The History of Neuroscience in Autobiography

VOLUME 8

The History of Neuroscience in Autobiography

VOLUME 8

Edited by Larry R. Squire

Society for Neuroscience

Society for Neuroscience

The Society for Neuroscience publishes works that advance
the understanding of the brain and nervous system.

Copyright © 2014 by the Society for Neuroscience

Published by the Society for Neuroscience
1121 14th Street, NW
Washington, DC 20005
www.sfn.org

All rights reserved. No part of this publication may be reproduced,
stored in a retrieval system, or transmitted, in any form or by any means,
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without the prior permission of the Society for Neuroscience.

Library of Congress Control Number: 2014931971

ISBN 978-0-615-94079-3

Printed in the United States of America

Contents

Previous Contributors

Preface to Volume 1

Preface to Volume 8

Akil-Watson

Ascher

Berlucchi

Jan-Jan

McEwen

Miles

Milner

Nottebohm

Poggio

Raichle

Rudomin

Treisman

Young

Index of Names

Previous Contributors

Volume 1

Denise Albe-Fessard

Herbert H. Jasper

Julius Axelrod

Sir Bernard Katz

Peter O. Bishop

Seymour S. Kety

Theodore H. Bullock

Benjamin Libet

Irving T. Diamond

Louis Sokoloff

Robert Galambos

James M. Sprague

Viktor Hamburger

Curt von Euler

Sir Alan L. Hodgkin

John Z. Young

David H. Hubel

Volume 2

Lloyd Beidler

Jerry Lettvin

Arvid Carlsson

Paul MacLean

Donald Griffin

Brenda Milner

Roger Guillemin

Karl Pribram

Ray W. Guillery

Eugene Roberts

Masao Ito

Gunther Stent

Martin Larrabee

Volume 3

Morris H. Aprison

Ainsley Iggo

Brian B. Boycott

Jennifer Lund

Vernon B. Brooks

Edith and Patrick McGeer

Pierre Buser

Edward R. Perl

Hsiang-Tung Chang

Donald B. Tower

Claudio A. Cuello

Patrick D. Wall

Robert W. Doty

Wally Welker

Bernice Grafstein

Volume 4

Per Andersen

Andrew F. Huxley

Mary Bartlett Bunge

JacSue Kehoe

Jan Bures

Edward A. Kravitz

Jean Pierre G. Changeux

James L. McGaugh

William Maxwell (Max) Cowan

Randolf Menzel

John E. Dowling

Mircea Steriade

Oleh Hornykiewicz

Richard F. Thompson

Volume 5

Samuel H. Barondes

Lynn T. Landmesser

Joseph E. Bogen

Rodolfo R. Llinás

Alan Cowey

Alan Peters

David R. Curtis

Martin Raff

Ennio De Renzi

Wilfrid Rall

John S. Edwards

Mark R. Rosenzweig

Mitchell Glickstein

Arnold Bernard Scheibel

Carlton C. Hunt

Gerald Westheimer

Volume 6

Bernard W. Agranoff

Lawrence Kruger

Emilio Bizzi

Susan E. Leeman

Marian Cleeves Diamond

Vernon B. Mountcastle

Charles G. Gross

Shigetada Nakanishi

Richard Held

Solomon H. Snyder

Leslie L. Iversen

Nobuo Suga

Masakazu Konishi

Hans Thoenen

Volume 7

Floyd E. Bloom

Terje Lømo

Joaquín Fuster

Michael M. Merzenich

Michael S. Gazzaniga

John Wilson Moore

Bertil Hille

Robert Y. Moore

Ivan Izquierdo

Michael I. Posner

Edward Jones

Peter H. Schiller

Krešimir Krnjević

Gordon M. Shepherd

Nicole M. Le Douarin

Robert H. Wurtz

Preface to Volume 1

Before the Alfred P. Sloan Foundation series of books began to appear in 1979, the scientific autobiography was a largely unfamiliar genre. One recalls Cajal’s extraordinary Recollections of My Life, translated in English in 1937 and the little gem of autobiography written by Charles Darwin for his grandchildren in 1876. One supposes that this form of scientific writing is scarce because busy scientists would rather continue to work on scientific problems than to indulge in a retrospective exercise using a writing style that is usually outside their scope of experience. Yet, regardless of the nature of one’s own investigative works, the scientific enterprise describes a community of activity and thought in which all scientists share. Indeed, an understanding of the scientific enterprise should in the end be accessible to anyone because it is essentially a human endeavor, full of intensity, purpose, and drama that are universal to human experience.

While writing a full autobiographical text is a formidable undertaking, preparing an autobiographical chapter, which could appear with others in a volume, is perhaps less daunting work and is a project that senior scientists might even find tempting. Indeed, a venture of this kind within the discipline of psychology began in 1930 and is now in eight volumes (A History of Psychology in Autobiography). So it was that during my term as president of the Society for Neuroscience in 1993 to 1994, I developed the idea of collecting autobiographies from senior neuroscientists, who at this period in the history of our discipline are in fact pioneers of neuroscience. Neuroscience is quintessentially interdisciplinary, and careers in neuroscience come from several different cultures, including biology, psychology, and medicine. Accounts of scientific lives in neuroscience hold the promise of being informative and interesting, and they could be a source of inspiration to students. Moreover, personal narratives provide for scientists and nonscientists alike an insight into the nature of scientific work that is simply not available in ordinary scientific writing.

This volume does have a forerunner in neuroscience. In 1975, MIT Press published The Neurosciences: Paths of Discovery, a collection of 30 chapters in commemoration of F. O. Schmitt’s 70th birthday, edited by F. Worden, J. Swazey, and G. Adelman. The contributing neuroscientists, all leaders of their discipline, described the paths of discovery that they had followed in carrying on their work. While writing in the style of the conventional review article, some authors did include a good amount of anecdote, opinion, and personal reflection. A second, similar volume, The Neurosciences: Paths of Discovery II, edited by F. Samson and G. Adelman, appeared in 1992.

In any case, neuroscience writing that is deliberately and primarily autobiographical has not been collected before. This project, The History of Neuroscience in Autobiography, is the first major publishing venture by the Society for Neuroscience after The Journal of Neuroscience. The book project was prepared with the active cooperation of the Committee on the History of Neuroscience, which serves as an editorial board for the project. The first chairperson of the committee was Edward (Ted) Jones; its members were Albert Aguayo, Ted Melnechuk, Gordon Shepherd, and Ken Tyler. This group compiled the names and carried out the deliberations that led to the first round of invitations. In 1995 Larry Swanson succeeded Ted Jones as chair of the committee, and as we go to press with volume 1 the committee members are Albert Aguayo, Bernice Grafstein, Ted Melnechuk, Dale Purves, and Gordon Shepherd.

In the inaugural volume of the series, we are delighted to be able to present together 17 personal narratives by some of the true pioneers of modern neuroscience. The group includes four Nobel Laureates and 11 members or foreign associates of the National Academy of Sciences, USA. The contributors did their scientific work in the United States, Canada, England, Australia, France, and Sweden. It is difficult to imagine a finer group of scientists with which to inaugurate our autobiographical series. The auto biographical chapters that appear here are printed essentially as submitted by the authors, with only light technical editing. Accordingly, the chapters are the personal perspectives and viewpoints of the authors and do not reflect material or opinion from the Society for Neuroscience.

Preparation of this volume depended critically on the staff of the book’s publisher, the Society for Neuroscience. The correspondence, technical editing, cover design, printing, and marketing have all been coordinated by the Society’s central office, under the superb direction of Diane M. Sullenberger. I thank her and her assistants Stacie M. Lemick (publishing manager) and Danielle L. Culp (desktop publisher) for their dedicated and skillful work on this project, which was carried out in the midst of demands brought by the first in-house years of the Society’s Journal of Neuroscience. I also thank my dear friend Nancy Beang (executive director of the Society for Neuroscience) who from the beginning gave her full enthusiasm to this project.

Larry R. Squire
Del Mar, California
September 1996

Preface to Volume 8

This eighth volume of The History of Neuroscience in Autobiography includes 13 chapters by senior neuroscientists. The authors tell about the experiences that shaped their lives; the teachers, colleagues, and students with whom they worked; and the scientific work that has absorbed them during their careers. Their stories relate a lifetime of investigation and discovery. We are particularly fortunate to be able to include contributions from two long-time husband and wife research teams: Lily and Yuh-Nung Jan and Huda Akil and Stan Watson.

Volume 8 was prepared with the advice of the Publications Committee of the Society for Neuroscience, which serves as editorial board for the project. With input from the committee, from the Council of the Society for Neuroscience, and many others, names were compiled for this volume.

Beginning with this volume, the Society for Neuroscience has taken over full responsibility for the project under the capable direction of Suzanne Rosenzweig (Director, Scientific Publications). The contents of the volume will be posted on the Society’s Web site, under Publications, where one can also find the 105 autobiographical chapters that appeared in the first seven volumes. Copies of volume 8 will also be available for purchase. I hope readers will find volume 8 as interesting and useful as the earlier volumes.

Larry R. Squire
Del Mar, California
September 2013

Huda Akil

BORN:

Damascus, Syria

May 19, 1945

EDUCATION:

American University of Beirut, Lebanon, BA (1966)

American University of Beirut, Lebanon, MA (1968)

University of California, Los Angeles, CA, PhD, (1972)

Stanford University, Palo Alto, CA, Postdoctoral Fellowship (1974–1977)

APPOINTMENTS:

Adjunct Assistant Professor, Psychology Department, Stanford University (1974–1978)

Assistant Professor of Psychiatry, University of Michigan (1978–1981)

Associate Professor of Psychiatry, University of Michigan (1981–1987)

Professor and Senior Research Professor, Department of Psychiatry and Molecular & Behavioral Neuroscience Institute (MBNI), University of Michigan (1987–present)

Co-Director (with S. Watson), MBNI, University of Michigan (1995–present)

HONORS AND AWARDS:

Rockefeller Scholarship, American Univ. of Beirut, 1963–1968

Penrose Award, American University of Beirut, 1968

Sloan Foundation Postdoctoral Fellowship for the Neurosciences, 1974–1976

NIDA Pacesetter Award, 1993

Member, Institute of Medicine of the National Academy of Sciences, 1994

Robert J. and Claire Pasarow Foundation Award for Neuropsychiatric Research, 1994 (with S. J. Watson)

Bristol Myers Squibb Award for Distinguished Achievement in Neuroscience, 1998

President, American College of Neuropsychopharmacology, 1998

Fellow, American Association for the Advancement of Science (AAAS), 2000

President Elect, President, and Past President, Society for Neuroscience, 2001–2004

Named as one of the most highly cited researchers in neuroscience by the Institute for Scientific Information (ISI), 2002

Member, American Academy of Arts and Sciences, 2004

Henry Russel Lecturer Award, University of Michigan, 2006

John P. McGovern Award in Behavioral Sciences, AAAS, 2006

Mika Salpeter Lifetime Achievement Award, Society for Neuroscience, 2007

Goldman-Rakic Prize for Achievement in Cognitive Neuroscience, National Alliance for Research in Schizophrenia and Affective Disorders (NARSAD), 2007

Council, Institute of Medicine, National Academy of Sciences, 2006–2012

American College of Neuropsychopharmacology, Paul Hoch Award, 2010

New York Academy of Medicine, Thomas W. Salmon Award (with S. Watson), 2010

Member, National Academy of Sciences, 2011

Rhoda and Bernard Sarnat International Prize in Mental Health, 2012 (with S. Watson)

Stanley J. Watson, Jr.

BORN:

Henrietta, Oklahoma

May 30, 1943

EDUCATION:

University of Southern Mississippi, Hattiesburgh, MS, BS (1965)

University of Iowa, Iowa City, IA, PhD (1970)

Tulane Medical School, New Orleans, LA, MD (1974)

Stanford University, Palo Alto, CA, Postdoctoral Fellowship (1974–1977)

APPOINTMENTS:

Internship, Pacific Presbyterian Medical Center, San Francisco (1974)

Psychiatric Internship and Residency, Stanford University School of Medicine (1974–1977)

Assistant Professor and Assistant Research Scientist, University of Michigan (1978–1981)

Associate Professor and Associate Research Scientist, University of Michigan (1981–1987)

Associate Director, Mental Health Research Institute, University of Michigan (1984–1995)

Research Professor, Mental Health Research Institute, University of Michigan (1987–1993)

Associate Chair for Research, Department of Psychiatry, University of Michigan (1993–2002)

Co-Director (with H. Akil) and Research Professor, MBNI, University of Michigan (1995–present)

AWARDS:

National Merit Scholarship Finalist, 1960

Academic Honors Scholarship at Tulane and University of Southern Mississippi, 1961–1964

Member Psi Chi (Psychology Honor Scholarship), graduated with honors, 1964

Merck Award, Tulane Medical School, 1974

Bank of America—Giannini Fellowship in Biomedical Research, 1977

McAlpin Award Winner (with Dr. Floyd Bloom), 1980

Grass Foundation Lecturer, University of Pittsburgh, 1984

Visiting Professor, University of Hawaii, 1985

University of Michigan Senior Research Scientist Lectureship Award, 1988

Theophile Raphael Professor of Neurosciences in Psychiatry, 1993

Pfizer Visiting Professorship in Psychiatry, Johns Hopkins University Med. Ctr., 1994

Co-recipient (with H. Akil) of the Robert J. and Clair Pasarow Foundation Award for Neuropsychiatric Research, 1994

Member, Institute of Medicine of the National Academy of Sciences, 1994

Fellow, American Association for the Advancement of Science, 2000

Named “Highly Cited, Influential Researcher in Neuroscience” by ISI, 2000

Ralph Waldo Gerard Professor of Neurosciences in Psychiatry, 2006

New York Academy of Medicine, Thomas W. Salmon Award (with H. Akil), 2010

Rhoda and Bernard Sarnat International Prize in Mental Health (with H. Akil), 2012

Huda Akil and Stanley Watson have made seminal contributions to our understanding of the neurobiology of emotions and affect, including pain, stress, depression, and addictive behavior. They began their research work at the time of the discovery of endorphins and participated in the development of that field through a combination of behavioral, anatomical, molecular, and translational studies. Throughout their careers, they have developed new technologies for studying the function and regulation of neural circuits, as well as new paradigms and animal models of affective behavior. This includes the study of the neurobiology of temperament and its relevance to differences in mood and addictive disorders. They are currently engaged in large-scale studies to discover new genes and proteins that cause vulnerability to major depression and bipolar illness. The hallmark of their work is its multidimensional, collaborative, and integrative nature.

Huda Akil and Stanley J. Watson, Jr.

Tales of Endorphins and Other Adventures

In science, unlike the usual situation in human affairs, reality frequently exceeds expectations.

Daniel Klepner, 1998

In this chapter, we describe what led us to become neuroscientists, and then we focus our recollections on the birth and early years of the field of endorphins—the brain’s naturally occurring opiates. We were privileged to witness the dawn of that field and to contribute to its development. We each came at it not only from different scientific angles but literally from different worlds—Huda having grown up in Damascus, Syria, and Stan in New Orleans, Louisiana. Our collaboration has been a journey that has defined our scientific and our personal lives.

We tell this tale from our unique perspective while trying to acknowledge the huge influence that many great scientists have had on our lives—first and foremost, our mentors who have shaped our thinking and given us unimaginable opportunities. But also, scientists we met along the way who influenced us through their ideas, their example, their generosity, their collaboration, their advice, and even their doubt. We also touch on some lessons learned—the importance of considering contrary opinions but also the power of having a strong hunch about the nature of a system or an approach; the value of using the right technology at the right moment, or if need be, inventing new technologies to advance the field; and mostly, the remarkable power of teamwork.

Our only regret is that by limiting these recollections to the early days, we have not recounted some equally exciting and more recent scientific adventures, nor have we given proper credit to many of our trainees and colleagues who came along since then. Our trainees have a chimeric name, the Wakils—for Watsons and Akils. Had we been writing about the future of neuroscience, it would have been all about them. Instead, we dedicate this chapter to all the Wakils, the scientific branch of the family—our students and postdocs—and to the biological branch of the family—our children and grandchildren. May your lives be filled with adventure!

Huda

I was standing on a table looking out of a large window watching an airplane take off. I must have been about three years old, and the airplane carried my mother away to be with my dad. I knew she was going to be gone for a long time, and something felt heavy inside me. But I was mostly wondering how that plane was able to fly. Standing beside me, my uncle and grandmother congratulated me on being a big girl and not crying about my mother’s departure. My cousin, who was my age and very attached to my mother, was screaming and asking to go with her.

This is my first fully fleshed memory, and it is very vivid. We were in Damascus, Syria, in the late 1940s and I was around two to three years old. I had been allowed to go up on the airplane to see the inside—in retrospect, quite an unusual opportunity. I retain the impression of a very narrow space, the presence of people dressed in military uniforms, and a vague sense of worry about my mother being trapped in there. I knew she was flying to England to be with my father while he completed his doctorate in London, and I could tell she was sad to be leaving me.

Looking back on that moment, I recognize many elements that were to define me. That education was of paramount importance, enough to warrant long separations from those I love, proved to be one the consistent themes of my young life. But equally strong was the abiding sense that my parents loved me. Separations never felt like abandonment but rather like a sacrifice we all made together toward a shared and important goal. Now that I study the neurobiology of stress and resilience, I can recognize the elements in my life that were stressful without being overwhelming, and I can see how they combined with my emotional makeup and family structure to give me the resilience to emigrate from Syria to the United States to become a scientist. But chance and good luck played an equal role in this improbable journey.

Damascus—Early Life

My early childhood was spent in the context of an extended family revolving around my maternal grandmother and her five sons, two daughters, and one stepdaughter, headquartered in a building owned by my grandparents. The bottom floor of my grandparents’ residence was a large and comfortable home. It had a courtyard with a fountain in the back, and the building was surrounded by a garden with a kumquat and a lemon tree, blooming forsythias, and the scent of jasmine on summer evenings. This is where my grandmother lived together with the unmarried members of the family. There were smaller apartments above, and my nuclear family occupied one of them. So, when my parents went away, I simply moved downstairs to be next door to my aunt, whose big room was filled with magical knickknacks such as a vessel that holds kohl for eye makeup, which I now own. Even my paternal uncle called my grandmother’s place home. He was much younger than my dad and had a sweet tooth, so he took me out regularly on special outings to eat chocolat mou, the local equivalent of a chocolate milkshake. I had a special plan for each of my relatives—something sugary that I loved to buy when I was out with them, and together they made me feel special and cared for. But there was no denying the hole in my heart until my parents and I were reunited.

In later years, the separations were due to my father’s work. He was a professor at the University of Damascus, quickly becoming very well known within Syria and throughout the Arab world, in part due to several lay books and articles he wrote introducing psychological concepts to the Middle East, including coining Arabic terms for concepts such as “reinforcement” and “feedback.” He was also in demand by the United Nations Educational Scientific and Cultural Organization (UNESCO) and would take positions in remote places that needed his expertise to create new educational communities. Sometimes we all moved with him, and at other times he went alone for several months at a time.

One such UNESCO assignment took us to Egypt in 1953–1954, when I was in third grade. Because my father was stationed in a remote rural place that did not have a decent school, I was sent to a boarding school for girls run by French nuns, called Le Collège de la Mère de Dieu, in Garden City, Cairo. Looking it up on the Internet, I can see that it is an impressive place that offers a great education, but it is fair to say that I was utterly miserable there. Once again, I missed my mother, father, and little brother (who was two), and this time I did not have an extended family to turn to. I also could not understand the Egyptian accent, and the other kids made fun of mine. The nuns seemed remote and spoke only in French, which I understood but barely. The only highlight of my day was the 3 p.m. break when they distributed chocolate and French bread as a snack. I spent weekends with my parents, sometimes in Cairo where they kept an apartment, and sometimes in Sers El-Layan, the village that was the site of the UNESCO project. I remember holding onto my composure tightly as my parents came to pick me up for the weekend, trying to remain strong and to prepare for my eventual return to school. I have to believe that these separations, stressful as they were, gave me the ability in my early twenties to pick myself up and move away from my family, friends, and country—once again for the sake of education.

That year in Egypt was memorable in many ways. They had a great zoo, and I begged to go there on the weekends. I spent hours watching the monkeys interact, groom each other, take care of their young, eat, and play. Little did I know then that I would spend much of my adult life studying animal behavior. But it was also an education in local politics. Then, as today, Egypt was in turmoil. Its first president, Muhammed Naguib, resigned shortly after we arrived, and I recall seeing pictures of Gamal Abdul-Nasser plastered all over Cairo. My dad, who was passionately interested in Middle Eastern politics and who was missing his Damascene friends, discussed the developments with my mother at every opportunity. The issues of military rule versus democracy, regional tensions with Iraq, the fate of Sudan as well as the Suez Canal dispute were common conversations at the dinner table. At one such dinner, my parents talked about the escalating tension between Cairo, Israel, and the West and the fact that the U.S. Sixth Fleet was moving in the Mediterranean. Consequently, all the UNESCO experts had to leave Egypt immediately. It was probably the start of the tension that led to the Suez Canal crisis a few years later, but I had no idea what any of it meant. Still, these developments made “the Americans” sound as though they had the power to change our lives.

The rest of my schooling through grade, middle, and high school took place in Damascus in a single school also run by French nuns—L’Ecole des Franciscaines, Missionnaires de Marie. My parents must have known that my boarding school experience had been painful, so they resolved to keep me in the same school and let me live with relatives whenever they needed to leave on UNESCO assignments—this happened over four years between fifth grade and the end of high school. I missed my parents, my younger brother Bisher, and my much younger sister Mayada. But I loved school and was at the top of my class, which was very important to my family. It was in that school that I consciously started dreaming of becoming a scientist.

