rigorous and analytical as mathematics. The biochemistry course was almost as stimulating. Most of the lectures were given by David Drabkin, whose enthusiasm was contagious, but excellent lectures were also given by others, for example, Samuel Gurin in lipid biochemistry. Drabkin lectured extensively on the physiological chemistry of diabetes and presented in great detail the procedures and experimental findings that documented the latest concepts about the disease. It seemed to me that if one understood the physiological chemistry of diabetes, one would have mastered most of the biochemistry that existed at that time. One of my most prized possessions is my collection of notes on the lectures on glycolysis by the great Otto Meyerhof, a refugee from Germany and then a professor at the University of Pennsylvania. Pharmacology was probably the best-taught course, mainly as a result of the efforts of an extraordinary trio of teachers, Carl Schmidt, Julius Comroe, and Seymour Kety. They emphasized physiological mechanisms, and the physiology of each system was comprehensively reviewed before the specific actions of drugs were examined. We probably learned as much physiology in pharmacology as in the physiology course. I can still remember Comroe’s lecture on cardiac glycosides, a masterpiece of exposition on cardiac rhythms and contractility of heart muscle, Kety’s lecture on pain and analgesics, and Schmidt’s lectures on respiration and the cerebral circulation. All the lectures laid heavy emphasis on the scientific method and scientific medicine as the basis of rational diagnosis and therapy, and experimental findings were critically presented, evaluated, and interpreted. A healthy skepticism permeated each lecture. For example, in the first lecture of the course, Schmidt warned us not to be seduced by the dictum, “Post hoc, ergot propter hoc.” By the end of the course many of us had become therapeutic nihilists.

Most of the other courses in medical school were clinical and less interesting to me. I was clearly stimulated more by basic science than by clinical medicine. I enjoyed neurology because with reasonable knowledge of neuroanatomical pathways and neuropathology one could usually deduce the locations and natures of lesions. Surgery, gynecology, and obstetrics were not intellectually challenging; pediatrics required dealing with children who were always crying and difficult to examine. Of the clinical courses, internal medicine was the most appealing. I found metabolic and endocrine diseases most interesting, probably because they so often involved physiological chemistry. I found nothing in my experience in medical school that would divert me from basic biomedical research to the practice of medicine. My orientation did change, however, from cellular physiology to mammalian physiology and biochemistry.

The war ended in August 1945. A few months later, I graduated from medical school and in March 1946 began my internship at the Philadelphia General Hospital, a city hospital with 2,500 beds. We were discharged from the Army and commissioned in the reserves with the stipulation that we would be recalled to active service as medical officers after we had completed our internships and passed the state board examinations for licensure. Rotating internships were then required in Pennsylvania, and I rotated through internal medicine, tuberculosis service, surgery, orthopedic surgery, clinical laboratory medicine, neurology, psychiatry, obstetrics, and gynecology. Psychiatry was my first rotation, and it was quite an eye-opener. The psychiatric department had about 300 beds in a separate building and functioned mainly as an acute receiving facility. Its responsibility was to observe, diagnose, and treat all treatable patients. Chronic patients not responsive to treatment were transferred to state facilities for long-term custodial care. The treatments we offered were insulin-shock or electroconvulsive therapy for schizophrenia and electroconvulsive therapy for manic-depressive psychosis, involutional melancholia, and reactive depression. Paresis was treated with fever therapy, produced by malaria in whites and by intravenous typhoid vaccine in blacks. Penicillin was not yet available to us. Of course, all patients were given that esoteric, mystical, highly individualized “magic bullet” known as psychotherapy. There were also many admissions with alcoholic hallucinosis, delirium tremens, hysterical paralyses, amnesia, drug intoxication, which at that time was mainly chronic bromidism that bore a remarkable resemblance to schizophrenia, and occasionally brain tumors that presented themselves with psychosis. I must confess that I was intrigued by this incredible world of the mind. The strange and bizarre behaviors, irrational thoughts, delusions, and hallucinations had to be seen to be believed. They were beyond any comprehension based on physical science but seemed to be real phenomena nonetheless. Psychoanalysis was then in its ascendancy in American psychiatry, and psychiatrists ignored physical and chemical mechanisms. They were fully satisfied with explanations based on early childhood experiences and the id, ego, superego, unconscious mind, and entities in the mind without physical or biochemical structure or properties. Psychiatry was an unknown domain and a challenge to anyone committed to the scientific method and explanations of biological phenomena, even those of the mind, in terms of basic physical and chemical mechanisms.

Internships had been integrated with the accelerated programs of the medical schools during the war, and their duration had been curtailed from the normal one year to nine months. Although the war had ended several months earlier, the accelerated program was still in effect when my internship began, but near its end the one-year internship was reinstated. To do so, it was necessary for scheduling reasons to extend our internship by six months, and we overlapped the next class by three months. The original schedule of rotations still had to be completed during the first nine months, and the additional six months were restricted to a single service. I had already served six weeks in psychiatry, but was assigned to psychiatry for the extra six months. As a result, my internship included almost nine months of neuropsychiatry. Furthermore, immediately after the war’s end, many physicians returned from military service seeking specialty training under the G.I. Bill of Rights. Psychiatry was a popular choice, probably because of the nation’s concern about the shockingly high rate of rejections from the draft and medical discharges from the services ascribed to psychiatric causes. A commonly heard quip at the time was, “Everyone in this country is psychoneurotic but thee and me, and sometimes I have my doubts about thee.” Our hospital became a teaching center in psychiatry for such returning veterans, and classes and clinics were organized to teach them but were open to us as well. When the new class of interns arrived three months before our class finished, they took over the interns’ duties, and I was free to attend the training classes and clinics and to serve essentially as a resident in psychiatry. That experience enhanced my knowledge and competence in psychiatry and with it my interest in mental functions.

The Army Years

My internship ended in June 1947. It was during my internship that I married my wife Betty, who was then enrolled in Ohio State University. At completion of her first year, she joined me in Philadelphia just before my internship ended. The Army allowed me two months to take the state board examination and then ordered me to active duty at the Medical Field Service School, Fort Sam Houston, Texas. There we were given about four weeks of training in basic military medicine. Near the end of the training, a planeload of high-ranking officers arrived from Washington, D.C. and interrogated each of us in the class as to our preferences for subsequent assignments in the Army. They promised to be accommodating, and encouraged us to choose permanent careers in the Army. The representative of the U.S. Army Air Force told us that candidates for flight surgeons had to be smarter than physicians in other branches of the Army because of the complexities of aviation medicine, but on the other hand, they could not be too smart because they would then insist on keeping both feet on the ground. We were given three choices in order of preference for specialty and three more for location. My specialty choices in order were physiological research, internal medicine, and neuropsychiatry. My choices for location were Fort Knox, Tennesse, where there was a major research facility for environmental physiology, followed by the European theater of operations and, finally, the west coast. In typical Army fashion, they granted me my last choice of specialty and a location that I had not selected at all. Because of my experience in neuropsychiatry during internship, the Surgeon General of the Army ordained me a neuropsychiatrist and assigned me to Camp Lee, Virginia.

The medical installation at Camp Lee was a 150-bed station hospital that provided a full complement of medical and surgical services to the Army personnel and their dependents. Before I arrived in the fall of 1947, there had been no psychiatrist there for several months, and neuropsychiatric functions were covered by the Medical Service. My arrival was eagerly awaited, and I was immediately appointed chief of neuropsychiatry. It was left to me to decide whether to keep neuropsychiatry within the Medical Service or restore it to an independent service. Because my interests were still more in internal medicine than in neuropsychiatry, I chose the former so that I could still participate in diagnosis and care of medical patients. It was a wise choice because we saw a variety of interesting medical problems such as cardiovascular and pulmonary diseases, leukemia, and metabolic diseases such as diabetic coma and hepatic insufficiency, in which I was most interested.

Relatively few of my neuropsychiatric patients were neurological, and they were of limited variety because of the restricted age span of the population. Most of them had head, spine, and peripheral nerve injuries, and subarachnoid hemorrhages usually caused by cerebral aneurysms. There was an occasional brain tumor, stroke, or early multiple sclerosis, and one unusual case of dystrophia myotonica. All patients requiring neurosurgical treatment were transferred to Walter Reed General Hospital in Washington, D.C. Psychiatric patients were plentiful, and most were treated as outpatients. There were occasional psychoses that required hospitalization; these included schizophrenia, manic-depressive disease, psychotic depression, alcoholic hallucinosis, delirium tremens, and one case of acute amphetamine intoxication. Patients with functional psychoses were either transferred to Walter Reed or else granted medical discharges from the Army. Most of the outpatients suffered from alcoholism, personality disorders, or psychoneuroses, such as anxiety neurosis, hypochondriasis, psychosomatic disorders, and conversion reactions (such as hysterical paralyses and amnesia). Acute situational maladjustments were common in new recruits away from home for the first time, and there were numerous character disorders, mainly constitutional psychopathic inferior (CPI), the nomenclature used at that time for what is now called sociopathic personality. Psychotherapy was all we had to offer the patients, and although I was skeptical of its validity or value, I had the responsibility of doing whatever I could for my patients. I therefore provided a type of psychotherapy that I thought was consistent with the best teaching of the time and within the limits of my own competence. Psychoanalysis was then predominant; it appeared to be the most dynamic school of psychiatry and to offer patients, at least neurotics, the best chance of help. I studied psychiatric texts and journals intensively, read much of Freud’s work and that of his disciples, and ended up practicing a sort of diluted, modified version of psychoanalysis. There was no couch; I sat at my desk facing the patient and wrote notes while the patient talked spontaneously or in response to leading questions. Usually at the end of each session, generally once or twice a week, I would offer some interpretative remarks and suggestions. Sometimes I prescribed sedatives and occasionally used amytal interviews (that is, “twilight sleep”), particularly in conversion reactions. Results were probably no better or worse than those obtained by fully qualified psychiatrists at that time. Patients sometimes actually improved. I remember a soldier with a conversion reaction who regained the use of his paralyzed arm, an amnesic who recovered his memory, and a nymphomaniac who gave up sex for Lent. There was one patient who made a particularly strong impression on me. She was in her thirties and had had various systemic symptoms for many years. The internal medical service had studied her thoroughly and could find no organic basis for her complaints; thus, they concluded that she was suffering from psychosomatic disease and referred her to our neuropsychiatric clinic. She certainly exhibited enough psychopathology to make the diagnosis creditable, and I undertook to treat her with my usual type of psychotherapy in two one-hour sessions per week. I often began each session with the question, “How have you been feeling since I last saw you?” On one such occasion after about six months of therapy, she replied, “Wonderful! I haven’t felt this well in 11 years.”

“You do?” I stammered incredulously, wondering how her talking and my listening could possibly have so altered her brain as to dispel the psychosomatic symptoms. For me, mind and brain were inextricably linked, a linkage that was irrelevant to psychiatry at that time. This case and others like it stimulated in me a growing interest in physiological and biochemical mechanisms in the brain in mental disease, and I began to consider the possibility of venturing into this field after completing my two years of Army service.

Return to the University of Pennsylvania

In 1948 I learned that S.S. Kety and C.F. Schmidt (1948), my former teachers at Penn, reported the new nitrous oxide method for measuring rates of blood flow and metabolism in the conscious human brain. This method appeared to offer a unique and powerful tool to study the human brain in psychiatric disorders, and I began to entertain thoughts of possibly joining them to learn and to use their method. In August 1949, I left the Army, and my wife and I returned to Philadelphia where my parents lived. My plan was to visit Kety and inquire whether I might possibly work with him, but I procrastinated for several weeks because I really did not think that there was much chance. In fact, I was already contemplating a backup option, completion of clinical training in psychiatry. Many relatively well-paying residencies were still available because of the huge demand for psychiatrists in the post-war era. Finally, I screwed up my courage, went to see Kety in the medical school building at Penn, and learned that he had transferred from Schmidt’s Department of Pharmacology to a new Department of Physiology and Pharmacology in the Graduate School of Medicine chaired by Julius Comroe and located in the basement of the same building. After a short wait I was able to see Kety, and I explained to him the purpose of ethods, no brilliant research my visit, making it explicitly clear that I was bringing nothing—no skills, no methods, no brilliant research ideas—only a desire to work with him and his group and learn from them as much as I could. It was a fortunate time. He had just been notified that his NIH grant had been approved and funded, and it included support for a still unspecified fellow. Kety pointed out that he had wanted and had set the salary level for someone more experienced and senior than I. He did, however, remember me from medical school and was willing to take a chance with me. Besides, he added, because of my inexperience the stipend would be lower, and perhaps he could use the rest of the allocated salary for a second fellow at my level. I accepted but still had to be interviewed by Chairman Comroe, who would have to approve the appointment. The interview with Comroe occurred about two weeks later, and he did approve the appointment but then immediately asked me about my plans for the future. I was puzzled; we had just agreed that I would come to work in his department.

“I mean your long-term professional goals,” he explained. “Will you work here for a year or two before returning to clinical medicine, or do you plan to make a career in physiology?”

I responded that I did not know. On the basis of my past experience I would guess that I would like basic research, but I still did not know how well I would do in it. He replied that he remembered me from medical school, was confident that I would do well, and hoped that I would decide to make a career in physiology. This was very flattering, but before I could express my appreciation, he added, “But not here.”

I was stunned and asked, “What did I say wrong? You just said that you thought that I would be suitable for basic research and hoped that I would stay in physiology.”

“It’s nothing personal,” he replied. “It’s just that this department has only three people on university salaries, me—Dr. Kety, and Mrs. Sullivan, the department secretary. I am 38 years old and in good health and have no plans to leave. Kety is 35, and as far as I know, he is also in good health and does not plan to leave. And as for Mrs. Sullivan, I don’t think you could do her job. Therefore, if you have any thoughts of replacing any of us, forget them. You are here to help us do our research. In return we will teach you how to do research, and if and when you learn it well enough to be able to do your own research, we will be glad to help you to find a place to do it, but somewhere else.”

That seemed reasonable to me, and I assented. He then continued, “I may as well tell you now because you will find out anyway. Your salary will be $2,500 per year. Mrs. King, my senior technician, will be making $3,300 per year. That is not a mistake; it is a reflection of the relative worth of the two of you to this department at this time.”

That was putting it right on the line, but he had said nothing with which I could disagree. I eventually came to appreciate that his forthrightness and honesty were reflections of his total commitment to physiology and good science. He was constantly challenging us to do our very best and even more. Behind his gruff exterior there was actually a kind, considerate, and generous soul.

Although I had come to work with Kety to study cerebral circulation and metabolism, I was exposed to a much wider experience. The grant from which I was paid was on peripheral circulation to be studied by another method developed by Kety in 1949, the ²⁴Na⁺ clearance method. I therefore had to divide my time between cerebral blood flow and muscle blood flow. This was fortunate because the ²⁴Na⁺ clearance method introduced me to radioisotopic techniques and forced me to study the physics of radioactivity, which had not been included in my college physics courses. Also, the clearance method was based on the design and mathematical analysis of a kinetic model. I found physiological modeling to be new and fascinating, but my knowledge of mathematics was weak. I therefore made intensive efforts to review and extend my knowledge of mathematics to the point where it was adequate for the problems with which I was dealing. In this I received valuable help from a graduate student, Reuben Copperman, who had a bachelor’s degree in mathematics, a master’s degree in theoretical physics, had completed his course work for a Ph.D. in theoretical physics, and had come to our department to do his thesis research in biophysics with Kety. I once again was a student and studied every night until early morning hours. It was not difficult; with an income of $2,500 per year there was little left over to permit many other activities. My wife, who had been a nurse in the Navy during the war, was completing her college education at Penn under the auspices of the G.I. Bill of Rights and could not help financially. Then by 1952 when my salary had been raised to $4,000, our son was born, further straining our financial resources.

Richard Wechsler was Kety’s first postdoctoral fellow; I was his second. Wechsler and I overlapped for about a year, and it was from Wechsler that I learned the technical aspects of the procedure of the N₂O method. Both of us learned the theory of the method and the principles of inert gas exchange between blood and tissues directly from Kety, who was then writing his now classic review of the subject (Kety, 1951). As more fellows arrived, Kety’s team grew and included Renward Mangold from Switzerland, who studied sleep; Charles Kennedy, a pediatrician who adapted the N₂O method for use in children; Benton King, an anesthesiologist, who worked with Wechsler and me on the effects of norepinephrine and epinephrine on cerebral blood flow (CBF) and cerebral O₂ consumption (CMRO₂); and Jerome Kleinerman and Eugene Conners, both of whom worked with us on sleep studies. It was an intellectually active and interactive group. We regularly discussed and analyzed the rationale and results of our studies as well as publications in our immediate fields of interest and in physiology in general. There were various aspects of the overall research program, and we all worked together as a team on each of them as though it were our own project with no detectable rivalry among us. There were no prior decisions and no concerns about who would be first authors on the papers. This was decided by natural selection; each of us gravitated in our reading and thinking selectively to specific aspects of the overall program, and it soon became obvious who was most knowledgeable of the literature and, therefore, best qualified to write the first draft of the manuscript. The author of the first draft became first author. How different the situation then and there was from what exists today. It is only relatively recently that I became aware of rivalries and conflicts among co-workers with regard to order of authorship.

In addition to the scientific interactions within the laboratory, there was also considerable exchange of broader scope among ourselves and with Kety. Kety and his fellows often ate lunch together, usually hamburgers at the Quad Shop, a simple eatery in a dormitory near the medical school. At lunch we generally discussed politics and foreign affairs, news and magazine articles, political science and scientific politics, and science in general. At these lunches, Kety and I sometimes argued about psychiatry. Although I harbored skepticism about formal psychiatric theory and practice, the experience of having had to deal with suffering psychiatric patients and being obligated to try to help them had softened my opposition to psychiatric doctrines. Kety was a “hard-nosed,” rigorous, and critical physiologist; he had little regard for the psychiatry of that time, which he considered to be unscientific. I felt compelled to defend it and argued that it was not psychiatry itself that was at fault, but psychiatrists. That was not an original idea. I had read an article by Iago Galdston (1950) in which he compared Freud’s impact on psychiatry with the inauguration of the Eiffel Tower at the Paris Exposition in 1889. At the moment of inauguration, a powerful lantern at the top of the tower was turned on and directed downward; it produced a giant circle of intense light on the ground below. It was night, and those who were outside the circle were in the dark and could see nothing, but those who were within the circle of light were so blinded by its brilliance that they also could see nothing. I too believed that many psychiatrists and disciples of Freud had interpreted and extrapolated too far and had exceeded the bounds of logic and reason, let alone scientific rigor. In our arguments about psychiatry, both Kety and I must have been persuasive because I eventually gravitated deeper into basic science while Kety drifted toward psychiatry with his studies on the genetics of schizophrenia.

The staff of the Department of Physiology and Pharmacology was outstanding and provided a superb environment for training in physiology. Contact between fellows and staff was continuous and close, and expectations and standards of performance were high. There was little tolerance for pomposity or verbal gymnastics. It was not safe to open one’s mouth without knowing precisely what one was talking about. The weekly department seminars were held on Saturday mornings, and each professional member of the department was scheduled to present his work. There were no excuses, even if the work was not yet ready for presentation; that itself might be revealing. These seminars were to the fellows what the Roman Coliseum must have been to the Christians; it was like being fed to the lions. Every statement might be challenged and questioned. Every method or conclusion could be criticized. The speakers were usually stretched to the limits of their knowledge of the subject that they were presenting. One dared not make a rash statement that could not be backed up by facts or reason. We learned to be as critical of our own work as we were of the work of others, an attitude that has remained with me and has stood me in good stead. In science it is more important never to be wrong than ever to be right. The scientific literature should never be polluted with the results of bad science. A corollary of this attitude, of course, is that we expect others to be as critical of their work as we are of our own, an expectation that is becoming increasingly more unrealistic. It seems nowadays that many consider it more important for publications to contribute to bibliographies than to scientific knowledge.

The first research project on which I had been designated as the first author was on the effects of hyperthyroidism on CBF and CMRO₂ in man. The objective was to find a condition in which energy metabolism in brain was increased. After its development, the N₂O method had been applied to many clinical conditions. In all cases in which consciousness was depressed (such as diabetic acidosis and coma, hepatic coma, renal failure, brain tumors, anesthesia, and so on), O₂ consumption of the brain was decreased, but no conditions had yet been found in which CMRO₂ had been increased. We speculated that hyperthyroidism might be a condition in which CMRO₂ would be increased, partly because of the marked anxiety suffered by these patients and, even more so, because of the large increase in their total body metabolic rate. We had carefully designed a long-term study in which patients with Graves’ disease would be studied not only before and after treatment but also in comparison with normal subjects of comparable age. In the first few experiments it became obvious that, contrary to expectations, CMRO₂ remained normal in hyperthyroidism. A few months later, an abstract was published by others reporting the major finding: no change in CMRO₂ in human hyperthyroidism. We had been scooped. Indicative of the scientific attitude of our group and probably of many others at that time, Kety consoled me by saying, “Don’t feel bad. It must not have been such a great idea. Somebody else thought of oidism. What was different about it too.” It was a time when scientists were valued more for their uniqueness than for their speed.

We did eventually complete the study (Sokoloff et al., 1953), but by then I had become intrigued by the question of why the brain failed to participate in the body’s general increase in metabolic rate in hyperthyroidism. What was different about the brain’s biochemistry from that of other organs? I searched the literature back to the end of the 19th century when thyroid diseases were first recognized and thyroid physiology began to evolve. It became obvious that we still did not know why thyroid hormones stimulated metabolic rate in those tissues that did respond to thyroid hormones, such as liver, muscle, and kidney. How could we then explain why these hormones did not have the same effects in brain tissue? From the review of the literature, it appeared to me that thyroid hormones must have some special influence on protein metabolism. The mature brain was known to derive almost all of its energy from the oxidation of glucose. The testis was the only organ other than the brain known to have a respiratory quotient of one, indicating oxidation of only carbohydrate, and it too was reported to have a rate of O₂ consumption that was unaffected by thyroid hormones. It might have been coincidence, but it also suggested that thyroid hormones might be acting primarily on protein metabolism and only secondarily on energy metabolism, and their effects might, therefore, not be apparent in organs with low rates of protein turnover as compared to those of carbohydrate. The question remained whether it was protein synthesis, protein catabolism, or both that were affected. The fact that thyroid hormones did stimulate energy metabolism and was required for normal growth and maturation in developing brain suggested an effect at least on protein synthesis. The mature brain has relatively low rates of protein synthesis and turnover and should be expected to be relatively insensitive to thyroid hormones.

This was our hypothesis, and to test it would require examination of the effects of thyroid hormones on protein synthesis. There was, however, no practical method for studying protein synthesis in vivo at the time, and biochemical experiments in vitro would be required. I had a fair knowledge of biochemistry from extensive reading and continual discussions with my biochemical colleagues, but I was not a biochemist and not trained in laboratory biochemical techniques. Instead, I tried to persuade biochemists to undertake such studies. One biochemist with whom I often discussed the problem was Beryl D. Polis, a close friend from whom I learned a great deal of biochemistry. He was one of Otto Meyerhof’s only two Ph.D. students in America. Polis had previously collaborated with Kety on studies of diabetic coma (Kety et al., 1948) and had remained closely associated with Kety’s group. Polis encouraged me to undertake the biochemical studies myself and assured me that with his guidance I could do so. I was, however, too busy with other projects on cerebral and peripheral blood flow and metabolism to undertake such studies.

The Years at the National Institute of Mental Health

In 1951, about two years after I joined him, Kety left Penn to become the first scientific director of the combined Intramural Research Programs of the National Institute of Mental Health (NIMH) and the National Institute of Neurological Diseases and Blindness (NINDB). Because I had become the most senior member of his group, it became my responsibility to continue the research projects that had been initiated by him. He returned almost every other Saturday to discuss our progress. Our department had two major programs: pulmonary function, which was Comroe’s chief interest, and cerebral circulation and metabolism, which were Kety’s interests. After Kety left, however, his group withered because it lacked a magnet to attract fellows and investigators. We were reduced to the graduate student, R. Copperman, one technician, and me, and I began to feel quite isolated. Comroe invited me to join his group in respiratory physiology, but despite their high quality and the challenging problems that they were investigating, I could not develop any great enthusiasm for studying lungs rather than brain. I therefore began to explore opportunities elsewhere. At the time I was collaborating with the Aviation Medical Acceleration Laboratory of the U.S. Naval Air Development Center in Johnsville, Pennsylvania, to develop a method for rapid continuous measurement of cerebral blood flow and metabolism in man; the Navy wanted such a method to study blackout in aviators pulling out of dives. The laboratory’s scientific director offered me the position of head of physiology, and it was an attractive offer, particularly since Polis had gone there as head of biochemistry. Comroe, however, strongly objected to my taking that position; he thought it was a bad choice for my career and tried to dissuade me. After I explained my reasons for wishing to leave his department, he called Kety at NIH and suggested that he talk to me. Kety then called me and invited me to join him at the NIMH. He explained that he had not invited me previously because he had not wished to raid the department at Penn when he left. I accepted, and in December 1953, arrived at the NIMH. The Intramural Research Program of the NIMH had a basic science division and a clinical division. Because of my past experience, I could choose appointment in either division. The clinical program a higher grade and salary, I chose basic science.

My position was in the section on Cerebral Metabolism of the Laboratory of Neurochemistry. Kety was both the section chief and the acting chief of the laboratory until a permanent laboratory chief was recruited. There were two other sections in the laboratory: the section on Lipid Chemistry, headed by Roscoe Brady, and the section on Physical Chemistry, led by Alex Rich. The Intramural Research Program of the NIMH also contained the Laboratory of Cellular Pharmacology, in reality a biochemical laboratory, directed by Giulio Cantoni, the discoverer of the methionine-activating enzyme and S-adenosyl-methionine and their roles in methylation reactions. Another member of this laboratory was Seymour Kaufman, who had identified succinylCoA as an intermediate in the conversion of α-ketoglutarate to succinate in the tricarboxylic acid cycle and had characterized the role of this intermediate in substrate phosphorylation. Biochemistry was, therefore, well represented, and a biochemical journal club was organized in which we all took turns presenting. In the first cycle each of us presented research we had done before coming to NIH. I presented my work with thyroid hormones, including my extensive review of the literature, and ended with my hypothesis that many of the physiological effects of thyroid hormones could be explained by a stimulation of protein synthesis and turnover. The hypothesis stimulated considerable interest and discussion, and the session lasted well beyond its scheduled one hour. Shortly thereafter, Kaufman came to see me and said that he found the hypothesis to be attractive; in fact, he had come to a similar conclusion from an entirely different perspective. He then asked what I intended to do about it. Once again, I pointed out that the problem was biochemical and that, though I might have sounded like a biochemist…. I really was not. He then offered to collaborate with me, provide the biochemical expertise, and supervise and train me in biochemistry. It was also convenient because our laboratories were just around the corner from each other. I enthusiastically accepted his offer, and thus began my career in biochemistry.

With Kety’s encouragement, Kaufman and I initiated our experiments in 1955 to develop and characterize an appropriate assay system for protein synthesis that could be used to examine the effects of thyroid hormones. Progress was slow because both of us had to devote time to other projects to which we were already committed, in my case the studies of cerebral circulation and metabolism. We eventually did develop a satisfactory assay system and found that thyroid hormones did, indeed, stimulate protein synthesis (Sokoloff and Kaufman, 1959, 1961). Kaufman turned out to be an outstanding teacher. He was knowledgeable, scholarly, and rigorous with uncompromisingly high standards. His attitudes and mine meshed perfectly; we shared the same commitments to the traditional values of science. This experience and the capability that biochemistry seemed to offer for definitive solutions seduced me away from physiology and, in 1959 when my projects on CBF were essentially completed, I turned my efforts fully to biochemical research. My main research project was still on the mechanisms of actions of thyroid hormones, but my interests broadened and became oriented generally toward relationships between biochemical processes and physiological functions, particularly in the nervous system.

When I arrived at the NIMH, my first goal was to continue studies of cerebral blood flow and metabolism in man in conditions with normal and abnormal mental and neurological functions. I therefore set up the Kety/Schmidt nitrous oxide method and used it to study normal aging and dementia (Dastur et al., 1963) and the effects of LSD in normal subjects and schizophrenic patients (Sokoloff et al., 1957). The N₂O method measured average blood flow and metabolism in the brain as a whole; this was sufficient to provide much of our present knowledge of the physiology and pharmacology of the cerebral circulation and to demonstrate decreases in cerebral energy metabolism in disorders associated with depressed levels of consciousness or dementia. It did not, however, reveal changes in cerebral energy metabolism during physiological alterations in mental function or in functional psychoses. For example, no changes in CMRO₂ were found during mental exercise (that is performance of mental arithmetic), slow-wave sleep, sedation or tranquilization, schizophrenia, mild alcoholic inebriation, or LSD intoxication. There were at least three possible explanations for these negative results: (1) altered mental functions not associated with altered levels of consciousness are unrelated to changes in cerebral energy metabolism; (2) there are changes in local metabolic rates, some increases and some decreases, which are distributed throughout the brain without affecting the average metabolic rate of the brain as a whole; (3) the regions of the brain involved in specific mental changes are too small and localized to be detected in measurements of average metabolic rate in the brain as a whole. We leaned toward the latter two possibilities because of evidence obtained in other tissues, such as heart, skeletal muscle, and kidney, that energy metabolism and functional activity of the tissue are closely correlated. What was clearly needed was a method to measure local cerebral metabolic rates that could be used in conscious animals in various functional states.

There was then no obvious way to measure local metabolic rates in the brains of unanesthetized, conscious, behaving animals, but Kety (1951), in his conceptualization of the principles of inert gas exchange between blood and tissues, had derived an equation that suggested an approach to the measurement of local CBF. Blood flow is, of course, not metabolic rate, but under most normal circumstances local blood flow can be expected to adjust to and, therefore, indicate local energy metabolism. The development of such a method was initiated by Kety and two neurophysiologists, William Landau and Walter Freygang, shortly after Kety’s arrival at NIH. When I arrived in 1953, I joined the team to aid in the development of this method. The outcome was the [¹³¹I]trifluoroiodomethane ([¹³¹I]CF₃I) method (Landau et al., 1955; Freygang and Sokoloff, 1958; Kety, 1960). This method was applicable to conscious animals and measured local rates of blood flow simultaneously in every region of the entire nervous system. A unique feature of the method was its use of a quantitative autoradiographic technique that was developed specifically to achieve the anatomical resolution of the method and to provide visual images of the distribution of the relative rates of local blood flow in the brain. Applications of this method proved unequivocally that local cerebral blood flow does change with local neural activity. For example, it showed that retinal stimulation with light flashes stimulates blood flow in all components of the visual system of the cat (Sokoloff, 1961); to my knowledge this was the first example of imaging of local cerebral functional activity.

Although the quantitative autoradiographic technique was initially designed for ¹³¹I, it was obvious that it could be adapted for use with other isotopes, such as ¹⁴C, which would be more appropriate for studies of metabolism. Local energy metabolism could be more specifically related to local functional activity than blood flow, which was believed to be only secondarily adjusted to metabolic demand and was known to be sensitive to factors other than local tissue metabolism, such as pCO₂, pO₂, and pH of the arterial blood. In 1955 to 1956 I tried to develop a kinetic model for a method to measure local cerebral glucose utilization (lCMRg1c) which used [¹⁴C]glucose as the substrate and took advantage of the spatial localization provided by the quantitative autoradiographic technique. It soon became apparent that the early loss of labeled products of [¹⁴C]glucose metabolism, mainly ¹⁴CO₂ and possibly lactate and other metabolites, would necessitate extremely short experimental periods to minimize significant loss of product. With such short periods, however, the time-integrated specific activities of the precursor pools of glucose in the local cerebral tissues, which had to be known, could not be accurately determined from measurements in blood or plasma because of the lag of the tissue pools behind that of the plasma. I therefore abandoned the project.

In 1957, I was preparing a chapter on energy metabolism in the central nervous system in vivo for the Handbook of Physiology and, in discussions about it with Donald Tower, I learned about a compound, 2-deoxyglucose (DG), which in pharmacological doses produced a comatose state that was indistinguishable from hypoglycemic coma even though it also caused hyperglycemia. The mechanism of its effect was unknown. Earlier studies by Sols and Crane (1954) had shown that 2-DG could be phosphorylated just like glucose by hexokinase, but its product, 2-DG-6-phosphate (DG-6-P), could not be isomerized to fructose-6-phosphate (F-6-P), the next step in the glycolytic pathway, because of the lack of a hydroxyl group on its second carbon. Subsequent studies by several groups indicated that DG-6-P could competitively inhibit the conversion of glucose-6-phosphate (G-6-P) to F-6-P. DG appeared to produce coma by blocking glycolysis and, therefore, glucose utilization in brain. The glycolytic blockade, however, was not attributable to competitive inhibition of the transport of glucose across the blood-brain barrier or its phosphorylation by hexokinase because glucose concentrations in blood and brain tissue are relatively high. The blockade resulted from accumulation of DG-6-P to concentrations eventually exceeding those of G-6-P in the cells; the DG-6-P then competed with G-6-P for the enzyme glucose-6-isomerase, and blocked its conversion to F-6-P and, therefore, glycolysis. DG-6-P could accumulate in brain to such relatively high levels because it was a poor substrate for most enzymes in brain that might metabolize it, and also because glucose-6-phosphatase (G-6-Pase) activity was low in brain tissue (Hers, 1957). When this picture emerged, it occurred to me that radioactive DG in tracer amounts might be used to measure local cerebral glucose utilization by the autoradiographic technique. The development of an operational method would, however, require considerable time and effort, and I was then too deeply engaged in studies on the actions of thyroid hormones to undertake it. I filed the idea away as something for future work but did make use of the properties of DG in biochemical experiments in vitro. For example, in studies of oxidative phosphorylation by crude brain mitochondria, we had to use a combination of glucose and hexokinase to trap the generated ATP to protect it from the high levels of ATPase activity in the preparations. Crude brain mitochondrial preparations, however, contained glycolytic enzymes that metabolize the G-6-P formed by the trap and generate additional ATP above that produced by oxidative phosphorylation. I therefore used DG instead of glucose in the trapping system, and this solved the problem. The DG-6-P, once formed, was neither hydrolyzed to release inorganic phosphate nor metabolized further to generate additional ATP.

In 1963 William Windle, chief of the Laboratory of Perinatal Physiology, NINDB, invited Kety, Charles Kennedy, and me to his laboratory in San Juan, Puerto Rico, to study local CBF in fetal and newborn monkeys. There were major obstacles to the use of [¹³¹I]CF₃I in these studies. Because the compound was not commercially available and ¹³¹I has a half-life of eight days, it would have been necessary for us to spend half of our time on its synthesis. Furthermore, it was a radioactive gas, and special facilities needed to synthesize and handle radioactive gases were not available in the San Juan laboratory. We decided, therefore, to modify the [¹³¹I]CF₃I method for use with a nonvolatile tracer labeled with a longer-lived isotope, one with low energy β-radiation, such as ¹⁴C, that would allow better autoradiographic resolution. First we tried [¹⁴C]thiopental, which would have been suitable except for the inconvenience of its widely different tissue-blood partition coefficients in the various structures of the brain. [¹⁴C]antipyrine appeared to be a better choice because of its uniform brain:blood partition coefficient throughout the brain. In 1964, Martin Reivich and Jane Jehle joined our laboratory, and by 1965 they had modified the quantitative autoradiographic technique and the [¹³¹I]CF₃I method for use with [¹⁴C]antipyrine (Reivich et al., 1969). [¹⁴C]antipyrine was later found to diffuse too slowly across the blood-brain barrier and was replaced by the more freely diffusible [¹⁴C]iodoantipyrine (Sakurada et al., 1978). Now that quantitative autoradiography with ¹⁴C was available, the idea of measuring local cerebral glucose utilization with [¹⁴C]DG was resurrected. Kety, Reivich, and I frequently discussed this possibility but again left it for the future.

Reivich left NIMH in 1966 and returned to the University of Pennsylvania. In 1967 he called me and asked if I was still interested in DG and willing to undertake a collaboration with him to develop the method for measurement of local cerebral glucose utilization with [¹⁴C]DG. I accepted the collaboration but pointed out that commitments of my own laboratory to other projects made it temporarily impossible for any of the experimental work to be done there; the experiments would have to be done in his laboratory. He agreed, and the project began. The initial studies were carried out with brain slices in vitro and demonstrated that [¹⁴C]DG and glucose were taken up from the incubation medium in proportionate amounts. These results encouraged us to design a model that was essentially the same as that for the local blood flow method, except that it included a metabolic trap for the tracer in the tissue. An equation was derived which would allow the calculation of local glucose utilization, provided that local blood flow and other factors which were difficult to determine, were also known. This early attempt was reported in 1971 (Reivich et al., 1971). The model was not wrong, but the operational equation derived from it required information that was difficult if not impossible to obtain. The project then stagnated.

In 1968 I became aware that if I were ever to take a sabbatical year, it would have to be then and I interrupted my research at NIH to spend a year in Jean Roche’s Laboratory of General and Comparative Biochemistry at the College de France in Paris. There I worked with Jacques Nunez and Jacques Pommier in studies of peroxidase-catalyzed iodination of proteins. We used horseradish peroxidase, radioactive iodide, and serum albumin or lysozyme in a reaction that was a model for the iodination of thyroglobulin in the pathway of thyroid hormone biosynthesis in the thyroid gland. This reaction exhibited unusual kinetics that intrigued me (Pommier et al., 1973). Because of my previous experience in the design and mathematical analysis of physiological models, enzyme kinetics always attracted me. While working on the kinetics of this reaction in Paris, I developed considerable facility with enzyme kinetics. It was then that it occurred to me that a new model based more on enzyme kinetic principles than on only blood flow and principles of tissue-blood exchange might be more productive in the development of the [¹⁴C]DG method.

When I returned to NIH in September 1969, I found the project in my laboratory on the action of thyroid hormones to be in shambles. I could try to resurrect it or take advantage of the opportunity to introduce a new project, and I chose the latter. After a period of reorganization of the laboratory, I initiated the development and mathematical analysis of a new enzyme kinetic model for the autoradiographic DG method for measuring local cerebral glucose utilization. The first animal experiment was carried out in February 1971 by Charles Kennedy, Michael Des Rosiers, Jane Jehle, and myself. Soon after, Clifford Patlak, Karen Pettigrew, Osamv Sakurada, and Mami Shinohara were added to the team. All played unique and important roles, and progress was relatively rapid. The method was fully developed for use in rats in about three years and formally presented for the first time at the meeting of the American Society for Neurochemistry in New Orleans, March 1974. It took two more years to complete the experiments needed to adapt the method for use in monkeys.

At first we did not know if local energy metabolism was linked to local functional activity in nervous tissues as in other tissues, and if it was, whether the DG method could localize regions of altered functional activity on the basis of altered metabolism. We therefore embarked on a series of studies that were largely exercises in neurophysiology but were equivalent to what biochemists call “recovery experiments.” Specific regions in the nervous system were functionally activated or depressed by conventional physiological procedures, and the [¹⁴C]DG method was applied to determine if we could recover changes in 1CMRglc in the appropriate regions. The results of such studies in auditory, visual, and motor systems provided unequivocal evidence of the linkage between local functional activity and energy metabolism in the nervous system. The effects of altered functional activity on 1CMRglc were often so pronounced that they could be visualized directly in the autoradiograms without the need for quantification. A particularly dramatic example was the visualization of the nature, extent, and distribution of the ocular dominance columns and the loci of the representation of the blind spots of the visual fields in the striate cortex of the monkey. These results were published as examples of the usefulness of the method for mapping functional neuroanatomical pathways even without quantification (Kennedy et al., 1975, 1976). Full and detailed descriptions of the theory and procedure of the fully quantitative method and the results obtained with it were published later (Sokoloff et al., 1977; Sokoloff, 1977, 1981, 1982).

The quantitative [¹⁴C]DG method yielded massive amounts of data. It required manual densitometric analysis of the autoradiograms, which was tedious, laborious, and, therefore, limited to relatively few selected structures. Valuable information contained in the autoradiograms was being lost when the data were organized and presented in tabular form. A means to combine the quantitative strength of the method with the spatial resolution of the autoradiograms was needed. Therefore, in collaboration with Wayne Rasband, a computer scientist at the NIMH, we assembled a computerized image-processing system that scanned and digitized the autoradiograms, computed 1CMRglc for each pixel, and reconstructed on a monitor the autoradiographic images in pseudocolor with the metabolic rates quantitatively encoded in color in accordance with a calibrated color scale that was simultaneously displayed. Charles Goochee, a chemist in our laboratory, developed the computer program (Goochee et al., 1980). This technique facilitated rapid, quantitative survey of the entire nervous system for regions with altered rates of glucose utilization. It also provided dramatic quantitative metabolic maps of the nervous system in various functional states in which regions of altered activity were easily visualized by the color changes. Such color-coded metabolic maps were first presented at the annual meeting of the Society of Neuroscience in St. Louis, Montana in 1978, by Charlene Jarvis, who used them to illustrate the local metabolic consequences of visual deprivation of one hemisphere in the monkey observed in collaborative studies between our laboratory and Mort Mishkin’s Laboratory of Neuropsychology at the NIMH. They caused a sensation. In fact, the issue of Chemical & Engineering News, which reported on the meeting, featured on its cover a color-coded autoradiograph of the striate cortex showing the markedly reduced metabolism in the deprived hemisphere, with the caption “Visualizing Brain Chemistry in Action.”

Shortly after the [¹⁴C]DG method was developed, Reivich urged that we undertake its adaptation for use in humans. The theoretical basis of the method was fully applicable to humans, but autoradiography could not be used to measure tracer concentrations in localized regions of brain tissue. A noninvasive technique for measuring local tissue concentrations of isotope by external detection was needed. David Kuhl, then in the Department of Radiology at the University of Pennsylvania, had previously constructed a section scanner that could measure local concentrations of γ-emitting isotopes in cross-sections of human brain by external scintillation counting. Reivich brought him into the project. Another problem was the introduction of a γ-emitting isotope into the deoxyglucose molecule to allow external detection of the radioactivity. Deoxyglucose contains only hydrogen, oxygen, and carbon, but there are no γ-emitting isotopes of hydrogen, and the γ-emitting isotopes of oxygen and carbon, 150 and 11C, have half-lives of 2 and 20 minutes, respectively, much too short for radiochemists at that time to be able to synthesize deoxyglucose labeled with them. An alternative possibility was to use a fluorinated derivative of deoxyglucose, one labeled with ¹⁸F, a positron-emitting isotope with a halflife of 110 minutes. Because fluorine is so small an atom, metabolic substrates fluorinated in appropriate positions in the molecule often retain biochemical properties of the natural compound. Alfred Wolf, a radiochemist at Brookhaven National Laboratory, was brought into the project, and he and his team developed a rapid synthesis of 2-[¹⁸F]fluoro-2-deoxy-D-glucose ([¹⁸F]FDG). Initial experiments carried out in our laboratory at NIMH with 2-[¹⁴C]FDG demonstrated that the fluorinated derivative retained the essential biochemical properties of deoxyglucose. Soon afterward, the [¹⁸F]FDG adaptation of the DG method was developed and used for the first time in humans with Kuhl’s Mark IV Section Scanner (Reivich et al., 1979). Shortly thereafter, Kuhl moved to UCLA with two of his coworkers, Michael Phelps and Edward Hoffman, both pioneers in the design and use of positron-emission tomographic instruments. Positron-emission tomography (PET) offered better spatial resolution and accuracy than Kuhl’s single photon scanner. ¹⁸F is a positron-emitter and its γ-radiation consists of 0.51 MEV annihilation γ-rays produced when positrons are absorbed in matter. The group at UCLA acquired a PET scanner and adapted the [¹⁸F]FDG technique for use with PET (Phelps et al., 1979). They and many others around the world have used the [¹⁸F]FDG technique with PET to study the human brain in a variety of nervous and mental diseases; the technique is also used extensively to study coronary artery insufficiency. It is the method that first demonstrated the usefulness of PET to study local metabolism and function in the human brain.

The [¹⁴C]deoxyglucose method was warmly received at first, and I was awarded several prestigious honors for it. I was therefore unprepared for the controversy that soon engulfed it. In our development of the method we were acutely aware that glucose-6-Pase activity, if present in brain, could present problems, namely loss of labeled product and therefore underestimation of 1CMRglc We therefore took pains to assure ourselves that effects of G-6-Pase activity were negligible. We scrupulously studied the effects of time following administration of [¹⁴C]DG on the estimates of lCMRg1c; any effects of G-6-Pase activity would be time dependent and become more prominent with increasing time. The results showed no significant effects with experimental periods less than 60 minutes, and we therefore adopted 45 minutes as the standard and maximal permitted length of the experimental period in rats and monkeys. The initial report of the method in 1977 (Sokoloff et al., 1977) presented the results that showed no significant differences in estimates of 1CMRglc obtained with 30 and 45 minute experimental periods. Nevertheless, an extended argument developed about whether the DG method was invalid because of effects of G-6-Pase activity. It began with a report by Hawkins and Miller (1978) that purported to show loss of more than 50 percent of [¹⁴C]DG-6-p due to G-6-Pase activity in brain tissue. They measured brain [¹⁴C]DG-6-P content directly and compared it with the predicted amount calculated with a transposed version of the operational equation of the DG method that assumes no loss. This equation contains a combination of kinetic constants, named the “lumped constant,” which we had measured and reported in our initial paper. Hawkins and Miller used a value more than twice its measured value, and this, not G-6-Pase activity, was responsible for the discrepancy between their measured and calculated values for brain [¹⁴C]DG-6-P content (Sokoloff, 1982). Their error arose indirectly from the fact that their measured and calculated time courses of [¹⁴C]DG-6-P content were for the whole brain, but the operational equation of the DG method on which the calculated values were based applies only to tissues that are homogeneous with respect to rates of blood flow, metabolism, transport, tracer concentrations, and so forth, a requirement not met in the heterogeneous mixtures of tissues in the whole brain (Nelson et al., 1987; Schmidt et al., 1991, 1992).

Before this issue was resolved, Huang and Veech (1982) reported that when a mixture of glucose uniformly labeled with ¹⁴C ([U-¹⁴C]glucose) and glucose labeled in the 2-carbon position with tritium ([2-³H]glucose) was presented to the brain, the pool of glucose in the brain lost its ³H more rapidly than its ¹⁴C. Their explanation for this phenomenon was that both species of labeled glucose were phosphorylated at equal rates to G-6-P and then isomerized to fructose-6-phosphate, a reaction in which the ³H on the 2-carbon would be lost but the ¹⁴C retained. The isomerase reaction is reversible, and G-6-P without the ³H but with the ¹⁴C would be regenerated. Then, and only then, if there were G-6-Pase activity in the brain, the labeled G-6-P would be hydrolyzed back to free glucose without the ³H but with its ¹⁴C. Although widely accepted at first, their explanation also turned out to be wrong. Tom Nelson, Gerald Dienel, and Nancy Cruz in our laboratory were able to reproduce the findings of Huang and Veech when they used the same procedures that Huang and Veech had used. When they used a more thorough and rigorous procedure to isolate the free glucose from the brain, however, then no differential loss of ³H and ¹⁴C was observed (Nelson et al., 1985; Dienel et al. 1988). It took them several years to examine critically all the steps in the procedures used by Huang and Veech and to pinpoint the sources of error in their study. There were a number of errors, the most important of which was the presence of labeled impurities in the glucose fraction that they had isolated and presumed to be pure; only 40 percent of the total ¹⁴C in their so-called glucose fraction was in glucose. The fraction contained at least six other labeled contaminants, mainly ¹⁴C-labeled products of glucose metabolism beyond the fructose-6-phosphate step that would have lost the ³H but not the ¹⁴C. The effort required to find the sources of these errors was a major detour from and damaging to the overall research program of the laboratory, but it was necessary to resolve the controversy. In a multidisciplinary field like neuroscience, there were many who used the DG method without being adequately educated in the basic principles to comprehend the biochemical and physiological intricacies of the issue; they knew only that there was a controversy, and that was enough for them to be skeptical. They would not be convinced until the exact sources and nature of the errors made by those who raised the issue in the first place were identified and proved. It took most of a decade to do this, but it was necessary to save the DG method from unwarranted extinction (Nelson et al., 1985, 1986, 1987; Dienel et al., 1988, 1990).

It is gratifying to note that the methods that have come out of the basic physiological and biochemical research of our laboratory have led to the birth and growth of essentially a new field, perhaps, even an industry, in neuroscience: the field of functional brain imaging. When we first started, we did not know for certain if there was any relationship between local functional activity and local blood flow and/or energy metabolism in the nervous system. Methods to determine this were not available, and we had to develop methods to measure local blood flow and metabolism in the unanesthetized brain. These new methods also made it possible to examine blood flow and metabolism not only in selected regions but simultaneously in all regions of the brain. With these methods, we were able to establish that local blood flow and energy metabolism are, indeed, linked to local functional activity and can be used to map regions of altered functional activity in the brain. The development of new technology, like PET, made it possible to adapt these methods for use in humans. It is exciting to know that their applications may provide valuable information about normal brain function and its abnormal function in neurological and mental disorders.

Reflections on Then and Now

I would be remiss if, with the perspective of more than 45 years in biomedical scientific research, I failed to comment on the changes that have occurred in the state of the biological sciences today. Certainly the most striking and important changes have been in the vast expansion of our fundamental biological knowledge as well as the technology that made it possible and continue to support it. The material support supplied by industry in the form of equipment, apparatus, chemicals, enzymes, kits, and so forth is incredible; scientists can now concentrate on the experiments that answer biological questions rather than on the preparation of materials and tools needed for the experiment. Little time needs to be spent on synthesis of compounds, enzyme purification, assembly of apparatus, and so on. The pace has accelerated, and knowledge is flowing in at an explosive rate as witnessed by the proliferation of new periodicals and the growing size of the established journals. Concomitantly, computerized techniques to access and manage all this information are becoming ever more available and sophisticated. It would seem to be a wonderful time for science, but I wonder if is equally good for scientists. It reminds me of the slogan in the cigarette advertisement shortly after filtered cigarettes became fashionable, “Are you smoking more and enjoying it less?”

When I first entered my scientific career, research was almost purely an academic pursuit, at least in research-minded universities. It was supported largely to advance knowledge for the sake of knowledge and also to educate and train the next generation of scientists. Life in scientific research was, in truth, like that in an ivory tower or monastery where we could leisurely ruminate, discuss and debate with our colleagues, and enjoy the process of inquiry and learning. Indeed, the process of research was itself almost as enjoyable as the discovery. When I returned to Penn after my Army service, I was paid from an NIH grant but Kety himself received no salary from the grant. The NIH policy then was that principal investigators could receive no salaries from their own grants, and the maximum overhead was 15 percent. Principal investigators were, therefore, individuals who had already been evaluated and selected by their institutions for salaried positions; their grants provided salaries for fellows and support staff. The rationale, I suppose, was that it was to the nation’s advantage to support scientific research conceived and initiated by already-qualified faculty members, provided, of course, that the proposed research was subjected to peer review and deemed worthwhile. Some time late in the Eisenhower or early in the Kennedy administration (I do not recall which) the policy changed: principal investigators were allowed to receive salaries in proportion to their time on the project, and the limit on overhead was removed and made negotiable. Universities and other institutions were quick to take advantage of this golden egg. Faculties and departments expanded, and everyone was expected to apply for grants as soon as possible. Fellows were rushed through their postdoctoral training to achieve so-called independence, an absolute requirement for tenure. Independence no longer necessarily means true scientific or intellectual independence; it means having one’s own grant support. The result is that we have a multitude of well-trained and not so well-trained scientists competing for funds that are growing but cannot possibly keep pace with the growth in the number of grant applications. Many grant applications fail, and the applicants, whose salaries and appointments depend on grants, spend more and more of their time preparing grant proposals and less and less on research and training of the new scientists. Indeed, they often misuse their fellows in their pursuit of grants. Because in most institutions one needs a grant to have a salary, research proposals are often contrived more to get money than to advance knowledge. At scientific meetings, the corridor and dinner conversations are almost entirely about grant seeking rather than the substance of science.

Such was not the case when I was a fellow. Fellows could then devote all of their time exclusively to research and study, and they could continue to be supported by grants of senior investigators for extended periods of time until they became truly mature scientists. The search for money to support the research was the responsibility of the principal investigators who had an institutional salary and could develop grant proposals based on good scientific questions rather than on criteria deemed most likely to obtain a funded grant. New researchers had time to develop under the umbrellas of senior scientists who usually found their disciples positions elsewhere when they were ready. The net result is, as I see it, that biomedical research is now less an academic and scholarly pursuit and more like a commercial or industrial endeavor. Indeed, the influence of industry has already made an impact on the climate of biomedical research, and I fear that the academic environment will eventually suffer as a result. The current atmosphere in biomedical research is such that if it had been so when I made my choice, I might well not have chosen it.

Selected Publications

Dastur DK, Lane MH, Hansen DB, Kety SS, Butler RN, Perlin S, Sokoloff L. Effects of aging on cerebral circulation and metabolism in man. In: Birren JE, Butler RN, Greenhouse SW, Sokoloff L, Yarrow MR, eds. Human aging. A biological and behavioral study. Public Health Service Publ No. 986, Washington, D.C.: U.S. Government Printing Office, 1963;59–76.

Dienel GA, Cruz NF, Mori K, Sokoloff L. Acid lability of metabolites of 2-deoxyglucose in rat brain: implications for estimates of kinetic parameters of deoxyglucose phosphorylation and transport between blood and brain. J Neurochem 1990;54:199–1448.

Dienel GA, Nelson T, Cruz NF, Jay T, Crane AM, Sokoloff L. Over-estimation of glucose-6-phosphatase activity in brain in vivo: apparent difference in rates of [2-³H]glucose and [U-¹⁴C]glucose utilization is due to contamination of precursor pool with ¹⁴C-labeled products and incomplete recovery of ¹⁴C-labeled metabolites. J Biol Chem 1988;263:19697–19708.

Freygang WH, Sokoloff L. Quantitative measurements of regional circulation in the central nervous system by the use of radioactive inert gas. Adv Biol Med Physics 1958;6:263-279.

Galdston I. Psychiatry without Freud. AMA Arch Neurol Psychiat 1950;66:69–81.

Goochee C, Rasband W, Sokoloff L. Computerized densitometry and color coding of [¹⁴C]deoxyglucose autoradiographs. Ann Neurol 1980;7:359–370.

Hawkins RA, Miller AL. Loss of radioactive 2-deoxy-D-glucose-6-phosphate from brains of conscious rats: implications for quantitative autoradiographic determination of regional glucose utilization. Neuroscience 1978;3:251–258.

Heilbrunn LV. An outline of general physiology. Philadelphia: WB Saunders, 1938.

Hers HG. Le Metabolisme du Fructose. Brussels: Arscia, 1957;102.

Hogeboom GH, Schneider WC, Palade GH. Isolation of intact mitochondria from rat liver; some biochemical properties of mitochondria and submicroscopic particulate material. J Biol Chem 1948;172:619–635.

Huang M-T, Veech RL. The quantitative determination of the in vivo dephosphorylation of glucose 6-phosphate in rat brain. J Biol Chem 1982; 257:11358–11363.

Kennedy C, Des Rosiers MH, Jehle JW, Reivich M, Sharp F, Sokoloff L. Mapping of functional neural pathways by autoradiographic survey of local metabolic rate with [¹⁴C]deoxyglucose. Science 1975;187:850–853.

Kennedy C, Des Rosiers MH, Sakurada O, Shinohara M, Reivich M, Jehle JW, Sokoloff L. Metabolic mapping of the primary visual system of the monkey by means of the autoradiographic [¹⁴C]deoxyglucose technique. Proc Natl Acad Sci USA 1976;73:4230–4234.

Kety SS. The measurement of regional circulation by local clearance of radioactive sodium. Am Heart J 1949;38:321–328.

Kety SS. The theory and applications of the exchange of inert gas at the lungs and tissues. Pharmacol Rev 1951;3:1–41.

Kety SS. Measurement of local blood flow by the exchange of an inert, diffusible substance. In: Bruner HD, ed. Methods in medical research, Vol. VIII. Chicago: Year Book Publishers, 1960;228–236.

Kety SS, Polis BD, Nadler CS, Schmidt CF. Blood flow and oxygen consumption of the human brain in diabetic acidosis. J Clin Invest 1948;27:500–510.

Kety SS, Schmidt CF. The nitrous oxide method for the quantitative determination of cerebral blood flow in man: theory, procedure, and normal values. J Clin Invest 1948;27:476–483.

Landau WH, Freygang WH, Rowland LP, Sokoloff L, Kety SS. The local circulation of the living brain: values in the unanesthetized and anesthetized cat. Trans Am Neurol Assoc 1955;80:125–129.

Mazia D, Clark JM. Free calcium in the action of stimulating agents on Elodea cells. Bio Bull 1936;71:306–323.

Nelson T, Lucignani G, Atlas S, Crane A, Dienel GA, Sokoloff L. Re-examination of glucose-6-phosphatase activity in brain in vivo: no evidence for a futile cycle. Science 1985;229:60–62.

Nelson T, Lucignani G, Goochee J, Crane AM, Sokoloff L. Invalidity of criticisms of the deoxyglucose method based on alleged glucose-6-phosphatase activity in brain. J Neurochem 1986;46:905–919.

Nelson T, Dienel GA, Mori K, Cruz NF, Sokoloff L. Deoxyglucose-6-phosphate stability in vivo and the deoxyglucose method: response to comments of Hawkins and Miller. J Neurochem 1987;49:1949–1960.

Phelps ME, Huang SC, Hoffman EJ, Selin C, Sokoloff L, Kuhl DE. Tomographic measurement of local cerebral glucose metabolic rate in humans with (F-18)2-fluoro-2-deoxy-D-glucose: Validation of method. Ann Neurol 1979;6:371–388.

Pommier J, Sokoloff L, Nunez J. Enzymatic iodination of protein. Kinetics of iodine formation and protein iodination catalyzed by horse-radish peroxidase. Eur J Biochem 1973;38:497–506.

Reivich M, Jehle J, Sokoloff L, Kety SS. Measurement of regional cerebral blood flow with antipyrine-¹⁴C in awake cats. J Appl Physiol 1969;27:296–300.

Reivich M, Sano N, Sokoloff L. Development of an autoradiographic method for the determination of regional glucose consumption. In: Ross-Russell RW, ed. Brain and blood fiow. London: Pitman Publishing Co., 1971;397–400.

Reivich M, Kuhl D, Wolf A, Greenberg J, Phelps M, Ido T, Cassella V, Fowler J, Hoffman E, Alavi A, Som P, Sokoloff L. The [¹⁸F]fluoro-deoxyglucose method for the measurement of local cerebral glucose utilization in man. Cire Res 1979;44:127–137.

Sakurada O, Kennedy C, Jehle J, Brown JD, Carbin GL, Sokoloff L. Measurement of local cerebral blood flow with iodo[¹⁴C]antipyrine. Am J Physiol 1978;234:H59–H66.

Schmidt K, Lucignani G, Moresco RM, Rizzo G, Gilardi MC, Messa C, Colombo F, Fazio F, Sokoloff L. Errors introduced by tissue heterogeneity in estimation of local cerebral glucose utilization with current kinetic models of the [¹⁸F]fluorodeoxyglucose method. J Cereb Blood Flow Metab 1992;12:823–834.

Schmidt K, Mies G, Sokoloff L. Model of kinetic behavior of deoxyglucose in heterogeneous tissues in brain: a reinterpretation of the significance of parameter estimates fitted to homogeneous tissue models. J Cereb Blood Flow Metab 1991;11:10–24.

Sokoloff L. Local cerebral circulation at rest and during altered cerebral activity induced by anesthesia or visual stimulation. In: Kety SS, Elkes J, eds. The regional chemistry, physiology and pharmacology of the nervous system. Oxford: Pergamon Press, 1961;107–117.

Sokoloff L. Relation between physiological function and energy metabolism in the central nervous system. J Neurochem 1977;29:13–26.

Sokoloff L. Localization of functional activity in the central nervous system by measurement of glucose utilization with radioactive deoxyglucose. J Cereb Blood Flow Metab 1981;1:7–36.

Sokoloff L. The radioactive deoxyglucose method. Theory, procedure, and applications for the measurement of local glucose utilization in the central nervous system. In: Agranoff BW, Aprison MH, eds. Advances in neurochemistry, Vol. 4. New York: Plenum Press, 1982;1–82.

Sokoloff L, Kaufman S. The effects of thyroxine on amino acid incorporation into protein. Science 1959;129:569–570.

Sokoloff L, Kaufman S. Thyroxine stimulation of amino acid incorporation into protein. J Biol Chem 1961;236:795–803.

Sokoloff L, Perlin S, Kornetsky C, Kety SS. The effects of d-lysergic acid diethylamide on cerebral circulation and over-all metabolism. Ann NY Acad Sci 1957;66:468–477.

Sokoloff L, Reivich M, Kennedy C, Des Rosiers MH, Patlak CS, Pettigrew KD, Sakurada O, Shinohara M. The [¹⁴C]deoxyglucose method for the measurement of local cerebral glucose utilization: theory, procedure, and normal values in the conscious and anesthetized albino rat. J Neurochem 1977; 28:897–916.

Sokoloff L, Wechsler RL, Mangold R, Balls K, Kety SS. Cerebral blood flow and oxygen consumption in hyperthyroidism before and after treatment. J Clin Invest 1953;32:202–208.

Sols A, Crane RK. Substrate specificity of brain hexokinase. J Biol Chem 1954;210:581–595.

Additional Publications

(with King BD, Wechsler RL) The effects of 1-epinephrine and 1-nor-epinephrine upon cerebral circulation and metabolism in man. J Clin Invest 1952; 31:273–279.

(with Mangold R, Therman PO, Conner EH, Kleinerman JE, Kety SS) The effects of sleep and lack of sleep on the cerebral circulation and metabolism of normal young men. J Clin Invest 1955;34:1092–1100.

(with Mangold R, Wechsler RL, Kennedy C, Kety SS) The effect of mental arithmetic on cerebral circulation and metabolism. J Clin Invest 1955; 34:1101–1108.

(with Freygang WH) Quantitative measurements of regional circulation in the central nervous system by the use of radioactive inert gas. Adv Biol Med Physics 1958;6:263–279.

The action of drugs on the cerebral circulation. Pharmacol Rev 1959;11:1–85.

Local cerebral circulation at rest and during altered cerebral activity induced by anesthesia or visual stimulation. In: Kety SS, Elkes J, eds. The Regional Chemistry, Physiology and Pharmacology of the Nervous System. Oxford: Pergamon Press, 1961;107–117.

(with Kaufman S) Thyroxine stimulation of amino acid incorporation into protein. J Biol Chem 1961;236:795–803.

Cerebral circulatory and metabolic changes associated with aging. Res Publ Ass Neru Ment Dis 1966;41:237–254.

(with Klee CB) Changes in D(-)-β-hydroxybutyric acid dehydrogenase activity during brain maturation in the rat. J Biol Chem 1967;242:3880–3883.

(with Kennedy C, Des Rosiers MH, Jehle JW, Reivich M, Sharp F) Mapping of functional neural pathways by autoradiographic survey of local metabolic rate with [¹⁴C]deoxyglucose. Science 1975;187:850–853.

(with Kennedy C, Des Rosiers MH, Sakurada O, Shinohara M, Reivich M, Jehle JW) Metabolic mapping of the primary visual system of the monkey by means of the autoradiographic [¹⁴C]deoxyglucose technique. Proc Natl Acad Sci USA 1976;73:4230–4234.