Thinking Science Thoughts

Like most scientists, I was a curious child. I asked a lot of questions about how things worked, how they were made, or why they happened as they did. I am grateful that my parents never dismissed these questions as annoying. Rather, they took them seriously and answered me thoroughly. An example that has stayed with me is my query about grapes. I must have been six or seven years old, and I had inquired about how plants grow. My father explained about seeds and pits and how they contain all the information needed to grow the plant. One day, I was eating a seedless grape and asked how such a plant could grow. He said he was not exactly sure but would try to find out. A few days later, a friend of his who was an agricultural engineer came to our house and explained to me all about propagation and grafting of seedless fruits. The meta-message from that one episode has stayed with me since—the integrity to admit one’s ignorance and the importance of searching for knowledge wherever one can find it. More importantly, it told me that I was asking reasonable questions that were worth a real answer. It is only in retrospect that I have come to realize how amazing a gift my parents gave me, and how unusual it was for a little Syrian girl to receive it.

But it was one of the nuns that helped me go from being an inquisitive child to dreaming of becoming a scientist. I remember the one-room library in my Damascus school with the desk of the librarian nun near the door. I must have gone there often because the librarian seemed to know me well. I was around 10–11 years old when, one day, as I was leaving the otherwise empty library, she handed me a thin volume in French and told me that she thought I would be interested in it. It was an abbreviated biography of Marie Curie, and it transformed the way I thought about the world. That a young woman from Poland could pick herself up and move to Paris to study science was a revelation. I thought that science, even though it had flourished in the Arab world in the Middle Ages, was now the domain of the lucky few—the French, the British, the Americans. But here was someone who was none of these nationalities and yet was able to be a scientist! I also had never heard of a woman scientist. The fact that she went on to win two Nobel Prizes and that she worked with her husband and raised a daughter who herself won a Nobel Prize was breathtaking. Going to Paris to become a scientist became my secret dream.

From that point on, I tried to get a hold of French or Arabic books about the lives of scientists, but they were not easy to come by in Damascus. By the time I was in high school, I could read English well enough to a have a few more options. I vividly recall reading the life of Sir Alexander Fleming, discoverer of penicillin for which he received the Nobel Prize. I was struck by the fact that his discovery was accidental—he was culturing staphylococcus, left his cultures on a laboratory bench during a holiday, and returned to find that a fungus had grown in one of the dishes, and it had inhibited the growth of the bacteria around it. Rather than being disappointed by the contamination, he pursued it, grew the fungus systematically, tested it against a range of bacteria, and discovered its actions. He also struggled to extract it and to get it accepted as an important breakthrough. This awakened me to the power of observation, the importance of turning an apparent setback into an opportunity for discovery. I could tell that for Alexander Fleming and Marie Curie, the glamour came after much obscurity, frustration, and disappointment. But the discovery of penicillin held a personal meaning for me. My mother had suffered from tuberculosis soon after I was born and had gone to a sanatorium in Lebanon for more than a year. I had no memory of that particular separation, but she often spoke of it with great sadness and bemoaned the fact that she had had no access to antibiotics, even though they had already been discovered. The juxtaposition of my mother’s illness with reading the story of the drug gave me a personal sense of how science can impact people’s lives.

Stan

Early Life

One of my earlier memories is lying in the tray of our family sedan, the area between the top of the back seat and the rear window, as my dad drove down very dark roads, looking at the night skies and searching for patterns in the stars. In fact, most of my very early recollections are visual. A few years ago, when our family was exchanging tales of first memories, I described a specific ceiling pattern that I used to watch as I was falling asleep. It was distinctive enough that my mother could pinpoint it to a particular apartment where we lived for a short period of time. Apparently, I was still in my crib when this image was imprinted in my mind! So, maybe it is not too surprising that I grew up to be a neuroanatomist, with astronomy as my other serious endeavor.

The long nighttime trips that began my star fascination took place because my father, Stanley J. Watson, Sr., took us along on trips for his work as a minister, as he would “substitute” all over Oklahoma in small churches that needed a pastor. When he was younger, my dad would hitchhike to the church, often halfway across the state, preach and counsel, then go back to college. It did not pay much but kept him in school. It was on one such trip that he met my mother, Johnie Lee Butler, and they married shortly thereafter. Both families were prototypical European-American families from that era. My father’s family came to the United States in the late 1700s as carpenters and farmers, and some became sheriffs and ministers, with one U.S. marshall in the Oklahoma Territory. The Butlers, remotely related to President Andrew Jackson, were farmers and small businessmen, and my grandfather, John Butler, was relatively successful as a farmer, proprietor of a small coalmine, general storekeeper, and as an owner of the local “movie house.” They lived through the Dust Bowl of the 1930s and the Depression in a comfortable way. Both families were oriented toward physical work and survived through intelligent and careful management.

I grew up in Oklahoma playing outside, running hard, and walking alone to my grandmother’s house, even though I was four years old and she lived more than a mile away on a dirt road. I remember listening to my dad preach and loving my mom’s smile. My mother was fairly ill for several years, during which time I took care of my younger brothers, Mark and Dave, and cleaned house (sort of).

We moved from Oklahoma to New Orleans for my father’s seminary education, back to Oklahoma for more education, and finally settled into an apartment at the New Orleans Baptist Theological Seminary, where my father had a faculty position. The years from five to twelve were both positive and challenging. I changed schools four times, but I always did well and learned how to fit in. My favorite subjects were math, science, and oddly, history.

Throughout my childhood and adolescence, I worked any job I could find in order to buy bicycles, telescopes, movie tickets, radios, and eventually a motorcycle and a car. When I was 10, I had earned enough to buy my first bike and a year later my first telescope (a three-inch Newtonian). It was that telescope that provided me with my first taste of science. As a child, I was a tinkerer and was often testing some idea or another. If I did not understand something, I wondered if it was really true—it bothered me until I figured it out for myself. My first such effort with thinking about astronomy was during an event called the “opposition of Mars” when the Earth passes between the sun and Mars, and the planet can be seen in the “opposite” direction from the sun. Through my telescope, I could see the white polar caps (largely CO2) and a hint of other features in the more equatorial areas. But I had placed my telescope in a position where I could be blinded by a street lamp—so I moved it. I then began to worry that, by moving, I was actually looking at a different part of Mars! It took me a couple of weeks and some effort with my astronomy to realize what parallax was and how silly my worry was. I finally began to understand the small angle I was working with, and I came to realize that Mars from any angle on Earth would look the same.

Growing up, I did everything from cleaning rain gutters to selling shoes and tools, to working on the docks on the Mississippi and cutting trees to make paper—work was a point of pride as well as money, and my parents were intent on raising “thoughtful, skilled, and independent children.” For example, when my brother Mark was 14, he worked on the wheat harvest at our grandmother’s home in western Oklahoma. My parents let him leave to follow the harvest all the way to mid-Canada. He was a superb mechanic and was in charge of the repairs for all the wheat harvesting machinery (combines) during that trip. At the end of the summer, he bought a 50cc Honda motorbike and rode the 2,000 miles home, looking very tanned and happy. I too was very interested in understanding how machinery works and how to repair it when it malfunctioned, and eventually I made a living in college partnering with my friend at repairing old cars and selling them.

My junior high school in New Orleans was a very tough place—knives, 18-year-old seventh-graders, and a principal who tried to jump off the building twice! Being a 70-pound 12-year-old, I was at a significant disadvantage! Within a month of starting school, a large 18-year-old with an alcohol problem demanded my math homework. So, I made a deal with him: I would let him copy my math homework only if he would let me explain the problem and its solution. It worked! He became a great ally for that entire year, and the experience taught me the importance of forming strategic alliances! During my eighth and ninth grade years we had a new principal—a large, ex-Marine who was tough but fair to students and faculty alike. He restored some order and school was fun again, especially math and science. In fact, during my eighth-grade year, I had a superb teacher who taught us general science and encouraged more independent thinking. I selected as my project the mapping of sunspots during the solar maximum (an 11-year cycle). I was proud to confirm the work of real astronomers, which showed that sunspots moved faster at the equator than at the poles. I am sure they were relieved!

During my last year of junior high, I was approached by the school counselor to see if I was interested in attending Benjamin Franklin Senior High School in New Orleans. It was, and still is, a very selective public school that draws students from the entire area with a tough evaluation process for admission. I was lucky enough to be selected as one of the 50 students admitted in 1958. That education was the hardest I have ever experienced—including college, graduate school, medical school, and residency training. My peers were exceptionally bright, the teachers and the courses very strong and challenging. To my love of math, science, and history, I now added Latin and German. I was encouraged to prepare a science project for the tenth-grade competition, and I chose to explain the Kant-La Place theory of the origin of the solar system. It basically hypothesized that a dust cloud condensed into the sun and the smaller eddies turned into planets. I chose to demonstrate the theory with a fluorescent painting of the proto-planetary disk placed in a darkened box illuminated by black light. The project did not win but was very popular. It was very visual, and it strikes me that I have not gone very far from that work even now. In general, Franklin High School taught me a great deal of specific academic information but also enhanced my social skills and gave me a clear perspective on my academic strengths and weaknesses. I felt ready for college!

Huda

Beirut—College Years (1963–1968)

I had always expected to go to college at the University of Damascus, where my father was a professor. Typically, Syrian girls who were lucky enough to go to a university were not sent away for their education. But one day, my father sat me down in his study and told me that I had the opportunity to receive a scholarship to attend the American University of Beirut (AUB), his alma mater. He had discussed my options with the chair of psychology at AUB, had sent him a copy of my transcript, and his colleague had encouraged my application. Miraculously, I received a Rockefeller Scholarship to AUB that covered my tuition, room, and board. I was thrilled and petrified. One big hurdle was that the curriculum was American, a big change away from my French education. I had taken English as a requirement for the French baccalaureat, but it was a distant third language for me and I could not imagine managing my entire education in it. I was also accepted directly as a sophomore because the French baccalaureat was considered the equivalent of completing the freshman year. It seemed like a recipe for failure. Both my parents encouraged me to take a chance, but it was my mother’s regret at never having had such an opportunity herself that made me realize how lucky I was.

I worked very hard that first year. A requirement for keeping my scholarship was maintaining an A average, and the combination of skipping a year and studying everything in English was a challenge. But at one point, I realized I had done it before—that year in Egypt. I had started near the bottom of my class and ended up near the top. That early experience helped me regain confidence in myself, and soon it felt easy and then downright fun.

My years at AUB transformed my life. I met people from all over the world and established close friendships that have lasted until today. It also gave me a taste of what it must be like to be American. During my first year, I had an American roommate, Patty, whose father was a diplomat in the Middle East. Pretty, perky, and flirtatious, she was very popular among the male contingent at AUB and went on fabulous dates but still missed her all-American high school boyfriend. She explained concepts to me such as going steady and being pinned, and I was shocked to hear that her parents wanted her to date around rather than focus on a single person. I, being a nice Syrian girl, had never had a date in my life.

During my first term in college, President Kennedy was assassinated, and Patty and her older sister, who lived down the hall, were devastated because they had a direct personal connection to the Kennedy family. This made the United States seem less remote, more human, and accessible. It was not just a superpower that influenced Middle Eastern politics, it was made of people I was meeting, and their president was connected to someone I lived with! That moment may have been the seed of my notion that I could actually live there someday and realize my educational dreams.

Early Research and Scientific Interests

In spite of my desire to differentiate myself from my father, I became a psychology major because I found the subject fascinating. I wanted to understand thinking and felt that language was a window into that. But I was also very interested in social psychology, in belief systems, and in the role of culture in thought. As an undergraduate, I conducted a research project on the social beliefs of Syrian women across generations and socioeconomic levels. I visited several families and spoke to grandmothers, mothers, and daughters and systematically asked them a set of questions about their lives using a questionnaire I had devised. But I also collected stories they wanted to share with me—tales of being married before reaching puberty, of being disciplined by stepchildren who were older than them, of never having a normal cycle because of being either pregnant or nursing continuously, and of secret attempts at abortions that were mostly unsuccessful. The voices of these women still reverberate within me—the combination of resignation and courage even among those who considered themselves more lucky than not. Even though some of them had never known another life, they seemed to glimpse other possibilities, a sense that the world could be different. My mere presence, without a hijab and coming from a university abroad to conduct this research, was enough to confirm that women could have different lives. But they did not seem to resent me; they wanted to be heard, to share their stories, and to impress upon me their uniqueness. Just as Marie Curie had shown me one way that life could unfold, these women showed me its polar opposite. Coupled with the voice of my own mother, who seemed to have yearned for a greater measure of self-determination, these women’s voices shaped my desire for self-definition, rather than being tossed around by various rules and customs.

Late into my undergraduate work, I decided to focus on psycholinguistics as a means to probe the process of thinking. I had a British mentor, Professor Ernest Darlymple-Alford, who taught cognition, learning, and memory as well as psycholinguistics. Here again, my first research project was focused on cultural aspects of language and thought. I wondered whether bilingual individuals think differently when they are using different languages. To test this notion, we relied on the pool of bilingual (Arabic–English) students at the AUB and administered a personality scale that tests the degree of authoritarianism. This scale (the so-called F-scale) was devised after World War II to understand the propensity to be authoritarian and follow figures of authority—presumably the behavior that contributed to the spread of fascism. The scale was known to be very culturally sensitive, with Western cultures scoring lower than Middle Eastern or Asian cultures. So, we asked: Would native Arabic speakers be equally high on this scale regardless of which language they were operating in? Because the scale had split-half reliability, we administered to each subject one-half in Arabic and the other half in English (the two halves were counterbalanced across subjects). Remarkably, every person tested had a higher F-score when functioning in Arabic than when functioning in English! I never published this work, but it was my first foray in personality testing, something to which I have returned more recently in the context of understanding the neurobiology of temperament.

Early Exposure to Behavioral Neuroscience

I decided to pursue a master’s degree in psycholinguistics at AUB, under Professor Darlymple-Alford, while also working as a teaching assistant. My master’s thesis had a more classical “verbal learning” topic that did I did not find as exciting. But it was during that graduate year that I took a course in physiological psychology from Professor Conrad Consalvi that I found fascinating. I still recall being in the stacks of the AUB library and discovering a paper by James Olds about self-stimulation in rats. I knew next to nothing about the brain, its organization, or its function—back then psychology was quite separate from biology and neuroscience as a field was barely in existence. After reading a Science paper by Olds on using self-stimulation to test psychoactive drugs, I remained in the library for more than eight hours and tracked down every paper I could find written by him and others on intracranial stimulation. Feeling dazed, my heart hammering, I thought: “I want to do that! Get right in the brain and figure out how it controls behavior!” The fact that it was possible was stunning. But I also felt that this was clearly beyond my reach—I had no access to animal research, electrical stimulators, or any means of looking directly at the brain. I could not have imagined that I would wind up doing exactly that sort of work, in some of the very institutions where Jim Olds had worked (UCLA and University of Michigan), working under someone who had been his student (John Liebeskind), and even meeting Olds in person.

Coming to America (1968)

As I was completing my bachelor’s and master’s degrees, it was becoming evident that my parents were increasingly worried—had they created a geeky monster who would never fit within the expected framework of Damascus society? Arranged marriages are still the norm in Syria, and during my junior year at AUB, I had become engaged under such an arrangement, only to discover that the groom-to-be was much more religiously conservative than my parents had estimated and would not abide my dress style and independent habits, much less my long-term professional goals. As importantly to me, he seemed to resent the company of my younger siblings, Bisher and Mayada, and they were wary of him. My father helped me dissolve that relationship. After a year hiatus, another engagement was arranged. I was more enthusiastic about this second one because the fiancé was a physician completing his residency in the United States. Here, suddenly, was my ticket to go to America! Better yet, he seemed open-minded and willing to see me apply to graduate schools. I was in heaven. My fiancé, whom I had barely gotten to know during his vacation away from his residency, returned to the United States. But something was obviously wrong because his letters were progressively less frequent and more cryptic. And then one summer day, in June 1967, while I was home in Damascus because of the Six-Day War, I received an uncharacteristically thick envelope from him. He explained to me that, before we met, he had been in love with an American nurse. His parents were opposed to the relationship and had made him promise to break it off and marry someone from Damascus. And although he had done his best to honor his promise to his parents and to me, he was still in love with his previous girlfriend and was feeling very guilty toward me. I wrote him back immediately absolving him from the arrangement and encouraging him to stick to his guns with his parents and marry the woman he loved. I was finishing the letter when my father walked in and found me in tears. I recounted what happened, and my father asked me whether I had fallen in love with the guy. I had to laugh and explain that my disappointment was entirely because I had lost my opportunity to go to the United States and pursue my studies!

I believe it was my mother who convinced my father to still allow me to apply to graduate schools in the United States. I marvel, once again, at my parents’ remarkable behavior for that time and place. Maybe they decided I was not cut out for arranged marriages or that they had somehow failed to arrange the perfect one because they left me to my own devices during that last year at AUB. I applied to and was accepted in a number of programs (although my current academic home, the University of Michigan rejected me summarily!). But the big hurdle was money. Even if my parents could afford it, there was no way to move money out of Syria and get it to the United States. The only positions available in these graduate programs were teaching assistantships, and they were not being offered to some foreign candidate, sight unseen. So, I resigned myself to staying in Beirut, working for a year to save enough money to go to the United States, and to convincing one of the programs to give me an assistantship.

It was July 1968, toward the end of my master’s thesis, when I opened my mailbox at AUB and found a letter from the University of Iowa, where I had been accepted with no financial support. It told me that one of the graduate students slated for a teaching assistantship had been drafted to Vietnam, and they were willing to offer me that position. The surge of joy I felt quickly died when I realized that the letter had been dated weeks before but sent with insufficient postage to be sent first class. I immediately placed a call to Iowa and almost fainted with relief when they told me the position was still available!

Suddenly, it was a mad scramble. Rather than job hunting, I needed to complete my thesis, pack my bags, and get myself to the United States! But a passport with an “exit visa” from Syria allowing me to go to the United States presented yet another hurdle. Syria had cut off its relationship with the United States, and if I ever wanted to return home, I needed legitimate papers. Once again, I found myself in Damascus, despairing from ever achieving my dream. And once again, my parents came through. My father used his connections and secured a visa for me at a time when no one else was getting one. Armed with a thesis in need of revisions, a suitcase of clothes that were woefully inadequate for life in Iowa, and $200 in cash, I tearfully said goodbye to my family and began my journey to the United States. My friends were taking bets on how long I would last—I believe six months was the longest period anyone bet on.

Stan

University and Graduate School (1961–1969)

My undergraduate college years were generally unremarkable with the exception of an academic “vacation” when I drifted for a while and two courses that revived my interest and led me to my fascination with the brain. Early in my college years, I felt bored and uninterested in academic life. But I became significantly more engaged after a course on basic psychology by Professor Irving Tucker (I later learned that he subsequently moved to Beirut and taught Huda, half a world away!). The second course was one on behavioral analysis by a PhD student of B. F. Skinner’s. Both courses deeply interested me but felt, in the final analysis, incomplete. Neither presented much about the brain itself, except for one slide that Tucker showed from the Swedish histochemical group demonstrating catecholamine pathways in the brain—now that fascinated me! In retrospect, my interest in machines and fundamental mechanics was the key to my desire to migrate from pure psychology to neurobiology. It took some years for me to recognize that my fascination was not just in behavior or psychopathology but in the underlying physical nature of the brain and how it functions.

During my senior year in college, I applied to several graduate schools, based on Tucker’s suggestions. I was admitted to the psychology department at the University of Iowa. It was almost as “tough” a place as my high school. Iowa was a bastion of behaviorism and stimulus-response theory, very much in competition with the more cognitive/social modeling style on the West Coast. The focus at Iowa was on behavior with the brain as an unknowable “black box.” It was a driven, tense department, although many of the faculty members were pleasant. My personal interest turned toward clinical-experimental pathology, mainly schizophrenia, which I viewed as the most severe of the major mental illnesses. My perspective was shaped by my faculty mentor, Dr. Robert Callahan—a bright and charismatic psychologist who had served as a World War II navigator and bombardier. Somehow, I hoped to learn more about the brain by focusing on this illness.

During the third year of graduate school, clinical psychology students typically took a full-year clinical internship. Mine was at the Palo Alto Veterans Administration Hospital. The residents and faculty were from the department of psychiatry at Stanford’s school of medicine. It was arguably the most prized internship in the nation, and I was overjoyed. I loved the San Francisco Bay area. That internship was spectacular and represented a major influence on my life and career. The ward had about 30 inpatients, an excellent staff, and superb Stanford psychiatry residents. I worked with one resident (Warren Crick) who countersigned my orders—resulting in a “Watson-Crick” duo, much to the amusement of everyone. This unit was for acute and subchronic cases. Outside of severely disturbed patients on a locked ward, we took the worst cases. The range of illness was huge, covering the full spectrum of psychopathology. We saw overt psychoses, post-traumatic stress disorder (PTSD), psychiatric depression, panic disorders, and sociopathic behavior. The patients ranged from World War II vets to Vietnam vets, Special Forces, bikers, mathematicians, and doctors. All in all, it was a very rich, yearlong experience, one that stood me in good stead for all my subsequent clinical work.

By the end of my psychology internship, I realized that I wanted to focus on the biology of severe mental illness. I considered postdoctoral training as a psychologist but decided that, with a bit more time, I could become a psychiatrist. Upon returning to the University of Iowa and informing the members of the department of my decision, many seemed upset and angry about my choice. I explained that I was not abandoning my PhD but continuing and expanding it. It was a fascinating view of how closely related fields viewed each other with suspicion.