Relation between physiological function and energy metabolism in the central nervous system. J Neurochem 1977;29:13–26.

(with Reivich M, Kennedy C, Des Rosiers MH, Patlak CS, Pettigrew KD, Sakurada O, Shinohara M) The [¹⁴C]deoxyglucose method for the measurement of local cerebral glucose utilization: theory, procedure, and normal values in the conscious and anesthetized albino rat. J Neurochem 1977;28:897–916.

(with Des Rosiers MH, Sakurada O, Jehle J, Shinohara M, Kennedy C) Functional plasticity in the immature striate cortex of the monkey shown by the [¹⁴C]deoxyglucose method. Science 1978;200:447–449.

(with Sakurada O, Kennedy C, Jehle J, Brown JD, Carbin GL) Measurement of local cerebral blood flow with iodo[¹⁴C]antipyrine. Am J Physiol 1978; 234:H59–H66.

(with Phelps ME, Huang SC, Hoffman EJ, Selin C, Kuhl DE) Tomographic measurement of local cerebral glucose metabolic rate in humans with (F-18)2-fluoro-2-deoxy-d-glucose: validation of method. Ann Neurol 1979;6:371–388.

(with Reivich M, Kuhl D, Wolf A, Greenberg J, Phelps M, Ido T, Cassella V, Fowler J, Hoffman E, Alavi A, Som P) The [¹⁸F]fluoro-deoxyglucose method for the measurement of local cerebral glucose utilization in man. Circulation Res 1979;44:127–137.

(with Wechsler LR, Savaki HE) Effects of d- and 1-amphetamine on local cerebral glucose utilization in the conscious rat. J Neurochem 1979;32:15–22.

(with Mata M, Fink DJ, Gainer H, Smith CB, Davidsen L, Savaki H, Schwartz WJ) Activity-dependent energy metabolism in rat posterior pituitary primarily reflects sodium pump activity. J Neurochem 1980;34:213–215.

Localization of functional activity in the central nervous system by measurement of glucose utilization with radioactive deoxyglucose. J Cereb Blood Flow Metab 1981;1:7–36.

The relationship between function and energy metabolism: its use in the localization of functional activity in the nervous system. Neurosci Res Prog Bull 1981;19:159–210.

(with Smith CB, Crane AM, Kadekaro M, Agranoff BW) Stimulation of protein synthesis and glucose utilization in the hypoglossal nucleus induced by axotomy. J Neurosci 1984;4:2489–2496.

(with Kadekaro M, Crane AM) Differential effects of electrical stimulation of sciatic nerve on metabolic activity in spinal cord and dorsal root ganglion in the rat. Proc Natl Acad Sci USA 1985;82:6010–6013.

Cerebral circulation, energy metabolism, and protein synthesis: general characteristics and principles of measurement. In: Phelps ME, Mazziotta JC, Schelbert HR, eds. Positron emission tomography and autoradiography: Principles and applications for the brain and heart. New York: Raven Press, 1986;1–72.

(with Smith CB, Deibler GE, Eng N, Schmidt K) Measurement of local cerebral protein synthesis in vivo. Influence of recycling of amino acids derived from protein degradation. Proc Natl Acad Sci USA 1988;85:9341–9345.

(with Schmidt K, Mies G) Model of kinetic behavior of deoxyglucose in heterogeneous tissues in brain: a reinterpretation of the significance of parameter estimates fitted to homogeneous tissue models. J Cereb Blood Flow Metab 1991;11:10–24.

Sites and mechanisms of function-related changes in energy metabolism in the nervous system. Dev Neurosci 1994;15:194–206.

(with Adachi K, Takahashi S, Melzer P, Campos KL, Nelson T, Kennedy C) Increases in local cerebral blood flow associated with somatosensory activation are not mediated by nitric oxide. Am J Physiol 267 (Heart Cire Physiol 36): 1994;H2155–H2162.

(with Takahashi S, Cook M, Jehle J, Kennedy C) Lack of effects of inhibition of nitric oxide synthesis on local cerebral glucoase utilization in the rat brain. J Neurochem 1995;65:414–419.

(with Takahashi S, Driscoll BF, Law MJ) Role of sodium and potassium ions in regulation of glucose metabolism in astroglia. Proc Natl Acad Sci USA 1995;92:4616–4620.

James M. Sprague

BORN:

Kansas City, Missouri

August 31, 1916

EDUCATION:

University of Kansas, A.B., 1938; A.M., 1940 (Zoology)

Harvard University, Ph.D. (Biology, 1942)

APPOINTMENTS:

Johns Hopkins University School of Medicine (1942)

University of Pennsylvania School of Medicine (1950)

Professor of Anatomy (1958)

Joseph Leidy Professor (1973)

Director, Institute of Neurological Sciences (1973)

Professor of Cell and Developmental Biology and Neuroscience Emeritus (1992)

HONORS AND AWARDS:

Fellow, John Simon Guggenheim Foundation (1948–1949)

Faculty Award, Josiah Macy Foundation (1974–1975)

National Academy of Sciences USA (1984)

James Sprague was initially trained in Evolution and Comparative Anatomy, but early on began work on the central nervous system. He carried out fundamental anatomical and physiological research on the spinal motor system, the spinocerebellar tracts, and the zonal organization of the efferent paths of the cerebellum. He performed classical studies that contrasted functions of lemniscal and reticular ascending systems of the brainstem. These studies evolved into research on the mammalian visual system: the cortical and midbrain mechanisms of visual orienting, of form perception and discrimination in the cat, and the interhemispheric transfer of these functions.

James M. Sprague

I was lucky enough to be born into a well-to-do family in Kansas City, Missouri. My mother, Lelia Mather, and my father, James P. Sprague, were both descendants of two of the oldest families in New England that had settled in the Boston area before 1630. This affluence allowed me to have a boyhood experience each summer that was an important determinant for the future. My grandfather Mather, a physician in Kansas City, purchased a cottage on Mackinac Island in 1900. The island lies in the strait connecting Lakes Michigan and Huron, an idyllic spot steeped in the history of the opening of the Northwest by fur traders and Jesuit missionaries. Largely covered by a mixed hardwood-conifer forest, the island is full of birds and small mammals. The handsome fort that dominates the harbor and small village was built in the mid-1700s. Standing in the village of Mackinac is the house in which William Beaumont, an Army physician, in 1822 to 1823 observed the process of digestion through a fistula in one of his patients—a classic study in medicine. Transportation on the island was and still is entirely by foot, horse, or bicycle; no cars are permitted except for emergencies. Because the island was free from hay fever, which plagued my mother throughout her life, we happily traveled to the cottage each summer until I was 12-years-old. The island is small and there is no way to get lost, so I was allowed to roam freely into the forests, to the old fort, along the woodland paths, and the lake—an experience that imprinted a love of nature and a desire to become a naturalist and explorer. My nursemaid, Eliza Nawagezik, was a remarkable woman—an Indian of the Chippewa (Ojibwa) tribe—who lived on Mackinac Island but had graduated from Carlisle College in Pennsylvania.

All of this came to an abrupt end with the collapse of the stock market in 1929 and the advent of the Great Depression. My father, along with many other businessmen, saw his job fall apart; he lost his steel distributorship and much of our livelihood with it, and we could no longer spend summers on this enchanted island.

Nevertheless, my early interest in natural history was sustained by field trips with the Boy Scouts and a friendship I struck up with one of my high school teachers, with whom I tramped the Missouri River bottoms on ornithological trips. This area is one of the major flyways of migrating birds going north in the spring to their nesting areas and south in the fall to Central and South America to spend the winter. The predictable rhythm of the multitude of species moving so faultlessly toward an imprinted destination enhanced my sense of being a part of nature and not some “superior” observer. This cognizance was reinforced during summer months in camps in the Missouri Ozarks and Colorado Rockies. I spent any time free from camp routine seeking the habitats of birds and mammals and immersing myself in nature. It was a stimulating time of life despite family deprivation.

High school, on the other hand, was for the most part mediocre and not stimulating—a pleasant enough experience, in retrospect, due primarily to the positive attitudes of the instructors. Standards were rather lax and instruction was not rigorous. The exception was English literature, a subject in which I received considerable reinforcement from my mother, an inveterate reader. Biology was taught by a kindly lady, but was so routine and uninspired that I almost failed. Even worse was physiology, taught by the football coach!

The big surprise came with ROTC, in which I reluctantly enrolled under parental pressure. ROTC was taught by a regular Army sergeant, a ramrod straight, crew-cut man with unblinking green eyes. Despite his demands for strict discipline and disdain for anything other than clear-cut objectives, I flourished and emerged two years later as second lieutenant with a medal inscribed “Most Military“!

By the time I finished high school in 1932 (with a mediocre scholastic record), the Depression was at its worst point and family finances required “the graduate” to forget the former country club environment of his parents and face the reality of earning a living. Compounding my problems was the separation and divorce of my mother and father. The money put away during former affluent days for my university education was needed to live. Jobs were scarce, but through family connections, I was hired to run an elevator and do various house-cleaning chores in an office building owned by an insurance company. This was indeed an abrupt change in lifestyle, but it proved to be an important learning experience.

I was plunged into a harsh milieu. My fellow workers resented my being given a job that was needed, as one worker said, “about as much as a thrashing machine.” I was incredibly naive and took a lot of ribbing, but basically the men were a decent lot and they finally accepted me. In addition to running the elevator and changing light bulbs, I quickly learned how to wash windows and scrub washrooms and as a bonus was tutored in the vocabulary of four-letter words. President Roosevelt had just been elected and among the changes he made was the increase in the minimum wage. Thus, for a 48-hour week I received $62.50 per month, a figure that still sticks in my mind. The chief engineer was worth $100 per month and the building superintendent $150. It was obvious to me that these people had dead-end jobs and little chance for an improved life. I vowed to start working my way out of that depressing situation.

Preliminary Steps

Despite my optimistic attitude, the situation was not promising—my family’s finances were extremely low. One factor in my favor was that I had a general idea of what to do with my life (at least in the immediate future) and that was to become a zoologist. Realization of this aim, however, required much more education. Luckily, Kansas City had a two-year junior college with rather lenient admission requirements, plus a faculty of men and women who were serious and rigorous educators. For the most part they did not hold doctorates and were not qualified for university jobs, but they were excellent teachers and I am forever grateful to them.

Finding the time to go to Kansas City Junior College, however, was the major problem. I started the solution by seeing the building superintendent and explaining my desire. To my great surprise he was quite sympathetic. Apparently, he had always wanted to go to college. He immediately agreed to change my schedule, allowing me to work half-time in the afternoons and evenings. This left the mornings free to go to school, but also reduced my salary to $31.25 per month. The next step was to approach my uncle and aunt (my father was in bankruptcy) for a loan of enough money to make a go of it. My uncle, Harry F. Mather, was a physician and surgeon and was sympathetic to my interests in science, but he had two sons of his own to educate. Nevertheless, a loan was agreed on. So the “end of the beginning” came about and I cannot begin to express the joy I felt to see this small window of opportunity before me.

I entered junior college the fall of my second year after high school with great enthusiasm and found the material fascinating. In the beginning, eagerness exceeded ability. I had not cultivated good study habits in high school, to say the least. Learning to study and to organize material from books was not an easy accomplishment and I struggled, but did it well enough to receive a tuition scholarship for the second year. Life was rigorous and disciplined to an extreme, with me rising at 6 a.m., reaching school at 8 a.m. and going to work at 2 p.m., leaving at 7 p.m. for dinner and study, and going to bed at midnight. I partly compensated for sleep deprivation on the weekends but managed to continue the trips to the rivers and woods around Kansas City, winter and summer.

At that time, a new government office building was being constructed in the center of the city and the Kansas City Star announced that fossils were found at the site of excavation. I hurriedly applied to the contractor for permission to go into the pit. Here were piles of gray-black shale, which, when split, revealed a multitude of fossils—pelecypods, brachypods, crinoids, and ferns—and I returned home with backpack bulging. I identified the fossils using library books and placed them lovingly on the shelves of my room along with Indian artifacts, bird nests, animal skulls, and minerals. Only one more trip to the pit was possible before construetion continued, after which I grieved that those remnants of long-past lives from ancient seas were lost forever. I would have saved them all!

At junior college, a requirement of the biology course was to make an original effort in the form of a mounted skeleton of animal or bird. Through friends I obtained the carcasses of a fox and a pheasant and mounted them with the help of books. William Hornaday’s Taxidermy gave instructions how to skin, stuff, and mount the pheasant; the result certainly would not have won any prize, but I was enormously proud of my work and received an “A” from the instructor. I have the fondest memories of that school’s rather shabby building and those exacting, but supportive instructors.

At the time of graduation from the two-year college in 1936, good luck struck again in the form of two wealthy and powerful family friends. One, Clifford C. Jones, was the president of a large insurance company in Kansas City. He and his wife each presented me with a check on graduation, not a princely sum, but for a struggling student a significant one. The second piece of luck came from my godfather (Episcopalian, not Mafia!) who was a dermatologist and sportsman and a friend of the then chancellor of the University of Kansas. My godfather (Richard Sutton, M.D.) gave me two important gifts: he obtained a job for me in the Natural History Museum and he paid my out-of-state tuition for the next four years at the University of Kansas until I completed my bachelor’s and master’s degrees in zoology. So I was on my way to the future that I had dreamed about—developing into a naturalist and explorer.

University Years: Kansas

At the University of Kansas I spent half of each day in class and half at my job, learning about the local fauna in the museum. The curator (Charles D. Bunker) was a man old enough to have seen the piles of skeletons and skulls of the thousands of bison slaughtered on the Kansas and Nebraska plains in the 1870s and 1880s. Another reminder that the Old West was not far behind was located in the museum—the mounted specimen of the horse Comanche, the only survivor of the Battle of the Little Bighorn, when General Custer and his entire command were wiped out by the Sioux and Cheyenne in 1876.

My job at the museum was to care for the large collection of mammal skins and skeletons, and during the summers I went on field trips to different parts of Kansas with an assistant curator (Claude Hibbard) to collect specimens not well represented in the museum’s collection. Many of these expeditions were to the fossil beds of western Kansas, a semiarid country of rolling hills and dry washes, of eroded Pliocene and Oligocene rocks loaded with fossils of rodents, carnivores, and small horses. Often these fossils could be picked up after a rain, exposed in the ground of stream beds. More frequently, their recovery required sifting large amounts of sand and earth through a wire mesh to recover the broken remains of a fauna that lived 20 to 40 million years ago. One summer I was the camp cook for four men with voracious appetites, fortunate for me because my experience was limited to preparing food to qualify for a Boy Scout merit badge! By summer’s end I could serve up a complete chicken dinner, including biscuits and pie cooked over a two-burner Coleman stove and oven.

My museum job began at $30 per month and topped off at $50 and required laboratory teaching in the comparative anatomy course. The hours were long, the pay low—lunch was frequently a chocolate bar with peanuts and for dinner I ate more chili than in all the rest of my years. In those days my scientific interests were limited to taxonomy, comparative anatomy, evolution, and wildlife distribution and behavior. One of my mentors, Charles Bunker, stimulated the budding careers of many Kansas boys who worked in the museum—Alexander Wetmore, who became director of the Smithsonian Institution; Remington Kellogg, who was curator of mammals and then director of the U.S. Natural History Museum; Raymond Hall, who became curator of mammals at the University of California, Berkeley; Theodore White, who collected fossils for the Museum of Comparative Zoology at Harvard University; and William Burt, who became curator of mammals, and Claude Hibbard, curator of paleontology, both at the University of Michigan. Later, the signatures of these luminaries and many others covered the scapula of a bull bison in Bunker’s office. Eventually, I was asked to sign along with these men (and two women) and did so proudly with the knowledge that I was now a qualified naturalist.

The University of Kansas at Lawrence has a beautiful site atop a geological formation called a monadnock, which looks over wooded rolling hills and farm country. The university was dependent on appropriations from a practical-minded state legislature, so surplus funds were hard to come by. Nonetheless, teaching was of a high quality, some of the faculty did research, and the spirit of faculty and students was good. It was an optimistic time for me, and I am indebted to more people than I can acknowledge here for support and encouragement. I found the courses in biology and paleontology fascinating and was attracted especially to Norman Newell, who became professor of paleontology at Columbia University and the American Museum of Natural History. Many years later I met him again at the annual meeting of the National Academy of Sciences, in Washington. Also present on the university faculty at that time was Loren Eiseley, the anthropologist and renowned writer who eventually went to the University of Pennsylvania (Penn), where we made contact again 15 years later.

I was at the University of Kansas for four years, two of which were to accumulate the credits to receive a baccalaureate degree in zoology, and two additional years to qualify for a master’s degree, under the supervision of the herpetologist, Edward Taylor. The university required a thesis of original research for a master’s and my choice of subject revealed a personal and lifelong characteristic—that is, to work in a field of study off the beaten track. The choice was modest enough in the beginning. The small mammals trapped during the museum’s field trips were skinned, treated with alum and arsenic, and stuffed. The carcasses were then placed in separate boxes containing a population of dermestid beetles. These remarkable insects ate the soft parts of the carcasses, leaving complete, articulated skeletons, including the small hyoid bone normally attached to the base of the skull and supporting the base of the tongue and pharynx. The use of that bone was fascinating—for instance, whether the hyoid arch (as it is called) is bony or ligamentous in felines determines whether a specific species can or cannot roar. This hyoid bone had not been described in rodents and appealed to me as a good subject for a master’s thesis. The faculty supervisors agreed and I put together a fairly interesting, but limited and not too rigorous, thesis. It was, however, an important step for me to organize my first scientific study, and I laud the wisdom of the university in requiring an experimentally based thesis for a second-level degree. In preparing the thesis I became acquainted with the writings of some of the great European comparative anatomists, chiefly English and German, of the 19th century.

Harvard

Before completion of my thesis in 1940, I began seriously considering where to apply for training leading to a Ph.D. For a variety of reasons, I had strong interest in three possibilities—the University of Michigan, the University of California, Berkeley, and Harvard, each having an active museum of natural history. A visit was therefore necessary to become a serious candidate for a scholarship, so I once more turned to my godfather for the wherewithal. He again supported my ambition and covered travel expenses; we chose Harvard for the first, and as it turned out, only visit. Lady Luck again played a role as my first appointment was with Professor Alfred S. Romer, the noted vertebrate paleontologist, who taught a major course in comparative anatomy for undergraduates. This course was popular because of Romer’s charismatic personality, and it filled a key spot in premedical preparation. I nervously knocked on the front door of the Romer house on Brattle Street, Cambridge. He was confined at home with the flu, but the worst was over and when I arrived he was lying on a chaise lounge covered with a blanket. Soon after I entered the room, however, he got to his feet and greeted me by chanting with full body participation the football cry of the University of Kansas—“Rock-chalk, Jay Hawk, K.U.“—beginning slowly and working up in speed and volume to a crescendo. I joined him in this amazing performance and we got along famously. Before the “interview” was over, he offered me a scholarship, assuming that Harvard would admit me as a graduate student, which it did. I was floating on cloud nine when I returned to Lawrence, and reported to my pleased godfather, friends, and mother (who had had a strong preference for Harvard right along).

Naturally, I was high on the manner in which the gates of higher education had opened to allow me to work on a Ph.D. at Harvard. Although I did not realize it, I would be leaving the Midwest for good and making my home on the East Coast in Cambridge, then Baltimore, and finally Philadelphia. While working for the master’s degree I had met Isabelle Baird, a young woman who was a graduate student in entomology. We became engaged before I moved to Cambridge and were married a year later in Fort Knox, Kentucky, where her parents lived. She broke off her graduate work at Kansas and went with me back to Harvard for my final year. Soon after my graduation in 1942 we moved to Baltimore where I had an appointment in anatomy at Johns Hopkins Medical School and where our son, Jim, was born. Unfortunately, our marriage was not successful and after several years we separated; she returned to the University of Kansas to finish her doctor’s degree and then joined the biology faculty at Mt. Holyoke College, in South Hadley, Massachusetts. Jim was raised in South Hadley, went to Harvard College and the University of Pennsylvania Medical School. He now has a successful practice in pediatric ophthalmology in McLean, Virginia, and lives in Washington, D.C., with his charming wife Elsie (née Youngman) and adopted children, Lena and Julie. He is a fine doctor and a wonderful person and I feel proud to be his father.

When I first went to Harvard I was assigned a small apartment in old Perkins Hall Dormitory, and I shared it with another biology graduate student, Peter Morrison. Peter had a major interest in biochemistry and eventually became director of the Institute of Arctic Biology at the University of Alaska, Fairbanks. In contrast to Perkins, the biological laboratories were in a relatively new building, the entrance of which was framed by two life-sized, bronze figures of the African rhinoceros. I shared a large and beautiful room on the second floor overlooking the rhinos with Dillon Ripley, who later became director of the Smithsonian Institution in Washington, D.C., and George Bartholomew, now professor of biology at the University of California, Los Angeles. They were delightful companions in the stressful pursuit of a Ph.D. degree. This large room, by the way, was the most spacious office, with the best view, that I occupied until I took over the chairman’s office at the University of Pennsylvania 27 years later.

I went to Harvard with the full intent of some day becoming a museum curator, specializing in comparative anatomy and life history of mammals. So I attached myself to two people in Harvard’s Museum of Comparative Zoology—Alfred Romer, curator of vertebrate paleontology, and Glover Allen, curator of mammals, both men of impressive scholarship. At the end of one of our conversations, Dr. Allen pointed out a large collection of pickled bats from all over the world that had been on the museum shelves for many years and suggested that I dissect these animals for my thesis. Not surprisingly, I chose to study the structure of the hyoid apparatus which, as these were intact specimens and not just skeletons, included the associated pharynx, larynx, and musculature. My area of research opened up in a stimulating way in this environment.

Harvard had a mature attitude toward graduate education, which suited me perfectly. A thesis advisory committee of five faculty members was assembled for each student and because the degree was in biology, the committee was broadly constituted. Mine consisted of Professors Romer, Allen, Hisaw (endocrinologist), Weston (botanist), and Wyman (biochemist and geneticist). No courses were required, although some were recommended to patch up my weaknesses. I was left alone to pursue my education, which hopefully would get me through a comprehensive (and terrifying) oral examination at the end. Once a week the faculty and student body gathered in a common room for tea and a faculty lecture. This “mixer” was a bit stiff, but educational and occasionally inspiring. Attendance was voluntary, hence the more reclusive or belligerent faculty and students were never seen.

I spent a good part of the next two years cheerfully dissecting and describing the hyoid and associated structures of 39 species of 32 genera of bats and writing a monograph on my findings. Of the 17 known families of bats, 13 were available in the Harvard collection. At least one member of one genus of each family was dissected by me and the origin and insertion of 19 muscles were described and figured; in one species the innervation of these muscles was also worked out. In examining my thesis now, I am absolutely amazed at the amount of work accomplished during those two years and by the energy of the young. The thesis was later published in the American Journal of Anatomy (1943). So far as I know, few read this work or referred to it subsequently and it is of historical interest only. Nevertheless it gave me much pleasure to complete it and, of course, it directed my reading and deepened my understanding of comparative anatomy and evolution. The only sorrow of those Harvard years was the death of Glover Allen. He was a gentle, shy man of deep erudition and was a model of modesty for his accomplishments and international reputation.

Postbaccalaureate Years: Johns Hopkins

As graduation day approached in the spring of 1942, Romer had lined up an ideal job for me in the Field Museum in Chicago as an assistant curator of mammals. But this was not to be. Ironically, and to my great disappointment, after all the years of study in preparation for just this kind of work, the restrictions imposed by World War II greatly affected museum activity, and the position was not filled. At the same time, the the job market in medical schools was opened up to prepare physicians needed in the Armed Services. I went to see George Wislocki, then professor of anatomy in the Harvard Medical School, and he generously made it possible for a classmate, Marcus Singer, and me to dissect a human cadaver during the summer of 1942 and to learn the rudiments of human anatomy sufficiently, but barely so, to teach first year medical students. With this accomplished, I was offered and accepted a teaching position at Johns Hopkins University Medical School. Romer’s advice was to continue my studies until the war was over and then return to my original objectives. But I found myself in a totally new research milieu in which the academic preparation for a career in evolution and comparative anatomy was only of marginal interest.

One of the strong points then in basic sciences at Hopkins was the study of the central nervous system in my home department of anatomy, in the physiology department, and in the Carnegie Institution of Washington’s department of embryology, located in the Medical Center. Making contact with these departments and reading the publications of their faculty opened a new world to me, both conceptually and in the possibility of doing experimental research. I was caught up in the fascination of the structure and function of the brain and, after several false starts, I picked up an interesting problem with considerable help from discussions with William Straus, comparative anatomist and physical anthropologist in the anatomy department.

Interestingly, the experimental problem grew out of embryology and comparative anatomy, of which I had some knowledge, and it had to do with the derivation of spinal musculature from embryonic myotomes or lateral plate and their respective innervations from dorsal and ventral rami of the ventral roots of the spinal nerves. The problem was to localize the position in the spinal gray matter of the motor neurons innervating myotonic or lateral plate muscles that had very different functions. Localization was achieved by severing dorsal or ventral rami respectively and waiting for retrograde chromatolysis to occur to identify the cell bodies of which the axons had been cut. In an unforeseen coincidence, I was not given rats, as might be expected for a beginner, but instead the study was done using rhesus monkeys, which were part of Marion Hines’ research in the department. My modest beginning of a career in neuroscience was helped in great measure by the supportive environment in which I worked, specifically by discussions with Bill Straus and Marion Hines in anatomy; Louis Flexner in the Carnegie Institution; Vernon Mountcastle, Jerzy Rose, and Reginald Bromiley in physiology; and by the critical reading of my manuscript by Clinton Woolsey.

Two men came into my life in important ways during this early period of my development—Donald Barron, professor of physiology at Yale, and Horace Magoun, professor of anatomy at Northwestern. Both contacts were serendipitous. Louis Flexner was my contact with Barron whom he knew from their days of working with Joseph Barcroft in Cambridge, England, and Flexner knew of Barron’s interest in the development of the brain in sheep. Barron was a wonderful person with whom I had marvelously exciting and formative discussions about science, and he loaned me a series of silver stained slides of the sheep spinal cord at various ages, fetal and newborn, which showed the differentiation of the dorsal and ventral primary rami. These I studied and later published on.

My relationship with Magoun began at a meeting when I delivered a paper, after which I sought him out for discussion about the possibility of spending a semester in his laboratory. After he returned to Chicago, he sent me a letter in which he agreed to my visit and provided financial support. In Chicago with Magoun, Donald Lindsley, and Leon Schreiner, I learned some neurophysiology and electroencephalography in a study of reticulospinal control of stretch reflexes. Tid Magoun was a brilliant investigator of mercurial temperament. He made great demands on his collaborators, but was a decent and generous man. At the time of my visit he was in full stride on a series of remarkable discoveries on the function of the brainstem reticular formation. When I went to Northwestern in the spring of 1948, I had already received a Guggenheim Fellowship and had made arrangements to spend a year in England. Otherwise I would have spent the following year with Magoun, who was joined by Giuseppe Moruzzi from Italy. Because of the timing I missed being a partner in the wonderful discoveries they made on the role of reticular formation in the control of arousal and wakefulness.

Soon after Moruzzi returned to Italy to accept the chair of physiology in Pisa, Magoun moved to the University of California, Los Angeles. With a series of colleagues he went on to work out the details of neural circuitry in midbrain, thalamus, and cortex by which the brain controlled waking, alerting, and attention. That research galvanized an entire area of research worldwide, including anatomy, physiology, and experimental psychology, and made him an international leader in neuroscience. The conceptual advances of Magoun’s research during the years 1948 to 1960 were such that he was a strong contender for the Nobel Prize and, in my opinion, should have received it.

Oxford and Cambridge

In the early summer of 1948, I boarded the Mauretania for Southampton and a wonderful year divided between Professor (later Sir Wilfrid) LeGros Clark in Oxford and Dr. Bryan Matthews in Cambridge. Both were distinguished investigators. Clark was professor of anatomy, widely known for his research on the connections of the mammalian visual system, and as a physical anthropologist. It was he, with his colleague Jeffrey Winer, who proved several years later that the Piltdown man was a fraud. Bryan Matthews had done brilliant work as a young man, growing up in the remarkable department of physiology at Cambridge, and he published what became a classical paper on a new neural mechanism—the gamma motoneuron and its influence on stretch reflexes. The onset of World War II had interrupted his developing career, but his services during the war earned him a knighthood. Later he succeeded Lord Adrian as professor of physiology in Cambridge. Matthews owned a 60-foot boat which he sailed to the Mediterranean each summer. I once crewed for him across the English Channel, up the river Scheld to Antwerp, and then via canals to Brussels where we attended an international physiology meeting. I came to know both LeGros Clark and Bryan Matthews as friends and we kept in touch until they died.

In Oxford I learned the silver technique developed by Paul Glees for staining degenerating axoplasm and through the use of it I worked out connections of the hippocampus in the rabbit with a colleague in the department, Margaret Meyer. The technique was a marked advance over the classical Marchi method for tracing pathways in the central nervous system. The classical method traced the degenerating axons only so far as they were myelinated, whereas the silver method impregnated the axon sheath itself and revealed the terminal arborization to the synapse.

While in Cambridge I lived in the house of a retired professor of German literature and his wife, whose dining room provided lively discussions of every sort. From there it was a short walk through a meadow, with cows and a millpond, to reach the physiology laboratories on Downing Street. The scientific environment was unique to me. The investigators were expected to do everything for themselves and few general facilities were available. I was joined in Matthews’ lab by Michael Fuortes from Torino, Italy, and each of us was given a set of directions on how to build an electronic amplifier from components that Matthews provided. I remember that Fuortes’ amplifier was more handsome than mine and when Matthews came around to take a look at it, I was discouraged and defensively stated that I had produced a pile of junk. He checked it out and said, “Yes, but a pile of junk that works.” Mike Fuortes later came to the United States, eventually moving to the National Institutes of Health (NIH) where he did outstanding research on the retina.

In any case, I scraped together enough electronic equipment to begin some recording experiments on the spinal cord of cats, but I ran up against a serious obstacle I had not foreseen. Matthews’ laboratory was heated totally by one electric glowing wire burner, which was insufficient to maintain the warmth of the investigator, much less that of an anesthetized animal in the months of January to March. I was intrigued to learn how Professor Adrian had solved this problem in his studies of the cortex. I asked his secretary for an appointment and one morning, some days later, he met me in his laboratory to show me his screened, recording cage that was encased in folds and twists of metal pipe through which he ran hot water from the sink to warm his preparation by radiation. This solution was beyond my reach as a young visitor in a famous laboratory, so I delayed the experiments until spring furnished the necessary warmth. Meanwhile, I read voraciously in the physiology library, attended lectures on Roman history as well as science, talked with many people, went frequently to Kings College Chapel for Evensong, and enjoyed fully exploring the myriad facets of Cambridge, both the university and the adjoining countryside. I learned there, without a doubt, that the opportunities afforded by sabbaticals should not be limited to working day and night in a laboratory.

One day Professor Adrian stopped by Matthews’ laboratory to chat and told me he had just returned from a visit to Sir Charles Sherrington, who was confined to a nursing home in the seaside town of Eastbourne. Sir Charles had been a scientific hero of mine since I read The Integrative Action of the Nervous System, and I asked if it would be possible to visit him. Adrian told me Sir Charles would enjoy visitors and kindly made the arrangements for me. Sir Charles was then over 90 and frail, but he asked what I was doing in research and we talked for several hours about various subjects, including Santiago Ramón y Cajal’s visit to Oxford many years before. Cajal had been invited to give some lectures in Oxford and stayed in Sherrington’s house. Cajal asked for a key to his bedroom and requested Mrs. Sherrington not to have the room cleaned or the bed made, and further asked that no one enter the room. This behavior was mystifying and never explained. Before leaving Eastbourne, Sir Charles gave me a signed copy of his book, Goethe on Nature and on Science, published and partly rewritten that year, 1949, in honor of the bicentenary of Goethe’s birth.