A few days after my return to Iowa City, I met a delightful young woman. She was sitting at the desk of my former girlfriend, and somehow I immediately knew that Huda and I were a good match. She was bright, humorous, and could compete with the best. That last year of graduate school was complex for me—beyond my relationship with Huda, I was completing my dissertation work, making plans for the following year, and helping my parents recover from the strongest Gulf hurricane ever seen. My PhD thesis on sensory processing in severe schizophrenic patients (Watson, 1969; 1974) proved interesting. My studies focused on the response of acute versus chronic schizophrenia under quite demanding and stressful stimuli, and the impact on the acutely ill subjects was clearly overwhelming. It convinced me that acutely psychotic patients were quite vulnerable to stress, but it clearly lacked a true biological approach. I was ready to move on.

Huda

A Year in Iowa (1968–1969)—Meeting Stan

As Ozark Airlines landed in Cedar Rapids, Iowa, I was revising my expectations about seeing skyscrapers. In all my American dreams, I had imagined New York, or the beaches of southern California, not the American Midwest. In the few days before school started, I felt completely alone in the world. Telephone calls to my family were very difficult, and I knew no one. The differences in culture were so much greater than I had expected. But as the term unfolded, I began to meet other graduate students. One of them was Stan Watson, who would become my husband and lifelong collaborator.

Stan walked into the office that I shared with two other female graduate students, greeted them, and asked me who I was. I was already leery of answering that question—giving my foreign name only to be asked where I came from, with Syria typically eliciting a blank stare. So, I decided to get it out of the way all at once and said: “I’m Huda Akil, and I’m from Syria. But I don’t imagine you know where that is.” “Sure I know,” he said, “You’ve been winning a few wars lately!” He was sarcastically referring to the Syrian losses during the Six-Day War, and I was incensed. He chuckled, told me I was sitting at the desk of his ex-girlfriend, asked me if I had any idea how cold it would get in the winter, explained that he had spent the previous year doing a clinical psychology internship at Stanford and had plans to go to Lake Tahoe on a ski vacation over Christmas break (he already had the ticket in early September), and sauntered out. I was fuming at his attitude—every other American I had met seemed so gentle and friendly! One of my office mates told me not to mind him—after all, he was from New Orleans and rode Harleys. She also warned me not to go out with him, and I explained that I had no interest, and was already dating a Lebanese physician, a friend of a friend, who was doing his residency at the university hospital. And yet, within a few weeks, Stan and I had progressed to a serious relationship that would survive three years of separation leading to a long-lived marriage.

A Year in Iowa (1968–1969): Lab Work and Local Politics

At the University of Iowa, I worked with a young professor and recent PhD from the University of Michigan, Dr. Stephen Fox, who was interested in studying electrophysiological mechanisms of learning in cats and humans. Steve was extremely creative. Instead of searching for neural correlates of learning, he was using operant conditioning to directly alter the late components of sensory evoked potentials and to determine the neurophysiological correlates of this learning within the area and in other components of the circuit. During my stay, the lab published two papers in Science demonstrating that such conditioning at the electrophysiological level was possible in cats and in humans (Fox and Rudell, 1968; Rosenfeld et al., 1969). So, in my first exposure to animal research, I began to learn electrophysiology, and I perfected the intricate surgery that introduced multiple recording electrodes aimed at various cortical and subcortical sites, along with a large cannula lodged into the cat’s palate to allow instantaneous delivery of the milk reward. The evoked responses were being computed online (using the then state-of-the-art PDP8), and the late components of the response were selected for shaping. When the criterion for a learned change was met, the system triggered delivery of the milk—a remarkable feat considering the computational capacity available at the time. Alan Rudell was the programming genius behind the operation, but there was a group of people (e.g., Chris Kaneko, Bob Norman) who loved to fiddle with computers and electrophysiology rigs and discuss technicalities for hours. I was in awe.

My Iowa year also introduced me to more biochemical and pharmacological aspects of neuroscience—particularly through an excellent course taught by the late John Harvey (who later became chair of pharmacology at Drexel University). John was the first person to ask me what I hoped to do with my graduate training. He suggested that I might wish to incorporate pharmacological approaches into my research because they would be more “portable” and less technically demanding should I wish to return to Syria and establish a research operation there.

By the spring term of that year, several faculty members, including the department chair, were strongly suggesting that I should reconsider my choice of laboratory. For reasons that I did not fully grasp, matters had become quite tense between Steve and several of the senior faculty. But I liked Steve and my colleagues in the lab, and I felt that I was being pressured not necessarily for my own best interest but as a pawn in a battle that I did not fully understand. Stan, who was completing his PhD that year, encouraged me to get out of the situation and leave Iowa, a possibility I broached with Steve. When Steve discovered that I had been accepted to UCLA the year before, but without financial support, he told me he had a plan. He explained to me that one of his students at the University of Michigan, John Liebeskind, was a junior faculty member at UCLA and he would contact him and vouch for me as a scientist and as a teacher. He made the call immediately, and John asked to speak with me—a sort of mini-interview. A few days later, John called back to say that my previous acceptance had been re-activated and I was being offered a teaching assistantship at UCLA! Although Steve was losing one of his new students, he had the satisfaction that the department would also lose that student. The pawn had landed on her feet!

A New Phase: The UCLA Years (1969–1972)

Long before my move to UCLA had been arranged, Stan and I had decided to break up at the end of the academic year because there was no future in a relationship between an American guy and a girl from Damascus. But he needed to complete some premed courses and had chosen to return to Stanford to accomplish that, and we decided to make the cross-country drive together. Stan helped me locate a miniscule studio apartment in Los Angeles, bought me a tiny little TV to go with it, and we said our goodbyes as he headed north to the Bay Area. Once again, I was alone in a new place, and this time, I had broken up with someone I loved.

Los Angeles was yet another culture shock, but John Liebeskind was the nicest man in the world and one of the best mentors anyone could dream of—warm, supportive, modest, generous, funny, and yet erudite and extremely smart. His lab in the C floor (i.e., three floors below ground) of Franz Hall became my new home and the true foundation of my scientific career. John had completed his PhD at the University of Michigan, working first in the laboratory of James Olds before switching to work with Steve Fox. He had completed a sabbatical in Paris with Mme. Denise Albe-Fessard, and his research was focused on central mechanisms of pain control (see Terman, 1999). He had a small group consisting exclusively of graduate students. But we were surrounded by the laboratories of several newly minted faculty members whose work spanned the emerging field of neuroscience—Frank Krasne’s focus on neural plasticity using invertebrate models, Donald Novin’s work on mechanisms of motivation, Larry Butcher’s interest in creating animal models of Parkinson’s disease, and others. The atmosphere was both exciting and collegial, and several graduate students from across labs became my friends.

The UCLA Years (1969–1972): The Discovery of Stimulation-Produced Analgesia

It was at UCLA that I had my first taste of scientific discovery. As soon as I arrived and as part of my training, I was recruited to help Tom Wolfle, a veterinarian who was completing his PhD research under John. Tom was trying to model the central pain syndrome, a phenomenon that typically results from injury to the nervous system. The site of perception and processing of central pain was unknown, but Liebeskind had hypothesized that activation of some specific brainstem structures in the dorsal tegmentum would mimic this phenomenon. Tom was attempting to show that electrical stimulation of these brain sites was in fact noxious, and that rats would learn to escape it or even to actively avoid it. For comparison, he was alternating between the central stimulation and a peripheral pain stimulus (a shock to the paw) and testing escape behavior.

Tom had an easy manner, friendly ways, and a southern drawl. He was very patient with me and taught me a great deal about gently handling rats, programming electronics, and experimental design. But one afternoon, as we were holed up in the animal testing room, Tom seemed uncharacteristically frustrated. He pointed out to me that animals receiving stimulation in the brainstem periaqueductal gray matter (PAG) did not seem to learn to avoid the central stimulus as expected; moreover, they actually did not escape it for quite a while. Even stranger, they appeared to show greater tolerance of the peripheral pain after having been stimulated in the PAG. These anomalies were not helping Tom complete his thesis work as fast as he had hoped because he had a deadline for returning to his position in the armed forces. We decided that we needed to discuss the problem with John—this is when I learned one of my biggest lessons in science.

Instead of looking at it as a problem, John seemed fascinated. He wanted to see the phenomenon and to learn more about it. And he brought into the discussion David Mayer, a senior and very talented graduate student in the lab. We were all intrigued: Could stimulation of the PAG be doing the opposite of what was expected? The PAG was known to be a site that encoded distress and fear, and a very recent study had shown strong negative responses to stimulation of the brainstem in humans (Nashold et al., 1969). But our observations seemed to hold, and given Tom’s tight timeline a division of labor ensued. Tom would test whether the PAG site might be rewarding and could support self-stimulation, whereas David Mayer would take the lead in testing the effect on pain responsiveness. Tom completed his work promptly and published a paper (Wolfle et al., 1971) showing that although most areas of dorsal tegmentum supported escape and avoidance behavior, there were sites in the ventral PAG that did in fact support self-stimulation.

Meanwhile, Dave Mayer set out to ascertain whether stimulation could indeed block pain and if so, what other brain regions participated in that phenomenon. I was still in the “flunky” mode and was helping with various aspects of the study. We tried multiple pain tests, some classical (such as the tail flick test) and some improvised. We experimented with a wide range of current parameters to optimize the analgesia. We invented ways to prove that the animals were indeed analgesic but not otherwise impaired. For example, we would set the rats in a pan containing ice water. Within a few seconds, a control animal would escape, presumably due to the uncomfortable temperature. But if we turned on the PAG stimulation, the animal remained standing in the ice water, unperturbed. We could hand him a pellet of chow, and he would happily munch on it. As soon as we would turn off the current, he would escape. These and other demonstrations were completely convincing—we were producing a complete blockade of pain sensation while leaving other sensory and motor modalities intact. David, though only a few years older than me, was a great teacher as well as an imaginative and self-assured experimentalist. I learned from him the importance of extensive observation, of truly getting to know the animal’s behavior with some granularity rather than simply performing pre-designed tests.

It was around that time that we learned that Reynolds had observed a similar phenomenon and reported that he could perform abdominal surgery with no anesthesia in three rats that were receiving stimulation near the lateral edge of the central gray (Reynolds, 1969). Consequently, my next lesson was to learn how one moves past being “scooped.” John felt that the Reynolds study, although convincing, was rather limited in scope, and he thought that we would more fully characterize the phenomenon, map its extent and brain distribution, and ascertain whether or not it was associated with reward pathways (shades of James Olds!). So, David went on to do just that as part of his dissertation work. This body of work demonstrated that there is an extensive circuit that supports pain inhibition across the mesencephalon and diencephalon, particularly in periacqueductal and periventricular gray matter. It also showed partial overlap with reward pathways. Thus, some sites supported self-stimulation with no analgesia, others supported analgesia but not self-stimulation, and yet others supported both. We termed the phenomenon stimulation-produced analgesia (SPA). This was my first neuroscience publication (as third author after David Mayer and Tom Wolfle) and it was in Science (Mayer et al., 1971)!

Getting the paper accepted by Science was no mean feat, and once again John demonstrated his remarkable flexibility and scientific acumen. The paper was returned with positive reviews but insufficient enthusiasm for appearing in Science (presumably because of the Reynolds paper). I recall sitting with David in John’s office trying to decide how to better make our case. We were convinced that the depth of our characterization of the SPA phenomenon, the evidence that it was distinct from generalized sensory inhibition, the anatomical extent, and the relationship to reward pathways represented compelling evidence of a significant discovery. We wondered whether it would be useful to make the analogy to opiates, the only known class of drugs that could produce that degree of analgesia without being anesthetic. It was soon thereafter that John discussed the issue with Brooks Carder, a faculty member in the psychology department who was interested in substance abuse research. Brookes pointed John to an article in Scientia Sinica where the sites of action of morphine had been mapped in the rabbit, using microinjection (Tsou and Jang, 1964). Here was a new, key thought to add to the discussion—that the system we were describing was at least partially overlapping with the site of actions of morphine in the brain. This allowed us to make the case, albeit circumstantial, that brain stimulation and morphine activate a common system whose primary function was pain inhibition as opposed to pain appreciation: “We propose that brain stimulation attenuates pain by activating a neural substrate that functions normally in the blockage of pain” (Mayer et al., 1971). In the next phase, David and I went on to test this notion more directly.

The UCLA Years (1969–1972): James Olds’ Influence, Once Again

While I was working with David on the demonstration of SPA, I had the chance to meet James Olds and his wife and scientific colleague, Marianne, and once again, unbeknownst to him, he reshaped my scientific path! Stan had had a roommate at Stanford who was now a graduate student at Caltech working with the Olds. He was inviting Jim and Marianne over for dinner at his house and asked me whether I would like to meet them. I, of course, eagerly accepted and told John Liebeskind about it. Because John had briefly worked with the Olds at Michigan before joining Steve Fox’s lab, he wanted to make sure that I would get their input on our recent (yet unpublished) observations about electrical stimulation in the PAG and its effects on pain responses. I had the feeling that this went deeper than a desire for a scientific perspective, that John was hoping that they would be impressed by these recent discoveries.

The dinner consisted of only our host, the Olds, and myself, so I had plenty of chance to interact with them—and it felt like a parallel universe to be in the same room with the person who was the subject of my Beirut epiphany. They were both very friendly, with Marianne telling me about the challenges of being a female scientist and Jim seeming pleased by the depth of my knowledge about every paper he had published. When he asked me what I was working on and with whom, I excitedly told him about John and our analgesia story. He said that I should be careful to not over-interpret the observations—that sometimes it is easy to create a functional lesion through brain stimulation. In other words, the animals may be analgesic because we were functionally lesioning the pain circuitry during stimulation! I explained that pain sensation returned within minutes of terminating the current, and he pointed out that functional lesions are not permanent.

The next day in John’s office, as I relayed the conversation, I watched his initial disappointment turn into determination. He was sure the functional lesion hypothesis was wrong, but we needed to argue against it and maybe even prove the opposite. One can see the resulting argument being developed in the discussion of the (Mayer et al., 1971) Science paper—that this was an active mechanism not simply an interruption of pain perception. We were talking to Jim Olds in that paragraph! The analogy to morphine could have been problematic—after all morphine could work by creating a functional lesion in the processing of pain perception. However, as we state in the paper, “the integrity of certain neurotransmitter systems appears necessary for morphine to exert its analgesic effect” (Way and Shen, 1971).

The UCLA Years (1969–1972): Dissertation Work

The process of writing the discussion of the Mayer et al. paper, in order to get it accepted into Science and to implicitly respond to Olds’ alternative interpretation, framed the rest of David’s dissertation and defined mine. Before that dinner, I was supposed to identify brain sites that caused self-stimulation only when the animal was in pain but not under non-noxious conditions. However, following the discussion with Olds, it was more urgent to prove the true presence and active nature of the pain inhibitory circuit.

Thus, my thesis work had two goals: (a) to test the hypothesis that brain stimulation was indeed an active mechanism by demonstrating that it required intact neurotransmission in order to be effective—that is, that blockade of certain neurotransmitter systems would prevent SPA, their replenishment would restore SPA, and their basal activation would enhance it. We reasoned that if central gray stimulation were merely producing a functional lesion, then adding to the lesion by blocking various neurotransmitters would not prevent the analgesia; (b) to test the hypothesis that SPA activates the same circuit that morphine activates, by asking whether the same neurotransmitters that were implicated in morphine analgesia (e.g., serotonin) were also implicated in SPA. We also decided to use direct blockers of the action of morphine, in particular a drug that had been used by Tsou and Jang (1964), nalorphine. Meanwhile, David would look at the possibility that tolerance to morphine would alter the efficacy of SPA, in order to show that the two means of activating the system would exhibit cross-tolerance.

At that point, we were not specifically thinking about the molecular mechanism of morphine action or the existence of opiate receptors. Although opiate pharmacologists had suggested the existence of such receptors (Goldstein, Lowney, and Pal, 1971), and a race for demonstrating their presence in the brain was underway, this was beyond our ken. To us, morphine and other opiates were somehow able to activate a neural circuit that can block pain by releasing known neurotransmitters along its neural components, and we were accomplishing the same effect with direct electrical stimulation of that circuit. But which neurotransmitters should we focus on?

We focused on monaminergic neurotransmitters for several reasons. We were stimulating close to the dorsal raphe, a major cell group in the brainstem that synthesizes serotonin, so serotonin was clearly one of our targets especially because it had been implicated in morphine analgesia (Samanin et al., 1970; Samanin and Valzelli, 1971). We were very aware of the work of the Swedish histochemists, especially because our lab neighbor, Dr. Larry Butcher, had learned monoamine histofluorescence in Sweden and was establishing the Falck-Hillarp technique at UCLA. Others had implicated noradrenergic mechanisms in reward and because some of our sites supported self-stimulation that was a reasonable target. Finally, dopamine was gaining increasing attention not only for motor control but in reward pathways (Ungerstedt, 1971).

Indeed, this work demonstrated convincingly the importance of monoaminergic neurotransmitters in SPA (Akil and Mayer, 1972). The main paper that resulted from this work concluded: “Dopamine and serotonin appear to facilitate SPA, whereas noradrenaline appears to inhibit it” (Akil and Liebeskind, 1975). We discussed the results in relation to studies by others on the site and mechanism of morphine’s analgesic action and noted striking parallels between SPA and morphine analgesia. This body of work was used to support “the existence of a common pain-inhibitory system in the brain activated by morphine and by focal electrical stimulation” (Akil, Mayer, and Liebeskind, 1972, 1975; Akil and Mayer, 1972).

The UCLA Years (1969–1972): The First Physiological Evidence for Endogenous Opiates (Endorphins)

One of the pharmacological tools I had planned to use to address the analogy between SPA and morphine was nalorphine, a morphine analogue used by Tsou and Jang (1964) to block morphine analgesia. However, the drug proved problematic to use in our paradigm. When I gave nalorphine, it produced some analgesia in its own right, in the absence of brain stimulation. However, this effect would wear off, and I was able to find a time window where nalorphine no longer had an effect on the baseline pain responsiveness but was able to partially block stimulation analgesia. However, the timing was tricky and the results variable. This was rather baffling, until a chance meeting with an opiate pharmacologist helped me immensely!

John Liebeskind had planned to attend the 1971 Winter Conference on Brain Research in Colorado but changed his mind and sent me in his stead. Walking around the meeting wearing John’s nametag was an immediate icebreaker. One evening, at the bar where everyone gathered after meeting and skiing, a gentleman walked up to me and asked me with an impish smile if my name was really John. His name was E. Leong Way (Eddie Way). I had no idea that I was talking to the chair of pharmacology at University of California, San Francisco (UCSF), a world expert in opiate pharmacology! Around us, it was loud and people were drinking and dancing, but somehow I managed to tell Eddie about my work and especially my bewilderment over the results with nalorphine. He said: “My dear, you’re using the wrong drug! Nalorphine is a bear—it’s a mixed agonist-antagonist at the opiate receptor. You should use naloxone, it’s a pure antagonist.” Then he laughed and said, “You’ll probably get nothing though—giving naloxone is like giving water if the animal doesn’t have an opiate on board! But if they’re addicted, then watch out!” I was still processing all that when he added: “Get yourself an opiate pharmacologist on that dissertation committee” and then he asked me to dance! So I did as he suggested: I danced, I got a pharmacologist on my committee, and I used naloxone in my study.

In fact, I returned to Los Angeles and immersed myself in reading about opiates and opiate antagonists. I learned that, indeed, a pure opiate antagonist is expected to be inactive and works primarily by blocking the actions of opiate agonists. This did not augur well for my study. By then, it was early 1972, John was on sabbatical in Paris, and David was planning to join him there. I was on my own. But I had seen signs of blockade of SPA by nalorphine, albeit ephemeral. So, in spite of the literature and Eddie Way’s warning, I decided to trust my instincts and give the study a try. I obtained some naloxone and started playing around with doses and timing of administration to learn how it works. Indeed, it had no effect on the baseline pain response in several tests but was an excellent blocker of morphine analgesia. I was finally ready to test its effect against stimulation-produced analgesia.

I implanted my animals and tested them for SPA. By then, I was adept at recognizing a “good animal,” and I selected those with pure pain inhibition with no side effects of the stimulation (which meant hitting the ventral, rather than dorsal central gray). It was late in the evening, and I was alone in the basement of the psychology department, so I thought I would sneak a peek and test one animal. I gingerly tried my first dose of naloxone. And it worked! There was no effect of the drug on baseline pain responsiveness but a significant reduction in the analgetic impact of the stimulation. I decided to run another animal, and then another. I ran the controls with saline injections. I let the effects of naloxone wear off (because it is short-acting) and could see that the analgesia would return in the same animals that had previously lost it under naloxone’s influence. I stayed in the lab all night and through the early morning hours and completed the entire study! I felt a huge sense of excitement. I somehow knew this was important, even though I could not have explained why.

I immediately shared the results with David and sent them to John in Paris. He too seemed very excited. Shortly thereafter, he told me that he wanted to communicate the results as soon as possible through Dr. Fessard to the Comptes Rendus de l’Académie des Sciences, the French equivalent of the Proceedings of the National Academy of Sciences in the United States. The paper appeared (Akil et al., 1972) and included the study from that frenzied night of work. However, it is fair to say the opiate field did not take particular note of it.

By June 1972, I had wrapped up my experimental work for my dissertation and was getting ready for my final defense. I was getting increasingly interested in learning about pharmacology and the mechanism of actions of drugs on the brain, and because the Fifth International Congress of Pharmacology was taking place in San Francisco, I asked John to allow me to present our work there. This was to be my first public talk and although my submitted title was “Serotonergic Mechanisms Underlying Stimulation-Produced Analgesia,” I decided to use my allotted 10 minutes to summarize all my work—the SPA phenomenon, the hypothesis that it was a distinct system in the brain, the evidence for its active nature based on the monoamine studies, and its analogy to morphine based on the naloxone study. The session, focused on pain and opiates, was packed and I was beyond nervous.

At the end of my talk, a scruffy looking man walked up to the microphone in the middle of the aisle and asked belligerently: “Did I hear you right? Did you say you could stop pain?” I was baffled by the tone but decided he was objecting to my terminology so quickly apologized for using the word “pain” when I should have said “nociception” because the animals cannot report on their pain and it is inferred. My response did not have the expected effect of quieting the objection. Instead, my questioner seemed more agitated and started shaking his fist at me, yelling: “Only God can stop our pain! Do you think you are God?! You’re going to burn in hell!” I stood there stunned as two security guards pulled the man out of the room while he was still yelling and shaking his fist at me. I later learned that it was a mentally ill man who had wandered in from the street, and he had asked the first scientific question I ever received in a public talk!

I was still on the podium in a state of shock when a short, elderly gentleman with thick round glasses and a heavy German accent stood right in the front to ask the next question. He congratulated me on the work and said that the most remarkable finding was the naloxone effect—were we surprised by it? I said we realized that it was supposed to be an inert antagonist, but naloxone seemed to be blocking something that we were releasing through the electrical stimulation. I had never quite phrased it that way, but he nodded his head and seemed to agree with that notion. His next question was even more surprising: “So, are you currently purifying the chemical that you are releasing with your brain stimulation?” I said no, we were not (and wondered silently how one would go about doing such a thing!). He thanked me politely, and I went back to my seat next to Stan and felt everyone staring at me. The session ended shortly thereafter, and a man in front of me turned around, introduced himself as Ed Domino from the University of Michigan (again!) and said: “Good for you for confounding everyone!”

After the session many people walked up to me to discuss my talk—equal part interest in the results I had presented and in the homeless man episode. I gathered from these interactions that it was Hans Kosterlitz, a giant in the field, who had asked the second question about naloxone. I also came to understand that he, along with Avram Goldstein and others, had concluded (based on the body of pharmacological evidence) that opiates must work via their own unique receptors. But why would the mammalian brain have receptors for opiates unless it produced an opiate of its own? They reasoned that an endogenous opiate system must exist. But if it did, then one should detect physiological or behavioral consequences of preventing its actions (e.g., when blocking it with naloxone). Yet all previous attempts at showing an effect of naloxone in the absence of an exogenous opiate had failed. I had just handed them the first physiological evidence of such an effect of naloxone, and by implication, of an endogenous opiate system! I had even provided an explanation for why it worked for us and not in other studies: You had to first activate the system, as we did with electrical stimulation.

It was terrifying!

Stan

At Stanford—A Transition Year (1969–1970)

I was very fortunate to be accepted in the laboratory of Ernest (Jack) Hilgard at Stanford. This was not a formal postdoctoral position but a kindness on his part, to allow me to work with him in the morning and retake some required courses in the afternoon. Many states insist that the premed science requirements be taken within five years of applying to medical school, so I retook undergraduate chemistry and biology at Stanford. I then worked from 4 p.m. to midnight at the Psychiatric Emergency Room (ER) in the San Mateo County Hospital, located between San Francisco and Palo Alto. My job was to see ER patients and work with the psychiatrists moonlighting there—all psychoanalysts from Mt. Zion in San Francisco. Having been trained at Iowa, I had a limited perspective on the psychoanalytic tradition. However, after a few months of working with these psychoanalysts, I came away really impressed with their very sharp skills in reading people, sizing up the situation no matter how complex, and in dealing most effectively with a wide range of patients on an emergency basis.

The patient population was even more varied and complex than the one I had seen on the inpatient Veterans Administration (VA) ward. On an average night, I would see about 10 to 15 patients often with their families, friends, or the San Mateo police and occasionally with federal agents. The range of cases typified the San Francisco Bay Area at the peak of the Haight-Ashbury boom. Beyond the wide range of severe mental illnesses, we saw a huge number of drug patients including those on LSD, and numerous suicide attempts including by a couple of 10-year-old children. Patients included organized crime members, outlaw bikers, and children living in the woods that had been exposed to any and all the crude drugs that the drug camps could make. The stories were tragic and incredible, and the experience memorable and unique. This period, coupled with my earlier VA internship, taught me a great deal about the political, social, governmental, and practical aspects of the mental health system in California. When I returned as a psychiatry resident, I had little to fear in terms of learning the ropes of the system.

At Tulane Medical School (1969–1974)

After that year in California, I was accepted into medical school at Tulane University, in my hometown of New Orleans. I had forgotten how complex and socially inbred that city was in those days. If you were a doctor or medical student, you received amazing support and forgiveness from everyone from the mayor to the cop on the beat. Louisiana’s legal system is based on the Napoleonic Code, not British Common Law, and under this codified legal system there were four seats of power: the mayor, the district attorney, the chief of police, and the coroner. The latter was a very powerful representative of “the crown” and had many responsibilities across civil society. If you were in medicine, it meant that he was your ally and a very powerful one at that. All of this was laid out to us on the first day of medical school. “If you are in trouble, just call us” and they meant it. I was amazed, baffled, and yet felt right at home!

The academic side of medical school was straightforward, with five to six hours a day of lectures. But the clinical aspect was another matter altogether. Charity Hospital was a free medical system put in place by the infamous Huey Long, former governor of Louisiana, for the poor population of the state. It had 2,800 beds, few nurses or attending doctors, and served 80 percent of the New Orleans population. It was the closest thing the United States had to the medical system seen in undeveloped nations. All medical matters were run by residents and fellows, and to some extent, by the medical students. It was a colorful, dynamic, primitive hospital. No medical experience since then has come close to Charity in complexity and in demonstrating the raw face of human illness.

During my first year of medical school, I had little time for anything but the standard curriculum, except for one elective—a three-hour per week course. For that, I chose a class on human anatomy, with a special focus on neural circuits, taught by a British surgeon/anatomist by the name of Jeff Ellison. I can see in retrospect that Jeff was decades ahead of the field. His area of emphasis was understanding the cholinergic and monoaminergic systems, and especially developing better methods for studying them. After that course, I asked to work with him, and spent all of my available time—nights, weekends, and holidays—setting up the monoamine fluorescent method, known as the Falck-Hillarp method (Falck, 1962; Falck et al., 1962). It was a tedious yet beautiful method. It was amazing to watch the fluorescent green signal of the catecholaminergic system and the yellow signal of the serotonergic system as they came to life. I mapped the cells and fibers of these monoaminergic systems throughout the brain, replicating the work of the Swedish histochemists—Fuxe, Hokfelt, Dahlstrom, and more than 20 other colleagues who pioneered that area of neuroscience (Agnati et al., 2010; Dahlstrom, 2010; Fuxe et al., 2010; Granholm et al., 2010; Hökfelt, 2010; Perez de la Mora et al., 2010). It was a thrill to finally have a glimpse of the brain’s operational systems.

But the Falck-Hillarp method was too unreliable for a humid environment like New Orleans. The freeze-dried blocks of rat brain rapidly absorbed water and the monoamine fluors were lost. Anders Bjorklund had proposed the use of glyoxylic acid as a substitute for formaldehyde in the freeze-dried tissue. But I felt that the need for freeze-drying the tissue to prevent monoamines from diffusing was a dogma of the histofluorescence method that was worth testing. Maybe there were alternative strategies to prevent diffusion. So, I decided to modify the technique and devised a perfusion technique using glyoxylic acid, rather than freeze-drying it (Watson and Barchas, 1975; Watson and Ellison, 1976; Watson et al., 1977a). It was a frustrating period, wrestling with a very complex method while being a medical student and working part time and knowing that I was trying to compete with world-class scientists. It took two years of playing with the conditions, but it finally worked! Somehow, maybe due to ignorance on my part, I never really doubted that it would. And in spite of the difficulties along the way, I enjoyed the technical challenge and the process of making it succeed. I was able to obtain a much brighter signal, and it was a bit longer-lived. It is important to recall that these were endogenous fluors that resulted from a ring closure with one or two carbon donors (Fuxe et al., 2010). The catecholamine fluors lasted about 1.5 minutes and the serotonin signal was visible for only 10 seconds under a fluorescent scope before it disappeared. Once it faded it was gone forever! Worse, I only had ASA 200 speed color film. Once I found the cells or fibers and focused, I only had one shot at producing an image! Thus, extending the time with glyoxylic acid felt like an important advantage. When I presented this new method at the 1975 International Union of Pharmacology (IUPHAR) meeting in Helsinki, Tomas Hökfelt and Kjell Fuxe came to my poster. They were pleasant to me, but I was very intimidated because of their fame and because they spoke to each other for at least a half an hour in Swedish! I was left wondering what they thought about my method. Years later, when I mentioned this to Tomas, he was surprised and amused. He had forgotten the entire episode.

In spite of these challenges, this experience crystallized my sense of excitement about the importance of understanding neural circuitry and of linking neuroanatomy to the function of specific neurotransmitter molecules—in this case, the monoamines. It also gave me a direct sense of the importance of advancing technology if we are to increase our understanding of brain structure and function.

The rest of my “free” time, while in medical school, was spent seeing patients as a licensed clinical psychologist and in helping my father set up a mental health system in rural Alabama. I also spent holidays and one summer at UCLA with Huda and worked at the Neuropsychiatric Institute at UCLA as a “fill-in” psychologist.

The summer between my first and second years of medical school was especially memorable. I spent it working for Dr. David Hamburg, then the chair of the psychiatry department at Stanford. David was a major influence on my career in psychiatry, and to this day, he remains a great colleague and mentor to Huda and to me. During that summer, he had me develop protocols for UNESCO for studying adolescent gang violence. But he also taught me a great deal about psychiatry in general as a field and as a social structure. And he would later facilitate my admission to the residency program at Stanford.

In the fall of 1972, Huda moved to New Orleans, and I finally convinced her to marry me. During 1972–1973, she worked as an instructor in neurosurgery studying the endogenous opioid systems, leading up to a series of amazing papers on humans. Near the end of medical school, I was admitted to Stanford for my residency in psychiatry and was allowed to take my last medical school rotation in Boston in the laboratory of Dr. Seymour Kety, the leading figure in the biology of severe mental illness at the time. The medical part of my internship (six months) took place in the Pacific Presbyterian Medical Center in San Francisco, which offered a striking contrast to Charity Hospital in terms of its setting and the condition of the patients.

Huda

A Year in New Orleans: More Naloxone Studies (1972–1973)

I defended my doctoral thesis in the fall of 1972 and moved to New Orleans, where Stan was a medical student at Tulane University. Stan and I had known each other for four years by then but had been in different cities for three of those years. We planned our wedding for December 1972. I needed to find a lab to work in for that one year, while Stan would apply for a residency in psychiatry and I would seek a longer-term postdoctoral position at the same university. So, Stan investigated options for me at Tulane and spoke to a number of researchers on my behalf. He eventually linked me up with a neurosurgeon, Dr. Donald Richardson, who was interested in pain research, had in fact read some of our brain stimulation papers, and seemed very willing to invite me for an interview.

Don and I hit it off immediately. A dashing, Southern gentleman who was talented and fearless, he explained to me that he was currently performing experimental surgery to relieve human patients from intractable pain by lesioning certain areas of the thalamus. But he thought SPA might represent an alternate approach because lesions were far from ideal and often produced irreversible side effects. Don did not have a research grant or a lab group, but he did have a laboratory that he supported out of his clinical practice, and where he took time from his clinical work to perform electrophysiological studies on cats—a gentleman scientist! He obtained a title for me as an instructor in neurosurgery at Tulane, used his personal funds to pay me—with the expectation that I would continue to conduct animal work but also bring my knowledge of SPA to his human patients. Here was my opportunity for “translational research”—a notion the importance of which would emerge decades later, but which I immediately found fascinating.

The first order of business was to set up the laboratory for testing SPA in rodents as well as cats. I had several follow-up ideas relating to my dissertation work that I needed to complete before publishing it. Moreover, the meeting in San Francisco had made me realize the importance of the naloxone study. Equally compelling was a telephone call from Dr. Avram Goldstein, who had somehow traced me to the lab at Tulane. He told me that he had missed the session in San Francisco but had heard about my presentation and wanted to ask me some questions. He proceeded to quiz me for almost an hour about every detail of the naloxone experiment—the dosages of the drug I had tried, the timing of administration and recovery, and possible alternative explanations. I knew him to be a major figure in the field of pharmacology, especially in the area of opiates, and I was quaking as I was answering his queries. I decided I needed to replicate the effects of the opiate antagonist on SPA in a different setting and across additional conditions. I was now operating solo, although I would occasionally chat with John Liebeskind on the phone about my progress. I was able to replicate my observations from the UCLA study, but once again, the reversal was incomplete—in other words naloxone diminished the magnitude of the analgesia induced by electrical stimulation but did not abolish it completely. I attempted higher doses of naloxone, but they did not seem any more effective. I also identified current parameters that produced partial analgesia, to ensure that the stimulation was not supramaximal. But even then, the naloxone reversal was partial. Therefore, in our eventual publication of this work (Akil et al., 1976), we argued for two important ideas: (a) The brain stimulation was releasing a “morphine-like substance” from the central gray that the naloxone was blocking; and (b) because the blockade was partial, we were also either bypassing the morphine-like synapse and activating the downstream mechanisms, or there were other endogenous mechanisms of analgesia that were non-opiate in nature.

A Year in New Orleans: Stimulation-Produced Analgesia in Humans (1972–1973)

Don Richardson was gracious enough to let me complete my own animal work, but we were both eager to test the approach in humans. After all, as I had politely explained to my unusual questioner in San Francisco, we can never be certain about the disappearance of pain without some sort of explicit corroboration.

Our first approach was to test SPA in five patients who were suffering from intractable pain and were slated for a thalamic lesion (Richardson and Akil, 1977a). We would first introduce the electrode, aim it at the brainstem periaqueductal gray matter, and then ask whether we could find current parameters to produce pain relief. The first surgery was memorable. It was my first time in the operating room, and I was truly curious to see whether what had worked in rats and cats had a chance of working in humans. The patient was a gentleman who had lost his foot to diabetes and suffered from phantom limb pain. He was not only distressed by the pain itself but deeply embarrassed for having this sensation in a nonexistent limb. The patient was awake during the surgery, and we were able to question him about his pain in the operating room. Several sites and current parameters proved ineffective. But at one point, as we stimulated the central gray matter, he suddenly reported that the pain had floated away! Even his sensitivity to pinprick was altered, but the pain relief was also accompanied by a number of other sensations, some of them unpleasant. This was in fact the pattern with each of the patients we tested acutely: Pain relief was evident but autonomic symptoms accompanied the brain stimulation including nystagmus, nausea, vertigo, and a feeling of a “rising vapor.” My task in the operating room was to manipulate the current parameters and adjust them to obtain maximal, side effect–free analgesia, but this proved almost impossible to achieve reliably in the periaqueductal gray.

However, my knowledge of David Mayer’s mapping study led me to suggest testing more rostral, periventricular sites. Don designed the electrode path in such a way that we could stop the penetration at several points in the medial thalamic region and test for pain sensations and pain relief. We were excited to find that a site in the periventricular gray area between the nucleus parafascicularis and the third ventricle, at the level of the posterior commissure, produced significant, bilateral pain relief of acute and chronic pain, with minimal side effects. The patients reported a feeling of relaxation, and remarkably, one minute of stimulation could result in pain relief lasting up to an hour. Therefore, we chose this region as the target of permanent implants to allow self-administration of brain stimulation for chronic pain control.

We carefully selected the next set of eight pain patients for chronic electrode implant with the hope that brain stimulation would suffice as the sole method for pain control (Richardson and Akil, 1977b). The surgery was conducted in two stages, on two separate days. On the first day, the electrode was introduced under local anesthesia and aimed at the previously identified periventricular site, and the patient was tested in the operating room for pain relief. The electrodes were connected to a temporary percutaneous lead to allow testing for pain relief in the hospital over a period of seven to 14 days. During the second stage of surgery, carried out under general anesthesia, the electrode was permanently connected to a Medtronics induction receiver and rectifying unit that was implanted over the pectoralis muscle. The patient could then use a pocket-sized Medtronics stimulator, connected to an inductance antenna, to transmit the pulse current when placed over the subcutaneous receiver.

We worked with each of the patients to ensure the best combination of stimulation parameters to ensure analgesia. We also remained in contact with them and tested them in the lab at regular intervals to track the effectiveness of the treatment on their chronic pain and on some acute lab tests of pain responsiveness (Richardson and Akil, 1977b). Seven out of the eight patients achieved good to excellent results and could obtain pain relief without classical pain medications. In some cases (n = 4), we relied on the antidepressant amitriptyline to augment the magnitude and/or duration of analgesia. This was a direct translation of my dissertation work on the role of monoamines in the pain inhibitory circuit, and we showed that the effect was immediate rather than the delayed timing of the antidepressant effect. A follow-up study of these and other patients (n = 30) showed that the effectiveness of deep brain stimulation as a primary means of achieving pain control was sustainable (Richardson and Akil, 1977c). Although deep brain stimulation is not a routine procedure for pain control, undoubtedly because of its invasiveness, its efficacy has been replicated across several medical centers. A relatively recent meta-analysis described results from 424 cases studied over a period of 20 years after we published our work and reported a success rate of approximately 80 percent for stimulation in the periventricular/periaqueductal gray areas (Bittar et al., 2005).

The experience of seeing our work in animals helping people with intractable pain was profoundly moving for me. My initial interest in neuroscience was entirely intellectual—a commitment to science for its own sake. But within a few years, I had witnessed personally the power of basic scientific discoveries to make a difference in the lives of people. Our patients would call to thank me because they could now pick up their kids for the first time in years or spend time with their family or have a good night’s sleep. One patient was terminally ill with cancer and was grateful to be able to spend his last few months of life with the ability to alleviate his own pain. Many continued to call me for several years after I left Tulane and moved to California. Science had gotten much more personal.

A Transition Year and a Memorable Meeting in Massachusetts, 1973–1974

During 1973–1974, we were in Boston. Stan was completing his senior year medical school rotation at Mass General, and I was writing up the work I had completed during my time at Tulane. I was also submitting proposals for awards (e.g., the Sloan Fellowship) that would be “portable” in order to increase my options at a postdoctoral position. We were once again facing the challenge of coordinating our careers, and because Stan was applying to residency programs, he had little control over the outcome.

It was David Hamburg who, once again, gave us wonderful advice when he pointed us to Jack Barchas as a potential mentor at Stanford. During our visit for Stan’s residency interview, I met with numerous distinguished scientists, but it was immediately evident that the Barchas lab would be my first choice. Jack was warm and thoughtful, had a great perspective on basic and clinical neuroscience, and ran a very exciting, energetic, and broad research operation. So, we felt extremely fortunate when Stan was accepted into the Stanford residency and Jack offered me a position in his laboratory starting in the summer of 1974.

While in Boston, I met Dr. Steven Matthysse, a young faculty member at the McLean Hospital under Dr. Seymour Kety. One day, Steve informed me that he and Solomon (Sol) Snyder were involved in organizing a special meeting in the spring focused on opiate receptors. This would be sponsored by the Neuroscience Research Program (NRP) series that was headed by Dr. Francis O. Schmidt of MIT. Steve indicated that the program was very exclusive because only a small number of leaders in the field would be invited to attend. Small books resulted from these NRP meetings, but because the participants were not asked to write chapters, NRP used “scribes”—young scientists would be asked to take notes, go over the taped lectures, and come up with the first draft of the book. The speakers would then be able to edit the summaries written by the scribes. As one of the organizers, Steve invited me to serve as one of the four scribes. I was thrilled! Two of the other scribes were from Snyder’s group and were to become major players in the field of neuropharmacology—Ian Creese and Gavril Pasternak.

The NRP meeting took place May 19–21 at a beautiful site in Brookline, Mass., called the Brandegee Estate. The wisteria bushes were blooming, all my heroes were in attendance, and I was in heaven. I met Solomon Snyder, Avram Goldstein, Floyd Bloom, Eric Simon, Lars Terenius, Leslie Iversen, Arnold Mandel, and several others, and most would become lifelong colleagues and some of them very good friends. I also met Candace Pert, the graduate student from Sol’s lab who was the first author of the opiate receptor paper. I reconnected with Eddie Leong Way and told him how much his input had influenced my research. My UCLA lab mate, David Mayer, now at the Medical College of Virginia, was representing our collective research at the meeting. Importantly, Hans Kosterlitz and his young colleague, John Hughes, were in attendance.

The atmosphere of the meeting was electric. The title was “Opiate Receptor Mechanisms” (Snyder and Matthysse, 1975), and the primary focus was intended to be on the recent exciting demonstration of opiate receptor binding in the brain—work independently published in 1973 by three separate groups led by Lars Terenius, Solomon Snyder, and Eric Simon (Terenius, 1973; Pert and Snyder, 1973; Simon et al., 1973). Indeed, there had been some very interesting developments about the nature of receptor binding and distinctive responses to ionic conditions that were beginning to hint at multiple conformations and types of opiate receptors (cf. Snyder and Matthysse, 1975). Moreover, from the outset, there were rumors that there would be revelations about an “endogenous ligand” for the opiate receptor.