Another time during that sabbatical I visited Charles Darwin’s house at Down, where he wrote The Origin of Species, among other books. The house was charming, overseen by the gentle presence of Sir Arthur Keith, the anthropologist who lived there. Sir Arthur invited me to lunch, after which he took an hour’s postprandial nap and left me to ruminate in Darwin’s study, which remained just as the great man had left it. I should not leave a description of England without comment on the wonderful friendliness and hospitality found everywhere in that beautiful country.

Hopkins—My Last Year

The return to Baltimore was a cultural wrench, made particularly difficult by the animosity of the newly appointed chair of the department of anatomy. His animosity was not reserved for me, but was carried through to all members of the department. He succeeded in driving out a distinguished faculty, including two members of the National Academy of Sciences.

During 1949 to 1950, my last year at Hopkins, I tried to continue using the Glees silver method for tracing degenerating nerve fibers but without success; the technique that worked well using Oxford tap water refused to cooperate with Baltimore city water! While in England, I had read a paper by Cooper and Sherrington that described large, multipolar neurons in the ventral horn of the spinal cord, which were not motoneurons; they proposed these cells as the origin of the ventral spinocerebellar tract. I began to study this system after making lesions in the ventrolateral funiculus of the thoracic cord, using chromatolysis of the Cooper-Sherrington cells below the lesion and Marchi degeneration of the ascending tract that terminated chiefly in the bulbar reticular formation, as well as the cerebellum. At the same time I sought job opportunities elsewhere, surreptitiously I might add, because had he known, my chair would have tried to run me down in any way possible! An attractive job in anatomy at the University of Pennsylvania was offered by William Windle and eagerly accepted. I moved to Philadelphia in the fall of 1950 and have remained there happily up to the present.

University of Pennsylvania

I went to Penn with reasonable experience in teaching gross and microscopic anatomy and neuroanatomy, but with only a modest research achievement. I had gone to Hopkins immediately after graduate school, with no postdoctoral experience. During my first three years in Baltimore (1942–1945) I taught medical students in the mornings and worked in the National Research Council in Washington, D.C. in the afternoons. Both Army and Navy had deferred me from active service because of minor physical deficiencies and, to make some contribution to the war other than training medical students for the Armed Services, I joined the “Army of the Potomac” working in the National Research Council. At that time I was chagrined not to be in the South Pacific, but in retrospect I was lucky. After the war was over, there remained the rather considerable problem of reorienting my research efforts away from comparative anatomy to the developing area of neuroscience. Eight years after obtaining my Ph.D., my modest bibliography listed five papers in comparative anatomy, five in neuroanatomy, and one in neurophysiology.

I found two colleagues at Penn working on the anatomy and physiology of the spinal cord—William Chambers and John Liu—and with them pursued the study of the spinocerebellar tracts in the cat and monkey. This work led naturally to investigation of the structure and function of the cerebellum, and Bill Chambers and I collaborated on the problem intensely for the next five years. With him, I discovered the value and pleasure of a long-term collaboration with a gifted colleague and friend. By that time in the early 1950s, Walle Nauta had introduced the first of a series of superior silver techniques for staining degenerating axons, and Bill and I applied these to trace, in greater detail than had been possible in previous studies, the efferent projections from cerebellar cortex to the three deep paired nuclei, and from these nuclei to the brainstem and thalamus.

These anatomical studies in the cat expanded those done earlier in Norway by Jan Jansen and Alf Brodal using the Marchi method; this study had shown that the cerebellar outflow was organized into three zones. The medial cortical or vermal zone projected to the medial fastigial nuclei, the lateral cortex projected to the dentate nuclei, and the intermediate or paravernal cortex projected to the interpositus nuclei. Our research demonstrated that each fastigial nucleus projected bilaterally to the medullary and midbrain reticular formation and vestibular nuclei and to the thalamus, including ventral and ventrolateral nuclei. Each interpositus and dentate nucleus projected contralaterally and heavily to the red nucleus of the midbrain and to the ventral and ventrolateral nuclei of the thalamus. These anatomical studies were done with Donald Thomas and Donald Cohen, first-year medical students.

Bill Chambers and I were interested in working out the functions of these three systems, and we approached this problem by making specific lesions in cortical or nuclear zones and following the animals’ deficits. In addition, we stimulated these zones electrically in intact and lesioned cats and after decerebration. The results indicated that vermal cortex and fastigial nuclei are involved in the control of gross postural tone, equilibrium, and locomotion of the entire body. The intermediate zone is involved only with skilled movements and tone of the ipsilateral limbs. The lateral zone (hemispheric cortex and dentate nuclei) is involved with spatially organized and skilled movements of ipsilateral limbs, but without regulation of posture and tone. All parts of the cerebellum exert influence via the thalamus on the motor cortex of the cerebrum. The functions of these zones were summarized by Sprague and Chambers in detail in 1959 after unilateral and bilateral lesions; deficits and recovery after cerebellectomy were studied by us over long periods of time.

Closely allied to the cerebellar research was our follow-up of the lesion studies of Magoun, Lindsley, and Moruzzi done at Northwestern; their important results had been obtained for the most part in acute animals or chronic animals of rather short-term survival. A significant conclusion of their work had sharply separated the function of the neural paths that ascended in the reticular core of the brainstem from those more peripheral sensory paths. They concluded that the latter, termed lemniscal systems, provided specific topographically organized sensory information to the forebrain; the reticular or extralemniscal path controlled wakefulness and sleep, arousal, alertness, and attention and many visceral functions.

We devised a battery of tests that were applied to cats for several months preoperatively and for long periods, up to two and a half years, after midbrain lesions. These lesions interrupted either the reticular core or the sensory systems that at the midbrain level included somatosensory, acoustic, and part of the visual sensory paths. Analysis of data obtained in this longitudinal study used electroencephalographic (EEG) recording and neurological and behavioral examinations; psychophysical and psychological testing; and, finally, anatomical evaluation of the lesions. Our results revealed a widespread spectrum of deficits in attentive, adaptive, and affective behavior after lesions that interrupted ascending sensory paths to the midbrain and forebrain as well as descending pathways from the cortex to the midbrain. The reticular lesions were followed by variable periods of somnolence with deficits in arousal, hypokinesis, catatonia, and spasticity; animals with such reticular lesions often showed considerable recovery with good attention to and localization of visual, acoustic, tactile, and nociceptive stimuli and full, often exaggerated, affective responses. This work provided a richer and more meaningful picture of the contribution of the sensory and reticular systems to the behavioral repertory of the animal than had previous studies using animals of short-term survival. The work was the result of collaboration over several years with Bill Chambers, Eliot Stellar, and John Liu and postdoctoral fellows Tom Meikle, Mel Levitt, and Ken Robson, who all contributed much to the rather arduous, but rewarding study (Sprague et al., 1961, 1963).

I found interesting the elegant physiological research on the spinal cord by David Lloyd and John Eccles, who differed in whether “direct” reciprocal inhibition by dorsal root la fibers on motoneurons was mono- or disynaptic. If the la inhibition was monosynaptic, then the axon terminals of the same cell that mediated both excitation and inhibition would be producing different transmitters at different terminals. This would be an important exception to the generally held “law” that a single neuron secreted a single transmitter. The pattern of degeneration in the spinal gray matter after section of dorsal spinal roots appeared to offer an anatomical solution to this controversy. I was invited by Dr. Lloyd to carry out some of these experiments in his laboratory at the Rockefeller Institute for Medical Research in New York City in the fall of 1955 during my sabbatical leave from the University of Pennsylvania. The second and third sacral segments of the cat spinal cord provided the necessary anatomical structure because these dorsal root fibers not only terminated ipsilaterally but also contralaterally. Ipsilaterally, degenerating fibers were found on cell bodies and dendrites of motoneurons controlling movements of the tail, but the contralateral fibers ended on dendrites only, suggesting that the reciprocal inhibition exerted contralaterally might be mediated monosynaptically by these axodendritic synapses (Sprague, 1958).

This hypothesis was put to the test by Karl Frank and myself (1959) using intracellular recordings. We found a difference in latency of 0.3 to 0.7 msec between ipsilateral excitatory postsynaptic potentials (EPSPs) and contralateral inhibitory postsynaptic potentials (IPSPs) in the same motoneuron. Because no adequate explanation could be found to account for this extra latency on the basis of monosynaptic connections, the presence of an interneuron in the direct inhibitory pathway was a definite possibility, confirming Eccles, Fatt, and Landgren (1956). A detailed study with Hongchien Ha of the terminal fields of dorsal root fibers in the cat spinal cord and of the dendritic organization of the motor nuclei was presented at a symposium held in Amsterdam and published in Progress in Brain Research in 1964. With this paper my active involvement with the spinal cord was over.

I must break at this point with a most important personal happening that began with the entrance of Dolores Joseph into my life. She had come to Penn from New York University to enter the graduate group in physiology, which required many of its students to take the introductory course in the nervous system. She was in my laboratory section, and after the course ended we became better acquainted as she visited my research lab to see animal experiments at first hand. One thing led to another. I found her marvelous company, and we were married in November of 1959 and recently celebrated our 37th wedding anniversary. She did not complete her Ph.D. but left the university and entered art school at the Philadelphia Museum of Art. She became an excellent graphic artist and her etchings and silk screens became well known in the Philadelphia art community.

To pick up the thread of the discussion of research, I noticed in analyzing the extralemniscal lesions in the midbrain, that there was always a wedge-shaped extension of the lesions below the superior colliculus into the lateral edge of the periaqueductal gray matter. This extension interrupted several afferent pathways into the deep layers of the colliculus and many efferent pathways from these same laminae, with cell loss in the middle and deep layers. Thus it was likely that the unexpected visual deficits found after lesions that severed the ascending lemniscal paths from spinal cord and brainstem might be due to involvement of the superior colliculi.

With Thomas Meikle, a postdoctoral fellow in my laboratory, I began a study of this fascinating and complex structure, the superior colliculi, in 1961, which would stimulate my interests up to the present, 35 years later. The results of our first step in this investigation (published in abstract form in 1962) were from unilateral ablation of the colliculus, which did not extend directly into the tegmental area destroyed by the lemniscal lesions as mentioned above. We found two major behavioral deficits—complete neglect of visual stimuli in the contralateral hemifield, and a motor asymmetry consisting of ipsilesional forced circling, with compulsive responses to ipsilateral stimuli. Both sensory and motor deficits lessened within a few weeks after collicular ablation, but persisted permanently in the form of contralateral extinction to bilateral stimulation and of heightened ipsilateral responses. This research on the neurological effects of unilateral and bilateral aspiration of the colliculi in the cat was published in full in 1965 with Meikle. The work postulated a new concept that visual attention was a tectal function in addition to the classically accepted control of head and eyes in orienting responses. I later related this attentional dysfunction of the colliculus to deficits in discrimination tasks after cortical lesions.

From 1962 on, my research was involved with the central visual system—anatomy, physiology, and discriminative behavior. Ophthalmologist Alan Laties and I restudied the projection of the retina onto the visual centers in the brain of the cat, using the Nauta silver technique after small retinal lesions made either by photocoagulator or laser. This approach made possible a lesion of a limited number of ganglion cells in an area of retina and the subsequent degeneration of their axons to midbrain and thalamus provided a detailed picture of the organization of this part of the central visual system not previously available. Our study coincided with a widespread, surging interest among neuroscientists in the organization of the visual system. In carrying out this particular study we were indebted to ongoing work of Peter Bishop, Jonathan Stone, and William Hayhow in Australia; and of Torsten Wiesel and David Hubel at Harvard.

Meikle and I wrote a review on the anatomical organization of the visual pathways in the cat as it was understood in 1964. Our research on visually guided behavior after collicular lesions, which resulted in profound sensory and emotional neglect and inattention, led to the question of to what extent these deficits were related to or dependent on the visual cortex. At that time, only visual areas 17, 18, and 19 had been defined, and lesions of these cortices indeed resulted in contralateral neglect which, however, showed considerable recovery. If this cortical lesion was followed by collicular lesion on the same side of the brain, the recovery following the former was abolished and the resulting loss of orienting was permanent.

So clearly, we discovered, there is marked interaction between cortical and midbrain levels in visual orienting. Only when the cortical lesions were much larger and included all of what is now recognized as visual sensory and association cortex, could the deficit be termed hemianopia with total and enduring loss of orienting. However, an astonishing recovery of orienting followed subsequent ablation of the colliculus on the opposite side of the brain (Sprague, 1966). This dramatic result, later called the Sprague effect, forced a new concept of brain function: the paired orienting centers in the superior colliculi have a reciprocal inhibitory mechanism that suppresses activity in one colliculus when the other is directing orienting responses toward contralateral space. This inhibitory mechanism is unbalanced by the effects of the cortical lesion so that the colliculus ipsilateral to the lesion receives a chronic influx of inhibition, resulting in lack of orienting contralaterally and the presence of visual neglect of contralateral space. This idea was supported by cutting the collicular commissure, which also restored orienting. These experiments were exciting for me because in them I had discovered a previously unknown neural mechanism that controlled visuomotor orienting and orienting of attention through interaction between cortex and midbrain. Discovery of a new system is a rare occurrence and formed a peak in my career.

Later experiments with Steve Wallace and Alan Rosenquist (1989, 1990) made a major advance in explaining this phenomenon by showing that the “cross-tectal” inhibition originated in the substantia nigra, and was mediated by the nigrotectal tract, the axons of which passed in the tectal commissure. In other words, it was not a tecto-tectal system as I originally thought. Important in our decision to initiate research on the substantia nigra was the elegant physiological exploration of that structure by Hikosaka and Robert Wurtz (1983) in the macaque and the anatomical studies of nigrotectal pathways in several species, especially the seminal work of Ann Graybiel (1978) in the cat. Linking the Sprague effect with the substantia nigra brought it into a larger neural mechanism controlling visual orienting that was being worked out in several laboratories in the hamster, rat, cat, and macaque.

The mechanism appears to work as follows. Visual input from the retina reaches extrastriate cortex, which projects to the striatum and there activates a striatonigral path (using glutamate), which terminates in the substantia nigra, pars reticulata. This system (using GABA) exerts a controlling influence on nigral neurons which project to the superior colliculus by way of a nigrotectal tract. The nigrotectal path is a tonically active GABAergic tract that suppresses firing of the orienting neurons in the colliculus; these nigral neurons are phasically inhibited by GABAergic activity in the striatonigral path, thus releasing the colliculus to trigger contralateral orienting responses.

About this time (1965) I asked for a sabbatical leave of absence from the university and spent most of 1966 in the Institute of Physiology in Pisa, Italy. The director, Giuseppe Moruzzi, had worked with Magoun at Northwestern in 1949 to 1950. The sabbatical was a marvelous choice for both my wife and me; she continued her art work making etchings and wood blocks of the beautiful parks, old buildings, and countryside of Tuscany. I was given a small office on the top floor of the institute, overlooking a garden of cypresses bounded by the medieval city wall, miles beyond which rose the peaks of the Appenines. I found stimulating and productive collaboration with three younger members of the institute.

Giovanni Berlucchi and I began training cats in a series of visual discriminations—brightness and shapes—to learn to what extent they depended on processing in the superior colliculi and in different visual cortical areas (Sprague et al., 1970; Berlucchi et al., 1972). Animals with optic chiasm and various commissures split mid-sagitally were used to isolate the input from each eye to the corresponding side of the brain. Lesions were then placed on one side of the brain in the colliculus and/or cortex. Training was carried out monocularly and performance could be compared using the eye on the lesion side of the brain with that obtained using the eye on the unoperated side; thus both experiment and control are contained within each animal. Marked deficits in learning form discriminations follow unilateral lesions in the superior colliculus and pretectum, compared to the unoperated side. When the discrimination tests were trained preoperatively, no loss in retention after collicular lesions was found. Additional removal of cortical area 17 did not worsen the deficit. The shape discriminations were degraded by the collicular lesions, probably because of the consequent defects in visuomotor orienting and in shifts of visual attention.

Other experiments while in Italy, with Lorenzo Marchiafava and Giacomo Rizzolatti, were among the first to record single unit activity in the superior colliculus of mammals. This study was unique in using alert, unanesthetized cats rendered pain-free by mid-pontine section. All three of these men became close friends and I continued research collaboration with Berlucchi for many years thereafter. We returned to Pisa numerous times—indeed those visits to that beautiful country were among the highlights of both my personal and my scientific life.

Development of the Department of Anatomy

Shortly after returning from Italy in 1966 I was nominated to fill the chair of anatomy at the University of Pennsylvania, which had been vacated by the retirement of Louis Flexner. Up to that point I had avoided major administrative positions, but this was a department that Louis had built to preeminence and one that had supported and nurtured me in more ways than I can mention. I had also played a significant role in 1953 to 1954 in organizing an Institute of Neurological Sciences (INS) that provided the nucleus for the development of a large and productive neuroscience community at Penn. The concept and initiation of INS was the brainchild of Louis Flexner and coincided with the great upsurge of interest in the nervous system in this country and abroad. The influence of the institute brought many distinguished faculty to Penn and regularly attracted some of the brightest graduate students and postdoctoral fellows.

I became director of the institute in 1973 and served in that capacity until 1980. Throughout the directorships of Flexner, Eliot Stellar, and myself (1953–1980) INS was a loosely organized institute supported by NIH, Ford, and Grant Foundations and the University of Pennsylvania. The institute’s academic focus was to foster multidisciplinary research and training, university-wide. The institute maintained skilled personnel in the machine, electronic, art, and photography shops that members of INS used for themselves and for their graduate students and postdoctoral fellows. When I was succeeded as director by Robert Barchi, the neuroscience community in this country had grown in size and influence to such an extent that it was time to restructure the institute with allocation of space and a Ph.D. graduate program with a separate budget. A large grant from David Mahoney established a named chair for the director and support of the programs. INS thus became known as the Mahoney Institute of Neurological Sciences. These timely changes were soon followed by the establishment of a department of neuroscience in the school of medicine, with Bob Barchi as chair.

All these factors led me to accept the chair for a term of nine years, from 1967 to 1976. At that time, research in the department of anatomy had three major areas—cell and tissue differentiation, neurochemistry and ultrastructure, and neuroscience. My colleague Bill Chambers and I organized an introduction to the nervous system course, an interdisciplinary neuroscience course which was a meld of anatomy and physiology and was pitched at a level to educate graduate students and fellows in the institute and first-year medical students. The position of the course in the medical curriculum was such that it was followed by neuropathology and clinical neurology, a sequence that directed many students toward a future in neurology.

One of the necessary but onerous responsibilities of the chair was to obtain funds from the university and various foundations for improvements in the department. Anatomy was housed in a wing of the medical school, which had lain untouched since 1926 to 1928 when the wing was built. Fundraising was certainly not a joy; nevertheless we were successful in obtaining the appropriate money and the physical facilities of the department and its appearance were considerably improved. On the other side of the coin of being chairman, however, was the pleasant and stimulating experience of appointing new young faculty to replace those who were retiring. This turnover provided me the chance to create a small group in the department working on the visual system—Paul Liebman, Peter Sterling, Alan Rosenquist, and Larry Palmer. The group acted as a focus with others in psychology and ophthalmology to obtained funds from the National Eye Institute (of NIH) to form a Vision Center to facilitate faculty research and obtain a training grant to attract and support graduate students. These efforts continue to the present day and are part of the research and educational program of INS.

The demands of the department and the institute, as well as a full teaching load, cut deeply into the time I could devote to research, despite allocating at least two hours every afternoon to go to the laboratory and participate directly in the occupation that had attracted me to academic life in the first place. Nevertheless, after six years of administrative responsibilities I began to wonder whether my capacity to “think” creatively about research was still intact, and I asked for a sabbatical away from Penn to find out. My close friend and colleague, Bill Chambers, agreed to look after the shop while I was away, so I applied for and received a Josiah Macy Foundation Faculty Award to help fund a leave of absence in Pisa in 1974 to 1975. Giovanni Berlucchi had maintained close contact with me since my sabbatical of 1966, and I was received again with warm hospitality from him and Giuseppe Moruzzi.

As before, the experience in Italy was both restorative and productive. Robert Doty’s work in 1971 had shown clearly that cats had impressive visual abilities, including pattern discrimination, after removal of area 17. Berlucchi and I pursued this seminal finding, beginning in 1971 and 1972. We expanded Doty’s finding by making our lesion include not only striate cortex (area 17), but also adjacent area 18; these two primary areas have many similarities in their parallel thalamic connections and in the responses of their constituent neurons. Our approach was to train cats in a number of discriminations—luminance (light-dark), patterns (gratings), and forms—preoperatively and again after lesions that removed areas 17 and 18. These animals retained criterion performance immediately, with perfect retention, which indicated that these suprathreshold discriminations do not require preoperative processing in 17–18. In contrast, after cortical lesions that left 17–18 intact, cats showed deficits in the pattern and form tasks, which required retraining to reach criterion. These results dealt a serious blow to the concept of serial cortical processing in pattern and form perception beginning with striate cortex (Berlucchi et al., 1981).

At least two major questions arise from these findings: what pathways are used to reach other cortical areas in the absence of areas 17 and 18, and what functions do depend on 17 and 18? The first question can be answered by the anatomy of the cat’s visual system reviewed by Rosenquist (1985). In contrast to the monkey, the lateral geniculate in cats projects not only to areas 17 and 18 but also to many parts of the extrastriate cortex, which also receive projections from the superior colliculus and pulvinar (the second visual system). Thus, several parallel paths exist between the thalamus and the visual cortices in the cat. It would appear that the suprathreshold or multicued stimuli can be perceived and discriminated by extrastriate cortex without using the geniculocortical path to areas 17 and 18.

Howard Hughes, then a postdoctoral fellow, and I investigated the cortical mechanisms for global and local analysis of visual space (1986). We used as stimuli orderly arrays of identical elements (dots) whose pattern could be perceived and discriminated only through grouping of the units by spatial proximity (i.e., global structure). This function using basic patternrecognizing components of the visual system was not affected by removal of areas 17–18. Similar results were obtained when small line-segments were used; deficits occurred only when high resolution was required (acuity).

The answer to the second question has been partly revealed in a collaborative study with Mark Berkley (department of psychology, Florida State University) in which cats were trained in a totally different way in threshold discriminations of elementary visual stimuli using only single cues—grating acuity, contrast sensitivity, vernier alignment, or line orientation. The thresholds of all of these difficult tasks were elevated after 17–18 lesions, the vernier test was the most severely affected; grating acuity was elevated only 25 to 30 percent. Multicued form discriminations similar to those described above were either normal or somewhat slowed postoperatively (Berkley and Sprague, 1979). Much of my subsequent research done in collaboration with Mark, including detailed studies of the effects of striate or extrastriate lesions on thresholds of contrast sensitivity and vernier alignment in the cat, has remained unpublished because of his untimely death in 1995 from pancreatic cancer.

Berlucchi and I also studied the role of different cortical areas in the interhemispheric transfer of form discriminations in the cat (Berlucchi et al., 1979). These experiments required splitting the optic chiasm to limit the direct input from each eye to the homolateral brain hemisphere, followed by unilateral lesions in either the commissural parts of areas 17, 18, and 19, or the adjacent suprasylvian cortex (areas 7, 21a, part of 19). Transfer of the form discriminations from the intact to the lesioned hemisphere was blocked by the second lesion, but was present after the first lesion. Thus, we found that this important function of interhemisphere communication in the brain was mediated by extrastriate cortex and did not depend on processing in areas 17 and 18.

I designed a study that used the findings of this research and those of the Sprague effect described earlier. Again, the cats had optic chiasm split and a unilateral lesion placed in the suprasylvian cortex. The animals were taught gratings and form discriminations using the eye connected to the intact hemisphere; transfer of the form to the lesioned hemisphere was lacking (confirming Berlucchi et al., 1979), but transfer of the gratings was excellent. Stimuli with global repetitive features (gratings) apparently can be discriminated using preattentive vision, but stimuli with local features (forms) that require serial exploration using focal vision and attention were not transferred. The next step was section of the tectal commissure and training in new gratings and forms. This commissurotomy, which restored orienting in the Sprague effect, also restored transfer of form discrimination. I hypothesized that the perceptual deficit on the lesioned side of the brain was due to poor spatial attention, and its restoration after midbrain lesion was due to improved function of those collicular cells that mediate orienting of attention (Sprague, 1991).

These interesting results provided evidence of an additional role of the midbrain in a function (form discrimination) that is widely considered wholly cortical, and as such sheds light on the neural mechanisms underlying visual perception. I repeated the experiment with the second lesion in the substantia nigra, pars reticulata (rather than the tectal commissure) that had restored orienting (Wallace et al., 1990), and obtained the same restoration of transfer of form discrimination. My application in 1992 to NIH for a research grant to follow up these findings was not, however, funded—my first failure since 1951. This was a blow because I felt these were original and significant findings, and despite the generosity of my colleague Alan Rosenquist in the use of his facilities, I was no longer able to do experimental research at the University of Pennsylvania after age 76.

Research in Belgium

I frequently attended the annual meeting of the Association for Research in Vision and Ophthalmology (ARVO), in Sarasota, Florida, and on several occasions my son Jim, a pediatric ophthalmologist, and I attended together. It was there that I met and began collaborating with Mark Berkley in 1972 and it was with Jim and Mark that I celebrated my election to the National Academy of Sciences in 1983. I also met Guy Orban at the ARVO meeting in 1983. Guy had organized a laboratory of neurophysiology and behavior at the University of Leuven, Belgium, and with his colleague Erik Vandenbussche was training cats in visual discrimination tasks using the testing methods devised by Berkley at Florida State.

The Belgian laboratory seemed to me the ideal place to study visual behavior in a way I had long dreamed of using anatomy, physiology, and carefully controlled paradigms of discrimination. From 1984 to 1995, Guy, Erik, Peter DeWeerd, Balázs Gulyás, Steven Raiguel, and I pursued an active collaboration that took me to Leuven once or twice a year. The overall plan was a psychophysical study—to train cats to discriminate singleoriented lines or bars, a simple stimulus considered a basic element, or primitive, of visual perception, upon which the brain composed more complex forms. Once stable thresholds were obtained, using parameters of length, width, and contrast comprising optimal visibility, lesions were made in specific cortical areas. These areas in the cat had been clearly defined by histological structure and connectivity, and by single neuron responses. We showed that the perception and discrimination of this visual primitive was processed primarily in visual cortex 17 and 18, that threshold was not determined by those neurons most tightly tuned for orientation, and that the task was achieved by population processing, spread across two cortical areas. Both areas were necessary. When lesions removed 17 and spared 18, or removed 18 sparing 17, no deficit in threshold discrimination occurred unless contrast was greatly reduced or bar length and width were diminished.

The next tasks used the same primitive element (oriented bars) but were more complex, consisting of illusory bar contours and textures composed of line segments. In contrast to the results obtained using single bars, both of these discriminations required processing in two cortical areas: 17–18, in which primary filtering took place, and extrastriate cortex, in which an additional step of the discrimination occurred. These findings require a modification of the widely accepted hypothesis that texture segregation is solely a function of early vision, that is, primary visual areas. It is important to point out that these results were derived from deficits in discriminative behavior performed by the animals and were not extrapolated from single-unit activity recorded in the cortical areas.

On all of those visits to Belgium I was housed in a beautiful facility (Begijnhof) owned by the University of Leuven. The renovated hospice had until recently been occupied by the Beguines, a semireligious order of women. Living in that remnant of old Flanders, in addition to the friendship and warm hospitality of my colleagues, made that final scientific collaboration not only productive but a distinct pleasure.

Winding down an active life of research is not an easy adaptation to make, but one that must be faced by every investigator. Certainly, I have had an exciting and rewarding life of discovery, and as a professor I had the unique privilege of controlling the use of much of my time for scholarship and teaching. Over a span of 50 years many wonderful colleagues and stimulating students added to the richness of my life. A large number of others—postdoctoral fellows, technicians, and secretarial staff—contributed in numerous ways to create a harmonious research environment in the department over the years. Few of them have been specifically mentioned here because a proper account of what they did and what they are doing now would not be possible in the space allowed. Some mention is essential, however, of colleagues other than those mentioned in the text, with whom I collaborated from Penn (Alan Epstein, Adrian Morrison, Larry Palmer, Murray Sherman, Howard Hughes, Louis Flexner, Alan Church), from Japan (Kahee Niimi, Takeshi Kaneseki, Syosuke Kawamura), from England (Ray Lund), from Italy (Mirko Carreras, Franco Lepore, Antonella Antonini), from France (J. Flandrin, J. Courjon), and from Duke University (Irving Diamond).

Selected Publications

The hyoid region of placental mammals with especial reference to bats. Am J Anat 1943;72:385–472.

The hyoid region of the Insectivora. Am J Anat 1944;74:175–216.

A study of motor cell localization in the spinal cord of the rhesus monkey. Am J Anat 1948;82:1–26.

(with Schreiner LH, Lindsley DB, Magoun HW) Reticulo-spinal influences on stretch reflexes. J Neurophysiol 1948;11:501–508.

(with Meyer M) An experimental study of the fornix in the rabbit. J Anat 1950;84:354–368.

(with Chambers WW) Differential effects of cerebellar anterior lobe cortex and fastigial nuclei on postural tone in the cat. Science 1951;114:324–325.

Spinal “border cells” and their role in postural mechanism (Schiff-Sherrington phenomenon). J Neurophysiol 1953;16:464–474.

(with Chambers WW) Regulation of posture in intact and decerebrate cat. J Neurophysiol 1953;16:451–463.

(with Chambers WW) Control of posture by reticular formation and cerebellum in the intact, anesthetized and unanesthetized and in the decerebrate cat. Am J Physiol 1954;176:52–64.

(with Chambers WW) Functional localization in the cerebellum I. Organization in longitudinal cortico-nuclear zones and their contribution to the control of posture, both extrapyramidal and pyramidal. J Comp Neurol 1955;103:105–129.

(with Chambers WW) Functional localization in the cerebellum II. Somatotopic organization in cortex and nuclei. Arch Neurol Psychiatr 1955;74:653–680.

The distribution of dorsal root fibres on motor cells in the lumbosacral spinal cord of the cat, and the site of excitatory and inhibitory terminals in monosynaptic pathways. Proc R Soc Lond B Biol Sci 1958;149:534–556.

(with Cohen D, Chambers WW) Experimental study of the efferent projections from the cerebellar nuclei to the brainstem of the cat. J Comp Neurol 1958;109:233–259.

(with Chambers WW) An analysis of cerebellar function in the cat, as revealed by its partial and complete destruction, and its interaction with the cerebral cortex. Arch Ital Biol 1959;97:68–88.

(with Frank K) Direct contralateral inhibition in the lower sacral spinal cord. Exp Neurol 1959;1:28–43.

(with Chambers WW, Stellar E) Attentive, affective and adaptive behavior in the cat. Science 1961;133:165–173.

(with Levitt M, Robson K, Liu CN, Stellar E, Chambers WW) A neuroanatomical and behavioral analysis of the syndromes resulting from midbrain lemniscal and reticular lesions in the cat. Arch Ital Biol 1963;101:225–295.

(with Ha H) The terminal fields of dorsal root filters in the lumbosacral spinal cord of the cat, and the dendritic organization of the motor nuclei. In: Eccles JC, Schadé J, eds. Prog Brain Res Amsterdam: Elsevier Press, 1964;11:120–152.

(with Meikle TH Jr) The neural organization of the visual pathways in the cat. Int Rev Neurobiol 1964;6:149–189.

(with Meikle TH Jr) The role of the superior colliculus in visually guided behavior. Exp Neurol 1965;11:115–146.

Interaction of cortex and superior colliculus in mediation of visually guided behavior in the cat. Science 1966;153:1544–1547.

Visual, acoustic, and somesthetic deficits in the cat after cortical and midbrain lesions. In: Purpura D, Yahr M, eds. The thalamus. New York: Columbia Univ. Press, 1966;391–414.