I have a very strong visual memory of the presentation by John Hughes on May 20, 1974. But I am also in possession of the audiotapes from this NRC meeting and have since listened to his talk. Against the scraping of chairs, Hughes began with the statement: “There are noradrenergic, cholinergic serotonergic, and GABAergic neurotransmitters. I shall now complicate the picture by suggesting the existence of morphinergic transmission.” He then proceeded to describe the use of the guinea pig ileum (a tool optimized by Hans Kosterlitz to characterize opiate receptor function) for purifying an endogenous “morphinergic” substance. He reported the extraction of material from the brainstem and the use of naloxone reversibility as a criterion for identifying the fractions that contain opiate-like material. The enriched fractions were successively purified and “sent to the chemist” for characterization. Hughes stated that they were proposing the name “-enkephalin”—from kephalē (Greek) or cephalon, meaning from the “head.” This is in analogy to adrenaline, which was purified from the adrenal gland. At the end of John’s talk, there was a flurry of questions, especially about whether the material resembled an opiate alkaloid. Lars Terenius, who shortly thereafter spoke of early evidence for the existence of an endogenous opiate factor, said he believed it was a peptide (Terenius and Wahlstrom, 1974). I remember making note of his statement even though I was not completely sure what a peptide was. Leslie Iversen, who was the meeting discussant, stood up at the end and said in his summation that what we had heard “boggles the mind”—and proceeded to imagine the repercussions of such a discovery. It was indeed mind-boggling to me! Here was the material we were releasing with our electrical stimulation, our own natural opium! I literally was unable to sleep all night from the excitement. As I worked with the other scribes, the sense of anticipation was palpable—this was the start of a new era.

Huda and Stan: Stanford (1974–1978)

Thanks to the generosity of David Hamburg and Jack Barchas at Stanford, we had finally aligned our careers with positions that allowed us to continue our training and pursue our research interests—Stan as a research resident in the psychiatry department and Huda as a postdoctoral fellow in the Barchas lab. Nowadays, our son, Brendon, refers to Stanford as the “mothership” because of the number of times our family has gone back to it at critical points—including our daughter, Katie, who currently works there. Back in 1974, we made the trip from Boston to the West Coast in our trusty Volkswagen van, amid the gas crisis and with news of Patty Hearst on the radio. The first few months, we lived in San Francisco so that Stan could complete his internship at Pacific Presbyterian and Huda could start her training in neurochemistry—an entirely new area of research for her. We then moved to Palo Alto in June of 1974 and remained there until September 1978.

This was the start of a relationship with Jack Barchas that has proven to be one of the most important in our lives, scientifically and personally. Jack’s mentorship, collaboration, and support have continued unabated for four decades. The Barchas lab was unlike any other we had encountered. Jack was still young, in his late thirties, but ran a large and diverse research operation with a sense of excitement and with state-of-the-art technology. His interests spanned the entire range of neuroscientific analysis, from in vitro studies of synaptic function to the pathophysiology of psychiatric illness. This intellectual and technical breadth was based on his implicit and explicit view that these different levels of discourse can and should be integrated to achieve a real understanding of brain function and dysfunction. The lab felt mature—dominated by postdoctoral fellows and senior technicians. It also included MD–PhDs such as the late Roland Ciaranello, who was starting his child psychiatry residency after returning from a fellowship with Julius Axelrod. Even then, Jack was very aware of psychiatry’s need for a new brand of physician–scientists, and he consistently went out of his way to nurture their careers and to ensure that they received the strongest basic research training while honing their clinical and translational skills. But possibly the most remarkable aspect of Jack’s research enterprise was the freedom he gave lab members to come up with their own research projects. Rather than assigning each person to a specific sub-project of an existing grant proposal, Jack challenged us to express our original scientific ideas, enunciate our questions, and to elaborate our plans. Once he was convinced about the value of the project, he would go out of his way to ensure that we had the tools, equipment, and support needed to make it a success. He encouraged our attendance at meetings to represent the lab and our involvement in grant writing and site visits. His fundamental respect for different perspectives and ideas and his unwavering commitment to developing the careers of young scientists are values we have tried to emulate in our own research. And Jack seemed as excited as we were about the challenges offered by the new field of endogenous opiates!

A New Function of Endogenous Opiates—Coping During Stress

Our work in Jack’s lab began shortly after that famous 1974 NRP conference. The book was not yet published, but news of the endogenous “morphine-like” factor was spreading. An obvious study for us was to prove that this system was indeed activated during stimulation-produced analgesia and to determine how it might mediate that analgesic function. That meant we needed to be able to measure it in specific brain regions of individual animals—no mean feat because we did not know its structure at the time, only its activity. During the NRP conference, it had become clear that one way to measure the morphine-like factor of Hughes was by using the opiate receptor binding assay. Indeed, the Snyder group was detecting and characterizing the endogenous opiate(s) by using brain extracts to compete with radioactive ligands at the opiate receptor (Pasternak and Snyder, 1975; Simantov and Snyder, 1976). So, it was critical to set up opiate receptor binding as a technique in the lab and to adapt the extraction method of Snyder’s group to be able to analyze changes in levels of endogenous ligands before or after analgetic brain stimulation. Each one of these steps proved challenging, especially in the hands of a behaviorist (Huda) who had never held a pipette, much less set up new assays and biochemical extraction methods. The rest of the lab had expertise in monoamine assays and other neurochemical methods, and a fellow postdoc biochemist, Robert Patrick, was extremely helpful in getting us over these initial challenges.

A fundamental question in the field was: Why should the brain have its own endogenous opiate system, with a morphine-like substance and a receptor? Given his interest in addiction, Avram Goldstein, who was now our Stanford neighbor, suggested a role of endogenous opiates in eliciting the thrills of pleasure—for example, while listening to music (Goldstein, 1980). To us, an obvious physiological function of our own opiate was the control of pain—as demonstrated by the body of work with stimulation-produced analgesia. But aside from direct brain stimulation, what would trigger this anti-pain protective mechanism? Discussions with Jack and a graduate student in the lab, John Madden, led to the hypothesis that during stress, pain needs to be inhibited in order to allow the organism to fight or flee. We therefore set up the behavioral model and demonstrated that, indeed, stress was accompanied by significant pain inhibition, a phenomenon we termed “stress-induced analgesia.” Similar to SPA, stress-induced analgesia is naloxone reversible. Using our newly minted assays, we were able to demonstrate that it was accompanied by significant changes in the levels of the “opiate-like factor” in several brain regions (Madden et al., 1977). This work provided early evidence of one of the adaptive functions of the endogenous opiate system—pain inhibition to allow coping with other environmental demands. We should note that there is also a non-opioid form of stress-induced analgesia that was described by Liebeskind’s group, who went on to contrast the opioid and non-opioid forms of pain inhibition during stress (Lewis et al., 1980).

The Endorphins—Endogenous Opiates Galore (1974–1976)

Through the remainder of 1974 and throughout 1975, an intense race was underway to identify the endogenous morphine-like factor (see North and Hughes, 2013). The Goldstein group was relying on the bioassay used by Hughes and Kosterlitz—the guinea pig ileum—to identify the nature of the ligand and its naloxone reversibility (Teschemacher et al., 1975), while Snyder’s group was relying on the opiate receptor binding assay (Pasternak and Snyder, 1975). By late 1975, however, we heard that Hughes and his colleagues had indeed identified the chemical nature of their “enkephalin.” We saw a preprint of the Nature paper (Hughes et al., 1975), which was published in December, and the big surprise was that there were two pentapeptides: tyrosine-glycine-gycine-phenylalanine-methionine, which was termed met-enkephalin, and tyrosine-glycine-gycine-phenylalanine-leucine, which was termed leu-enkephalin. We immediately swung into action—we finally had a chemical structure and needed to have these peptides in hand to test their impact on behavior and to raise antibodies for radioimmunoassays and for anatomical studies. We promptly located a local peptide synthesis company (Peninsula Labs) and ordered the synthesis of one gram of each of these peptides. Before the end-of-year holidays, when we called to inquire about the status of the synthesis, the company founder asked: “What is this that you ordered? Yours was the first request, but since then everyone in the world wants this stuff!” We were off to the races!

In their seminal paper, Hughes et al. (1975) pointed out that the sequence of met-enkephalin could be found within the sequence of a previously identified pituitary hormone called beta-lipotropin (β-LPH). It was known that smaller peptides were derived from the processing of larger peptides or proteins via enzymes that cleaved at specified sites. Given that all of met-enkephalin was embedded in β-LPH, it was reasonable for them to propose that β-LPH could be the precursor of met-enkephalin. That sequence identity triggered a series of questions and threw the field into a state of confusion that was only resolved through the use of anatomical approaches.

β-LPH had been isolated from the pituitary gland by C. H. Li at the University of California in San Francisco. Li, a prominent biochemist, who had purified and sequenced many of the major pituitary hormones, was searching for a molecule that might control obesity and had identified β-LPH as having “fat mobilizing properties,” hence, the name. But the enkephalins had been isolated from the brain and β-LPH was in the pituitary—what was their relationship? Some scientists suggested that the primary source of endogenous opioids was indeed the pituitary and that the smaller peptide products represented retrograde flow back to the brain. Another issue was the precursor for leu-enkephalin. Was there a β-LPH equivalent with leucine in position five that would serve that function? And were both forms of β-LPH present in the brain?

Meanwhile, a new opiate-like peptide was born. The laboratory of C. H. Li isolated a 31 amino acid peptide from camel pituitary extracts and determined its structure (Li and Chung, 1976). Remarkably, the structure was identical to the sequence of carboxyl-terminal 31 amino acids of ovine β-LPH. The authors noted that this “peptide possessed very low lipotropic activity but significant opiate activity.” Indeed, Li, Loh, and their colleagues showed that it has remarkable analgesic activity that seemed to far exceed that of the enkephalins (Loh et al., 1976). Meanwhile, Roger Guillemin at the Salk Institute (who had received the Nobel Prize for his work on neuropeptides) was also identifying fragments of β-LPH and showing that they had opiate activity (Ling and Guillemin, 1976). At a meeting in 1974, Eric Simon had proposed the use of the term “endorphin” to indicate all the endogenous opiate molecules being discovered. This terminology was rapidly embraced, and C. H. Li termed his peptide β-endorphin because it was a fragment of β-LPH. Guillemin named the shorter fragment he had isolated α-endorphin. Another term for endogenous morphine-like or opiate-like molecules was adopted: opioids.

Once again, the discovery of β-endorphin threw the field into confusion, evident especially in discussions at scientific meetings. Because β-END appeared more potent and longer lasting in its behavioral effects relative to met-enkephalin, showing analgesia, cross-tolerance to morphine, as well as “catatonic” effects (Bloom et al., 1976; Loh et al., 1976: Tseng et al., 1976), some argued that it was the true endogenous opioid, while met-enkephalin was merely a breakdown product. Kosterlitz countered that long-lasting activity is not typical of classical neurotransmitters because they are typically rapidly degraded and suggested that β-endorphin might be a hormone (given its pituitary origin), whereas the enkephalins might be neurotransmitters (especially considering their neural origins).

Neuroanatomy to the Rescue!

A major thrust of our efforts in the Barchas lab was for Stan (who was carrying a full load as a psychiatry resident) to establish techniques for functional neuroanatomy, in order to allow us to study the neural circuitry implicated in pain control, including the monoamines and the endorphins. Jack Barchas secured the funds for the purchase of a cryostat and microscope and provided Stan with a darkened room in order to set up this technology in the lab. Indeed, the first joint Watson-Akil publication married our two research experiences up to that point by demonstrating an overlap between the brain sites that support stimulation-produced analgesia and the dorsal periventricular catecholamine bundle (Watson et al., 1977b).

In the early 1970s, Boyd Hartman and colleagues published their method for immunocytochemical visualization of dopamine-β-hydroxylase, the final enzyme in the biosynthesis of nor-epinephrine (Hartman et al., 1972), and the Swedish histochemist Thomas Hökfelt and his colleagues pioneered the use of immunocytochemistry to describe the distribution of the monoamine synthetic enzymes and of neuropeptides including somatostatin and substance P (Goldstein et al., 1971; Hökfelt et al., 1974, and cf. Hökfelt, 2010). These and similar papers opened up the entire world of protein and peptide visualization in the nervous tissue. And remarkably, although biochemistry and peptide biology had been critical in the discovery of the endorphins, it was immunohistochemistry that provided the answers to key questions that were plaguing the field.

Jack Barchas was one of the organizers of a meeting that was held at Asilomar, Calif., in January 1976, soon after the description of the enkephalins by Hughes and colleagues. John Hughes was invited at the last moment and stayed at our home in Los Altos on the way to the meeting site. This was the start of many years of friendship with John. Tomas Hökfelt was also at the meeting and asked us to introduce him to John. Hökfelt approached Hughes about a possible collaboration centered on mapping the distribution of the enkephalins in the brain, but John had already made other collaborative arrangements. Instead, each of their labs set out to develop their own antibodies against the enkephalins. By early summer of 1976, while at a meeting in Aberdeen, Scotland, we learned that Hökfelt’s group, in collaboration with Lars Terenius, had mapped leu-enkephalin in the brain (Elde et al., 1976). This was particularly important because it put to rest the idea that enkephalin was merely a breakdown artifact. Meanwhile, we raised our own antibodies to met-enkephalin (Sullivan et al., 1977) and used them in immunohistochemical studies to characterize its distribution in the brain—a pattern that appeared to resemble that of leu-enkephalin (Watson et al., 1977c).

But a key remaining question was the relationship of the enkephalins to β-LPH and β-endorphin. To this end, we requested a meeting with Dr. C. H. Li at UCSF, and he agreed to see the two of us. Being young scientists—a newly minted postdoc and a first-year resident—negotiating with Dr. Li was quite intimidating. A tall, regal, and reserved man, he clearly had his own agenda for us—for example, he wanted us to use behavioral techniques to show that β-END was important in memory and to develop a plasma radioimmunoassay that could be used in humans. But he also was interested in the mapping studies and finally agreed to provide us with the necessary antisera.

These antisera were great and terrible. Their working titers were quite high and thus gave a strong signal, but the antigens were purified from pituitary, which meant they were far from pristine. Unfortunately, protein purification in the mid-1970s was rather flawed in that many molecules of roughly the same size and charge were co-purified. For example, the β-LPH antibody also detected growth hormone, neurophysin, and prolactin. To handle this problem, it was necessary to pre-absorb the β-LPH antiserum with all of the aforementioned pituitary hormones in order to visualize the single population in the pituitary that expressed β-LPH (Watson et al., 1977d). Eventually, we raised our own antibodies against β-endorphin using synthetic peptide coupled to a carrier antigen.

A central question was whether β-LPH/β-END existed in brain. The idea that retrograde flow from the pituitary into the brain was responsible for the brain analgesia needed to be addressed, especially because it was espoused by some very distinguished scientists, including Nobel Prize winner Rosalyn Yalow. So, it was very exciting to visualize for the first time the presence of β-END in brain! Using immunohistochemistry, we identified a major cell group that expressed these peptides—the arcuate nucleus of the hypothalmus (Watson et al., 1978b). It was also quite revealing because the anatomy was so distinctly different from that of leu- and met-enkephalin and contrasting them became critical.

Two Distinct Opioid Circuitries in the Central Nervous System—or When Science Meets Everyday Life

By the fall of 1977, we had compelling evidence that there were two separate opioid systems in the brain—the two enkephalins that were widespread in their distributions and that appeared to overlap in their location and β-END, which had a single major cell group in the hypothalamus with long projections both rostral and caudal. (Our later studies showed a smaller β-END cell group in the brainstem nucleus of the tractus solitarius [Khachaturian et al., 1984]). Indeed, our Nature paper (Watson et al., 1978b) was entitled: “Evidence for two separate opiate peptide neuronal systems.” This was remarkable news because it laid to rest many questions in the field while raising new ones. Yes, the enkephalins and β-END appeared to be bona fide neurotransmitters—not just breakdown products and a pituitary hormone; and no, it did not seem as if met-enkephalin derived from β-END. So, the synthetic origin of the enkephalins remained in question. We were aware at the time that Floyd Bloom at the Salk Institute was working on this same neuroanatomical question in collaboration with Roger Guillemin, and we were hoping that our findings were consistent with his—and indeed they were (Bloom et al., 1978).

Meanwhile, we were expecting our first child in early December. But an important meeting was looming large—that of the American College of Neuropsychopharmacology (ACNP) taking place December 14–16, 1977, in San Juan, Puerto Rico, where a whole symposium was devoted to the latest developments in the opioid field. This was before our anatomical studies or Floyd’s were published, so we decided that the meeting was important enough that Stan should try to attend it even if it was a few days after Huda’s delivery. But that baby was not following our schedule and would not arrive for another two weeks, so Stan had to cancel his trip to the meeting. With Jack’s encouragement, we decided to contact Floyd Bloom, whom we knew would be talking at the meeting and ask him whether he would be willing to show some of our slides on the anatomy of the two opioid systems. He generously agreed. In the midst of false labor cramps, we stayed up late preparing a set of slides for him to choose from, along with a cassette tape describing the experimental details for each of them. We remained in Palo Alto awaiting the baby’s arrival and news from the meeting with baited breath. To our utter amazement, we heard that Floyd spent most of his talk presenting our slides, saying that he had similar data but that our images were more clear-cut. He explained the reason for Stan’s absence and apparently the baby’s delivery became a topic of frequent inquiry at the meeting! We were awed that, at a time of such heated competition, Floyd would be so incredibly generous and rise above the fray! In so doing, he set an example of scientific values that we have never forgotten. And his generative style appeared contagious. Not only did many people contact us with warm personal and scientific messages, but Avram Goldstein took extensive notes at the meeting, had them typed up, and sent them as a “baby present.” Meanwhile, C. H. Li had wished us the best of luck on the delivery, urged us to have a son, and encouraged us to collect blood from mother, child, and umbilical cord to ascertain changes in levels of β-END during delivery! We followed his advice, which meant we had to first establish a plasma radioimmunassay for β-END. It also meant that Stan had to be collecting blood during the delivery! We subsequently published a paper showing that β-END was in fact increased during pregnancy and labor, although its functions in the circulation remain unknown (Akil et al., 1979).

Endorphins and Stimulation-Produced Analgesia—Direct Evidence

With radioimmunoassays in hand, we finally had the opportunity to directly test the hypothesis that was put forward at UCLA—that analgetic brain stimulation activates an endogenous pain inhibitory system and releases opiate-like factors. We collaborated with Don Richardson at Tulane University who was continuing to use the deep brain stimulation approach in human subjects, and he collected cerebrospinal fluid from the third ventricles of these patients during the course of the surgery. We obtained evidence of enhanced levels of both enkephalin and β-END following electrical stimulation (Akil et al., 1978a, 1978b). The elevation of β-END was more sustained, and given its highly analgesic effects when exogenously administered and the reversal of the analgesia by naloxone including in humans, it was reasonable to conclude that it was a critical player in SPA. This was supported by the anatomy of β-END, whereby the descending projection from the arcuate cell group runs along the medial periventricular sites coincident with those that elicit analgesia (and in the opposite direction to the ascending periventricular catecholamine bundle). However, we also showed that enkephalin could be rapidly degraded (Sullivan et al., 1978, 1980), which suggested that it might produce local modulation of pain responses but might not survive long in the cerebrospinal fluid. The findings on release of endogenous opioids in humans upon deep brain stimulation represented the integration of animal and human studies culminating in a remarkable “translational” outcome.

But Wait—There’s More! A Molecule of Pain, Addiction, Stress, and Skin Pigmentation

As if the endorphin tale were not exciting enough, there arose a whole new dimension associated with β-END/β-LPH. As noted earlier, β-LPH was isolated from the pituitary gland, and anatomical studies showed that it was localized exclusively to the corticotrophs—that is, the cells of the pituitary that synthesize and release adreno-corticotropin hormone (ACTH), the stress hormone. It should be noted that the N-terminal region of ACTH (ACTH1–13) can be cleaved and modified by N-acetylation and C-terminal amidation to give rise to alpha-melanocyte stimulation hormone (α-MSH). This hormone was known to be important in skin pigmentation as well as playing a role in stress responses in certain animals (e.g., frogs). Remarkably, β-LPH contained a homologous sequence in its N-terminal domain termed β-MSH, which also possessed the ability to alter pigmentation. Recall that β-LPH also contains the entire sequence of β-END at its extreme carboxy-terminus. Thus, beyond the presence of β-LPH in the corticotrophs, there was evidence of some structural and functional relationships between β-LPH/β-MSH/β-END on the one hand and ACTH/α-MSH on the other. But what exactly was that relationship?

It was the elegant work of Edward Herbert and his students, James Roberts, Richard Mains, and Betty Eipper, that moved the field dramatically (Mains and Eipper, 1977; Roberts and Herbert, 1977a,b; Eipper and Mains, 1978). They showed that all of these active peptides derive from a common precursor protein that came to be known as pro-opiomelanocortin (POMC). The name is descriptive because this common precursor encodes β-LPH (and therefore β-END and β-MSH) at its carboxy-terminal end and encodes ACTH (and therefore α-MSH) in its middle region. It was clear that there was a large N-terminal region of this precursor of unknown sequence and function. Painstaking work showed that the active peptide hormones derived from the systematic cleavage of this precursor via specific enzymes that recognize appropriate dibasic cleavage sites. Different lobes of the pituitary gland process these peptides to different extents, with the anterior lobe making ACTH and a mix of β-LPH and β-END, whereas the intermediate lobe processes POMC more fully to α-MSH, β-MSH, and β-END.

Given that we had seen β-LPH and β-END in the brain, could we provide evidence of the existence of other POMC related peptides in the central nervous system? To this end, we demonstrated the existence of ACTH immunoreactivity in the arcuate nucleus and the co-existence of ACTH with β-LPH/ β-END in the same area (Watson et al., 1978a).

In a landmark paper showing the first cloning of a mammalian gene, Nakanishi et al. (1979) provided the full nucleotide sequence (1,091-base pair) of a cDNA encoding bovine POMC. The amino acid sequence revealed that the heretofore-undescribed N-terminal domain of the precursor encodes a third melanotropin sequence that they termed gamma-MSH. Thus, the cloning of POMC revealed that a single gene could encode multiple active products (ACTH, MSH, β-END) as disparate in their function as skin pigmentation, stress control, and pain and affect control. It also demonstrated that a given gene could have repeated motifs (i.e., the MSH core sequence). But equally notable was the fact that there was no evidence of a sequence that could give rise to leu-enkephalin, further supporting the anatomical evidence that suggested that the enkephalins were distinct from β-LPH/β-END and did not derive from the POMC precursor. Interestingly, a collaborator on the Nakanishi et al. (1979) paper was the pioneer in molecular engineering, Stanley Cohen, who worked one hallway away from the Barchas lab. Even though both our groups were studying POMC and had some key reagents (e.g., antibodies) that might have been helpful, the two labs were unaware of these parallel efforts.