(with Laties AM) The projection of optic fibers to the visual centers in the cat. J Comp Neurol 1966;127:35–70.

(with Berlucchi G, Levy J, DiBerardino AC) Pretectum and superior colliculus in visually guided behavior and in flux and form discrimination in the cat. J Comp Physiol Psychol (Monograph) 1972;78:123–172.

(with Palmer LA, Rosenquist AC) Corticotectal systems in the cat: their structure and function. In: Frigyesi T, Rinvik E, Yahr M, eds. Corticothalamus projections and sensorimotor activities. New York: Raven Press, 1972;499–522.

(with Berlucchi G, Rizzolatti G) The role of the superior colliculus and pretectum in vision and visually guided behavior. In: Jung R, ed. Handbook of sensory physiology, central processing of visual information B, Vol. VII. Berlin: Springer Verlag, 1973;27–101.

(with Kanaseki T) Anatomical organization of pretectal nuclei and tectal laminae in the cat. J Comp Neurol 1974;158:319–338.

Mammalian tectum: intrinsic organization, afferent inputs and integrative mechanisms. In: Ingle D, Sprague JM, eds. Sensorimotor function of the midbrain tectum. Neurosci Res Prog Bull 1975;13:204–213.

(with Levy J, DiBerardino A, Berlucchi G) Visual cortical areas mediating form discrimination in the cat. J Comp Neurol 1977;172:441–488.

(with Berkley M) Striate cortex and visual acuity functions in the cat. J Comp Neurol 1979;187:679–702.

(with Antonini A, Berlucchi G, Marzi CA) Importance of corpus callosum for visual receptive fields of single neurons in cat superior colliculus. J Neurophysiol 1979;42:137–152.

(with Berlucchi G) The cerebral cortex in visual learning and memory, and in interhemispheric transfer in the cat. In: Schmitt FO, Worden FG, Adelman G, Dennis JG, eds. The organization of the cerebral cortex. Cambridge: MIT Press, 1981;415–440.

(with Hughes HC) Cortical mechanisms for local and global analysis of visual space in the cat. Exp Brain Res 1986;61:332–354.

(with Wallace SF, Rosenquist AC) Recovery from cortical blindness mediated by destruction of nontectotectal fibers in the commissure of the superior colliculus in the cat. J Comp Neurol 1989;284:429–450.

(with Orban GA, Vandenbussche E, De Weerd P) Orientation discrimination in the cat: A distributed function. Proc Natl Acad Sci USA 1990;87:1134–1138.

(with Wallace SF, Rosenquist AC) Ibotenic acid lesions of the lateral substantia nigra restore visual orientation behavior in the hemianopic cat. J Comp Neurol 1990;296:222–252.

The role of the superior colliculus in facilitating visual attention and form perception. Proc Natl Acad Sci USA 1991;88:1286–1290.

(with Vandenbussche E, De Weerd P, Orban GA) Orientation discrimination in the cat: Its cortical locus I. Areas 17 and 18. J Comp Neurol 1991;305:632–658.

(with De Weerd P, Raiguel S, Vandenbussche E, Orban GA) Effects of visual cortex lesions on orientation discrimination of illusory contours in the cat. Eur J Neurosci 1993;5:1695–1710.

(with De Weerd P, Vandenbussche E, Orban GA) Two stages in visual texture segregation: a lesion study in the cat. J Neurosci 1994;14:929–948.

Additional Publications

Cooper S, Sherrington CS. Gowers tract and spinal border cells. Brain 1940;63:123–134.

Doty RW. Survival of pattern vision after removal of striate cortex in the adult cat. J Comp Neurol 1971;143:341–369.

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Curt von Euler

BORN:

Stockholm County, Sweden

October 22, 1918

EDUCATION:

Karolinska Institute, B.M., 1940

Karolinska Institute, M.D., 1945

Karolinska Institute, Ph.D., 1947

APPOINTMENTS:

Karolinska Institute (1948)

Professor Emeritus, Karolinska Institute (1985)

HONORS AND AWARDS (SELECTED):

Norwegian Academy of Sciences (foreign member)

Curt von Euler conducted pioneering work on the central control of motor systems, brain mechanisms of thermoregulation, and on neural systems that control respiration.

Curt von Euler

Background

How did I come to devote my life to neurophysiology rather than to a clinical discipline? Why, in the first place, did I choose to study medicine rather than another branch of biology or other subjects within the natural sciences? And what guided me to make the turns on the road and follow what appeared to be bypaths? There are no simple answers to such questions, but certainly a number of accidental circumstances have intervened in important ways.

In attempting to give a brief account of the development of my personality and my research, I will try to point to some of the essentials as I see them—how one thing led to another and the intellectual flow of ideas, concepts, and research activities.

I am well aware of my inability to give a just and comprehensive account of the strong conceptual influences that scientific advances exerted on me and of the large number of colleagues in my own and other fields with whom I have exchanged ideas and facts.

My Family

I was born just before the end of World War I, on October 22, 1918, and grew up in a suburb of Stockholm. I arrived into a family devoted to science. My father, Hans von Euler, was professor of biochemistry at the University of Stockholm (Stockholms Högskola at that time). My mother, Beth, was also a chemist.

My father, born in 1873 in Augsburg, Germany, grew up in Munich. After a brief period as a student of art and painting, he decided to turn to the natural sciences. In less than three years, he earned his Ph.D. degree in Berlin and was offered a postdoctoral position in Walther H. Nernst’s laboratory in Göttingen. In 1897 my father received an offer from Svante Arrhenius to work with him for three years. However, before this period was finished, my father was offered a permanent position at Stockholms Högskola, first in physics, later in chemistry, and finally in biochemistry. In 1902 he married Astrid Cleve, herself a prominent scientist. She is the mother of my older half brothers and half sisters. Of these, Ulf S. von Euler is well known to the scientific world as a professor of physiology at the Karolinska Institute, and he became a Nobel laureate in 1970.

My father and my mother, Beth Uggles, married in 1913. I am their third son. Their fourth child, my youngest brother, was born in 1929, the year my father won his Nobel Prize in chemistry. In autumn 1929, my father’s new Institute for Biochemistry was inagurated, financed by generous donations from the Rockefeller and Wallenberg Foundations. The Institute, which was located in central Stockholm, also contained a private residence for my father and his family. Thus, from the age of 11, I grew up in the private apartment in the Institute for Biochemistry. The large number of prominent scientists whom I met as guests of my parents had a strong impact on me and my future. Among these I have strong memories and lasting impressions of Sir Henry Dale, Sven Hedin, Albert von Szent-Györgyi, Hans Spemann, Herman Staudinger, Adolf Butenandt, The Svedberg, Paul Karrer, and Ragnar Granit.

During my last years in high school, my interest in biology grew increasingly stronger, and I decided to devote my coming university studies to biology. I was advised by several people, including my older half brother Ulf (who was already an associate professor in physiology at the Karolinska Institute), that a medical school might provide a better biological education than a university faculty of natural science. I followed this advice and applied for entrance to the Karolinska Institute.

Immediately after finishing high school in 1937, and before beginning my studies in medicine at the Karolinska Institute, I spent four months at the University of Freiburg im Br. in Germany. There I attended lectures in chemistry by Herman Staudinger and in physical chemistry by Walter and Ida Noddack. I also had the opportunity to listen to some lectures and seminars on embryology given by Hans Spemann. I had met him the year before at home in Stockholm when he received his Nobel Prize “for his discovery of the organizer effect in embryonic development.” In 1937 he had been forced to retire several years before the normal retirement age, because of his courageous opposition to the Nazi regime. He had, however, retained a laboratory in his old institute and was allowed to give some seminar lectures to the staff members. It was a great privilege for me to be able to meet him again and to attend his seminars.

My Time as a Student at the Karolinska Institute

I began my medical studies at the Karolinska Institute in the autumn of 1937. My teachers in medical chemistry were Professor Einar Hammarsten, a leading biochemist and a powerful figure on the faculty; Professor Hugo Theorell, who later became head of the Nobel Institute for Biochemistry; and Assistant Professor Torbjörn Casparsson, who later became the head of the Nobel Institute for Cytology. The chair in physiology was vacant. This vacancy was filled by Associate Professor Yngve Zotterman, who later became professor of physiology at the Veterinary College of Stockholm, and by Ernst Barany, who later became professor of pharmacology at the University of Uppsala. In 1939 Ulf von Euler was given the chair in physiology. Pharmacology was taught by Professor Göran Liljestrand, a prominent physiologist and an influential member of the faculty and of the Nobel Committee.

My clinical studies began in the spring of 1940. In parallel with the courses and hospital duties, I devoted time to working on neurophysiological problems in my brother’s department.

In 1940 Ragnar Granit, professor of physiology at the University of Helsinki, accepted an offer by the Karolinska Institute to become the head of a new department of neurophysiology established especially for him. He accepted this offer over a similar offer from Harvard Medical School for him to become director of the Howe Laboratory of Ophthalmology in the Massachusetts Eye and Ear Infirmary. I had already met Granit on a few occasions and was impressed by his work on the retinogram and his evidence for inhibitory mechanisms in the retina. I saw a great opportunity to work under him and to receive some guidance for my steps on the road toward Minerva.

During the later part of my medical studies, I became more and more interested in cognitive science and problems of mental disturbances in psychiatric disorders. I spent almost a year working in psychiatric clinics and hospitals, with the idea of devoting myself to experimental psychiatry. Granit gave me the good advice that if I wanted to accomplish something of scientific importance in experimental psychiatry, I should first acquire solid knowledge in the physiology of the nervous system. He offered me a place in his department doing full-time research with the aim of accomplishing a doctoral thesis.

The Nobel Institute for Neurophysiology

Ragnar Granit had devoted himself to research on vision since the beginning of the 1920s. When he arrived at the Karolinska Institute, his main research project was to determine the neurophysiological foundation of color discrimination and color vision. However, he was anxious to ensure that the research activity in his new department had a broader neurophysiological base than only his own area of interest and urged his younger collaborators, Carl Gustav Bernhard and Carl-Rudolf Skoglund, to develop research territories of their own. Skoglund performed important studies on the problems of accommodation. He also dealt with the “artificial synapse” at the cut end of a mixed peripheral nerve. The many problems pertaining to impulse propagation in the peripheral nerve have been an important part of the research at the Nobel Institute, a field which came to be pursued mainly by Bernhard Frankenhaeuser and his many collaborators.

Granit also wanted to promote clinical application of neurophysiology and develop neurophysiological research within clinical departments. Therefore, soon after his arrival in Stockholm, he asked his nearest clinical colleagues, the professors of neurology Nils Antoni, neurosurgery Herbert Olivecrona, and ophthalmology Wilhelm Nordensson, to recommend staff members who would do neurophysiological full-time research leading to a doctoral thesis. The idea was that these researchers would subsequently be in a good position to start new lines of clinical research in their own areas based on solid theoretical ground. The call was soon answered by Drs. Erik Kugelberg in neurology, Lars Leksell in neurosurgery, and Gösta Karpe in ophthalmology. All three later became professors in their fields and introduced neurophysiological research facilities in their clinics, an approach that also spread to the other medical schools in Sweden.

In 1948, the Nobel Institute of Neurophysiology moved to the new campus of the Karolinska Institute. The solemn inauguration took place in June 1948. Among the foreign guests were Professor E.D. (later Lord) Adrian of Cambridge and Professor Detlev Bronk, then president of the Johns Hopkins University, later president of the Rockefeller University.

The move to the new building and new campus meant a large expansion in space, facilities, equipment, and technical staff. In addition, the scientific staff was enlarged and its profile broadened. The neuroanatomist Bror Rexed was asked to join the staff; I had been promoted to associate professor; and Anders Lundberg and Bernhard Frankenhaeuser, both assistant professors, had been recruited. From then on, there have always been five to seven well-educated postgraduate guest scientists from different parts of the world working in the department for one or two years, contributing to the flourishing and multifaceted scientific and social atmosphere.

At the end of the 1940s Granit was about to leave his research in retinal physiology, to which he had devoted 25 years of his life. He had decided to take up motor control problems and analyses of those mechanisms at different levels of the central nervous system that guide our movements. Lars Leksell had just finished his fundamental work, under Ragnar Granit’s supervision, on the gamma fibers and their efferent control of muscle spindles. This work opened up a new and virgin territory to be explored.

My Start and Early Development

I joined a productive department in October 1945 shortly after my marriage. My wife, Marianne, was a hospital nurse specializing in x-ray and surgery. Our lifelong companionship and our growing family have been of great importance during all stages in my career.

Granit had suggested that I start by studying problems of the peripheral nerve. He gave me a recent paper by Carl Gustav Bernhard and himself on peripheral nerve as a model sense organ. They had shown that rapid local temperature changes stimulate peripheral nerve fibers to discharge action potentials in the manner of a sensory organ. Granit suggested that I investigate the thermal sensitivities of nerve fibers of different diameters and different functional types. Thick myelinated fibers, I found, were selectively excited by local cooling, whereas thin fibers in the delta and C-range were excited by local warming but not by cooling. These differential excitabilities were associated with corresponding differences in membrane potential equilibrium. From these studies I turned toward investigating the temperature-sensitive structures in the hypothalamus and their role in control of body temperature.

I have had a preference for selecting my research projects across the borders of conventional disciplines. I have also tried to choose projects that, in addition to being of basic scientific importance, seem to have some clinical relevance. My inclination has had a mutually beneficial effect both on my own research and that of many guest scientists who had clinical backgrounds.

My investigations of the central thermosensitive mechanisms and temperature regulation set out from the fundamental work of Horace Magoun, Stephan W. Ranson, Harrison, and John Brobeck. They had demonstrated the presence of warm-sensitive structures in the anterior part of the hypothalamus and showed that warming these structures elicited panting. In my work I showed that these thermoceptive structures respond to temperature changes by eliciting local “generator potentials” or “receptor potentials.” The sensitivity was high—10 mV per 0.1°C temperature change. The structures from which these temperature potentials could be recorded correspond closely to those from which thermoregulatory reactions could be elicited by focal warming, suggesting that these structures are causally involved in the elicitation of thermoregulatory reactions.

I found similar specific potential changes could be obtained in response to alterations in the osmolality of the blood from an area in the hypothalamus between the supraoptic and paraventricular nuclei. This area had been described by Ernest B. Verney in Cambridge and Bengt Andersson in Stockholm as being responsive to changes in osmolality of the blood and giving rise to changes in urine excretion.

The next step in my search for structures in the brain exhibiting sensory receptor properties took me into the area of chemical regulation of respiration. It had long been known that an increase in metabolic carbon dioxide production and a decrease in the oxygen level in the blood lead to compensatory changes in ventilation. With Ulf Söderberg, a graduate student, I investigated the mechanisms by which the carbon dioxide concentration in the blood is sensed and causes adaptive changes in ventilation.

At that time it had only recently been established that oxygen-sensitive structures are located in the carotid body, a discovery that had earned Corneille Heymans the 1939 Nobel Prize in physiology or medicine. Yngve Zotterman with Ulf von Euler and Göran Liljestrand had been able to record the afferent impulse traffic in the nerve from the carotid body in response to changes in Po₂. However, the neural or receptive mechanisms underlying the ventilatory responsiveness to CO₂ or pH were still unknown. The common belief was that the excitability of respiratory neurons in the medulla oblongata was directly influenced by these humoral factors.

I was able to demonstrate, in work with Söderberg, that there is a genuine and specific receptor system sensitive to carbon dioxide in the medulla. This system responded with slow potential changes proportional to the stimulus in a manner similar to the receptor potentials in the hypothalamic temperature-sensitive and osmosensitive structures. Furthermore, we recorded tonic impulse discharges in proportion to the alterations in PCO², resembling the characteristic behavior of a sensory organ.

These and other findings enabled us to conclude that the chemoreceptive structures in the medulla are involved in the chemical regulation of respiration and are sensory receptors in the general sense of the concept. These results were soon confirmed by my colleague in clinical physiology, Professor Hakan Linderholm. He reported that certain groups of poliomyelitis patients showed a specific absence of ventilatory response to carbon dioxide, whereas their respiratory responses to a lack of oxygen and other respiratory stimuli were unimpaired.

Later, in the 1960s, Professor Hans Loeschcke in Bochum and his collaborator Marianne Schlaefke, reported in a long series of excellent papers on the localization and properties of these central chemoreceptor structures at the ventral surface of the medulla. Still later, in the 1970s, jointly with Professors Neil Cherniack, Fred Kao, and Dr. Ikuo Homma in my laboratory, I obtained strong evidence in support of this view, as will be mentioned in more detail.

My Sabbatical Year in Cambridge

In 1950 I attended my first international congress of physiology in Copenhagen. There I came to know, among many others, the Cambridge physiologists Alan Hodgkin, Andrew Huxley, and Richard Keynes, and the neuroendocrinologist Geoffrey Harris. By this time I had abandoned my plans for a career in experimental psychiatry. Instead, I wanted to expand my knowledge of central control functions and homeostasis mechanisms. I was fascinated by the work of Professor Harris on the hypothalamic control of the pituitary gland and the endocrine system. I talked with Ragnar Granit about venturing (for a while) into neuroendocrinology. Granit responded positively to this idea and encouraged me to discuss the matter with Harris. Harris generously offered me an opportunity to spend a year with him in the Physiological Laboratory in Cambridge.

Supported by a British Council Scholarship, I arrived in Cambridge in early September 1951. Only shortly before, Harris, with Dr. John D. Green, had established that the blood flow in the hypothalamo—hypophysial portal vessels was directed from the hypothalamus down to the anterior pituitary gland, contrary to the opinion held by many other researchers. Furthermore, Harris had demonstrated that the release of gonadotropic hormones was controlled by hypothalamic structures via this vascular route.

Harris invited me to join him in studies of the central nervous control of thyroid-stimulating hormone. We developed a method to follow the rate of release of thyroid hormone in intact, awake animals by the use of radioactive iodine. In a series of papers we reported on profound changes in the release of pituitary thyrotropic hormone in response to various central nervous stimuli and showed that these effects were mediated by the hypothalamo—hypophysial blood flow.

My collaboration with Harris gave me a solid insight into this new field. It also brought me into contact with important people in this area, including Wilhelm Feldberg, Marthe Vogt, Edith Bühlbring, and Herman Blaschko. It was Feldberg who had drawn Adrian’s attention to the brilliancy of Geoffrey Harris and suggested that he deserved a staff position and facilities in the Physiological Laboratory.

The year in Cambridge also gave me the opportunity to follow closely the work of Alan Hodgkin, Andrew Huxley, and Bernard Katz, who frequently came up from London. William Rushton, whose friendship I had gained during his sabbatical year in Stockholm with Granit in 1948 to 1949, had invited me to stay with he and his wife Marjorie during my sojourn in Cambridge—hospitality which I greatly enjoyed and benefited from in many ways.

Shortly after my arrival in Cambridge, Adrian, whom I had met several times in Stockholm, was appointed Master of Trinity College and resigned from his position as head of the Physiological Laboratory. I had the great privilege of being present at the interesting and special installation ceremony, unique for Trinity College, that took place in the Great Court of Trinity.

Back home in Stockholm I continued the studies on the control of thyroid-stimulating hormone, in part with a Swedish-Chilean guest scientist, Björn Holmgren, on leave from the University of Santiago de Chile. Our aim was to determine where and by what mechanisms the thyroid hormone exerts a self-regulating feedback control of the pituitary secretion of thyroid-stimulating hormone. By employing a new microinjection technique it was possible to show that thyroxin exerts its thyrotropin-inhibiting action directly on the anterior lobe itself, without the mediation of central nervous structures. However, we also showed that intact vascular connections with the hypothalamus are necessary for this self-regulation to be “set” and adjusted to the levels of thyroxin production required by the highly variable metabolic and other kinds of demands.

These investigations concerning control of thyroxin secretion were followed up by Ulf Söderberg in his extensive doctoral thesis. In elegant experiments he was able to measure continuously the arterio-venous radioiodine difference, with a temporal accuracy of a few seconds. He further demonstrated that in the presence of thyrotropin, the rate of thyroxin secretion is controlled not only by thyroid-stimulating hormone but is also dependent on the rate of blood flow through the thyroid gland.

Return to Temperature Regulation

In parallel with my studies on the homeostasis mechanisms controlling thyroid hormone secretion, I returned to problems of temperature regulation. With Söderberg, I showed that the temperature-sensitive structures in the anterior hypothalamus exert a strong influence on the fusimotor system innervating the muscle spindles in the body’s skeletal muscles. Warming these structures “silenced” the spindle discharges effectively, whereas cooling enhanced their rate of discharge. Thus, we demonstrated that the fusimotor mechanisms controlling muscle activity participate in the regulation of body temperature.

In light of this discovery we turned our attention to the reactions of cerebral cortical activity to small changes in body and hypothalamic temperature. A slight lowering of the temperature induced a low-voltage, fastactivity pattern in the electrical activity of the cortex characteristic of wakefulness, attention, and arousal. A modest increase in temperature, on the other hand, led to a slow-wave, high-voltage sleep-type pattern. Body temperature obviously exerts important influences on the general activating and inhibiting systems as described by H.W. Magoun, G. Moruzzi, and their schools.

Our studies further suggested that the concept of homeostasis had to be redefined. We found that the homeostatic mechanisms seem to strive for an optimization of the factors controlled—optimal with respect to the demands of the whole organism—rather than for maintenance of constancy, as originally suggested by Walter B. Cannon. Optimization is beginning to be regarded as an important mechanism providing the great adaptability characteristic of higher animals and especially prominent in humans. This view recently has been emphasized by several researchers, such as N.S. Cherniack, C.S. Poon, and M.C. Moore-Ede.

Our results also had bearing on the intricate interactions that arise because different homeostatic mechanisms employ, to a certain extent, the same effector mechanisms. For example, ventilation for gas exchange and polypnea for temperature regulation both involve the breathing apparatus, and regulation of water and salt balance is used both in the control of osmolality and as a mechanism involved in temperature regulation. In conditions of lowered oxygen availability, energy and thereby oxygen, can be saved, for example, by raising the temperature threshold for shivering. Demands on one control mechanism cause considerable changes in the thresholds or “set points” of other controllers. The different systems influence one another like the different parts in a mobile sculpture.

Sabbatical Year at the University of California, Los Angeles

The bridge that our work had built between temperature regulation and the work by the Magoun school on the general action of the activating and inhibiting systems of the reticular formation made me keen to work for a year in Magoun’s group. With my wife and two of our boys, I spent the academic year of 1955 to 1956 in south Long Beach and the department of anatomy at the University of California, Los Angeles (UCLA). There, however, I became engaged in studies on the electrical responses of cerebrocortical structures to direct and indirect afferent stimuli.

In collaboration with Professor John D. Green (whose earlier work with Geoffrey Harris is mentioned above) and Dr. Giovanni Ricci, I analyzed the potential responses which in the earlier literature had been attributed to activity in the dendrites of pyramidal cells. We demonstrated that certain previous conclusions did not hold up against critical analysis.

In other related projects, Green and I took advantage of the relatively simple design of the cortical networks in the hippocampus. Among the many results of this collaboration, which continued at the Nobel Institute in Stockholm during Green’s sabbatical year with us, was the interesting finding that the hippocampal pyramidal cells frequently exhibit an “inactivation process.” This process initially causes a brief excitation which, as the depolarization continues to deep depths, turns into inhibition by inactivation. In the hippocampus the inactivation process was often followed by another type of inhibition, hyperpolarization.

My collaboration with John Green in Los Angeles and Stockholm led to a warm friendship, which was broken by his sudden and tragic death in early November 1964. A heart attack while working in the laboratory ended his life in the middle of his career.

During my stay in Magoun’s department and during meetings and extended travels on the American continent with visits to many laboratories, I made many important and inspiring contacts, and made some longlasting bonds of friendship, a few of which will be mentioned later.

Motor Control of Breathing Behavior

I felt a growing desire to return to studying the control of respiration. Our rapidly increasing knowledge about motor control, gained to a great extent by Ragnar Granit and his group, offered valuable models for studies of the control of respiratory movements. Conversely, the respiratory system offered unique opportunities for analyses of physiologically induced and naturally occurring movements in anesthetized or decerebrate animals, whereas experiments on the motor control of limb muscles depended largely on reflex activation and artificially induced movements. Studies of the breathing apparatus offered the additional advantage that the movements of this system are rhythmically recurrent and physiologically well controlled. The aims of the breathing movements are definable in terms of the quantitative relationship between the chemical drive and the magnitude and rate of respiratory movements. Thus, it seemed possible that respiratory control could serve as a model for the control of volitional movements.

My return to problems of respiratory control systems was directly attributable to Dr. Harry Fritts, who had come from Professor André Counand’s laboratories at Columbia University and Bellvue Hospital in New York to work with Ragnar Granit. However, Harry Fritts wanted to work with me on respiratory problems. I saw this as a valuable opportunity to benefit from his knowledge and clinical experience in cardiovascular and respiratory physiology. This association led me into a long period of research on different aspects of respiratory control mechanisms and breathing behavior. Fritz and I performed an extensive quantitative analysis of the different proprioceptive and other afferent control systems involved in respiratory motor control. Among the different results of these studies I would like to mention only the findings that the vagal Hering-Breuer reflexes are not mediated by the fusimotor muscle spindle route, that inspiratory motor activity is facilitated proprioceptively, and that manifest stretch reflexes were demonstrated in the intercostal muscles.

The next step was to investigate the presence, properties, and functional roles of intercostal muscle spindles during spontaneous breathing, with and without intact gamma efferents, and to record impulse activity in the gamma fibers innervating the intercostal muscle spindles. In a long series of studies with Drs. Vaughn Critchlow from Baylor University in Texas, S. Rutkonski from Warsaw, Gösta Eklund from Uppsala, and Mario Corda from Florence, we showed that during inspiration the fusimotor activation of the inspiratory intercostal muscle spindles is strong enough to provide an additional excitatory drive on the inspiratory motoneurons. This was the first report on fusimotor contribution to the performance of physiologically induced movements. Later, such studies were performed by Karl-Erik Hagbarth and Ake Vallbo in humans and by Grigori Orlovski and Marc Shik in decorticate cats walking on a treadmill.

In the beginning and middle of the 1960s, Dr. T.A. Sears in Canberra and later in London, studied the activity of intercostal motoneurons and their reflex activation using intracellular recording techniques. The results, both from Sears’ group and our own, have demonstrated that control of breathing is designed in much the same way as control of other skeletal motor systems. However, there is an important difference between the control of intercostal muscles and of the diaphragm with respect to the role of muscle spindles. Whereas the intercostal muscles are well supplied with spindles, the diaphragm has only a scanty supply of these proprioceptors. With Mario Corda I performed a semiquantitative analysis of proprioceptive afferents from the diaphragm, which revealed a clear dominance of Golgi tendon organ afferents over the few muscle spindle afferents present.

This finding explains why a stretch reflex could not be demonstrated in the diaphragm. However, intercostal-to-phrenic reflexes act to control the diaphragm, as I demonstrated in collaboration with Dr. Emilio Decima from UCLA.

Dr. Moran E.J. Campbell of Middlesex Hospital, London, and his colleague Jack B.L. Howell of Manchester University had advanced the hypothesis that muscle spindles in the respiratory musculature might, under certain conditions, cause the pathological sensation of dyspnea, or breathlessness. We could now provide evidence that the intercostal muscles have a rich supply of fusimotor-controlled muscle spindles. Whether these, under certain circumstances, can be responsible for the sensation of breathlessness has been an interesting issue of discussion at many international symposia. It remains an open question.

Systems Analysis

My devotion to studying homeostasis and central error-correcting mechanisms had led me toward the science of “systems analysis,” control theory, and cybernetics. The term cybernetics, originally coined by André Ampere to denote the science of “government,” was revived by Norbert Wiener who used it to mean the “science of control and communication in animal and machine.” Norbert Wiener’s classical book on Cybernetics, which appeared in 1948, had a great impact.

However, information processing, regulation, and control mechanisms had been important issues for a long time in the physiological sciences. I have already mentioned the fundamental experimental and conceptual achievements of Claude Bernard and Walter Cannon. As early as 1868 Joseph Breuer and his teacher and mentor Ewald Hering had published their classical work on “self-steering of respiration through nervus uagus,” in which they demonstrated the powerful feedback control of tidal volume and respiratory rate, although they did not use the term feedback.

The application of information theory and the mathematics of systems control and feedback regulation to problems of biological control functions, inspired by Norbert Wiener, opened new and quantitative approaches. In respiratory physiology, for instance, these new concepts provided possibilities for formalized quantitative analysis of the chemostatic control of ventilation and rhythmogenesis.

In 1956, during a visit with Professor Walter Rosenblith at the Massachusetts Institute of Technology, he introduced me to Norbert Wiener, a memorable event for me. I met Wiener briefly again in Stockholm in 1964 a couple of hours before his last lecture, which I also attended. In the intermission between the two lectures scheduled for him, he had a heart attack which tragically ended his life.

Could a systems analysis approach be fruitful in my work? To obtain guidance in this question, I contacted Professor Lazlo von Hàrnos, head of the department of regulation and control sciences at the Royal College of Technology in Stockholm, and an eminent expert in the field. Von Hàrnos was one of the many brilliant Hungarians who, for political reasons, left their country after World War II and enriched the cultural and scientific communities in many Western countries. This contact led to a long lasting and fruitful collaboration between our departments.

Among other beneficial effects this collaboration had an important impact on the work of my graduate student, Gunnar Lennerstrand, concerning quantitative analysis of static and dynamic properties of primary and secondary muscle spindle receptors in the intercostal muscles. Lennerstrand’s extensive work also included mathematical model simulations, which led to new and more detailed quantitative understanding of the functional roles of fusimotor-muscle spindle control of movements. Lennerstrand’s interests later shifted to problems of eye motor control. He is now a leading expert in that field and is professor of ophthalmology at the Karolinska Institute.

I had suggested to another of my graduate students, Jörgen Fex (now professor and head of the department of cochlear research at the National Institute on Deafness and Other Communication Disorders (NIDCD) in Bethesda, Maryland), that he extend the work of Robert Galambos on the crossed efferent fibers destined for the cochlea. Galambos had shown that stimulation of these fibers causes a reduction in the impulse potentials of the acoustic nerve. Jörgen Fex’s work developed into an extensive and impressive study of the sensory feedback control system of auditory activity in centrifugal and centripetal cochlear fibers.

Control of Respiratory Pattern

I then turned to problems concerning the quantitative relationship between the ventilatory parameters tidal volume and respiratory rate in response to alterations in the demand for ventilation. Our aim was to elucidate the mechanisms involved in optimization of these parameters to ensure minimal respiratory work (Otis, Fenn, and Rahn, 1956) or minimal muscular effort (Mead, 1960). My starting point was the work by the Oxford group, led by Drs. D.J.C. Cunningham and B. Lloyd. They had shown that in humans there is a linear relationship between ventilation and tidal volume as ventilation increases in response to increased chemical drive. The slope of this relationship was independent of the kind of chemical drive. In contrast, changes in body temperature caused selective changes in respiratory rate, altering the slope of this relationship.

With Drs. Fernando Herrero from Madrid (now professor of neurology in Seville) and Ira Wexler from the Downstate University in Brooklyn, New York, we confirmed and extended the results of the Oxford group. We showed in cats that after vagotomy there is hardly any change in respiratory rate in response to increments in chemical drive; only the tidal volume gets larger. Thus, the increase in respiratory rate and the shortening of inspiratory duration caused by chemical stimulation depend almost entirely on volume feedback from the pulmonary stretch receptors.

The next steps along these lines were taken with Drs. Francis (Frank) Clark from Purdue University and Charles Knox from the University of Minnesota. We analyzed the central reflex excitability curves of the Hering-Breuer vagal inspiration inhibiting reflex. The volume threshold for this reflex decreases steeply as a function of time from the beginning of the inspiratory phase. This volume threshold curve determines, we found, the vagal reflex control of the inspiratory duration. Because we also found that the expiratory time depends mainly on the preceding inspiration, the whole cycle time, and thus the respiratory rate, are largely determined by the volume threshold curve.