Moving to Michigan

We began our search for faculty positions while still expecting our first child. We faced the issue of coordinating two careers at a time when there was less awareness of such issues. But we were also very lucky to wind up with several options. Gardner Quarton, the director of the Mental Health Research Institute (MHRI) at the University of Michigan, was a patrician, thoughtful, and sophisticated man who clearly understood our individual and combined career needs. Bernard Agranoff and Bernard Carroll were also members of the MHRI, and Bernie and Barney (!) were very critical in our recruitment. As importantly, the institute (now renamed the Molecular and Behavioral Neuroscience Institute–MBNI) represented an ideal setting for us. We were both interested in fundamental neuroscience research, but we were also interested in moving between animal and human work—-translational science, before it was so designated. Our interests were moving toward not only understanding the basic biology of opioids in brain and pituitary but also exploring their functions in drug abuse and in the biology of stress—especially considering our work on stress-induced analgesia. In many ways, the sequence of POMC was our research program. Moreover, while at Stanford, we had also pursued work on the potential role of endorphins in schizophrenia (Watson et al., 1978, 1979), and the institute’s close ties to the psychiatry department were a major draw. But so was the fact that this was, in fact, a neuroscience institute. Indeed, Ralph Waldo Gerard, one of the founders of the Society for Neuroscience who had coined the term “neuroscience,” was also one of the original members of the institute. The director, Gardner Quarton, had worked at the Neuroscience Research Program (NRP)—the same entity that had sponsored the opiate receptors meeting where Hughes had revealed the existence of enkephalins. And Bernard Agranoff had carried out his landmark work on the biochemical nature of memory. By December 1977, at about the time that the ACNP meeting took place and our first child was born, we decided to make the University of Michigan our next academic destination. We, our son Brendon, and our daughter Kathleen (Katie), who was born in Ann Arbor, have called it home ever since!

For Huda, in particular, there were several ironies in this choice—for example, an early rejection of her graduate school application from the University of Michigan Psychology Department. But more positively, the fact that three important people in her life had worked not only in this same university but in this very institute: James Olds, Steve Fox, and John Liebeskind! In fact, while awaiting the arrival of new furniture for our labs, we dug out some lab stools from storage and on the bottom of several of them was written boldly: “Olds Lab.” It seemed fated.

Indeed, the MBNI, the department of psychiatry, and the University of Michigan more broadly have proven to be a wonderful academic home to both of us, and Bernie Agranoff is yet another remarkable mentor who taught us how to remain passionate about science while navigating the administrative world thoughtfully, strategically, and with humor.

The Regulation and Function of Pro-Opiomelanocortin and Its Products

Moving to Michigan, we began to define a research program that would integrate our combined interests and skills. We had two separate labs, but we knew we would be collaborating actively. Although many issues were still swirling in the field, it seemed to us that a central one was how to think about the function of these opioid peptides in the central nervous system—not just as neurohormones or pituitary releasing factors but as bona fide neurotransmitters. We were used to thinking about monoamines, but the biosynthesis, release, regulation, and receptor actions of neuropeptides remained a mystery. Moreover, POMC presented a unique challenge. It contains so many different active peptides, and we knew that it was processed to different extents in the anterior versus intermediate lobes of the pituitary. How was it handled in the brain? And how do we conceive of an integrated function of these POMC peptides, when one could regulate pain and pleasure and the other could encode stress or modify skin color? Finally, although we understood some mechanisms of cellular regulation of classical neurotransmitters, we had no insights regarding these neuropeptides. Pharmacological tools that interact with the opioid receptors abounded, but no tools were available to manipulate the availability or release of the opioid peptides. Finally, the role of the endorphins in opiate tolerance, dependence, and addiction remained unexplored. There was clearly no shortage of questions for us to tackle.

Our early work clearly showed that the processing of POMC was distinctive in the brain—more complete than what is seen in the anterior pituitary corticotrophs but with fewer post-translational modifications than what is seen in the intermediate lobe, where β-END is N-acetylated, thereby losing its ability to activate opiate receptors (Akil et al., 1981). Further, ACTH was processed in the arcuate to α-MSH (Watson and Akil, 1979), although it would be many years before its function in controlling feeding would become evident. But our work suggested that the different POMC products, which are presumably released simultaneously at the synapse, could work in a coordinate fashion; thus, when we microinjected α-MSH in the periaqueductal gray, we observed analgesia similar to what is seen with β-END, although the α-MSH induced analgesia was non-opioid in nature (Walker et al., 1980). This suggested that peptide products deriving from the same precursor could work coordinately on the same target function, albeit via different receptor mechanisms.

We also pursued the question of interplay between stress and opioids (which we had initiated at Stanford) in much greater depth, acquiring a mechanistic understanding of how stress triggered changes in the biosynthesis, processing, and release of POMC in the pituitary and in the brain (Akil et al., 1985; Young and Akil, 1985a,b). Finally, we examined the impact of chronic morphine on the regulation of POMC and especially on the synthesis of various forms of β-END that differed in their opiate potencies (Bronstein et al., 1988). This was a way of addressing the dynamic regulation of this system. Thus, we stated in a review (Akil et al., 1984): “It is conceivable that the modification of β-END 1-31 into β-END 1-27, which is ten-fold less active as an opioid, may serve a physiological function. Furthermore, such a modification appears to require time, and may not take place if β-END 1-31 is freshly synthesized. Thus, a measurement of the ratio of these two forms may yield an index of activity in the system and may correlate with various functional states of the animal.” These types of questions required that we establish methods such as pulse-chase studies, high-pressure liquid chromatography (HPLC) coupled to radioimmunoassays, as well as receptor-binding assays to study the dynamics of function and regulation of POMC in the brain and pituitary, under physiological conditions.

These and other regulatory studies revealed a pattern of POMC communication and regulation that greatly broadened our views of synaptic transmission—it no longer seemed to be a simple on/off system but rather relied on a host of molecules of different lengths, post-translational modifications, receptor selectivities, and durations of action. Moreover, the exact mix changed under different physiological conditions such as pain, stress, or addiction. In other words, although we began by thinking that synapses were monosyllabic, neuropeptides taught us that they actually spoke in sentences.

One More Opioid Family

In 1979, Avram Goldstein’s lab identified a new 13 amino acid opioid peptide termed “dynorphin 1–13,” which they characterized as “an extraordinarily potent opioid peptide” because it was 700 times more potent than enkephalin in the guinea pig ileum. Remarkably, the first five amino terminal residues of dynorphin were identical to the full sequence of leu-enk. Could this be the missing precursor for leu-enk, or was it a situation similar to β-END, where the sequences were overlapping but the anatomy was distinct?

Soon after our arrival at Michigan, Avram approached us about mapping this new peptide in the brain. And once again, the anatomy proved to be highly revealing. Dynorphin distribution was distinctly different from that of either the enkephalins or POMC. Thus, dynorphin immunoreactivity was most prominent in the paraventricular nucleus of the hypothalamus and overlapped with the expression of arginine vasopressin, with projection to the posterior pituitary (Watson et al., 1981, 1982a). We carried out a systematic analysis, using improved antibodies against a host of opioid peptides to compare the distribution of dynorphin versus the enkephalins in brain. This paper concluded, “It thus appears that the brain contains at least three separate opioid neuronal networks: an enkephalin family . . . , a beta-endorphin family, and a dynorphin family” (Watson et al., 1982b). These anatomical observations proved to be completely consistent with biochemical studies showing the existence of three separate precursors for these peptides (see following).

However, at the behavioral level, dynorphin appeared to be an unusual sort of opioid. In spite of its potency in the guinea pig ileum, it did not produce very good analgesia. Moreover, we showed that intracerebroventricular administration of dynorphin produced potent and long-lasting effects on motor function and on the electroencephalogram in rats, and local iontophoretic or pressure ejection of dynorphin consistently inhibited hippocampal unit activity. None of these effects were significantly affected by naloxone even at high doses. Moreover, a fragment of dynorphin that failed to displace any number of tritiated narcotics from rat brain homogenates produced similar effects on these physiological measures in vivo. We suggested that dynorphin was an unusual opiate and that its sequence also contained a second biologically active site that is capable of quite potent but non-opiate effects (Walker et al., 1982). These behavioral observations added to a host of findings (e.g., differential profiles in the guinea pig ileum and mouse vas deferens) that suggested the existence of multiple opiate receptors (see following), as well as activities mediated via non-opioid peptide products.

Everyone Finds a Home

In 1984, we wrote a review of the opioid field (Akil et al., 1984) that began with the following summary statement: “While most would agree that the mid-seventies were vintage years for endorphin research, 1982 is certain to be ‘a very good year.’ Less obvious to the public eye, it is nevertheless a turning point in endorphin research because it is the year in which all the brain opioids found a home.” Indeed, after several years of uncertainty about the relationships between the various opioid peptides, a combination of biochemical studies and molecular cloning in peripheral tissues such as the pituitary and the adrenal clarified the major structural issues. By the early 1980s, more than a dozen opioid peptides had been isolated from the brain, pituitary, and adrenal medulla. They all shared the Tyr-Gly-Gly-Phe sequence followed by either met or leu at their N-termini. And then they either stopped at five residues (enkephalins) or had various extensions ranging from two to 26 amino acids. Molecular cloning showed three distinct families: POMC (as described earlier) containing β-END that could be processed to various forms; pro-enkephalin, which contained seven copies of the Tyr-Gly-Gly-Phe core—these included leu-enkephalin, four repeats of met-enkephalin, and two extended forms of met-enkephalin (with two and three additional amino acids following methionine); and pro-dynorphin, which included three copies of the Tyr-Gly-Gly-Phe core, each followed by leucine and with various extensions yielding the peptides dynorphin A (the first one cloned by Goldstein), dynorphin B, and neo-endorphin. Many of these peptide domains could be further modified post-translationally with additional cleavage, N-acetylation, or carboxy-terminal amidation to alter their stability, opioid selectivity, and potency at the receptor and in vivo (Nakanishi et al., 1979; Comb et al., 1982; Kakidani et al., 1982; Noda et al., 1982).

These cloning results corroborated the body of work carried out on the brain distributions of these peptidergic systems across several laboratories. In turn, the co-expression of opioid peptides from the same precursor within the same neurons was confirmed by immunohistochemical studies (e.g., Khachaturian et al., 1983a, 1983b, 1985; Watson et al., 1983) and by extensive characterization in particular brain loci (Dores et al., 1985).

Multiple Opioid Receptors

The original receptor binding studies in the brain characterized a receptor that was “classical” in its pharmacology in that it recognized opiate drugs with affinities that were consistent with their analgesic potencies and with their effect in the guinea pig ileum. In effect, this was the classical morphine receptor. However, in the mid 1970s, Martin and his colleagues (1976) suggested that there were multiple opiate receptors based on studies of analgesia, tolerance, and cross-tolerance in the dog. In particular, they proposed the existence of a mu (for morphine preferring) and a kappa (ketazocine preferring) opiate receptor. A third receptor they suggested, sigma, eventually proved to be non-opioid in nature. However, Kosterlitz and his colleagues had suggested that the mouse vas deferens contained an opiate receptor that had properties distinct from those of the guinea pig ileum, which they termed the “delta opiate receptor.” The enkephalins appeared to be particularly good ligands at that delta site, whereas dynorphin was not (Goldstein et al., 1979). Thus, by the early 1980s, the field had identified three types of opiate binding sites: mu, delta, and kappa (Kosterlitz et al., 1980; Gillan and Kosterlitz, 1982).

In the same review (Akil et al., 1984) in which we summarized the existence of three precursors that encode all the known opioid ligands, we addressed the issue of multiple opioid receptors by stating: “Less clear, but equally critical, is the issue of multiple opioid receptors. Unquestionably, the heterogeneity exists. What remains to be established is whether each of the three families of opioids has its own receptor, or whether a given family can interact with more than one subtype, and each receptor subtype with more than one family. More critical to physiology is whether these unique combinations result in different biological events and are involved in different functions.”

Of course, the answer turned out to be the more complicated one. The most straightforward relationship between the opioid ligands and their receptors is the one between pro-dynorphin and the kappa opioid receptor, in that kappa has high affinity only to the products of the pro-dynorphin family. However, there is no symmetry in that members of the pro-dynorphin family also interact with other opioid receptors, especially mu. The delta opioid receptor recognizes with high affinity the members of the pro-enkephalin and of the POMC family. Finally, the classical mu opioid receptor can interact with high affinity with members of each of the three precursors. Each of these receptors also has a unique profile vis-à-vis synthetic peptides and opiate alkaloids (see Gutstein and Akil, 2006, for review). It should be noted that whether based on their signaling properties or their anatomy, activation of each of the three types of opioid receptors yielded a different pharmacological and behavioral profile. For example, activation of the kappa receptor can be analgetic but can cause dysphoric responses, unlike the combination of analgesia and positive responses elicited by activation of the mu receptor.

The complexity of peptidergic neurotransmission was evident once again—a given precursor gives rise to multiple opioid (and non-opioid) peptides that are capable of interacting with multiple opioid receptors. The signaling in any given location would depend on the exact juxtaposition of neuropeptides and specific receptors determining the eventual functional signal. It was therefore critical to map the distribution of the three types of opioid receptors, an extensive effort that we undertook in the brain of multiple species and across development (Mansour et al., 1987, 1988, 1995 a,b). Maps of the three opioid peptide families and the three opioid receptors produced by our group appeared very popular and hung on many lab walls.

However, the purification and the cloning of the opioid receptors proved remarkably stubborn. It was not until 1992 that two groups, using functional cloning strategies, succeeded in cloning the delta opioid receptor (Evans et al., 1992; Kieffer et al., 1992). This allowed other groups including ours to clone the other two opioid receptors, mu and kappa (Meng et al., 1993; Thompson et al., 1993; Xie et al., 1994). This opened the door to extensive studies on the anatomy, regulation, function, and structure activity relationships of these receptors. For example, we generated numerous mutants and chimeras of these receptors to identify the domains that are critical to selectivity and discrimination among the various opioid peptides (Meng et al., 1996; Watson et al., 1996).

Developing Technology to Study Gene Expression and Regulation in Brain—In Situ Hybridization

The history of opioids brought home the importance of developing technologies that are both powerful and aimed at understanding neurobiology at the level of neural circuits. Techniques that married neuroanatomy with the ability to examine specific functional molecules had transformed neuroscience in the 1960s and 1970s. These techniques included monoamine fluorescence and immunocytochemistry. Yet both had significant limitations that made the study of regulation in a neuroanatomical context challenging.

Monoamine fluorescence was not only limited to a small set of neurotransmitters, but the fluors decayed rapidly, rendering quantitative studies very difficult. Immunohistochemisty (ICC) had clear advantages because the fluorescent signal lasted up to a few hours, and subsequent staining methods (horseradish peroxidase or alkaline phosphatase) produced color precipitates that were essentially permanent. Yet ICC had several pitfalls, especially when dealing with a novel target molecule. The size of the average epitope for most antibodies is in the range of four to six amino acids, and yet this short sequence is the key determinant of the specificity of antibody binding. This results in numerous issues of cross reactivity with other proteins, such that any one serum can provide misleading information. There are some reasonable solutions to this issue—the use of multiple antisera aimed at the same peptide/protein, affinity purification of the antibody to isolate a specific population, or the use of monoclonal IgGs. However, polyclonal antibodies offer certain advantages because they can contain subpopulations that prefer different forms of a given molecule—for example, the full length POMC precursor, or an intermediate such as β-LPH, or a final product such as β-END. This flexibility is particularly helpful when the exact nature of the product in the brain is still unclear.

But arguably the biggest drawback of ICC is that it is poor for quantitation, and therefore not readily conducive to regulatory studies. The variation in structure of the target protein coupled with the variation in IgG pools combine to make a quantitative analysis less than optimal. Moreover, the methods of preparing an epitope for immunization need to be adapted to the nature of the sequence and the three-dimensional structure of the target protein. Essentially, each antibody is custom-prepared and requires specialized methods for effective visualization—rendering comparisons between proteins extremely difficult.

So, how could one circumvent these issues and study gene expression and regulation in a neuroanatomical context? Given the revolution in molecular biology at the time, it became evident (to us and to others) that adapting the tools of that field to neuroscience would be extremely powerful. In the 1980s, developing a tool to visualize messenger RNA (mRNA) in a neuronal context became a major thrust of the Watson lab in a close collaboration with the lab of James Roberts. Jim had been in the Herbert lab in Oregon and had played a critical role in the early identification of the common ACTH/LPH precursor (Roberts and Herbert, 1977a,b). He had moved by then to Columbia University, and he brought to the collaboration his great knowledge of molecular biology, his warm and generous style, and a wonderful sense of humor and adventure. Other key members of the team were Connie Gee, in Jim’s lab, and Robert Thompson in the Watson lab (now a friend and faculty colleague at the Michigan). Together, this team developed a technique that came to be known as in situ hybridization (ISH), and they published the first paper using this tool in the brain, aptly showing the presence of POMC in the arcuate nucleus of the hypothalamus (Gee et al., 1983). The power of ISH was immediately recognized by the neuroscience community—our poster at the Society for Neuroscience annual meeting in 1984 was mobbed, suggesting that this was a tool whose time had come.

At the time of our first efforts at in situ hybridization, the world of molecular biology typically quantified mRNAs by Northern gel analyses—that is, by extracting the mRNA from tissue, running it on a gel, and identifying it by using a P32 labeled, double-stranded DNA probe. The method was reliable and quantitative but sacrificed the entire tissue block, leading to only very crude anatomical resolution.

There had been very few efforts toward a more anatomical approach. A notable one was a brief, two-page report by John Shine using ³²P double-stranded DNA probes to visualize POMC in a rat pituitary. The image was rather blurry with no cellular resolution because ³²P scatter is huge. Still, it was a proof-of-concept. But how do we ensure cellular resolution, quantitate the signal, and obtain high sensitivity? We also had to struggle with tissue fixation and probe penetration into the tissue section.

Our initial experiments with ³²P-labeled, double-stranded DNA led to the same blurry signal seen in Shine’s paper. We considered ³H-labeled probes, given that they have approximately 200 times less scatter, but they were weak emitters. In the end, we found ³⁵S to be a good compromise. It has a scatter of only one to three microns and is a considerably stronger emitter. Indeed, the next set of experiments using ³⁵S-labeled, double-stranded DNA yielded much better anatomy. Single cells were visible, even in the brain! But the method was rather variable in the intensity of the signals it produced. Quantitation was not reliable, and sensitivity to low copy number mRNAs (which are common for signaling molecules) was suboptimal.

We determined that the next hurdle was the biochemical nature of the probe (i.e., being double-stranded DNA). It defeated itself. After labeling, it was necessary to raise the temperature to melt the strands apart and to allow the antisense DNA strand to hybridize with the target mRNA; unfortunately, it could also re-hybridize with the sense strand DNA, interfering with quantitation and sensitivity. Ideally, we needed a single-stranded probe of a defined and consistent length. This would allow us to control hybridization kinetics and therefore accurately estimate the number of mRNA molecules of interest. But there was nothing available to resolve this problem at the time.

Even so, we made substantial progress at the technical, anatomical, and biochemical levels during this phase. For example, we were able to show that POMC neurons not only contained all the POMC products (Watson et al., 1977d, 1978a,b) but also the mRNA that coded for POMC (Kelsey et al., 1986; Lewis et al., 1986). Although such an observation is obvious now, it was critical in responding to the stubbornly lingering notion that POMC peptides flowed from the pituitary into the blood stream and then back into the brain where they were taken up and concentrated.

We soon began to consider the use of oligonucleotides (15–50 bases) as probes because they are single stranded and produce a reliable and semi-quantitative signal. However, we had to wrestle with their lack of sensitivity because we could only add one or two radioactive nucleotides to the ends of the probe. Then a postdoctoral fellow in the lab, Michael Lewis, came up with an ingenious solution (Lewis, et al., 1986). He suggested using 3’ deoxynucleotidal transferase to add a random radioactive tail to the oligo probes. This worked much better, and we could make tails of up to 50 nucleotides without much loss of stability.

The next breakthrough was the availability of tools for in vitro transcription of single-stranded, labeled mRNA. The transcription was high fidelity and produced a highly radioactive, antisense strand. Even with that first gel: a single band! We had achieved the clean, highly radioactive ³⁵S-labeled antisense probe we needed. It produced a lovely signal with greatly improved background at the single-cell level of resolution. Beyond the nature of the probe, the key was to treat the tissue with RNase after the label hybridized. This post-treatment would not digest RNA:RNA double strands but would digest unhybridized labeled RNA, thereby dramatically reducing the background noise.

Just as the Swedish histochemists at the Karolinska Institute explored any and all variables associated with their methods, we felt it was important to follow suit in optimizing this technique. We used more than 10,000 slides in this process, defining the conditions and strategies to ensure specificity of the signal and reliability of the quantitation. We were also committed to being explicit about these conditions and to training others in the use of this technique. It is gratifying that since our first paper appeared in 1983, thousands of researchers have relied on this tool as a means of studying gene expression and regulation in the nervous system.

In Situ Hybridization in Service of Understanding the Biology of Opioids and Stress Systems

Once a practicable version of in situ hybridization was developed, there was an obvious shift in the nature of neuroanatomical studies. Neuroscientists could see not only the anatomical value of ISH but its power to quantitate mRNA levels in their paradigms involving behavior, lesions, electrical stimulation, electrophysiology, pharmacological and physiological manipulations, and developmental studies. In a sense, neural circuits became measurable, in terms of their basal activity and their response to stimuli, and the connection between genes and function could now be more easily envisioned.