In humans we found that tidal volumes must be one and a half to two times greater than the resting tidal volume to reach the volume threshold and thus influence the duration of the inspiratory phase. Later, Dr. Ikuo Homma (now professor at Shiba University in Tokyo) demonstrated that in humans stimulation of intercostal muscle spindles by vibration causes a shift downward of this volume threshold, so that it becomes effective even at eupneic tidal volumes. This finding of Homma confirms in beautiful fashion the finding by Irja Marttila and John Remmers that the effects of secondary muscle spindle endings of intercostal muscles and pulmonary stretch receptors add together in inhibiting inspiration.

Next we studied the mechanisms by which inspiration is terminated in the absence of volume feedback. We found that the “off-switch” threshold increases with increasing chemical drive at the same time as the inspiratory activity increases. These two effects tend to affect the “off-switch” in opposite directions, and often they balance each other fairly well. Thus, in the absence of vagal feedback, inspiratory duration remains relatively constant. Only because of this increase in “off-switch” threshold can tidal volume increase in response to increased chemical drive. An increase in hypothalamic temperature also causes an increase in the rate of rise of inspiratory activity and volume. However, in sharp contrast to the effect of chemical stimulation, increased temperature causes practically no concomitant change in the “off-switch” threshold which, therefore, is reached earlier as the rise time is quickened. The result is that inspiratory duration is shortened and respiratory rate is increased.

An “Off-Switch” Model

A realistic computer model of the neural construct of the inspiratory “off-switch” mechanism was gradually developed by stepwise alternations between animal experimentation and computer simulation trials incorporating the latest experimental results. These model studies proved to be a valuable aid in designing the most crucial and elucidating experiments. This work was done in collaboration with Bertil Roos from Professor von Hàrnos’ department at the Royal College of Technology and Graham Bradby from the University of Bristol, England. The scheme of the network derived from these efforts is still considered relevant in essential details.

Influence from Structures in the Dorsal Pons on Respiratory Pattern—The Phenomenon of Apneusis

The anatomical structures of Lumsden’s “pneumotaxic center” were identified in 1971 by Morton Cohen at the Albert Einstein College, New York. Cohen found that this “center” of Lumsden’s corresponds to the medial parabrachial and Kölliker-Fuse nuclei (NPBM-KF) in the rostral pons. Lesions of these nuclei, combined with bilateral vagotomy, usually result in apneusis; whereas electrical stimulation within these structures causes either inhibition or excitation of inspiratory activity, depending on the precise site of stimulation. Cohen further found that the characteristics of the inspiration-inhibiting action of such stimulation in this area closely correspond to those of stimulation of vagal stretch receptor afferents and to lung inflation.

I wanted to build on Cohen’s results to explore further the inspiratory “off-switch” characteristics and to achieve better understanding of the functional role of the “pneumotaxic center” in the control of respiratory patterns. Projects with these aims were carried out with Dr. Theresa Trippenbach, a guest scientist from the Institute for Neurophysiology of the Polish Academy of Sciences in Warsaw (directed by Professor Witold Karczewski, with whom I have had a long-standing collaboration), Dr. John Remmers from Dartmouth College in Hanover, New Hampshire (now professor of physiology at the University of Calgary), and Dr. Irja Marttila from Helsinki, who had a background in neurosurgery. Trippenbach and I developed a technique for graded electrical stimulation of the inspiration-inhibiting loci in the NPBMKF, which allowed us to map the entire excitability curve for the inspiratory “off-switch” functions under conditions of different chemical drives and temperatures. Using this technique we showed the existence of a close neural link between the neurons generating the inspiratory activity—the inspiratory ramp—and neurons involved in the “off-switch” mechanism.

We also studied the functional role of the NPBM-KF in the respiratory control system. Our results suggested that the main role of these structures in the control of respiration was to provide tonic excitatory input to the inspiratory “off-switch” mechanism, thereby lowering its threshold. We could detect no other influence on the generation of respiratory rhythm, and we could not confirm the hypothesis that these structures play a role in the mediation or integration of the chemical drive.

Our experiments led us to believe that the inspiratory “off-switch,” when first activated, gives rise to complete inhibition in an “all-or-nothing” fashion. However, John Remmers, with Magdi Younes, showed in elegant experiments that when the “off-switch” threshold has just been reached, the inhibition is at first graded and reversible, and only thereafter develops into its final, irreversible second stage. Later, Diethelm Richter in Heidelberg (now in Göttingen) and his group identified the neural correlates of these two stages of the inspiratory “off-switch” using intracellular recording techniques. Current concepts of the design of the neural network and its synaptology originate largely from Richter and his collaborators.

In summarizing our findings concerning the excitability and the threshold of the “off-switch” function, we can conclude that these mechanisms are influenced by a corollary of the inspiratory ramp generator, chemical drive, input from the hypothalamic temperature regulating structures, vagal pulmonary stretch receptors, and intercostal muscle spindle afferents of the group II type, as well as by a tonic influence from the rostral pontine NPBM-KF.

Basic Rhythm Generation, Pattern Formation, and Drive Integration

Several researchers studying rhythmic motor activities such as locomotion and mastication, have advocated that it is advantageous to discuss the underlying mechanisms under two headings: mechanisms generating the basic pattern, and mechanisms for adaptive control and pattern formation. This, I have argued, is also useful when discussing control of breathing.

However, the generation and control of a behavior depends not only on the anatomical and functional connectivity of the pattern-generating neural networks but importantly also on the excitatory tonic drive inputs to those networks. This is certainly true for ventilation, the magnitude of which depends directly on the drive. The drive input to the respiratory pattern-generator originates both from the central and peripheral chemoreceptors, and from several other central and peripheral sources. Students of the chemical and neural control of respiration have paid little attention to the mechanisms that mediate and integrate these different drive factors. It can be assumed that there is a great deal of overlap and interaction among these three sets of control mechanisms. My collaborators (in different constellations) and I have been interested in all three of these aspects.

Much of the work on the control of breathing had been concerned with the neural mechanisms underlying central pattern generation. Thus, we have learned that these mechanisms are capable of producing a stereotyped rhythmical activity even in the complete absence of all extrinsic reflexes and feedback loops, that is, when operating in an “open loop” mode. We, as well as several others, including Morton Cohen and Witold Karszervski, have studied the mechanisms involved in “fictive” breathing.

Chemoreceptors at the Ventral Surface of the Medulla

Once more, I wanted to study intracranial chemosensitive receptors responsible for the CO₂/pH-dependent drive for ventilation. Professor Hans H. Loescheke in the department of physiology at the University of Bochum and his collaborator, Professor Marianne E. Schlaefke, had already shown that these receptive structures were localized at or close to the ventral surface of the medulla. They had also succeeded in recording action potential discharges from these structures in response to changes in Pco₂.

Despite our own results at the beginning of the 1950s and the impressive and extensive work of the Bochum school, some general uncertainty remained as to the functional significance of chemoceptive structures on the ventral surface of the medulla. I therefore decided to attack this problem with new experimental approaches using the technique of reversible, focal cold block.

Joining me as guest scientists in the 1960s and 1970s were Professor Neil S. Cherniack from the University of Pennsylvania at Philadelphia Medical School, Professor Fredrick F. Kao from the Downstate University at Brooklyn, and Dr. Ikuo Homma from Edi University of Tokyo. Neil Cherniack and I had first met in 1968 during my sabbatical term with Professor David Cugell at the medical school of Northwestern University. I met Neil again in 1974 at the International World Congress of Physiology in New Delhi and the satellite symposia in the Kashmir Valley arranged by my friend Professor Autar Paintal. There we agreed on a year of collaboration in Stockholm. I had known Fred Kao for a long time, an acquaintance mediated by Professor Chandler McC. Brooks, Dr. Ikuo Homma was with me for a second year. His father, Professor Saburo Homma, had spent a year with Ragnar Granit in 1958 and has since been a frequent guest in the laboratory; his son became a much appreciated member of our group.

Together, we explored the effects of transient focal cooling of areas on the ventral surface of the medulla. Cooling on certain small, restricted spots that had been described by the Bochum workers caused a temperature-dependent depression of ventilation, with complete apnea at temperatures around 20°C. This depression mimicked in great detail the effects of decreases in Pco₂ and could be compensated by increments in Pco₂ corresponding to 3–5 mm Hg per degree centigrade.

Focal warming caused increases in ventilation with Q₁₀ values between 4 and 5. Furthermore, we showed that focal cooling of the chemoceptive structures did not interfere with ventilatory responsiveness to changes in Po₂ or to other types of respiratory stimuli. Thus, the concept of central chemoceptors located on, or close to, the ventral surface of the medulla and responsible for the central ventilatory response to changes in Pco₂ had been strongly confirmed.

Using this technique of focal cooling together with other methods developed in my laboratory, we were also able to contribute to the understanding of the problems underlying instability in the pattern of breathing. These problems had interested Neil Cherniack and his collaborators for some time. By selective graded depression of the central chemoreceptors we could now confirm and firmly establish that instability, in the form of periodic breathing of the Chayne-Stoke’s type, can be caused when the drive from the peripheral chemoreceptors is stronger than that from the central CO₂-sensitive receptors. Furthermore, we showed that instability is also induced when the feedback gain is increased to certain levels, as predicted from the laws of feedback regulation by Cherniack and his collaborators.

Integration of the Drive Factors

At this point I turned to problems concerning the structures and mechanisms responsible for the mediation and integration of the various drive factors. As already mentioned, the chemoreceptors at the ventral surface of the medulla did not have this function. They provided only the CO₂-related drive component. With Drs. Krystyna Budzinska from Warsaw, Tito Pantaleo from Florence, Professor Fred Kao (who had come back for another year with me), and Dr. Yuji Yamamoto (a Japanese graduate student), I set out to investigate these problems using a specially designed instrument furnished with two thin needle thermodes for transient focal cooling of small preselected spots in the brainstem.

These efforts demonstrated that a certain limited locus close to the lateral paragigantocellular nucleus about 2 mm above the ventral surface of the medulla is responsible for these integrative functions. Focal block of synaptic transmission by cooling the structures within this area to a temperature of about 20°C led to strong ventilatory depression or complete apnea, even when applied only unilaterally. This effect could not be compensated for by increased drive inputs from any other source, in sharp contrast to the depression caused by cooling the structures at the ventral surface of the medulla.

In agreement with Professor H. Arita and his group in Tokyo, we found that the neurons of this “apnea region” are characterized by tonic discharge patterns without significant respiratory modulation. Furthermore, we found that these neurons receive convergent afferent inflow from peripheral and central chemoreceptors, muscle receptors and skin receptors, as well as from the “defense and alarm” areas in the posterior hypothalamus.

Forebrain Influences

The old problem concerning the mechanism behind the almost immediate increase in ventilation on onset of physical exercise was addressed with Drs. Richard Romaniuk from Warsaw and Antony DiMarco from Case Western Reserve University in Cleveland. A long time ago, in 1895, Jöns E. Johansson, professor of physiology at the Karolinska Institute, and later, in 1913, August Krogh and J. Lindhard of the University of Copenhagen, had advanced the hypothesis that the immediate increase in ventilation and heart rate might be mediated by corollary neural pathways from the executive motor areas in the forebrain to the respiratory and cardiac controllers in the medulla. However, experimental evidence for this kind of activation had never been reported. We decided to employ the technique of Grigori Orlovski and Marc Shik for studying the induced locomotion of decorticate cats walking on a treadmill. As a guest of the USSR Academy of Sciences, I paid profitable visits to Orlovski and Shik and their colleagues in Moscow. With the aid of their technique we showed that the respiratory controller receives direct corollary activation from suprabulbar motor control areas as soon as locomotion is initiated. Thus, we had obtained evidence suggesting that feedforward mechanisms are also at play in adapting the systems to expected changes in metabolic rate. Similar results were obtained at the same time and independently of our studies by Fred Eldridge and David Milhorn at the University of North Carolina.

My interest in systems analysis approaches to the control of breathing continued along several lines and led to the initiation of several projects jointly with Drs. Eugene W. Bruce from Case Western Reserve University and Sidney M. Yamashiro from the department of biophysics at the University of Southern California. Together, we performed dynamic studies, for example, of the neural mechanisms responsible for the control of the inspiratory ramp generation, with the aid of correlation, coherence spectral, and power spectral analyses. We found, among other things, that the trajectory of the inspiratory activity is subject to powerful feedback control. Later, the neural correlate to this mechanism was identified by Diethelm Richter and his group in Heidelberg.

Developmental Aspects of Breathing Control

For some time I had wanted to include developmental aspects in my research on respiratory control mechanisms. When Dr. Hugo Lagercrantz joined my group an expansion in this direction was assured. Hugo Lagercrantz was the last graduate student of my half brother, Ulf, and is now professor of pediatrics and neonatology at the Karolinska Institute. Lagercrantz’ doctoral thesis was an extensive and highly valued study of mechanisms underlying noradrenergic neurotransmission, with special reference to the structure and the release and uptake functions of the storage vesicles. As a postgraduate fellow he decided to shift his interest toward clinical research in pediatrics and neonatalogy. He developed a special interest in the respiratory problems of the neonatal period and the “sudden infant death syndrome,” as well as in developmental changes in the roles of neurotransmitters and neuromodulators in respiratory neural networks. When Lagercrantz joined my group, he provided important new ideas and perspectives.

Several projects on the development of respiratory control functions were then being launched focusing on, among other things, the effects of various neuroactive substances and changes in these effects during development. Dr. Nanduri Prabhakar, who had spent several years working with Professor Hans Loeschecke, made valuable contributions to several of these projects as a guest scientist in my laboratory.

Hugo Lagercrantz, Nanduri Prabhakar, and I demonstrated that substance P exerts stimulatory effects both on the central respiratory mechanisms and on the peripheral chemoreceptors of the carotid body, suggesting that substance P may act as a neurotransmitter in the oxygen-controlling mechanisms. We found both of these effects to be abolished by a specific substance P antagonist.

Another focus of interest introduced by Hugo Lagercrantz concerned the effects of adenosine on respiratory control mechanisms. Adenosine, which is liberated from neuronal structures during hypoxia, was shown to exert depressant effects on respiratory functions. This finding has strong implications for an understanding of the increasing depression of fetal breathing during the latter part of pregnancy.

Nanduri Prabhakar moved on to Neil Cherniack’s department at Case Western Reserve University where, among other research activities, he has continued his fundamental work on the role of substance P as a neurotransmitter in the chemoreception of the carotid body.

Psychophysics and Conscious Control of Breathing

Breathing, although highly automatic, is subject to willful intervention at any time. Even the automatically controlled breathing pattern can be altered by training. These facts raise several questions concerning the human’s ability to control breathing behavior consciously. A graduate student with a background in experimental psychology, Miriam Katz-Salamon, was interested in studying these problems. That humans have the ability to judge the magnitude of their breaths had been reported by Marsh Tenney of Dartmouth College. Katz-Salamon confirmed these results and performed an extensive and detailed psychophysical study on the ability of human subjects to estimate quantitatively different ventilatory parameters during normal and enhanced drive conditions and under different mechanical loads. All the parameters could be estimated with considerable accuracy by the subjects. She was able to show that their judgments follow Stevens’ law of psychophysics which says that the objectively and the subjectively estimated magnitudes of tested parameters can be described by power functions with exponents close to or above 1.0.

Another aspect of the control of breathing in human subjects that interested me had to do with the specific demands placed on the breathing apparatus when it is used for vocalization, speech, and singing. A series of investigations was performed in collaboration with Professor Johan Sundberg from the department of speech transmission and music acoustics at the Royal College of Technology in Stockholm and with Professor Rolf Leandersson of the department of phoniatrics and speech therapy of the Karolinska Institute and Hospital. These studies were performed on both professional singers and untrained volunteers. Many new results of theoretical and practical importance on motor strategies for the precise control of subglottal pressure came out of these studies.

On July 1, 1985 I retired from my post as head of the Nobel Institute for Neurophysiology and became professor emeritus. I was able, however, to retain laboratory space, research facilities, and project grants. Professor Sten Grillner was appointed as the new head of the department. The investigations concerning neuronal design of motor control mechanisms have continued and developed in new directions, combining systems neurophysiology with the molecular biology of membrane mechanisms and neurotransmitter and neuromodulator actions as well as sophisticated neurohistological studies of the elements involved in neural networks.

Developmental Dyslexia

Since the early 1940s I have had a steadily increasing interest in the cognitive sciences, information processing, and the development of the brain. Because of these interests, in the late 1970s I was asked if I would be willing to participate in organizing an international symposium on developmental dyslexia. Although my knowledge about this complex problem was almost nonexistent at that time, I promised to introduce myself to the vast literature on this subject and to help in designing the program. I thought that an international Wenner-Gren Symposium on this topic might strongly stimulate Swedish research on reading and reading disabilities. I knew Professor Ingvar Lundberg of the University of Umeą, who had a profound interest in the international dyslexia research community, and I knew that he felt rather lonely in his field in Sweden. With Ingvar Lundberg, Ragnar Granit, Yngve Zotterman, and Gunnar Lennerstrand, we arranged the symposium, which took place in 1980. This work led me into a steadily increasing engagement in the problem of developmental dyslexia and the work of leading scientists in the fields of linguistics, neurology, cognitive sciences, and genetics, including Norman Geschwind, Patricia Goldman-Rakic and Pasko Rakic, Verne Caviness, Albert Galaburda, Antonio and Hanna Damasio, Rodolfo Llinas, Jack DeFries, Isabelle and Alvin Liberman, Bruce McEwen, Patricia Kuhl, Oliver Zangwill, Paula Tallal, Ursula Bellugi, and many others. As a result of this activity I became deeply involved in an extensive interdisciplinary, longitudinal study of dyslexia in a region of Sweden.

At the symposium in 1980 I renewed my acquaintance with Dr. Per Uddén, whose strong personal interest in developmental dyslexia gave birth to the idea of establishing an international academy for dyslexia research. The aim of this academy was to establish a forum for interdisciplinary exchange of facts and ideas and for the fostering of research collaboration on the complex problems of developmental dyslexia and dysphasia. Norman Geschwind immediately supported the idea, as did Ragnar Granit, David Ottoson (secretary general of the International Brain Research Organization), Oliver Zangwill, Albert Galaburda, Günter Baumgartner, and I. The outlines of such an academy, its aims and goals, were drawn up at a conference hosted by Per Uddén. In 1984 the Academia Rodinensis Pro Remediatione (The Rodin Remediation Academy) was formally founded at a large international conference in St. Andrews, Scotland. Granit became its first president, with David Ottoson and I as vice presidents. Princess Marianne Bernadotte was elected Honorary President. The name of the academy was chosen to honor Auguste Rodin’s father for the excellent way in which he treated his gravely dyslectic, albeit superbly gifted son. The implication is that this handicap should not be allowed to be an obstacle to the full development of an individual’s talents and intellectual capacities, which often are above normal and sometimes eminent. The activities of the academy, which now has 100 active scientific members (seven are Nobel laureates) and 160 corresponding members, have focused mainly on arranging international symposia and conferences on different aspects of developmental dyslexia and dysphasia. The academy had arranged 23 such conferences by December 1995.

When Ragnar Granit decided in 1988 to step down from his position as president of the academy, I was elected to be his successor, a position which I now hold.

Developmental dyslexia, too, greatly attracted me because of the intriguing muldisciplinary nature of the problems involved, and the great practical importance of increased knowledge about this handicap and its often severe individual and social consequences. During the last decades, dyslexia research has entered the midst of modern neurosciences, cognitive neuropsychology, linguistics, and genetics. The advancements in these areas gained by international dyslexia research has opened new avenues for the development of new effective diagnostic and remedial methods and phonological training strategies. It is my sincere hope that the Rodin Remediation Academy will be able to continue and expand its important work to promote dyslexia research.

Selected Publications

Physiology and pharmacology of temperature regulation. Pharmacol Rev 1961;13:361–388.

The control of respiratory movement. In: Howell JBL, Campbell EJM, eds. Breathlessness. Oxford: Blackwell Scientific Publications, 1966;19–32.

On the role of proprioceptors in perception and execution of motor acts with special reference to breathing. In: Pengelly LD, Campbell EJM, Rebuck AS, eds. Loaded breathing. Longman, Canada, 1974;139–149.

Brainstem mechanisms for generation and control of breathing pattern. In: Cherniack NS, Widdicombe JG, eds. Handbook of physiology. The respiratory system, Vol 2. Control of breathing. Bethesda: American Physiological Society, 1986;1–67.

Forebrain control of breathing behaviour. In: von Euler C, Katz-Salamon M, eds. Respiratory psychophysiology. Wenner-Gren International Symposium Series, Vol. 50. Basingstoke, UK: Macmillan Press, 1988;1–14.

Neural organization and rhythm generation. In: Crystal EG, West JB, eds. The lung: Scientific foundations. 2nd ed. New York: Raven Press, 1996 (in press).

Rhythm generation. In: West JB, ed. Respiratory physiology. People and ideas. New York: Oxford University Press, 1996;251–288.

(with Söderberg U) Medullary chemo-sensitive receptors. J Physiol (Lond) 1952;118:545–554.

(with Trippenbach T) Excitability changes of the inspiratory “off-switch” mechanism tested by electrical stimulation in nucleus parabrachialis in the cat. Acta Physiol Scand 1976;97:175–188.

(with Galaburda A, Llinas R, Tallal P, eds) Temporal information processing in the nervous system: Special reference to dyslexia and dysphasia. Ann N Y Acad Sci 1993;232.

Additional Publications

Andersen P, Sears TA. Medullary activation of intercostal fusimotor and alpha motoneurones. J Physiol (Lond) 1870;209:739–755.

Bradley GW, von Euler C, Marttila I, Roos B. A model of the central and reflex inhibition of inspiration in the cat. Biol Cybern 1975;19:105–116.

Budzinska K, von Euler C, Kao FF, Pantaleo T, Yamamoto Y. Effects of graded focal cold block in rostral areas of the medulla. Acta Physiol Scand 1985;124:329–430.

Cannon WB. The wisdom of the body. 2nd ed. New York: W.W. Norton, 1938.

Cannon WB. The way of an investigator. London, New York: Hafner Publishing, 1968.

Cherniack NS. Potential role of optimization in alveolar hypoventilation and respiratory instability. In: von Euler C, Lagercrantz H, eds. Neurobiology of the control of breathing. Wenner-Gren International Symposium Series. New York: Raven Press, 1987;45–50.

Cohen ML. Switching of the respiratory phases and evoked phrenic responses produced by rostral pontine electrical stimulation. J Physiol (Lond) 1971;217:133–158.

Eldridge FL, Millhorn DE, Waldrop TG. Exercise hyperpnea and locomotion: parallel activation from the hypothalamus. Science 1981;211:844–846.

Granit R. The electrophysiological analysis of the fundamental problem of colour reception (Thomas Young Oration). Proc R Soc Lond B Biol Sci 1945;57:447–463.

Granit R. The basis of motor control. London, New York: Academic Press, 1970.

Grillner S. Control of locomotion in bipeds, tetrapods, and fish. In: Brookhart JM, Mountcastle VB, eds. Handbook of physiology. The nervous system. Bethesda: American Physiological Society, 1981;Sect. 1, Vol. II, Pt. 2, Chapt. 26, 1179–1236.

Grillner S, Matsushima T. The neural network underlying locomotion in lamprey—synaptic and cellular mechanisms. Neuron 1991;7:1–15.

Heyman C. The part played by vascular presso- and chemo-receptors in respiratory control. In: Nobel Lectures—physiology or medicine (1922–1941). Amsterdam: Elsevier, 1965;460–481.

Knox CK. Reflex and central mechanisms controlling expiratory duration. In: von Euler C, Lagercrantz H, eds. Central nervous control mechanisms in breathing. Wenner-Gren International Symposium Series, Vol. 32. Oxford, UK: Pergamon Press, 1979;203–216.

Lagercrantz H. Neuromodulators and respiratory control during development. Trends Neurosci 1987;10:368–372.

Lagercrantz H, Slotkin T. The stress of being born. Sci Am 1986;254:100–107.

Loeschcke HH. Functional aspects of central chemosensitivity. In: von Euler C, Lagercrantz H, eds. Central nervous control mechanisms in breathing. Wenner-Gren International Symposium Series, Vol. 32. Oxford, UK: Pergamon Press, 1979;13–24.

Mead J. Control of respiratory frequency. J Appl Physiol 1960;15:325–336.

Otis AB, Fenn WO, and Rahn H. Mechanisms of breathing in man. J Appl Physiol 1950;2:592–607.

Poon C. Optimal control of ventilation in hypercapnia and exercise: an extended model. In: Benchetrit G, Baconnier P, Demongeot J, eds. Concepts and formalizations in the control of breathing. Manchester, UK: Manchester University Press, 1987;119–131.

Poon CS. Optimal control of ventilation in hypoxia, hypercapnia and exercise. In: Whipp BJ, Wiberg DM, eds. Modelling and control of breathing. Amsterdam: Elsevier, 1983;189–196.

Prabhakar NR. Significance of excitatory and inhibitory neurochemicals in hypoxic chemotransmission of the carotid body. In: Honda Y, ed. Control of breathing: Modelling and perspectives. New York: Plenum Press, 1992.

Remmers JE, Baker JP Jr, Younes MK. Graded inspiratory inhibition: the first stage of inspiratory “off-switching.” In: von Euler C, Lagercrantz H, eds. Central nervous control mechanisms in breathing. Wenner-Gren International Symposium Series, Vol. 32. Oxford, UK: Pergamon Press, 1979;195–201.

Richter DW. Respiratory neural rhythmogenesis and afferent control. In: Human physiology: From cellular mechanisms to ingration. Berlin: Springer Verlag, 1996 (in press).

Sears TA. The respiratory motoneurone: integration at spinal segmental level. In: Howell JBL, Campbell EJM, eds. Breathlessness. Oxford: Blackwell, 1966; 33–47.

Sears TA. Breathing: A sensori motor act. In: Gilliand I, Francis J, eds. The scientific basis of medicine. London: Annual Reviews, Athlone, 1971;129–147.

Shik ML, Orlovsky GN. Neurophysiology of locomotor automatism. Physiol Rev 1976;56:465–501.

Wiener N. Cybernetics or control and communication in the animal and the machine. 2nd ed. Cambridge: MIT Press, 1961.

Younes MK, Baker JP, Remmers JE. Characteristics of inspiratory inhibition by phasic volume feedback in cats. J Appl Physiol 1978;45:80–86.

John Z. Young

BORN:

Bristol, England

March 18, 1907

EDUCATION:

Malborough College, Wiltshire, U.K.

Magdalen College, Oxford, M.A. (Zoology, 1928)

APPOINTMENTS:

Oxford University (1931)

Professor of Anatomy Emeritus, University College of London (1974)

HONORS AND AWARDS:

Fellow, Royal Society of London (1945)

Foreign Member, American Academy of Arts and Sciences (1957)

Royal Medal, Royal Society (1967)

Linnean Medal, Linnean Society (1973)

Member Lincei Soc., Accademia Nationale de Lincei (1973)

Honorary Fellow, British Academy (1986)

Foreign Member American Philosophical Society (1973)

John Z. Young carried out fundamental studies of invertebrate nervous systems. He discovered the squid giant axon and pioneered the use of the octopus for neurobiological studies. His work on octopus included studies of the radula, statocysts, eye muscles, visual behavior, and memory. His several books portray his broad interests in biology, zoology, brains, and minds.

John Z. Young

Ancestors and Relatives

If one can inherit scientific ability, I had a good start through both my parents. Dr. Thomas Young, F.R.S., was my great granduncle on my father’s side. Thomas not only discovered the wave theory of light and the three-color process of vision, but was the founder of all modern neurophysiology by his claims that nerves carry information by their varying types. His is an everyday name through Young’s module of elasticity. My maternal grandfather was John Eliot Howard, F.R.S. He was a chemist who discovered how to separate quinine from the toxic alkaloids in bark. His father, Luke Howard, F.R.S., was a meteorologist who studied the clouds and gave the names cumulus, nimbus, and cirrus. My second cousin, Henry Eliot Howard, F.Z.S., was a naturalist who established the function of song in territory in bird life.

Earliest Science

From childhood I was interested in how things change. At about age 10 I was given a chemistry set and became fascinated by the effects of heating, cooling, precipitation, and acids and alkalis. There were only simple inorganic chemicals in the set, but I began to supplement them by visits to the “chemist’s.” In those days, chemists were true pharmacists, who made up their own prescriptions. I used to go to these shops, past the huge flasks of water of various colors, which were the sign of the chemist. Inside the shops were rows of large drawers with label abbreviations such as Tinet. iod. I made friends with the chemists and tried to get them to sell me strong acids—which of course they would not do. Early on, I was interested in electrical communication. First, I learned about magnetism and made buzzers and bells all over the house. Then, it was telephones, and soon the wireless. In about 1920 I made a wireless receiver with a crystal set and coil and condenser, all homemade. This interest in wires and communication has stayed with me and is perhaps at the basis of my interest in nerves.

At my first school there was no science at all, but I developed some interest in history. During the first years at my secondary school, there was also little science. It was a public school—Marlborough—and I suffered the usual hardships of boys who are no good at games. But I cannot say that I was really bullied or unhappy, and I loved the Wiltshire countryside, over which we were sent for long “runs” when the weather was bad. There was little science in the middle school, and I found that dull after my own experiments with chemicals and wires. I found no interest in chemistry until I came across the periodic table, which made some sense of it all. Organic chemistry seemed to me more systematic, with the families of acids and alcohols. Physics was deadly dull; I could not see the point in weighing bottles and knowing the difference between weight and mass; there was nothing about atoms or modern physics. Physics became interesting only when the instructors got to electricity and taught me more of what I had already found out for myself—how a current is produced and how it can be made to work motors, bells, and the wireless.

Introduction to Biology

I had not studied biology except when, at about seven years of age, I found fairy shrimps (Chirocephalus) in a pond near our house. When I reached the VIth form at the age of 16, I was taken on by a remarkable man, A.G. Lowndes. He realized that I was no good at chemistry and suggested that I study biology. I loved it from the first day, dissecting a rabbit before breakfast. Living tissues are wonderfully beautiful, whether fresh or seen under the microscope. Lowndes was a great teacher and had had a mixed career. From age 13 to 26, he had been in the merchant Navy. Then he went to Cambridge and took a double first class degree. Next he became a successful teacher and also did valuable research on Crustacea. He drove his pupils hard but gave them real opportunities to find fascination in living things and the possibilities of exact investigation of them. Several of his pupils became fellows of the Royal Society.

Oxford, 1925–1928

After one year under the guidance of Lowndes, I became a Demy (scholar) of Magdalen College, Oxford, and there studied zoology under E.S. Goodrich and Gavin de Beer. They were both able comparative anatomists (especially of the skull) but knew little of how to study function. From them I learned a great deal of comparative anatomy and later combined it with functional studies in The Life of Vertebrates (Young, 1950b). The third edition, issued in 1981, still sells more than a thousand copies a year in various languages 45 years after its initial publication. To it I tried to add functional knowledge to the comparative anatomy I learned from Goodrich and de Beer. But there is little in it about the nervous system. I find it curious that my name, for many people, is associated with that book rather than with my research, especially my work with the giant nerve fibers. I often meet people who tell me that their introduction to biology was through The Life of Vertebrates.

Embryology and Evolution

Gavin de Beer had a great knowledge of the literature of experimental embryology. From him I learned of the experiments of Spemann and others on the induction of the sequence of processes of differentiation from the action of a limited region of the embryo, probably by diffusion of stimulants. Insight into the process of morphogenesis is essential if one is to understand how the effects of the genes unfold to produce an embryo. An idea of this is essential for an understanding of the whole process of evolution. With this background I have never had any difficulty believing Darwinian evolution. Understanding of the process of differentiation makes it possible to realize how change of genes may alter the gradient of concentration of morphogenetic molecules and so the shape, say, of a limb, giving selective advantage. I learned genetics early on through E.B. Ford, a disciple of R.A. Fisher. I found the genetical theory of natural selection provided a satisfactory account of how evolution proceeds. Throughout all the controversies of subsequent years, I have had no difficulty believing in the power of natural selection as the basic process in evolution.

Progress in Evolution

The problem of finding whether there is any direction in evolution is best attacked by considering the central fact of biology, namely that organisms maintain themselves distinct from the environment. I discussed the question of progress in a volume of essays presented to Goodrich in 1938. As I put it then, “Some organisms may be said to live in more difficult environments than others.” I quoted C.S. Sherrington in his belief that “some organisms are higher than others in the sense that they dominate (the environment) more variously and extensively than do other organisms.” I still believe that this concept of the varying difficulty of environments is useful though hard to quantify. Everyone must agree that there is some sense in which some complex organisms maintain themselves in situations that are inaccessible to those at a simpler level. As I put it in an article in 1938, “A marine protozoan is an aqueous salty system in an aqueous salty medium, but a man is an aqueous salty system in a medium in which there is but little water and most of that poor in salts.” I used this conception of the colonization of more difficult habitats as a basis for discussion of the evolution of the nervous system. As I put it in 1938, “During the period since the Cambrian there has been a tendency for some of the organisms to become provided with more complex systems of self-maintenance by redistribution of energy than were possessed by their ancestors. This is especially clear from study of the nervous system.” I went on to show how the evolution of receptor and effector mechanisms and of the central nervous system shows this development of more complex systems.

Nerve Fibers and Synapses

My interest in the nervous system came through the school of C.S. Sherrington, who was professor of physiology in Oxford. He was a nice man, small in stature. When I told him about the fusion of the giant nerve fibers, he looked up at me and said, “Well, Young, if you say so I should believe it—but I find it difficult.” He had, of course, been a champion with Santiago Ramön y Cajal of the independence of neurons and was against the reticular theory of Camillo Golgi. I went to visit Sherrington in 1945 when he was 88 years old and in a nursing home in Cambridge run by nuns. He greatly admired Goethe because of his nature worship: “How he admired the profligacy of nature. And why shouldn’t nature be profligate, think of the spermatozoa, Young, millions of them,” he said with a twinkle in his eye, deliciously innocent but naughty. I never went to his lectures but was greatly stimulated by his colleagues, especially Derek Denny-Brown and J.C. Eccles. Denny-Brown in particular taught me how to use the silver methods of Cajal to study nerve cells and their processes. I learned from these people about the problems of the brain and about the physiology of the nervous system, the study of which, then as now, was centered on the synapse.

I suggested to Eccles that the earthworm giant fibers would be interesting because they are interrupted by a series of membranes. He and I joined with Ragnar Granit, who was then working in Oxford. We showed that nerve impulses pass in either direction across these membranes. The paper by Eccles, Granit, and Young (1932) in Procedings of the Physiology Society must be an unusual example of cooperation in early work by later leaders.

I became fascinated by the question of the structure of nerve fibers and synapses. This subject has remained a central interest for me. All my thinking about how the nervous system works has been centered on the properties of nerve fibers and the connections between them. This has given me what I suppose could be called a rather mechanistic view of the brain and a reductionist attitude to the great problems of life and philosophy. I love diagrams of the patterns of organization of nerve fibers and the connections between them. This is evident in my later thoughts about memory as encoded in a series of matrices. With my early interest in electrical communication, I was naturally intrigued by the evidence that nervous conduction was an electrical process. I read about the work of Keith Lucas and Adrian but without understanding the details. I was fascinated by the fibrils within nerve fibers and found it difficult to understand that membrane properties were involved in nervous conduction. I was especially interested in the structure of synaptic junctions and fully accepted that there was no continuity at the synapse. I therefore readily received the evidence of chemical transmission at synapses. I was fascinated by Dales experiments showing the chemical action of the vagus on the heart. Some of my earliest research was on the adrenal glands in dogfishes. This work led me to questions of chemical correlation. I published an article in which I suggested that we can recognize chemical action at three levels—vascular hormones, tissue hormones, and intracellular hormones (Young, 1934). Of tissue hormones I said that “some workers would go further and suggest that all transmission across synapses from one neuron to another is mediated by the liberation of a hormone.” For this I quoted G.H. Parker, 1932, whose work in this context is often forgotten. For “intracellular hormones” I quoted the ideas of Goldschmidt that male and female sex determinants are produced by the chromosomes.

Naples, 1928–1929

Immediately after graduation I went to the Zoological Station in Naples, helped by a scholarship provided by Oxford. I went with the primary aim of studying the autonomic nervous system of fishes and was indeed fortunate to find satisfactory material in the fishes Lophius and Uranoscopus.

Autonomic Nerves

The sympathetic nervous system of the dogfish was the special subject for my degree in 1928, and I am still working on this subject in 1996. The general problem is to find out whether it is possible to recognize sympathetic and parasympathetic systems working in opposite directions in fishes as they do in mammals, according to the classical view of Langley. The answer is, briefly, “no.” The visceral nerves are highly complex. I have given a detailed analysis of the anatomy of the nerves of the gut of dogfish and also of two teleostean angler fishes, Lophius and Uranoscopus. These species proved to be especially suitable because they are flattened and have no air bladder, and the sympathetic system can therefore be clearly displayed. I studied the effects of electrical stimulation and drugs on isolated pieces of the muscular coats of the viscera. The results showed no evidence for recognizing distinct sympathetic and parasympathetic systems. “The pharmacological reactions are almost uniform for the muscles here studied, acetylcholine causing contraction and adrenalin relaxation in every case” (Young, 1936). This conclusion refers not only to the muscles of the gut but also to those of the bladder and ovary (which in these animals is a hollow sac!). Later experiments showed many further complications, including the effect of ATP in the action of the vagus (Young, 1980a and 1980b).

An interesting complication appeared early with the observation that the iris muscle of these animals is controlled by sympathetic nerves producing constriction when stimulated and the third nerve producing dilation (Young, 1931). This is, of course, the direction of action opposite to that in mammals. Unfortunately, there has been no explanation of this curious contrast.

In the elasmobranch fishes—dogfish and rays—I found results quite different from those in teleosts (Young, 1980a). Stimulation of the vagus nerve has little effect on the muscles of the stomach, but stimulation of the sympathetic nerve produces inhibition followed by a large rebound after the stimulus ends. These actions are initiated by serotonin and by ATP; acetylcholine and adrenalin have only smaller effects. These fishes have a characteristic short spiral intestine, the muscles of which contract in response to electrical stimulation; and this reaction is imitated by adrenalin. The reactions of the rectum and urinary bladder are especially interesting because they receive a distinct pelvic nerve. These muscles showed spontaneous contractions that were inhibited by stimulation of the sympathetic nerve and by adrenalin or ATP but activated by 5 HT. These complex results show that it is not possible to recognize distinct sympathetic and parasympathetic systems in fishes on either morphological or pharmacological grounds. The viscera are controlled by different nerves using various combinations of transmitters to meet particular functional requirements.

I have been able in recent years, with the cooperation of Paul Andrews, to make satisfactory applications of these results to actual movements of the stomachs of freshly killed dogfish and skate. Electrical stimulation of the splanchnic sympathetic nerves of the dogfish produced contractions of the longitudinal muscles of the stomach, moving the contents forward even to the point of vomiting. Later there were contractions of the circular muscles, mixing the stomach contents. These movements were simulated by 5 HT, the effects of which were blocked by antagonists such as methysergide. These results thus support the evidence of the importance of 5 HT in these fishes. There are many complications such as the effect of peptides for which we also found evidence. The motor effects are so complicated that it is most unlikely that a single transmitter is involved. The general lesson that I have learned from this excursion over many years of physiology and pharmacology is that the nervous control of any process is complex. Even the fibers running in a single nerve may consist of several types producing varying effects, even on one organ.

The value of such work on little known animals like the fishes is to explore the different means by which homeostasis is ensured. These questions are summarized in the books by Nilsson (1983) and Nilsson and Holmgren (1994). They follow exactly the object of my work, and I am proud that the latter book is dedicated to me.

Cephalopods

The most important effect of my visit to Naples in 1928, however, was my introduction to the cephalopods. This came about through Enrico Sereni, who was professor of physiology at the Stazione Zoologica. He was an active physiologist but, unfortunately, had a short career. He and his brother were communists and Enrico held meetings among workers at Castelamare, which was dangerous under the fascist regime. A year later he was found dead in his bath from causes never fully revealed. His brother became a prominent senator after the war.

The Epistellar Body: Photosensitive Vesicles

When I went to Naples, Enrico was studying various features of the physiology of Octopus, and with him I investigated the regeneration of their nerves. In the course of this, I found an undescribed organ—the epistellar body—attached to the stellate ganglion (Young, 1929). At the time I thought it was a gland, but 25 years later Alex Mauro showed that the processes in its center are rhabdoms, containing rhodopsin and responding to light. These extraocular photoreceptors, now known as photosensitive vesicles, have been seen in many squids where they may control counterillumination, turning the luminous organs on and off to match the wavelength and intensity of the down-welling light (R.E. Young, 1978).

Giant Nerve Fibers

It was while looking for the epistellar body in squids that I found the giant nerve fibers. There is no epistellar body at the hind end of the stellate ganglion in these animals, but there I saw a mass of small nerve cells, the processes of which fuse to form one giant fiber in each stellar nerve. At first I could hardly believe that these huge transparent strands were nerve fiber. They were more like veins. A simple experiment at the Marine Biological Laboratory in Woods Hole, Massachusetts then proved their action. You pinch the nerve close to the ganglion and a part of the mantle muscle contracts. Then you crush the fiber lower down and a pinch above this is no longer effective. Of course, we went on to show a sequence of action potentials after stimulating the fiber.

In the following years I worked out the detailed anatomy of the giant fiber system. It proved to be a curious mixture of conventional synapses and an unusual fusion of axons. The giant nerve cells in the brain had already been shown by Williams in 1909, but he supposed that their axons ran all the way to the stellar nerves. He gave no descriptions or illustrations of them. His work had not been referred to by anyone in the intervening years, so far as I can discover.

The two axons of the giant nerve cells in fact proceed only as far as the palliovisceral ganglion where they join, in Loligo, in a midline commissure. In other species of squids and in cuttlefish, the two axons do not fuse but make synaptic contacts with each other. This obviously ensures that the two sides of the mantle always contract together. This is an interesting demonstration that the law of neuron theory can be broken. Nerve fibers can fuse when they must always work together. This is “the exception that proves the rule” that discontinuity and synaptic action are necessary for usual nerve functioning. The giant fibers in fact provide, in the stellate ganglion, synapses that are particularly useful for study. There it is possible to record electrically on both sides of the synapse. A further interesting feature of the system is the graded size of the giant fibers. R.J. Pumphrey and I were able to show that the smaller anterior fibers are slower and that the velocity of conduction follows the square root of the diameter. Alan Hodgkin helped us with these experiments and so began his great series of investigations of the giant axons. Of course the most valuable feature of the fibers for physiologists is their large size and accessibility. This feature allowed Alan Hodgkin and Andrew Huxley, and later many others, to increase greatly our understanding of the excitability of the nerve membrane and conduction of the nerve impulse. Indeed, the giant nerve fiber of the squid has become the classic material for the study of excitable membranes.

I made many other studies of the giant nerve fibers. With D.A. Webb I studied their content of potassium and sodium for correlation with the size of the action potential. With R.S. Bear and Frank Schmitt I made a thorough study of the sheath components of the fibers (Bear et al., 1937). This study was especially valuable to me as an introduction to the use of polarized light microscopy.

Chicago, 1936

My detailed study of synapses led to the next large change in my career, which was started by a Rockefeller Fellowship in 1936 and a visit to Chicago and Woods Hole. I crossed the Atlantic Ocean with my first wife, Phyllis, on the Queen Mary and we went at once to stay with John Fulton and his wife at Yale. He was an active physiologist and one of the first to examine the physiology of the frontal cortex in a modern way. He was also a keen historian and built up a library, which I believe is now owned by Yale University. After a happy Christmas with the Fultons, my wife and I went on to Chicago. We went by air, which the Rockefeller officials considered unwise, and indeed we became grounded by the weather in Cleveland and had to continue by rail.

In Chicago I worked in the anatomy department to meet C. Bartelmez who, as an embryologist, had developed special methods for preparing tissue for microscopy. I wanted to apply these methods to synapses, which were then studied mostly by silver methods, involving severe fixation and artifacts. Curiously enough, David Bodian came to Chicago at the same time for the same purpose, his material being Mauthner cells of fishes, which have large synapses. I got to know him well, and we played handball in the baseball building later used to make the atom bomb. While I was in Chicago I met many biologists. Paul Weiss was in the zoology department and Ralph Gerard in physiology. With Gerard, I studied the electrical activity of the brain of the frog, which is remarkable in that the waves continue after the brain is removed from the head (Gerard and Young, 1936). Of the many other people I met there, perhaps the most interesting was H. Kluver, who made pioneer studies of how, after certain lesions of the brain, monkeys no longer show any fear of snakes.

From Chicago I went for a visit to St. Louis, where many people were working on the nervous system. Gasser and Erlanger were doing their classical studies on conduction in different sorts of nerve fibers. Gasser was a particularly nice man, tall and smiling with a high child’s voice. I later stayed with him in New York. He was especially interested in the large and small fibers in a squid. Frank Schmitt, with whom I stayed in St. Louis, and his brother Otto, were making some of the first electronic recordings of electrical activities. I remember my surprise going into Schmitt’s lab where a nerve was being stimulated—in absolute silence. I was used to labs in Sherrington’s department that were an untidy maze of wires and where recording was done by a Matthews oscillograph after stimulation with a clanking Lucas pendulum.

Lorente de No came to my lecture and showed incredulity at the fusion of the giant fibers. He was an expert on the histology of the nervous system and did not like anyone else explaining the facts to him. Also there were George Bishop, always skeptical, and Peter Heinbacher. I went especially to see Kuntz but found that he was not very interested in the evolution of the autonomic nervous system of lower vertebrates. This visit to St. Louis was especially profitable because I arranged to join Frank Schmitt for work at Woods Hole the following summer.

Woods Hole, 1936

Before going to Woods Hole I went to a meeting at Cold Spring Harbor, where I lectured on the squid giant fibers and met K.C. Cole, who later made such good use of them. We tried to get squids from fishermen on Long Island, and we carried the squids back in large milk cans, but none survived. However, at Woods Hole squids are plentiful and we soon made the first studies of their action potentials. I tried to do this with Ralph Gerard, Det Bronk, and Keffer Hartline, but at first even these great men could not operate the stimulator and oscilloscope. So one day when Ralph and Det were out I suggested to Keffer that we put a crystal of oxalate on the cut end of the nerve, and out came a wonderful buzz and series of spikes—the first of many thousands of giant fiber impulses.

Oxford, 1937–1945

Lampreys and Cephalopods

During 1937 to 1945 as a Fellow of Magdalen and demonstrator (lecturer) in zoology, I taught many aspects of zoology under Goodrich. I continued work on the giant nerve fiber at Plymouth, largely with R.J. Pumphrey. It was not easy to catch squids in good condition by trawling. The ship would make a special quick haul at the end of each day’s work and come in at 4 o’clock. Meanwhile we had been bathing off the rocks below the lab. As soon as the ship arrived we started work and went on into the night.

At Oxford I worked mainly with lampreys. I had the idea to study one species of animal thoroughly—its behavior, its brain, and its possibilities for research. The lamprey seemed to be a good candidate because the larvae (ammocoetes) are abundant in the rivers at Oxford, and the adults are caught for food as they come up the river Severn. The lamprey proved to be an interesting animal. I was able to show for the first time that the pineal body is truly a photoreceptor; without it the animals do not change color at night. There are photoreceptors also in the tail, the impulses of which (unexpectedly) pass forward in the lateral line nerve. We also showed that the pituitary controls reproduction.

However, the brain of the lamprey was hard to investigate. There seemed to be little behavior that could be studied in the laboratory, so I thought that my plan should be transferred to the cephalopods. While looking for the giant fibers in squids I had seen the wonderful higher centers of the brain, hitherto little known. In particular, there are lobes that stimulate one another reciprocally. With F.K. Sanders I found that cutting such connections in the cuttlefish (Sepia) made the animals unable to follow a prawn that had disappeared out of sight. This finding led me to study the memory of cephalopods (discussed later).

Regeneration of Nerves

During World War II, I organized a group in Oxford to study the possibility of improving the results of surgery after injury to peripheral nerves. A special Center for Nerve Injuries was set up under the orthopedist Professor H.J. Seddon, and I collaborated with him in clinical and experimental studies. Many nerve injuries in wartime do not result in complete interruptions of nerves but cause damage by compression. The problem for surgeons is to know how long to wait for “spontaneous” recovery. The solution requires study of the rate of regeneration under various circumstances, and this we studied experimentally in rabbits. We also studied the clinical literature to find what results might be expected. The group involved no fewer than three people who later became fellows of the Royal Society, and one Nobel Prize winner—P.B. Medawar. The rate of regeneration of course includes not only the time for regrowth of the fibers but also for their maturation to a state fit to function. We found that the process of increase of diameter and myelination depends on both conditions at the lesion and connection with a suitable periphery. This work also led to study of the dependence of nerves on the connection with the cell body. I showed that after severance the central cut end swells more than the peripheral (Young, 1944). This finding was evidence of axoplasmic transports found by Weiss at the same time.

A great problem for surgeons is the repair of gaps in damaged peripheral nerves. We experimented with various forms of grafting and showed that only nerves from the same individual were effective. This was Peter Medawar’s first contact with grafts, and I believe it was the background for his discovery of the immune responses to foreign tissues.

Part of our work involved studying the atrophy of denervated muscle and means of delaying it. This was the field of Ludwig Guttmann, who joined us as a German refugee. Not allowed to do clinical work, he studied muscle atrophy in rabbits and went on to study rehabilitation in humans. This work led him to found the special clinic at Stoke Mandeville and ultimately led to the International Olympic Games for the Handicapped.

Another discovery we made during this work was that the length of internodes in nerves is a function of growth. We found that they are unusually long in eels, but short in nerves that have regenerated in adults. This finding has led to valuable diagnostic techniques for neurologists, which have been developed by P.K. Thomas, who worked with me on the eels. He is now a professor of neurology and has written a large work on the subject, to which I wrote a preface.

Professor of Anatomy, 1945–1974

University College of London was the first British medical school to appoint a zoologist as professor of anatomy. I insisted that all the staff do research and that the students take an extra year of biological work, for which we gave courses and awarded an honors degree, which has now become general practice. I happily meet old students who have become specialists in many aspects of medicine. A lot of postgraduate students and visitors came to University College and have become professors in many countries.

I tried to familiarize myself with human anatomy, but I was never able to teach the details. However, we devised methods of teaching anatomy as an experimental subject. These methods were published as a manual of anatomy that became widely used. The methods involved a system of studies in which students learned the action of bones and muscles by practical experiments on themselves or others. The emphasis was on discovery rather than demonstration by the teachers.

Perhaps my most useful contribution as professor of anatomy was a series of weekly lectures called “An Introduction to the Study of Man” (Young, 1971b). The lectures included discussions of many things such as philosophy, population numbers, and human evolution. These topics are often omitted by medical students who, at some colleges, do only two years of classes before becoming locked up in clinical work taught by dedicated but single-minded doctors.

The Flying Spot Microscope

One of my interests was to find ways to quantify microscopical data. It struck me as anomalous that one of our most powerful instruments yields only pictures. I therefore recruited an engineer, Frank Roberts, to apply scanning techniques to the microscope. With him and David Causley, I devised one of the first flying spot microscopes. We needed it especially to count the nerve fibers in normal and regenerating nerves. I was also interested in the subdivision of the cerebral cortex. The maps of cerebral areas by Brodmann were valuable but not quantitative. Exact delimitation of areas was obviously too difficult to do by eye and required automatic counts of numbers and sizes of nerve cells.

The microscope that we devised was technically successful and attracted wide attention, but it was not practically useful. The reason was that microanatomical preparations, even if well stained, do not define the edges of cells unambiguously. Successful counting was achieved only for simple black preparations such as those of dust particles. I gather that the problem of counting cells in brains is still only partly solved and essentially involves measurement of the size of each particle counted (Roberts and Young, 1951).

However, our engineering work changed course under W.K. Taylor into study of the recognition of patterns by machines. He devised, with D. Causley, a large machine that successfully recognized letters and faces, based essentially on the principles known a little later as a perceptron. This work was all in the 1940s and 1950s before the introduction of modern techniques. The instruments were large, involving hundreds of valves. Contacts with engineers gave me great help in understanding the problems of communication and vision.

Electron Microscopy

Being interested in the fine structure of tissues, I was naturally fascinated to hear of the possibilities of the electron microscope. My first direct contacts with it were with R.W.G. Wyckoff. He came to London as an official scientific representative and set up one of the earliest instruments within the American Embassy. On meeting him in 1953 and learning that he had no material to study, I prepared the spinal cord of a rabbit and we cut sections. The fixation in osmic acid was not good, but we made some of the first pictures of synapses with the electron microscope.

I was then able to recruit J. David Robertson in 1955 to set up an electron microscope department at University College where he continued his pioneer research on cell membranes and myelin sheaths of nerve fibers. We collaborated later on the brain of Octopus but I never learned the necessary techniques for myself. Dave remained with us for five years and we became great friends with him and his family. He became professor of anatomy at Duke University, and I often visited him there.

Anthropology

I became interested in primates and human history when working with Solly Zuckerman in Oxford. I made much further study of the fossil record of humans and of human diversity for my lectures to medical students, and for the book, An Introduction to the Study of Man (Young, 1971b). In this book I gave an account of the fossil evidence for human evolution and discussed the various theories of the climatic influences that were probably at work. I also tried to give an account of what is known about the origins of culture, language, and religion. I tried to connect these large subjects with what we know about the activities of the brain that are involved.

In this way I came to know many anthropologists in Britain and around the world. On a visit to Kenya as examiner in the university, I met Louis Leakey and his son Richard. On a later visit Richard flew me in his airplane to Olduvai Gorge. There Mrs. Mary Leakey showed me around the valley and what they called “the earliest human house.” This was a wonderful visit, and it gave me insight into the practical problems of field anthropology. I was especially impressed by Mrs. Leakey’s later discovery of the footprints of a family, presumably of Homo erectus. I was also impressed by the Leakeys’ discoveries of fossil skulls, though somewhat skeptical of their early naming of the specimens. I was strongly in favor of Zuckerman’s emphasis on the need to base human systematics on measurement.

With this background, I assisted in the joint organization by the British Academy and the Royal Society of a symposium on “The Emergence of Man” (1980). At this symposium I enjoyed meeting another group of anthropologists. I chaired a session and gave introductory remarks and tentative conclusions. I suppose it was useful to have a neurobiologist discussing these questions, but I never gave a really original contribution to the subject. I was therefore surprised when the British Academy offered me honorary membership. I suppose it was for my interest in anthropology, but I like to think that my other writings contributed as well. Randolph Quirk, president of the academy at that time, used various quotations from The Life of Vertebrates (1950b) as illustrations of the use of English. I should like to think that my contributions to current thought in the Reith Lectures and elsewhere played a part in my becoming F.B.A. as well as F.R.S.

The Radula of Cephalopods

In recent years I have spent a lot of time studying the radula—a toothed ribbon which moves in and out of the mouth of cephalopods during feeding. I first became interested in the radula because of a curious muscle involved in its movements, known as the “radula support” or “bolster” because of its shape. I saw in sections that the muscle fibers run across the bolster and are attached to the enclosing wall on one side but are free at the other side where they are simply covered by a membrane. These muscle fibers are not attached to the radula ribbon and seem to have no function. In fact, like many muscles of mollusks, the action of the bolster is hydromuscular (Kier, 1982). Tightly enclosed in its sheath, the bolster must stiffen and change its shape when the muscles within it contract. The bolster is free at its front end, lying just beneath the point at which the ribbon moves out. By stimulating the bolster of Octopus electrically, I showed that the bolster does in fact elongate and push out the teeth.

An interesting complication is that in decapods, the bolster contains a mysterious structure known as the “rod.” This rod contains large cells, which have been wrongly called cartilage. In fact, the bolster rod of cephalopods is a sac, with semiliquid contents. Enclosed in a membrane, the rod must change its shape when compressed. In fact, it elongates and in a cuttlefish actually protrudes from the bolster at the front end and pushes up the teeth of the radula. Bill Kier tells me that this is a unique case where a hydromuscular system transmits its force through a rod of this sort.

The question is of some general interest because bolsters with rods are found in the radula of many mollusks. I have examined them in many cephalopods. In Nautilus there is a large, watery rod attached to the front of the toothed ribbon. This may perhaps have been the original condition. The freeing of the front end allows more varied use of the teeth. In octopods, where there is no rod, the radula is used to bore holes in the shells of snails for the injection of poison. This highly sophisticated behavior involves recognition of a reward to be obtained later. Thus, there is a correlation between development of the radula and of a nervous system that is capable of a view of the future.

The Central Nervous System of Cephalopods

I have spent many years studying the anatomy and functions of the brain in cephalopods. This area was previously rather little studied, and I have tried to give a thorough account of it in Octopus, Loligo, Sepia, and Nautilus, and briefer accounts of a wide variety of other cephalopods. I have largely used light microscope sections stained by the method of Ramön y Cajal. This method works well, and I have made a large collection of sections of the brains of a great number of Cephalopod genera. The preparation of these sections has largely been the work of my technicians, especially James Armstrong, Pamela Stephens, and Tess Hogan. Such devoted attention to the preparation of long series of slides is essential for such work. We have also used Golgi methods, sometimes quite successfully.

In much of this anatomical work, I have been assisted by others. Brian Boycott was active from the start and is mostly responsible for the large book, The Anatomy of the Brain of Octopus vulgaris, to which he gave a generous preface. Martin Wells contributed greatly to study of the tactile memory system. Others who have helped have been R. Lund, J.B. Messenger, J.S. Stanier, J.R. Pariss, M.F. Moody, V.G. Barber, G.F. Savage, J.S. Altmann, and M. Hobbs. Recently, I have had much help from B.U. Budelmann. Throughout, I have had continuous support from Dr. M. Nixon. She has an outstanding knowledge of cephalopods, which she has made available to me in many ways. Without her cooperation I could never have achieved so much.

The results of these investigations have been recorded in a series of papers and in a large book, The Anatomy of the Nervous System of Octopus vulgaris (Young, 1971a). The brain of Loligo has been described in similar detail across five papers in the Transactions of the Royal Society. The brain of Sepia was described by B. Boycott in 1961. Further detail will appear in the book by Dr. Nixon and I titled The Brains and Lives of Cephalopods. This book will give some information on the brain in every family of cephalopods. Altogether, therefore, we have tried to describe the anatomy of the nervous system throughout the group, and to note something of its functioning.

Many of the tracts in the octopus brain have been traced by degeneration methods. Some of the lobes have been examined by electron microscopy with the help of Dave Robertson and George Gray. Much work has also been done on the function of the various lobes, using electrical stimulation and study of the effects of removal and survival for both short and long periods.

The brain of cephalopods is divided into many lobes. It has been possible to recognize a clear-cut hierarchy of centers, but there is a special problem in that a large part of the nervous system lies outside the central ganglia. The centers in the arms contain 350 million nerve cells, the optic lobes contain 92 million, and the central brain only 42 million. Most of the final motor neurons and the reflex centers are therefore in the arm ganglia; the brain centers are mostly concerned with coordinated movements. We can recognize lower and higher centers. Their functions still are not fully understood, but some of them show striking similarity to centers in the vertebrate brain. For instance, the peduncle and anterior basal lobes contain many rows of fine fibers like those in the cerebellum. They may be concerned with the proper timing and succession of movements. Many studies have been made on the effects of electrical stimulation on these centers and of the defects that follow their removal. The parts of the brain occupying the regions above the higher motor centers give no response to electrical excitation and are concerned with memory and motivation, as will be discussed later.

Besides describing the connections of the cells of the brain, I have counted the cells and measured samples in the various genera of cephalopods. I have measured the volume of 30 of the lobes in 63 species. With the help of L. Maddock, I then compared these measurements using principal component analysis. The results provided the basis for the detailed description and discussions in the book to be published with M. Nixon, Brains and Lives of Cephalopods. From this study I learned a great deal about the principles of organization that underlie the complex behavior of cephalopods. Comparison of Nautilus with the coleoids shows two conspicuous developments. First, new systems of motor control appeared in the higher motor centers—the peduncle and anterior basal lobes. Second, the higher supraoesophageal centers become developed for learning, memory, and motivation.

The modern coleoid brains are remarkably similar in their general organization, but their detailed differences are fascinating. The Decabrachia (squids) have especially well-developed visual systems and giant fibers for rapid movements and fins for steady movements. The Octobrachia have smaller optic lobes but specially developed centers for touch; the centers for the arms are greatly developed. The octopod brain shows great concentration and development of connection between the lobes, which are responsible for its highly integrated patterns of behavior.

These are only a few general characteristics. Within each group there are special developments correlated with the detailed habits of the species. For example, the deep-sea squid Mastigoteuthis has immensely long tentacles covered with minute suckers. Observations from submersibles have shown that this squid swims upside down, trailing its tentacles on the sea bottom to catch small crustacea. Our sections show that the tentacles and mantle both have connections directly with the magnocellular lobe, and this lobe has a complex internal structure and is larger than the vertical lobe. The magnocellular lobe has evidently become the main controlling agent for this special behavior. This and many other examples show the great capacity for evolutionary development involving quite wide departures from the general pattern. We hope that our descriptions of the nervous system of many little-known species will show similar correlations as their habits become known.

Statocysts of Cephalopods

I was attracted to the statocyst when I noticed that the crista of Octopus is a set of three ridges running in planes at right angles, like the semicircular canals of the vestibular systems of vertebrates (Young, 1960a). The ridges carry flaps, the cupulae, attached to sensory hairs, the movement of which registers the angular acceleration or velocity of turning in different planes. In cuttlefish and squids there is a series of projections. Some of these, which I called anticristae, partly enclose the crista. Others, called hamuli because they are hooked, limit the length of the cupulae. I suggested that the anticristae serve the same function as the vertebrate canals in limiting the flow of endolymph. In some squids the anticristae actually form a canal for part of the length of the crista. These restrictions by anticristae and hamuli reduce the flow of endolymph across the cupula flaps and alter the sensitivity to angular acceleration.

Measurements of the statocysts of Loligo and Sepia of different ages showed that the sacs are large at hatching and become relatively smaller with growth. The anticristae, however, are small or absent at first and grow faster than the body as a whole. These features limiting the endolymph are precisely similar to those imposed by the vertebrate canals. The cephalopods have evidently evolved a system functionally similar to that of vertebrates, using different materials. Measurements of the statocysts of a variety of cephalopods showed that they are large in 21 species of buoyant and deep sea forms, which move slowly and monitor slow turns by the large volume of fluid. These squids have small anticristae. Sixteen species of rapidly moving, nonbuoyant forms have small statocysts with large anticristae, which often form canals (Maddock and Young, 1984; Young, 1989).

I made a special study of the statocysts of cranchiid squids (Young, 1984). These squids have evolved a system of buoyancy by the use of their nitrogenous excretion to form ammonium chloride, which is lighter than sodium chloride. The liquid is stored in a special sac. Some species live in the deep sea and are transparent and slow moving. They have large statocysts, as would be expected, and they have few anticristae; one form, Bathothauma, is unique in having none at all. Conversely, some cranchiids move rapidly and have small statocysts with numerous anticristae. Egea has no fewer than 44 elongated rods. The significance of these extraordinary structures is still obscure. They show the great variety that has developed during cephalopod evolution, and they present great problems for future workers.