Of course, for us, one of the earliest applications of ISH was the study of the opioid system at the gene-expression level. This included the original demonstration of POMC mRNA in the arcuate nucleus (Gee et al., 1983), as well as the discovery of a small POMC cell group in the nucleus tractus solitarius (Bronstein et al., 1992). It also included the full mapping of the gene expression of two other opioid precursors as well as the opioid receptors (Mansour et al., 1995a,b)

But we also put ISH to a range of other uses all in service of understanding regulatory biology of specific molecules in the context of neural circuits. For example, we showed that in hypothalamic magnocellular neurons, dynorphin gene expression is coregulated with vasopressin and oxytocin genes by osmotic challenge (Sherman et al., 1988). Additional modifications of the technique allowed us to study the co-expression of multiple genes in a single neuron via dual ISH, thereby defining functionally distinct subpopulation of neurons in brain areas relevant to reward (e.g., Curran and Watson, 1995) and stress and negative affect (Day et al., 1999). We were also able to use ISH to assess c-fos gene expression and to couple it to track tracing in order to define specific circuits involved in the neural integration of the stress response (e.g., Herman et al., 1989; Cullinan et al., 1993). An underappreciated but extremely helpful tool is the use of intronic in situ hybridization. In this approach, the hybridization probe is aimed at specific introns within the gene of interest, allowing the detection of heteronuclear RNA (hnRNA). This is the primary transcript that exists briefly immediately following transcription and before the deletion of introns that results in mature mRNA. Because the half-life of a given intron is so short, the levels of introns directly reflect changes in the rate of hnRNA synthesis and can therefore be used to detect changes in transcription (Herman et al., 1991; Itoi et al., 1999). Thus, intronic ISH allows the study of dynamic changes in gene activity in the context of specific neurons and neural circuits.

But ISH also became the “go-to” approach for assessing the expressing of newly cloned genes of relevance to neural functions. Thus, our group relied on it to provide the initial mapping of gene expression upon the cloning of the dopamine receptors (e.g., Meador-Woodruff et al., 1989), the corticosteroid receptors (Herman et al., 1989), or of new peptide families such as orphanin/nociceptin (Neal et al., 1999). Coupled with other anatomical, functional, and molecular tools, it continues to be a cornerstone of studies of regulatory biology in the nervous system.

Telescoping to the Present Day

The study of opioids was the jumping off point for our broader interest in the study of regulation of emotions. The endogenous opioids exemplify the integrated way in which the brain and neuroendocrine system orchestrate a range of affective and motivated responses. Endorphins control pain, pleasure, stress responses, appetite, and sleep as well as autonomic, neuroendocrine, and digestive functions. Indeed a single gene, POMC, encodes peptides classically associated with the control of stress (ACTH), pain, pleasure (β-END), and appetite control (α-MSH). Our laboratories initially focused on the neurobiology of substance abuse on the one hand and of stress on the other as model systems of regulation of affective pathways. But it soon became clear that these two domains are closely intertwined—for example, in the way that stress contributes to various aspects of addictive behavior, and addiction, in turn, alters coping and stress responsiveness. Moreover, the interplay with stress applies not only to opiates but to many drugs, such as cocaine and alcohol.

Although the reductionist approach had clearly paid off in the opioid arena, a true understanding of affective behavior requires a more integrative approach. Given our combined interests in genetics, molecular biology, neuroanatomy, pharmacology, and behavior, we felt ready to face the broader challenge of understanding affect regulation under “normal” conditions and in pathological states. Our translational perspective, including our various studies in humans, had underscored the variability in affective responses among individuals and the fact that the same event is perceived as a stressor by one person and as a positive challenge by another. Yet, differences in vulnerability or resilience to environmental and psychosocial challenge, although hugely important in psychiatry, were rarely studied in basic neuroscience.

Indeed, epidemiological and genetic studies have consistently suggested that there are stable personality and temperamental styles that could predict the types of psychopathology that a person might develop. Thus, a more inhibited “internalizing” personality style is associated with vulnerability to anxiety and depression, whereas a more impulsive “externalizing” personality style is associated with a propensity to conduct disorders and substance abuse. Moreover, these behavioral traits were very stable characteristics of humans, evident during early childhood and greatly predictive of future behavior (Kagan et al., 1989; Mischel et al., 1989). Here was a fundamental dimension of behavior that defined not only affect but its relationship to cognition and psychopathology. Yet, at the time, the neurobiology of “temperament” was not a serious topic of neuroscientific analysis. We decided to tackle this issue, bringing to bear on it a combination of genetic, neurochemical, anatomical, behavioral, and translational perspectives. We have been successful in creating animal models of “internalizers” versus “externalizers,” and remarkably, our selective breeding of these behavioral phenotypes maps beautifully onto the human characteristics for predicting propensity to anxiety, depression, aggression, and substance abuse (Flagel et al., 2013). We have identified a number of molecular mechanisms, genetic and epigenetic, that lead to these stable differences (e.g., Turner et al., 2011) and shown that these animals respond differently to the world around them, from affective challenges to associative learning (Flagel et al., 2011, 2013). Importantly, this animal model of “temperamental” differences provides us with an excellent vehicle for studying the function of candidate genes that are emerging from human genetic and postmortem studies of psychiatric illness, especially in relation to mood disorders.

Arguably one of the most ephemeral targets of neurobiology has been to understand the basic biology of mood and the pathophysiology of mood disorders. The concept of mood is itself ephemeral in nature, and yet dysregulation of mood and affect represents one of the largest burdens of disease worldwide. Our work in opioids and stress biology, and the well-established role of stress as a trigger of mood disorders, sparked our initial interest in the study of brain mechanisms of depression (e.g., Young et al., 1994). But this work has mostly flourished in the context of an unusual, broad-scale and long-lasting collaboration called the Pritzker Neuropsychiatric Research Consortium. Beyond our group and colleagues at the University of Michigan, the consortium involves our mentor, Jack Barchas, who is now the chair of psychiatry at Cornell University, along with Alan Schatzberg at Stanford, William (Biff) Bunney at University of California at Irvine, Rick Myers at the HudsonAlpha Institute, and the late Edward (Ted) Jones at the University of California at Davis. This group of scientists and their colleagues bring together a range of scientific fields—genetics and genomics, informatics, neuroscience, and psychiatry, along with the rich and ever-evolving toolset of modern biology in order to investigate the brain biology of severe psychiatric illness. We rely on a world-class brain bank (headed by Biff Bunney) for postmortem analyses, along with the study of human subjects, animal models, and even in vitro systems. This collaboration has led to numerous insights regarding the neurobiology of psychiatric disorders (e.g., Evans et al., 2004; Scott et al., 2009; Bernard et al., 2011; Turner et al., 2012; Li et al., 2013) and deserves its own recounting. But it underscores the need for new scientific models to address the major challenges that the field of neuroscience continues to face because of the complexity of the problems that it tries to unravel.

Final Thoughts

The Danish scientist and mathematician Piet Hein said: “Problems worthy of attack prove their worth by attacking back.” We feel lucky that, in more than four decades of neuroscience research, we have been attacked back on a regular basis by the problems we have chosen. This has kept us energized, excited, and ready to pick a new fight. As we solve one little mystery about the functioning of the brain, dozens of new ones emerge. Our simplistic hypotheses have been crushed by biological reality on a regular basis, and the process is truly humbling. This is exactly why we treasure any contributions we have made that have stood the test of time.

During this journey, we have learned the importance of relying on each other—not just each other as a couple, but on our research group, our students, our mentors, our collaborators and colleagues, and our scientific community, including those who have come before us. We have come to understand the critical need for different kinds of minds working together to try to solve the ultimate mystery: how the mind works.

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Philippe Ascher

BORN:

Commercy, France

July 28, 1936

EDUCATION:

Ecole Normale Supérieure, Paris (1955–1959)

Faculté des Sciences, Université de Paris (1955–1959)

Doctorat d’Etat es Sciences Naturelles, Paris (1965)

APPOINTMENTS:

Assistant, Faculté des Sciences, Paris (1959–1961)

Maître-Assistant, Faculté des Sciences, Paris (1961–1965)

Chargé de Recherches, Centre National de la Recherche Scientifique (1966–1968)

Maître de Conférences, Faculté des Sciences, Paris (1969–1972)

Professor, Université Pierre et Marie Curie, Paris (1972–2000)

Professor, Université Denis Diderot, Paris (2000–2004)

Professor, Université Denis Diderot (emeritus)

HONORS AND AWARDS:

Forbes Lecturer (1977)

Academia Europea (1989)

Académie des Sciences (Membre correspondant) (1990)

Luigi Galvani (Fidia Foundation) (1991)

Ipsen Foundation Prize (1992)

Richard Lounsbery Prize (1992)

Ulf von Euler Lecturer, Karolinska Institute (1993)

Warner-Lambert Lecturer, Society for Neuroscience (1993)

Dana Foundation Award (1994)

Physiological Society (Honorary Member) (2013)

Most of the work of Philippe Ascher has been devoted to the electrophysiological characterization of receptors to neurotransmitters. In his early studies of Aplysia neurons, he characterized excitatory and inhibitory responses to dopamine as well as the mechanism of action of acetylcholine and of acetylcholine antagonists. After the introduction of patch-clamp methods, he moved to the study of glutamate receptors in vertebrate neurons. He is best known for the demonstration that extracellular Mg ions block the channels opened by activation of the N-methyl-D-aspartate (NMDA) receptors, and for the discovery that the activation of NMDA receptors by glutamate is allosterically modulated by glycine. He currently studies the motoneuron-Renshaw cell synapse that, in newborn mice, combines glutamatergic and cholinergic transmission.

Philippe Ascher

I was born in 1936 in the eastern part of France. My father, who was the general practitioner of a small village, realized that war was coming and that the German border was too close. Thus, in 1937, he moved our family to another small village, in a remote part of the Massif Central. This did not prevent him from being taken prisoner by the Germans for five years, but it meant that the rest of us were saved from the worst. When my father returned in 1945, he decided that it was time to move to a more urban setting, so we went to Metz, the city where my mother had grown up. This is where I entered high school.

Until my last year of high school, I thought that I would go to medical school. However, my biology teacher at high school, who had been my mother’s teacher as well and had taken an interest in my future, described the curriculum of the Ecole Normale Supérieure (ENS) in enthusiastic terms to me and to my parents. He suggested that I should try to enter this school. My parents liked this idea very much, mostly because they had enjoyed a series of novels by Jules Romains (Les Hommes de Bonne Volonté) in which the central characters are two students of the ENS. The series, which was a very ambitious and probably superficial attempt at describing French society, had had a vast readership in the 1930s. It painted the ENS as a wonderful place of freedom and intellectual exchange, the place to go if one wanted to pursue a career in academia, politics, or finance. For me, preparing for entry to ENS had the added advantage of necessitating a move to Paris, whereas going to medical school would have meant staying in a university near Metz. I therefore went to Paris, to the only lycée (school) at that time that gave the ENS entrance exam for studies in physics, chemistry, and natural sciences.

Neuroscience in Paris in the 1950s

After two years in an environment closer to that of a monastery than of a university, I entered the ENS in September 1955 with two other biology students: Jean Génermont, who would go on to become a geneticist, and Jean-Pierre Changeux, who at that time could probably have been described as a zoologist. While still in high school, he had discovered a new species—a parasitic marine copepod—and in the following years pursued his taxonomic studies in many French marine biological stations: Banyuls-sur-Mer, Roscoff, Arcachon, and Villefranche-sur-Mer. Although I did not share this particular passion, I accompanied him on many of these trips. I also participated in the geological and botanical excursions organized by the ENS, which proved to be the main educational contribution of the school’s natural sciences department. I have fond memories of these experiences, but they were peripheral to my main interest, which was the study of how the brain functions.

The word biology was nowhere to be found at the ENS. I had entered the section of natural sciences, which was divided into three laboratories: zoology, botany, and geology. Physiology was represented by a single person who had not done research for years. Biochemistry was absent. The laboratories organized the field trips that I mentioned earlier, but all of the courses were given at the Sorbonne, and these turned out to be deeply disappointing. The lectures on the nervous system were probably the worst. The head of the physiology laboratory at the Sorbonne, Alexandre Monnier, had been a respectable scientist, had worked with Graham Gasser, was a friend of Herbert Jasper, but he had espoused the theories of Louis Lapicque. Like many of his colleagues, Lapicque assumed electrical transmission from nerve to muscle but claimed that this required that the chronaxies of nerve and muscle be identical, and that curare altered the chronaxie of muscle. Both claims were wrong and, in the rest of the world, the articles of William Rushton and of Harry Grundfest in the 1930s had long led to the abandonment of this theory. Not in France, where it was the “official” explanation of synaptic transmission, the one that I had learned in high school and found presented again at the Sorbonne. The practicals in neurophysiology were all based on chronaxie measurements, using elaborate home made mechanical devices to measure delays. In his lectures about the action potential in 1956, Monnier was reading a text that had been printed for the first time in 1942. He never presented (neither at that time nor in the next 30 years) the work of Hodgkin and Huxley, although he knew them personally and was proud of having hosted them. Much later, when I asked him the reasons for this ostracism, he said: “At the beginning I did not believe it, and then it was passé.” A course on the organization of the nervous system was given by Marcel Prenant, who had commanded a military underground unit during World War II, had been arrested by the Gestapo, and had been deported. He had been elected to parliament after the war and was a member of the central committee of the Communist Party but had obviously lost touch with science in the making. He placed on equal footing the concept of synapse and the reticular theory. This was in 1955–1956, and in Boston and in Buenos Aires, electron micro-scopists were about to produce the first images of synapses. A third professor was Henri Laugier. He had been the director of the Centre National de la Recherche Scientifique (CNRS) in 1939; during the war, he had organized the transfer to the United States of a number of the best French scientists, and after the war he had been active at the United Nations. But why did he insist on giving lectures on circulation when all of his research had been in biometrics and exercise physiology? I wanted to study the nervous system but could not turn to any of these people for advice.

Fortunately, I discovered a neuroscience laboratory outside of the university: the Institut Marey, directed by Alfred Fessard. Fessard was a professor at the Collège de France. The Collège had been created in the 16th century “to teach disciplines which were not yet recognized at university level,” and that is the role it played after the war. Lapicque and Monnier had estranged French neurophysiology from the rest of the world, but Fessard had made contacts with scientists all over the world. Before the war, he had worked with Brian Matthews in Adrian’s laboratory in Cambridge, and in 1939, he had joined Wilhelm Feldberg and David Nachmansohn in Arcachon for experiments on Torpedo (an electric fish) that lent strong support to the idea that acetylcholine (ACh) was involved in the transmission of excitation from the nerve to the electric organ. In 1955, he had organized a meeting in Gif-sur-Yvette (near Paris) that brought together Eccles, Fatt, Hodgkin, Matthews, and a great many other leading neurophysiologists. This meeting symbolized the reestablishment of links between French neurophysiology and the rest of the scientific world.

The Institut Marey was located near the then-small Roland-Garros tennis stadium, in a cottage where Etienne-Jules Marey had done his experiments on chronophotography. One room was still occupied by “Monsieur Bull” (Lucien Bull), Marey’s assistant, who continued until his death in 1972 to build devices that allowed him to film very brief events, such as the explosion of hydrogen-oxygen mixtures. Alfred Fessard received me very kindly and offered me a choice between two advisors: Ladislav Tauc, who was studying Aplysia neurons, and Pierre Buser, who worked on the cortex of the cat. I was more interested in higher brain functions but still undecided. Then Alfred Fessard told me that the Aplysia preparation required quite a difficult dissection, and this statement (which was totally wrong, as I was to discover later) is what tilted the balance. I was not good at dissections, so I chose Pierre Buser. I have often thought of that conversation, which lasted only a few minutes. Alfred Fessard could have said more, and I could have asked for more. During the next 50 years, I had many talks of this type with students attempting to define their field of research and to choose their advisor, and I have tried to be a little more specific about the pros and cons of the laboratories that I described and to insist on their getting other opinions. But today the problem is often reversed—some students visit so many labs before choosing one that an excess of information seems to be the difficulty.

Pierre Buser

I worked in the laboratory of Pierre Buser from 1957 to 1965, with two major interruptions. In 1959–1960, I spent one year preparing for the agrégation, a competitive examination for teaching high school. I had no intention of teaching in a high school, but when I entered the ENS I signed a contract with the French government in which I committed to preparing for this exam. I nearly failed, having done poorly in genetics and revealing my incompetence in botany. At one point, the president of the jury told me that I might have to accept a position in a high school in Saigon (the French were still in Indochina). I finally passed with a rank high enough to allow me to return to preparation for my PhD. The second interruption occurred toward the end of my thesis, when I had to do my military service. After some military training, I was sent to an air force laboratory in Paris that prepared a mouse for a zero gravity flight of a few seconds. We implanted electrodes on the vestibular nerve of mice. One of the mice was eventually selected and sent up in the Sahara desert; but on its return, the rocket did not land where expected, and when it was finally located, there was little left of the mouse.

At that time, the preparation of a thesis stretched over many years. Obtaining a thesis was a prerequisite for the position of associate professor, and thus was more akin to the “habilitation” of German universities than to a simple PhD. But there were no fellowships for graduate students, who usually had to take on a teaching position either in a high school or at a university. When I left the ENS in 1959, I immediately obtained such a position. I became an “assistant” at the Faculté des Sciences de Paris. What might seem unbelievable today is that after one year this became a permanent position. I was 24. If I had stopped any research but continued to assume my teaching obligations, I would not have been promoted, but I would not have been fired. Indeed, I recently learned of the death of an ENS student who had been recruited a year before me, never presented a thesis, published very little, but who went on to teach zoology for 40 years and was liked by students and colleagues.

My thesis was entitled “The Startle Reaction of the Cat Anesthetized with Chloralose.” My first experiments with Pierre Buser were not on the startle reaction but on the pyramidal tract discharge elicited by various sensory stimulations in the cat anesthetized with chloralose (Buser and Ascher, 1960). We then realized that the multisensory inputs that reached the motor cortex were the same type as those that activated the “associative” cortical areas, and they likely originated in the reticular formation. But we also found that the striking startles observed under chloralose persisted in the absence of the motor cortex and thus probably involved some direct reticulospinal pathway. With a number of collaborators—in particular, Dora Jassik-Gerschenfeld and Gabriel Gachelin—we tried to sort out the circuits involved in the startle reaction. Toward the end of my thesis, I started becoming really excited about the fact that the startle reaction triggered by visual stimulation involved two pathways converging on the superior colliculus. Despite the fact that the anatomical lengths of the two pathways were very different, a compensation was introduced by the difference in the conduction speeds, bringing two synchronous signals to the superior colliculus and from there to the reticular formation (Jassik-Gerschenfeld et al., 1966; Ascher and Gachelin, 1967).

Pierre Buser had worked on the reticular formation with Horace Magoun at University of California Los Angeles (UCLA) in 1953, and it is there that he had decided that the study of multisensory integration would be the primary focus of his research. When, in 1963, I announced to him that Hodgkin, Huxley, and Eccles had received the Nobel Prize, he shrugged and told me that he would have awarded the prize to Giuseppe Moruzzi and Horace Magoun for the identification of the subcortical centers regulating awakening and sleep. I later learned that, in 1957, the media had leaked that Magoun had been selected for the Nobel Prize before the Karolinska Institute Assembly overturned the choice. As for me, as much as I shared Buser’s admiration for Moruzzi and Magoun, I had the feeling that (with the methods available to us at the time) we would not obtain a real understanding of the motor behavior that I had spent so many years studying. I was reinforced in this opinion by some nasty but pointed comments made by one referee of our papers. Thus, near the end of my PhD, I looked for another line of research. I considered analyzing sensory systems such as the visual system, which was the choice made later by my friend Michel Imbert, who had joined the laboratory of Pierre Buser shortly after me. I visited the laboratory of Yves Laporte, who analyzed the proprioceptive inputs from the muscle spindles. He invited me to Toulouse to observe an experiment. The experiment was programmed to last for two days. The dissection was started by Paul Bessou, a brilliant surgeon. Soon I knew I that I could not consider going in this direction because I noticed that Bessou had only taken five minutes for the laminectomy that I was doing in 25 minutes. I then considered another possibility, which was to try the second choice that Alfred Fessard had offered me, namely Ladislav Tauc and the Aplysia neurons. Hersch Gerschenfeld was a crucial influence on my making this decision.

Hersch Gerschenfeld

I first met Hersch and Dora Gerschenfeld in 1959 when they arrived at the Institut Marey from Buenos Aires for a stay of two years. Hersch has described in his (unfinished) autobiography his first encounter with Alfred Fessard, and the story (Gerschenfeld, 2009) actually ends on the statement by Fessard: “Le secteur, voilà l’ennemi, et la lutte contre lui ne finit jamais” (The fifty cycles [current interference], this is the enemy, and the fight against it never ends). Hersch worked with Ladislav Tauc, while Dora joined the group of Pierre Buser and worked with me. Hersch had an immediate influence on all the institute’s graduate students and “postdocs” because of his ability to start conversations and discussions on scientific and non-scientific subjects. He readily perceived but deliberately ignored the existing divisions between the various groups (which were linked to conflicts between the group directors) and, in a few months, convinced all the young investigators to lunch together and later to go to meetings together. At the scientific level, he brought us a view of the outside world and a historical perspective of the evolution of science. I was impressed by the fact that in his remote Argentina, where foreign visitors were rare, he had built a broad and critical picture of the world of neuroscience—its trends and its most active centers. I realized how limited and “Paris-centered” I had been until then.