Eyes and Vision

I became interested in the details of the visual system of Octopus after observing that learning to make distinct reactions to visible shapes depends largely on the vertical and horizontal extents of the figures. Regularities in the retina and optic lobes provide clues to the mechanisms for coding in these two directions (Young, 1960b). The retinal receptors are the processes of the 107 million cells directed toward the lens, and each carries microvilli attached to opposite surfaces. These receptors are in pairs, one with villi in the horizontal and the other in the vertical plane. The retina thus has a strikingly regular pattern of squares. Each cell sends an axon into the optic nerves and so to the optic lobe. A strip of longer, thinner retinal cells runs horizontally along the equator. This presumably is a region of special importance, related to the presence of a horizontal pupil. Study of the adaptation of the retina to light and darkness shows that there is migration of pigment within and among the retinal cells. This migration occurs differently along the horizontal strip (Young, 1963).

The axons of the retinal cells enter the optic nerves, which make a striking chiasma that inverts the image dorso ventrally. I interpreted this as attributable to the need for the visual system to work with the same orientation as the statocyst, involving gravity. This observation agrees with the finding that the dendrites of the second order neurons in the outer layer of the optic lobe are very long and are oriented largely, though not exclusively, in horizontal and vertical planes. Studies of form discrimination by N.S. Sutherland show that the animals can recognize rectangles in these two planes, but not when the rectangles are oblique. I therefore suspect that form recognition is accomplished by analysis of outlines, as suggested for mammals by David Hubel and Torsten Wiesel. Unfortunately, there has been no investigation of these cells (or any others) in the brain of Octopus using classical physiology. Attempts have been made by able researchers, but intracellular recordings had been impossible until done quite recently by B.U. Budelmann and T.H. Bullock. The reason for the difficulty is still not clear, but it may be the fragility of the finer blood vessels.

There are few suggestions for the functioning of the numerous large and small cells occupying the center of the optic lobes. In the outer part, the cells are arranged in columns, which are most marked in the species living in well-lit waters, and are reduced in those living deeper. Progressing inward in the optic lobes, there are more and more horizontal cells, presumably allowing for correlation between appearances in different parts of the field.

I have continued to be interested in the eyes of the various species of cephalopods, which show many variations. In some deep-sea forms, the Bolitaenidae, the eyes are elongated and transparent at one end but pigmented at the other. There thus seems to be an aphakic window allowing photosensitivity downward as well as laterally through the lens. A larger part of the retina is opposite the window, and the optic lobes are partly divided into two. In the deep sea, of course, the main light is bioluminescence. The eyes need to detect the direction of flashing prey; there is less need for form discrimination. Other visual simplifications are the absence of a lens in the cirrate octopod, Cirrothauma, and in Nautilus. In all these cases the optic lobes have few or no columns.

One of the most interesting questions about vision is the importance of visual search and movements on the retina. This question was emphasized for me by the importance of movement of the eyes in humans. I was impressed by the work of Yarbus (1967), who showed how eye movements pursue a search for items of interest. For example, when looking at a face, eye movements are mostly toward the eyes and mouth. I interpreted this finding in Programs of the Brain (Young, 1978). The direction of each eye movement depends on a forecast made by a program on the basis of information received as to what is likely to come next. Seeing in humans is thus not a matter of receiving a sort of photograph on the retina but is a dynamic process using a series of scans seeking answers to questions set by previous experience. The brain then constructs a hypothesis about what is there and produces appropriate action.

It would be most interesting to find whether vision in an octopus or squid consists of any such use of a program. Little information is available about any scanning process. An octopus bobs its head up and down when a new object appears. This movement would pass the image across the longitudinal strip at the center of the retina. Unfortunately, it is not possible to say any more yet about the process of vision in such animals, but I have been able to study the eye muscles with Ulli Budelmann, and they are certainly sufficiently developed to allow detailed scanning movements (Budelmann and Young, 1984, 1994).

Cephalopod Eye Muscles

In Octopus there are seven extraocular muscles, controlled by seven nerves. There are three recti muscles that produce linear movements and four oblique muscles, some of which pass halfway round the eyeball. We studied the movements of these muscles by stimulating the nerves and also recorded the constrictions and dilations of the pupil. By filling the nerves with cobalt we were able to identify the oculomotor center in the pedal suboesophageal lobe. Filling the nerves of the statocyst then showed that the static fibers run to many parts of the brain, including to the oculomotor center and to the higher motor centers of the basal and peduncle lobes. The statocyst-oculomotor system of Octopus thus shows two pathways from the receptors to the eye muscles, one direct and the other via higher motor centers where visual information is included with that from the statocysts. This system shows remarkable convergence with the vestibula-oculomotor system of vertebrates. Once again, we see how similar functional requirements have come to be met in similar ways despite differences in organization.

We went on to study the eye muscles of decapods and found a different situation (Budelmann and Young, 1993). There are 14 muscles in Loligo and 13 in Sepia. The extra muscles are all anterior and superior, and are concerned with the convergent eye movements used for binocular vision in fixating prey for capture by shooting out the tentacles. The muscles attached to the anterior face of the eye include two remarkable conjunctive muscles whose tendons cross the midline! Presumably the fibers on both sides contract together, moving both eyes at the same time during fixation. No such muscles are known in any other group of animals.

The other eye muscles of decapods are rather similar to those of octopods. The main actions of these muscles are linear, but three produce rotation. There are only four eye muscle nerves in decapods, and these nerves arise from an oculomotor center in the lateral anterior pedal lobe, as in octopods. An interesting feature of decapods is that the cell bodies for different nerves show different but overlapping distributions, which thus provides an opportunity to show that there are distinct motoneuron pools as in vertebrates.

Memory in Octopus

I first became interested in memory after seeing self re-exciting connections in the brain of cuttlefish, as discussed earlier. I then turned to the octopus, which has even more interesting memory centers than the cuttlefish and is much easier to work with. In Octopus the brain lies free in the cranium in a large cavity packed with jelly, and is accessible for operations. The animals are kept separately and their behavior can easily be studied. They are readily anesthetized, recover well from operations, and can be kept in the laboratory for months. I started experiments in Naples in 1947 with support from the Nuffield Foundation and also from the United States Air Force, which had shown interest in our work on the flying spot microscope. The Naples Zoological Station was ready to help with space and tanks. Octopuses are abundant in the Bay of Naples, and the fishermen of the station provided a constant supply.

Octopuses readily attack small crabs, and we fed them on these and dead sardines. Octopuses are ingenious at escaping through any small hole or crack, and we constantly suffered from escapes. Their arms can lift the lid of a tank, even if it is loaded with bricks. The octopus then forces its head and arms over the edge, drops the lid on itself, and dies. We found it necessary to design suitable tanks in which the octopus was given a home among bricks at one end and could be tested by showing it figures at the other end.

When an octopus is shown a strange moving object, it first watches it for a minute or more and then approaches it gradually, touches it with an arm, and takes it if it is eatable. Shown the same object again, it comes out more and more rapidly, finally attacking after only two or three seconds. This behavior shows a positive learning to attack. Conversely, if the octopus receives a shock, it remains at home. We tried various methods to automate this procedure, but the octopuses proved ingenious at removing anything attached to the tank. The problem was finally solved by Hector Maldonado with special tanks.

The training experiments used large sets of animals randomized between operations and controls. They were trained twice a day, and this involved many hours of work. I was helped in this by my wife, Raye, and daughter, Kate; also by students from University College, whom I brought out on my grants. This project gave the students some research experience and they enjoyed life with us in Naples.

The Two Sets of Memory Centers

In Octopus I soon found separate sets of centers for visual and tactile memory, with slight overlaps. Each set is composed of a sequence of four lobes that are similar in the two systems. Experiments have led me to give the following interpretation. The first lobe of each set receives fibers of taste from the lips and serves the positive learning to attack the object seen. This lobe sends fibers to the fourth lobe, which is a motor center. The second lobe serves to assemble groups of signals, representing the input and passes them to the third lobe, which reassembles them with fibers that indicate pain. The axons from this lobe also pass’ to the fourth lobe, where they activate cells that produce retreat. The whole set thus constitutes an “unless” system, indicating taking the object seen or touched, unless pain supervenes. The presence of these two similar sets is striking evidence that their organization is an essential part of the learning system.

The Visual Memory Centers

This interpretation of the function of the paired lobes has been reached after a great many experiments over many years. In the visual system, the fibers of the optic tract carry signals already analyzed in the optic lobe. In the first of the paired centers, the signals meet taste signals from the lips. If this lateral superior frontal lobe has been removed, an octopus no longer makes attacks at a crab seen far away, even though it is not blind and will reach out an arm to take a crab placed near it.

In the second visual lobe, there are many interweaving bundles of branching visual fibers synapsing with the million cells of this superior frontal lobe. Each visual fiber thus meets many others on these cells, and vice versa. The axons of the cells carry signals representing the joint action of groups of photoreceptors. Granted appropriate modifications of synapses, this process ensures firing of these cells when the same group of receptors (or a part of it) is stimulated again. These axons pass to the third visual center, the vertical lobe, lying on the top of the brain. This lobe is characterized by 25 million minute cells, the amacrines, the axons of which do not extend beyond the lobe. In addition, there are about 70,000 quite large cells, with many branched dendrites and axons reaching to the subvertical lobe and so to motor centers. The fibers coming in from the superior frontal synapse with the amacrine cells, with the large cells, and also with fibers entering the lobe from below. These are believed to be pain fibers, arising all over the body and the skin. The function of this lobe is certainly inhibitory. Brian Boycott and I found early on that after removal of the vertical lobe, an octopus is uninhibited; it will persist in attacking at crabs even when given electric shocks. It can be trained only slowly to attack, say, at vertical rectangles but not to attack horizontal ones. The mistakes it makes are always to attack when it should retreat.

The large cells of the vertical lobes thus build up representations of visual features that should be avoided. Their axons proceed to the subvertical lobe and so to motor centers. Recursive fibers also pass back to the lateral superior frontal, allowing recurring stimulation, increasing appropriate synaptic learning changes. It remains uncertain how the many amacrine cells assist in the memory process. Their large nuclei suggest that a synthetic process is involved. Perhaps they consolidate synaptic changes taking place at the ends of their short trunks.

The Tactile Memory Centers

In the tactile system, there is a strikingly similar set of four centers. The first lobe receives the tactile signals from the arms and associates them with taste fibers. Its axons proceed to the fourth tactile lobe, the posterior buccal, which contains large cells; some of these cause the arms and suckers to reach out and take the object, other cells innervate circular muscles that push the arm away. The median inferior frontal system, constituting the second tactile lobe, is built exactly like the superior frontal lobe, with bundles of crisscrossing fibers. The cells of this lobe receive the fibers from the arms and thus carry representations of the actions of groups of touch cells. The axons carry signals to the third center, the subfrontal lobe. This lobe is precisely similar to the vertical lobe, with many millions of small amacrine cells and a few large ones with many dendrites. Like the vertical lobe, the subfrontal lobe receives pain fibers and it prevents the taking of unwanted objects. These four lobes perform for touch exactly as the other four do for vision. For example, Martin Wells and I showed that after removal of the subfrontal lobe, an octopus can no longer learn tactile discrimination. It continues to take objects from which it had received shocks.

The tactile system also makes use of some lobes of the visual system. Part of the tactile input from the arms passes to the superior frontal and so around the entire vertical system. Thus, eight matrices are involved in the tactile system, and removal of any one of them interferes with tactile learning (Young, 1983). This is indeed a striking demonstration that the memory is distributed between many parts of the brain.

The Origin of the Memory System

From detailed study of the anatomical relations, I have been able to produce a hypothesis as to how the vertical and subfrontal lobes have come to function as learning systems. Many small cells, similar to the amacrines, occur in the motor centers of the suboesophageal lobes, several small cells lying close to each large motoneuron. These small cells probably serve as inhibitors of the large cells when the latter are involved in reciprocal reflex actions. Such inhibition is needed even in the simplest reflex system. Small cells having this inhibitory function occur in the spinal cord of mammals. Sections show that the rows of cells of the subfrontal and vertical lobes are directly continuous with the inner rows of small cells of the superior buccal lobe. This lobe is a motor center that operates reflexes concerned with movements of the jaws. Its small cells presumably provide the inhibition of the large cells that produce these movements. The subfrontal and vertical lobes are thus specially developed parts of the eating system. The taste fibers they receive promote actions of attack at objects that have provided food. The inhibitory fibers of the subfrontal lobe promote the formation of representations that prevent the intake of unsuitable materials. The functions of the vertical lobe, literally the highest part of the brain, have perhaps been extended to produce a balanced inhibition of the whole behavior. The memory system, as described, is simply an extension of the function of the buccal lobe in obtaining food. It remains to be seen whether it also extends to memories controlling other aspects of behavior.

Visual Discrimination

During the years 1955 to 1965, work in Naples was largely on the octopus’ capacity for visual discrimination. This work was done mostly by observers showing the figures at one end of the tank and rewarding attacks with either shocks or food. This method has the obvious disadvantage that the octopus may take clues given consciously or not by the observer. We took great trouble to avoid such a danger and obtained consistent results with different observers. However, the “talking horse” danger was finally eliminated by Hector Maldonado, who devised an entirely automated procedure (1963, 1964, 1965). With this procedure, he was able to confirm the conclusions reached with open tanks and to measure exactly the times of the various phases of attack and the effect on these of removal of various lobes.

A thorough study of the extent of the capacity to recognize shapes was made by Stuart Sutherland, who devised a theory to explain his findings. Many variables of learning were studied, such as the capacity to reverse learned discriminations and to learn with a delayed reward. Partial removal of the vertical lobes decreased the capacity to learn in proportion to the amount removed.

Tactile Discrimination

This topic was first studied by Martin and Joyce Wells. They found that an octopus has great capacity to discriminate between objects with different degrees of roughness but has limited power to recognize shape. They attributed this finding to the absence of joints in the octopus’ arms and the corresponding lack of proprioceptive determination of their position. I have made extensive further studies of the touch memory, some with M. Wells. We tested the animals with a series of plastic balls, each with a number of rings cut into it. The animal was given food for taking a certain ball, say three rings, and shocks for another, say nine rings. After a few trials, one ball was quickly taken under the web and the other ball was rejected. To avoid visual choice, the optic nerves were first cut; but in fact the octopus cannot make the distinction visually, and reliable results were obtained with intact animals.

After splitting the whole of the supraoesophageal lobe, we found that the two sides can be trained independently, even performing in opposite directions. Thus, it is possible to compare the effects of different lesions in the same animal. I studied the effect on learning of removing each of the lobes involved, both separately and in combinations, using a final test of the degree of accuracy achieved. We found that removing each of the lobes reduced learning to a different extent. The tactile memory is therefore distributed between them, as is the visual memory (Young, 1983). This was a long series of experiments, spread over several years in Naples. Approximately 30 to 40 animals with each type of lesion were used and trained twice a day.

Interaction Between Visual and Tactile Learning

Dave Robertson established an octopus laboratory at the marine station of Duke University in Beaufort, North Carolina. He found fishermen able to collect live octopuses and bring them in good condition to the laboratory. With his electron microscope studies, he believed that he showed that fine filaments, the filopodia, became more numerous in the tactile centers after training one side of a bisected brain.

I used the facilities in Beaufort to study the possibility of interaction between visual and tactile senses in learning. This is a possibility because learning with both senses involves the vertical lobes. We found that a negative visual memory, not to attack white, for example, blocks the effect of a previously learned positive tactile memory, such as to take rough. But the effect is seen only in the period immediately after seeing the color. There is no long-term effect on the positive tactile memory. The only interaction between the two memories is the result of sharing common pathways to the arms. There is no evidence of second-order conditioning (Allen et al., 1986).

Learning in Squids

In Beaufort we were also able to show the learning capacity of the estuarine squid, Lolliguncula. This squid can readily be trained to feed when a horizontal rectangle is shown but to avoid feeding when attacks after showing a vertical rectangle were followed by shocks. The discrimination can be maintained for nine days without showing the figures again. The squid also learned to discriminate between black and white balls. The negative responses in these trials were definite; the squid often shot ink at the figure from which it had received shocks (Allen et al., 1985).

Theories of Memory

My ideas about memory in Octopus changed as I found out more about the conditions in the centers responsible for memory and their relation to the mechanisms suggested for other animals and humans. I was first attracted in the 1930s by the reverberatory connections of the vertical lobe as a possible basis for memory in Sepia, as recounted earlier. Then, as I came to know more of the details of the connections, I developed other theories. I was perhaps unduly impressed by the finding of the long dendrites in the visual cells of the optic lobes and their orientation in vertical and horizontal directions. We were at the time mostly studying the process of learning to distinguish between orientation of rectangles, and I postulated that the visual classification was performed by these cells, rather like the findings of Hubel and Wiesel in mammals. I was also anxious to identify which cells or synapses are changed during learning. I emphasized that each classifying cell (one coding for “vertical,” for example) must have the possibility of access to motor channels for attack and retreat. I suggested that this access was through memory cells. During learning, one of these pathways was closed as a result of signals, in the form of either food or pain. The circuits through the frontal and vertical lobes maintain the address of the relevant cells during the period of delay between the initial signals and the advent of the reward. I suggested that the classifying cells and memory cells constitute a unit of memory or mnemon. This theory was put forward (Young, 1965a) and developed in a Croonian Lecture (Young, 1965b).

The concept of mnemons was never very helpful and now seems simpleminded. The descriptions of the anatomy of the visual and tactile centers were all new and have proved accurate, but theory gave too much attention to unknown units and unsupported hypotheses about their excitability and closure. However, a great advantage was that the memory process was recognized as a development of the reflex responses of the cells of the buccal lobes in eating. This finding shows the way memory has evolved in octopuses. It remains to be seen whether other memory systems can be found to have evolved out of reflex systems in the same way. This process is unlikely for the complex systems of mammals.

A great defect of this way of thinking was that it did not emphasize the large numbers of cells in the nervous system. For a long time, I felt that these numbers might mean that there is a useful analogy among learning, natural selection, and selection of an immune response. Such selection between large numbers is nature’s way of ensuring adaptation. I developed this theory in a lecture to the Australian Academy of Science (Young, 1973). The Australian immunologists Jerne and Burnet had already hinted at something similar. The idea was taken up by Edelman and developed in his book, Neural Darwinism (1987). He examines my treatment fully and I have been his guest in New York to discuss it. The question is, what are the units of selection and how are they generated? For me, these units are classifying cells produced during development. For Edelman, the units are groups of cells formed during development, and he stresses that this process gives great creativity to the system. Presumably this process is itself influenced by environmental events.

Matrices

In recent years I have realized that the Octopus systems can be understood as a series of matrices. I reached this conclusion by following work on the hippocampus, such as Rolls (1990). We know enough of the structure and connectivity in octopuses to see that the system provides a series of matrices allowing, with appropriate synaptic change, for the interaction of groups of input fibers on the cells so that they represent external situations. The succession of lobes provides for association of groups of groups and so of representations of whole scenes or events. Recursive pathways increase the opportunity for consolidation of synaptic change, perhaps by a Hebb mechanism. The lobes concerned with both visual and tactile memories have the character of such matrices. Injury to any of the four lobes concerned with vision or the eight concerned with touch reduces the learning capacity in proportion to the amount removed or injured (Young, 1983).

These matrices are thus networks of the type defined by Hopfield (1982) as providing efficient storage and recovery of information. The matrices allow for recognition of part of an input and can survive degradation by loss of part of the system. In octopuses the matrices are developed to control reflex systems concerned with the acquisition of food. I have come to realize that the octopus system is analogous to that of many other centers that we know to be the seat of memory storage. The hippocampus has a series of such matrices, with recurrent connections, both within it and with the neocortex. The cerebellum is a classical example of such a matrix, known to be concerned with memories of conditional reflexes.

Brains and Minds

Throughout my work on the nervous system, I have been concerned to show how knowledge about the functions of the brain can help in everyday human affairs. In 1950 I gave the second series of Reith Lectures for the British Broadcasting Corporation (Young, 1950a). These lectures were intended to promote wide intellectual discussion. The first series had been given by Bertrand Russell. My lectures focused on the idea of “Man the Communicating Animal.” I emphasized the human propensity to come together and worship at large meeting places, such as megaliths or cathedrals. The title of the lectures was “Doubt and Certainty in Science.” I used the idea that we achieve the certainty of true beliefs by the experiments of “doubting,” which establish a set of rules in the brain. I used the example of the demonstration by von Senden (1960) that a person born blind who later gained the use of his eyes had to learn to see. From various further examples I concluded that “the method I am going to suggest as a working basis is to organize all our talks about human powers and capacities around knowledge of what the brain does.”

I have tried in later books to show that recent work on the brain has revealed how these “rules” are actually embodied in the activities of the nervous system. The Withering Lectures, given at Birmingham, developed the concept of “A Model of the Brain” (1964). In “An Introduction to the Study of Man” (1971b) I included a discussion of the evolution of the powers of the human brain and of speech. Then, for the Gifford Lectures, “Programs of the Brain” (1978), I developed the theme, as Maudsley put it in 1867, that “we should treat mental phenomena from a physiological rather than a metaphysical point of view.” One example I quoted was the evidence of Libet et al. (1983) showing that there are electrical activities in the brain half a second before a person makes a conscious decision to move a finger. This clearly shows that actions of the mind depend on the brain and that it is absurd to consider oneself as two separate entities.

I explored how the whole range of human capacities can be related to known cerebral activities. These activities include not only the familiar bodily actions but also matters usually considered to be mental, such as knowing and thinking, valuing and enjoying, loving and suffering, and believing, obeying, and worshipping. I was especially eager to show how artistic activities, whether creating or enjoying art, depend on the brain. I later treated this topic in detail as “Beauty and the Brain” (Young, 1981), a lecture that I gave at the Tate Gallery.

In describing how the human brain operates in so many ways, I was, of course, going far beyond my own immediate research or knowledge. Nevertheless, I consider that discussion of such wide cerebral activities is stimulating for any researcher of the nervous system. It is also necessary to emphasize such an approach to all those concerned with problems of human life and well-being. Such knowledge is certainly useful to every parent and to teachers at all levels. It should be valuable to politicians, to judges, to religious leaders, and to all those concerned with social welfare, and of course to those who deal with mental illness. Some understanding of the actions of the brain is indeed useful to each one of us as we face the problems of our lives. It helps to understand how entirely we depend on our brains.

In dealing with such large questions, I have become involved in many philosophical problems. I had been partly prepared for this involvement from my Oxford and London days, when I met and conversed with many philosophers. A.J. (Freddie) Ayer organized informal meetings of what we called “The Metalogical Club.” I got to know Gilbert Ryle, Bertrand Russell, Karl Popper, Ted Honderich, and many others. I learned a lot from them but always suffered from not having studied classical philosophers from Aristotle and Plato to Immanuel Kant, John Locke, and David Hume. Philosophers depend on such knowledge for much of their discussion. However, I have always felt that it is difficult to take seriously the views even of such great thinkers when they did not have the advantage of the knowledge we now possess of science, and especially of the brain.

Philosophical discussion nearly always turns to looking inward; cogito ergo sum is the essential firm basis. I wonder whether “I think” is really our most fundamental experience. “I feel that I am alive” precedes thinking, if that is indeed a form of “knowledge.” I have tried to discuss this point of view in Philosophy and the Brain (1987). Philosophers of course do not like the book, but many people have said that they find it useful. The book has been translated into German and Japanese.

I do not regret these various diversions from conventional science. It is important for the practicing researcher to consider wider questions. Discussion of them is limited by lack of knowledge of the organization that produces “programs of the brain.” Realizing this ignorance may help those who make detailed studies of neurons to be ambitious in trying to decipher the language in which the programs are written.

Summary

I do not feel that I have yet reached the point at which I can write “Conclusion.” Indeed I have learned a lot from the difficulty of writing this scientific autobiography; however, I can make some sort of summary of my 88 years so far. I have discovered many previously unknown facts about fishes, lampreys, and especially cephalopods. These facts are recorded in books and papers, often with my own drawings. I have advanced knowledge of the operation of cephalopod brains and so helped toward the understanding of brains in general. I have shown that the two memory systems of octopuses consist of successions of matrices, and I have suggested how these have evolved from reflex operations of eating.

In addition to original discoveries, I have developed methods of teaching and research in anatomy and neurobiology. Many of my students have become successful doctors in general practice or research. I have helped to introduce many people to zoology through textbooks. I have emphasized the power of biological ideas in public lectures and books, which have been widely circulated in nine languages. In these books I have presented facts and ideas that I hope will help people to have richer and happier lives.

Acknowledgments

I am thankful for the help of so many institutions and individuals that it is impossible to mention them all. Magdalen College, Oxford, and Oxford University have been home for me since 1924, and I am proud to be honorary fellow and doctor of science there. University College of London cherished a zoologist as professor of anatomy for 29 years and enabled me to follow science at the same time, which has continued to help me. I have had much assistance from the Wellcome Trust, first with accommodation in Euston Road and then with finance. For the last 10 years, since returning to Oxford, I have been accommodated in the department of experimental psychology, through the kindness of Professor L. Weiskranz and then of Professor S. Iverson.

I have had help from many marine laboratories, including the Marine Biological Association at Plymouth, U.K. from 1924 onward, and I finally became its president (1975–1985). The Stazione Zoologica in Naples provided accommodation for my teams of assistants and a hundred or more octopuses for research on memory every summer from 1947 to 1975. In America I have enjoyed working at Woods Hole; the Duke University Marine Laboratory in Beaufort, North Carolina; the Marine Biomedical Institute in Galveston, Texas; and the Friday Harbor Laboratory in Washington. I am most grateful to them all.

When it comes to individuals, it is impossible to know which helpers to thank. I am thankful to all the scientists and technicians who have made my work possible. I shall only mention some of those who have helped recently and in the preparation of this autobiography. Dr. Marion Nixon has been a constant source of wisdom in all my work for 30 years. Miss P. Stephens was responsible for making most of the thousands of microscope sections that are at the center of my work. Recently Dr. P.L.R. Andrews helped me continue working on fishes, which age would no longer allow. Finally, in the preparation of this work, I have had secretarial help and much discussion with my wife, Raye. The typing of the final version and transferring to disk has been done by my daughter, Cordelia. I am deeply grateful to them all.

Selected Publications

Sopra un nuovo organo dei cefalopodi. Boll Soc Ital Biol Sper 1929;4:8:1–3.

The pupillary mechanism of the teleostean fish Uranoscopus scaber. Q J Micro Sci 1931;74:492–535.

(with Eccles JC, Granit R) Impulses in the giant nerve fibres of earthworms. Proc Physiol Soc 1932;77:1.

Hormones and chemical correlation. Sch Sci Rev 1934;60:502.

The giant nerve fibres and epistellar body of cephalopods. Q J Micro Sci 1936;78:367–368.

(with Gerard RW) Electrical activity of the central nervous system of the frog. Proc R Soc Lond B Biol Sci 1936;B122:343–352.

(with Bear RS, Schmitt FO) The sheath components of the giant nerve fibres of the squid. Proc R Soc Lond B Biol Sci 1937;123:496.

Fused neurons and synaptic contacts in the giant nerve fibres of cephalopods. Philos Trans R Soc Lond B Biol Sci 1939;B229:465–503.

Contraction, turgor, and the cytoskeleton of nerve fibres. Nature 1944;154:521.

Doubt and certainty in science; a biologist’s reflections on the brain. B.B.C. Reith Lectures. Oxford: Clarendon Press, 1950a.

The life of vertebrates. Oxford: Clarendon Press, 1950b.

(with Roberts F) High-speed counting with the flying-spot microscope. Nature 1951;169:963.

The statocysts of Octopus vulgaris. Proc R Soc Lond B Biol Sci 1960a;B152:3–29.

The visual system of Octopus. Regularities in the retina and optic lobes of Octopus in relation to form discrimination. Nature 1960b;186:836–839.

Light and dark adaptation in the eyes of some cephalopods. Proc Zool Soc Lond 1963;140:255–272.

A model of the brain. The Withering Lectures. Oxford: Clarendon Press, 1964.

A unit of memory. New Scientist 1965a;Dec 23:861–863.

The Croonian Lecture “The organization of a memory system.” Proc R Soc Lond B Biol Sci 1965b;163:285–320.

The anatomy of the nervous system of Octopus vulgaris. Oxford: Clarendon Press, 1971a.

An introduction to the study of man. Oxford: Clarendon Press, 1971b.

Programs of the brain (Gifford Lectures). Oxford: Clarendon Press, 1978.

Nervous control of stomach movement in dogfishes and rays. J Marine Biol Assoc UK 1980a;60:1–17.

Nervous control of the gut movements in Lophius. J Marine Biol Assoc UK 1980b;60:19–30.

Beauty and the brain (Art & Science Lecture to the Tate Gallery). Aspects 1981;26:984.

Philosophy and the brain, Shearman Lectures, University College of London. Oxford: Clarendon Press, 1982.

The distributed tactile memory system of Octopus. Proc R Soc Lond B Biol Sci 1983;219:135–176.

The statocysts of cranchiid squids. J Zool Lond 1984;203:1–21.

(with Maddock L) Some dimensions of the angular acceleration receptor system of cephalopods. J Marine Biol Assoc UK 1984;64:55–79.

(with Budelmann BU) Central nervous pathways for the arms and mantle of Octopus. Philos Trans R Soc Lond B Biol Sci 1985;B310:109–122.

(with Allen A, Michels J) Memory and visual discrimination by squids. Marine Behav Physiol 1985;11:271–282.

(with Allen A, Michels J) Possible interactions between visual and tactile memories in Octopus. Marine Behav Physiol 1986;12:81–97.

Angular acceleration system of diverse cephalopods. Philos Trans R Soc Lond B Biol Sci 1989;B325:189–238.

(with Budelmann BU) The statocyst-oculomotor system of Octopus vulgaris: extraocular eye muscles. Eye muscle nerves. Statocyst nerves and ocular motor centre of the central nervous system. Phil Trans R Soc Lond B Biol Sci 1984;306:159–189.

(with Budelmann BU) The oculomotor system of decapod cephalopods: eye muscles, eye muscle nerves, and the oculomotor neurons in the central nervous system. Philos Trans R Soc Lond B Biol Sci 1993;340:93–125.

Emerging ideas on memory in multiple matrices and with re-cyclic excitation. In: Elsner M, Menzel R, eds. Learning and memory. 23rd Göttingen Int Congr Thiel. Stuttgart: Verlag, 1995.

Memory as a selective process. Australian Academy of Sciences. Symposium on Biological Memory. 1972:25–45.

Additional Publications

Edelman GE. Neural Darwinism. New York: Basic Books, 1987.

Hopfield JJ. Neural networks. Proc Natl Acad Sci USA 1982;79:2554–2558.

Kier WM. The functional physiology of the musculature of the squid, arms, and tentacles. J Morphol 1982;172:179–192.

Libet B, Curtis AG, Wright EW, Pearl DK. Time of conscious intention to act in relation to onset of cerebral activity. Brain 1983;106:640.

Maldonado H. The visual attack learning system in Octopus vulgaris. J Theor Biol 1963;5:470–485.

Maldonado H. The control of attack by Octopus. Z Vergl Physiol 1964; 47:656–674.

Maldonado H. The positive and negative learning process in Octopus. Influence of the vertical and median superior frontal lobes. Z Vergl Physiol 1965; 51:185–203.

Nilsson S. Autonomic nerve function in vertebrates. Berlin: Springer Verlag, 1983.

Nilsson S, Holmgren S. Comparative physiology and evolution of the autonomic nervous system. Geneva, Switzerland: Harwood, 1994.

Rolls ET. The representation and storage of information in the neural networks in the primate cerebral cortex and hippocampus. In: Durbin R, Miall C, Mitchinson G, eds. The computing neuron. Wokingham, UK: Addison-Wesley, 1990.

von Senden M. Space and sight. London: Methuen, 1960.

Yarbus AL. Eye movements and vision. New York: Plenum Press, 1967.

Young RE. Vertical distribution and photosensitive vesicles of pelagic cephalopods. Fish Bull 1978;78:533–615.