Hersch introduced me to the study of neurons and synapses, and he communicated his enthusiasm to me. The description of ACh receptors in Aplysia neurons (Tauc and Gerschenfeld, 1962) impressed me— not only by its content but also by its aesthetics. I thought that the figures looked nicer than those of the papers I was reading or writing, and I decided that it was due to the fact that they were describing “basic” processes. Hersch made me discover pharmacology, a subject I had never heard of until I saw the dose-response curves that he was constructing with Enrico Stefani on snail neurons after his return to Argentina. Hersch also introduced me to the comforting notion summarized in the title of the book, From Neuron to Brain (Nicholls and Kuffler, 1976): Working at the cellular level not only provides meaningful data on neuron physiology but can also significantly advance the understanding of higher functions of the brain.

My discussions with Hersch Gerschenfeld decisively impacted my shift to the cellular level, which was the line I was to hold for the next 40 years. As soon as I had defended my thesis, I applied for a position at the CNRS (which allowed me to pursue research full-time); I was accepted and entered the Tauc laboratory.

Dopamine and the Na-K pump

In 1965, there was no commercial supply of Aplysia in France; to obtain Aplysia, the Tauc laboratory transferred all its set-ups for two months to the marine biological station of Arcachon, where the animals entered the bay in September to lay their millions of eggs before dying. I joined the lab in September 1965. I once again met Hersch Gerschenfeld, who was visiting for the summer, and Jan Bruner whom I knew from my previous time at the Institut Marey. I also met Jacsue Kehoe, an American postdoc who had joined the Tauc group the year before. Shortly after that encounter, we decided to share our lives and for this reason, from this point on, my story partially covers the same ground as the chapter that she wrote in this same series (Kehoe, 2004).

In Arcachon, I collaborated with Tauc and Gerschenfeld on the study of a neuron that received two different synaptic excitatory inputs, only one of which was blocked by tubocurarine. We concluded that the neuron was excited by two different transmitters (Gerschenfeld et al., 1967) and were probably wrong. I suspect that the second synaptic potential was due to an electrical synapse. When we returned to Paris, Tauc suggested that I study the effects of dopamine on Aplysia neurons. That year, we began having Aplysia shipped to Paris from various places in France and soon from California; thus we could perform experiments all year long. I applied dopamine electrophoretically on various neurons and found that, depending on the neuron, dopamine could be excitatory, inhibitory, or both (Ascher, 1972). This extended to dopamine an observation that had been made for ACh and turned out later to be true in molluscan neurons for most neurotransmitters. I then became intrigued by the effects of dopamine on the giant cell called R15. Dopamine produced in this cell a hyperpolarization that, contrary to what was expected from an increased ionic conductance, could not be inverted by hyperpolarizing the cell. In the spring of 1968, I realized that one possible explanation was that dopamine activated the Na-K pump, which Roger Thomas had recently confirmed to be electrogenic in a series of spectacular experiments on snail neurons (Thomas, 1969). Indeed the dopamine effect was blocked by ouabain, a blocker of the Na-K pump. I sent a communication for the June 1968 meeting of the Physiological Society in Oxford. When the meeting opened, May 1968 disruptions had brought the lab to a near standstill, and I could not present much more than my initial observations. I returned to experiments in the autumn when Jacsue and I arrived in Cambridge for a sabbatical year. By that time, I had doubts about my interpretation because I had found that, in smaller neurons hyperpolarized by dopamine, the response could be inverted near the potassium (K⁺⁾ equilibrium potential. Then, in early 1969, Pinsker and Kandel proposed (Pinsker and Kandel, 1969) that, in another giant Aplysia neuron (R2), the hyperpolarization produced by ACh was due to activation of the electrogenic /Na-K pump. Under other circumstances, I would have been very depressed. But the interpretation of Pinsker and Kandel (like mine) was open to doubt; Jacsue had described a response to ACh in smaller neurons, which inverted exactly at the K⁺ equilibrium potential. It took her little time to show that, in these smaller cells, ouabain produced a depolarizing shift of the K⁺ equilibrium potential, which reduced or abolished the hyperpolarization seen near resting potential. We attributed the shift of the K⁺ equilibrium potential produced by ouabain to a loss of internal K⁺ until Alan Hodgkin convinced us that it was better explained by an accumulation of extracellular K⁺. We concluded that the absence of inversion in the giant cells was readily explained by the large electrical distance between the soma and the (axonal) ACh receptors (Kehoe and Ascher, 1970).

1968

The year 1968 rocked France. At the Institut Marey, work stopped for nearly three months, innumerable assemblies were held, and very violent exchanges occurred. Two authors of the History of Neuroscience series—Denise Albe-Fessard and Jacsue Kehoe—have described in contrasting ways how they perceived the same set of local events (Albe-Fessard, 1996; Kehoe, 2004), and one will not be surprised if I say that my perception was closer to Jacsue’s. Looking back at what happened, I think that inside the academic world, as elsewhere, the major cause of agitation was the desire of the younger generations to have some say in what was at that time exclusively decided by our elders. They were not dictators nor were they incompetent, but they considered that their experience and maturity gave them the right to make most of the important decisions alone. We felt that we were living in a patriarchal society. The revolt was spontaneous, and in many ways, healthy. But the spontaneity meant that that there was no plan for what was to replace the old system. Before 1968, many people had attempted to diagnose the problems of the French universities and research organizations and had proposed remedies. These discussions continued during the “events.” But when the agitation ended, we discovered that we had not changed the structures but only accelerated the transfer of power between two generations. The members of the new generation differed from those of the previous one in style, but they held just as firmly to their newly acquired powers. These powers were less extensive because they were shared by more people. This situation had a good side and a bad side because it complicated many collective enterprises. I have never regretted the old days, but in the following years, I noticed that some of the most successful French laboratories and institutions were those that preserved centralization and limited “democracy.” One of the reasons why the Ecole normale supérieure has fared better than most universities in organizing its research is probably that its director is chosen by the government, whereas French university presidents are elected by those that they administer and to whom they therefore must make promises.

In 1970, on the assumption that the explosion of 1968 had been due to an excessive number of students in the giant University of Paris, the government decided to split it into a series of smaller universities. Why not? But, fearful of starting new disagreements, it was decided that the split would not be organized by any committee and would simply follow the political lines of the time. I belonged to the faculté des sciences (science faculty), which occupied a massive complex along the Seine. We were told that the buildings would be divided between two universities that had expressed interest in science departments. They were initially named Paris 6 and Paris 7 (now “Pierre and Marie Curie” and “Denis Diderot”). The faculty members were free to choose which of the two universities they wanted to join. Paris 6 was to be controlled by an association of conservatives and communists, united by their belief in the need for order and hierarchy. Paris 7 would regroup the leftists, where tu (you) was the rule and where it was promised that every teacher, whether assistant professor or full professor, would have the same duties and the same rights. I was tempted by Paris 7, but I realized that most of the physiologists were planning to stay in Paris 6, which meant that choosing Paris 7 could result in an enormous teaching load. I decided to stay with the majority of the physiologists. For symmetrical reasons, the biochemists decided to move as a block to Paris 7. Thus, when the split was completed, Paris 6 had only one biochemist, and Paris 7 had only two physiologists. Paris 6 had also lost all social sciences and humanities; and Paris 5, to which I was to move later, had only medicine and law. Forty years later, we all agree that the process selected for the partition was absurd. The government has recently tried to encourage regroupings aimed at reconstituting “multidisciplinary” universities; but money is scarce, fiefdoms have been constructed, and the process will take many years—even if the political distinctions that had informed the splits in 1970 have long been forgotten.

On a personal level, 1968 taught me crowd control. For many years after 1968, teaching in a university lecture hall meant that one might be interrupted for reasons either futile or important but rarely linked to the subject of the lecture. Among the higher-ups, university presidents could expect to find themselves “sequestered” for a few days by committees of students, who might protest a decree requiring foreign students to have knowledge of French, a reduction in the length of the holidays, or a decision to discontinue a course on the history of cinema. In the innumerable meetings of 1968, I found that I had learned a number of tricks that allowed me to exercise a reasonable control over the students in my classes.

Cambridge (1968–1970)

I did not choose Cambridge in the logical way I recommend to students who look for a postdoc. In the middle of the 1968 events, Arnold Burgen—who was at that time the head of the department of pharmacology in Cambridge—gave a lecture at the Institut Marey. I liked it and asked if I could go to his lab. He agreed. He left me free to continue my current project on dopamine receptors in Aplysia neurons, gave me access to an electrophysiology setup, and offered to pay for the Aplysia, which were flown in every other week from California. I shared them with Jacsue (who was at the Cambridge anatomy department); she took the pleural ganglia, and I took the abdominal one. Because she worked on ACh receptors, the Aplysia were bought with a grant from the Tobacco Research Council. I did not realize at that time how compromising that could be.

We had just arrived in Cambridge when I learned that an associate professorship had just been opened at the University of Paris. I decided to apply. In comparison with the teaching-free CNRS position, rejoining the university meant an instructional load of three lectures a week (it would become much worse later). This was a handicap; but during the May 1968 events, our relationship with Ladislav Tauc had deteriorated and a position at the university was a way to attain complete independence. I was elected by a margin of one voice and felt a bit guilty about the result; my rival was the biology teacher who had prepared me for entry at the ENS and for whom I had great admiration. As a Jew, his career had been interrupted during the war (he had been expelled from his job), and he had completed his thesis by experimenting on frogs at home.

I then returned to Cambridge, but I still had to prepare and deliver my three weekly lectures (on subjects that I had never taught before: cardiac and renal physiology). I traveled to Paris each Friday evening, gave my three lectures on Saturday morning, and returned home in the evening. Despite this hard schedule, I have wonderful memories of that year. Probably my major surprise was how accessible senior scientists were. Alan Hodgkin, in particular, would meet with us as often as we wanted. You had to be prepared, though, because he kept his slide rule at hand and from time to time would ask for numbers rather than qualitative statements. Bernard Katz, whom we visited in London, was similarly welcoming. Until then (during my thesis years in France), I had had very few scientific discussions outside of the lab or of the Marey Institute. It was in Cambridge that I caught the “anglophilia,” which I shared with Alfred Fessard and Yves Laporte in France. Later, this exposed me to many attacks from French colleagues, some of whom were excellent scientists but also inveterate nationalists.

Starting the Laboratoire de Neurobiologie at the Ecole Normale Supérieure

When we returned to Paris in 1970, Jacsue and I were not well received. The tensions of 1968 had not completely abated, and we found ourselves “exiled” in a temporary building in Gif-sur-Yvette, where the Institut Marey was to be transferred in the following years. Teaching meant long commutes between Gif and Paris and many days without running experiments. I started filling my time doing theoretical work on the Na-K pump. I realized that the electrogenicity of the pump could be incorporated into the Goldman-Hodgkin-Katz equation describing the membrane potential. I showed my work to Alan Hodgkin and Roger Thomas, but when I tried to publish the modified equation, one referee found it uninteresting and suggested that I return to experimental work; the other kindly pointed out that the equation had been already proposed by Mullins and Noda in the discussion of a 1963 paper (Mullins and Noda, 1963). Following the advice of the first referee was then my only choice. This was greatly facilitated by the fact that, in the meantime, I had discovered empty lab space at my alma mater, the ENS.

I was informed of the existence of vacant space by a friend who told me that the ENS physics department was worried that zoology intended to occupy most of the nine floors of the new biology building that had just been completed. I contacted the ENS scientific director, Michel Hervé, who showed interest. There was no publicity about an opening. No other candidate was considered. I was not interviewed by any committee. I only met the head of the physics department, Yves Rocard. The only question that he asked was related to the ongoing split of the Paris University into 13 universities. Which university would I join? I said: Paris 6. It seems that he would not have accepted me if I had said Paris 7, which hosted a dissident group of physicists. He then handed me a bank check for a thousand francs, which I used the next week to purchase a water distiller. The machine never worked (the water pressure on the ninth floor was too low), but I kept it for many years as a souvenir of our arrival.

The ninth floor was large enough to allow us to invite colleagues to join us, and within a year we were accompanied by Jean Massoulié, Claude Bergman, and then Hersch Gerschenfeld. Hersch had fled the 1966 Argentinian coup, found hospitality in Stephen Kuffler’s lab in Harvard, and was now back in France—this time without any hope or intention of returning to Argentina. It was Hersch who proposed that our group call itself Laboratoire de Neurobiologie, a homage to Kuffler who had invented the word neurobiology. We received help from the CNRS and from the Délégation Générale à la Recherche Scientifique (DGRST), two national funding institutions. The DGRST, which disappeared in 1981, helped with the development of new research fields. It gave us a starting grant in the frame of a “concerted action” to develop the study of biological membranes. The CNRS then picked up where the DGRST had left off and provided us with regular support every four years. For the last 40 years, the CNRS has been attacked as insufficiently productive, and it has been repeatedly proposed that most of its powers should be transferred to universities. In my experience, the CNRS has done a better job of evaluating and supporting science than have our universities, and I hope that it resists further attacks.

Intracellular Chloride Ion Concentrations

The first postdoc who arrived at ENS was Diana Kunze (in 1971), followed by Tim Neild (in 1973). Diana knew how to make electrodes filled with liquid ion exchange resins, and we decided to measure the internal chloride ion (Cl⁻) concentration (Cli) in Aplysia neurons. There were reports that in some neurons there was a difference between the values of the Cl⁻ equilibrium potential, ECl, and the value of the resting potential, Em, suggesting the existence of active Cl⁻ transporters, which had not yet been identified. With Diana Kunze and Tim Neild, we measured Cli in Aplysia neurons and concluded that ECl was more negative than Em (this implied an active extrusion of Cl⁻) and that the resting Cl⁻ conductance was low (Ascher et al., 1976). This last claim contradicted the high values of the Cl⁻ conductance reported by Arthur (Buzz) Brown and John Russell (Russell and Brown, 1972). However, these authors had worked in high external K⁺, and we attributed their high values to the activation of synaptic Cl– conductances by transmitters released under these conditions. This did complicate the relation of Diana Kunze with Buzz Brown a bit but did not prevent her from marrying him. With Tim Neild, we also used the Cl– electrodes to measure Cli in the squid axon. Mauro (1954) and Keynes (1963) had reported a high Cli using Ag-AgCl microelectrodes, but Neild and Thomas (1974) had raised some doubts about these values. Tim and I went to Roscoff, the French biological station where squids could be obtained in good condition. We confirmed the values of Mauro and Keynes; ECl is indeed less negative than Em in squid axon.

Relaxation and Channel Block

In 1975, Alain Marty became my first graduate student. A former student of the Ecole Polytechnique, he had taken courses in neuroscience in Paris, had gone for a year to work with Alan Finkelstein at Albert Einstein, and had come back to start his PhD. We decided to characterize the kinetics of an excitatory current induced by ACh in a small group of Aplysia neurons, and to this end, we implemented the new approaches that had been developed for the study of the end-plate ACh receptors: noise analysis and voltage jumps (Ascher et al., 1978 a,b). The most surprising observation was made when we applied voltage jumps in the presence of ACh antagonists. We had applied voltage jumps in control conditions and observed what Adams (1975) and Neher and Sakmann (1975) reported at the endplate—during a hyperpolarizing voltage step, the current shows an instantaneous increase (due to the increase of the driving force) then a slow increase indicative of a voltage sensitivity of the closed-open reactions. However, in the presence of the ACh antagonist, tubocurarine (curare), the inward relaxation seen at negative potentials was followed by an outward relaxation, which indicated that the effect of curare was voltage dependent. This was surprising because curare was widely assumed to be a competitive antagonist, and we had expected that it would just scale down all the currents. Alain Marty was the first to understand what was happening, namely that curare was acting as a slow channel blocker and was entering the channels at a rate slower than that of the increased openings induced by the voltage step. In preceding years, the concept of channel block in the case of the voltage dependent ion channels had been strongly developed by Clay Armstrong, and it was already extended (Adams, 1976) to the ACh-activated channels of the endplate. What was surprising was the fact that the process occurred for curare, a prototypic competitive antagonist.

We had published our initial observation in Nature (Marty et al., 1976) but soon discovered that it did not have a strong impact. I understood why when I went to London in 1977 to discuss the possibility of a sabbatical year at St George’s Hospital with Humphrey Rang and David Colquhoun. I found that they attributed the bizarre behavior of curare to the fact that we were looking at Aplysia neurons rather than vertebrate neurons. The fact that Manalis (1977) showed a voltage-dependent block by tubocurarine in striated frog muscle barely changed their view. David Colquhoun half-jokingly said that they were only interested in “hairy animals.” Thus I decided that, during my stay in London, I would show them that what was valid for Aplysia was valid for vertebrates. And indeed, with Humphrey Rang and William Large, we showed that ACh antagonists in the submandibular ganglion of rats behaved very much as in Aplysia (Ascher et al., 1979). After Humphrey became convinced of the phenomenon, he became a powerful ally in propagating the gospel of channel block to interpret the effects of “ganglioplegics” and their sensitivity to the frequency of stimulation, enjoying the “upset (of) a number of apple carts” (Rang, 1997). He also analyzed why compounds that had a similar voltage dependent block had different functional effects and found that this could be explained by considering trapping, a notion that had also been proposed by Clay Armstrong but that we had not exploited in Aplysia.

Magnesium Ions Block the Channel of N-Methyl-D-Aspartate Receptors

When I returned from England, I started using patch-clamp, which Alain Trautmann and Steve Siegelbaum had already introduced in the lab (Alain Marty was still in Göttingen for his postdoc). With Sol Erulkar (who was on a sabbatical leave), we started dissociating snail neurons and looked for ACh-activated channels, but the success rate of our experiments was extremely low. After Sol departed, I realized that, with the arrival of tight-seal whole-cell recording, giant invertebrate neurons had lost one of their major technical advantages, even though their handicap as models for receptor pharmacology remained severe. It was time to shift to vertebrate neurons. With Linda Nowak, the new postdoc who had arrived from Ann Arbor, we decided to try primary cultures of mice cortical neurons. We had no hood, no incubators, and, for a whole year, we obtained the cultures from laboratories within walking distance—those of Jeanine Koenig or Alain Prochiantz. We wanted to see single channels opened by neurotransmitters, and I think that we selected glutamate because it was the cheapest drug to start with. For many weeks we did not see any response, until I remembered an article in which Jeff Watkins and his colleagues had described a “non-competitive” effect of magnesium ions (Mg²⁺⁾ on the glutamate receptors selectively activated by N-methyl-D-aspartate (NMDA receptors). We prepared a Mg²⁺-free ringer and readily observed that glutamate induced a large noisy current in the whole-cell mode and the expected single-channel currents in outside-out patches. Adding Mg²⁺ reduced the whole-cell current and introduced a negative resistance around resting potential. At the single-channel level, Mg²⁺ transformed long openings into bursts of briefer openings. Piotr Bregestovski then joined us and participated in the analysis of these effects. Alain Trautmann had written the programs required for the analysis of the records, and the model used by Neher and Steinbach (1978) in their study of the effect of local anesthetics on ACh nicotinic channels turned out to apply readily to our system (Nowak et al., 1984; Ascher et al., 1988).

The basic experiment was so simple that we were worried it might be published by somebody else before we had finished our analysis, and we were right to be afraid. We only overtook Mark Mayer and his colleagues by a few weeks (Mayer et al., 1984). They had not analyzed single channels, but they had a significant advantage over us: Mark Mayer had been Watkins’ student and knew the pharmacology of glutamate receptors. We had suspected that the voltage-dependent channels that we were looking at were those of NMDA receptors. But we did not try to confirm it by using specific agonists or antagonists, and we had not tried to understand why we did not see a “non-NMDA” component when we applied glutamate. (We understood later that our perfusion was so slow that the “non-NMDA” receptors were completely desensitized.) I viewed our observation from the point of view of a biophysicist rather than of a pharmacologist, and what I considered most exciting was that we had discovered a voltage-dependent system that was based on channel block by an endogenous ion and thus radically different from the voltage sensors involved in Na and K channels. Meanwhile, Mark Mayer and his colleagues characterized the NMDA receptors with the adequate pharmacological agents and developed Watkins’s suggestion that variations of the extracellular Mg²⁺ concentration could modulate the NMDA responses. Neither of our two groups could predict that what we had uncovered would be promoted to a key functional role in plasticity, coincidence detection and memory.

The success of the Mg²⁺ block as a mechanism involved in plasticity sent the studies of the detailed mechanisms of the block to the backseat. We, and many others, later used site-directed mutagenesis to try to understand this block, and we identified some crucial amino acids. For a time, the localization of the blocking site in the transmembrane electric field was slowed by the “crossing of the deltas,” namely the fact that the blocking site for external Mg²⁺ seemed paradoxically deeper in the membrane than the blocking site for internal Mg²⁺ (Johnson and Ascher, 1990). The problem was solved by Antonov and Johnson (1999), who found that the voltage dependence was strongly regulated by external and internal permeant ions. But a complete physical description of the block is still not available.

The Effect of Glycine on N-Methyl-D-Aspartate Receptors

Jon Johnson arrived in Paris in 1985. By that time, we had installed a culture room and had even recruited a technician (my sister, Dani Lévy) to take care of the cultures. Although the cultures looked alright, I was preoccupied by the fact that the responses that we induced with glutamate were ten to a hundred times smaller than those reported by Mayer et al. (1984), and I wondered whether we were missing some crucial technical procedure.

Jon’s initial project was to construct concentration-response relationships. While trying to evaluate the stability of the response to a given concentration of glutamate, he was confronted with bizarre effects. The amplitude of the response seemed to depend on the speed of application; it was larger when the perfusion was slower, and when we maximized the speed of application by using the “U-tube” method, which had been introduced by Krishtal and Pidoplichko (1980), the response seemed to desensitize very rapidly. Furthermore, an off response was observed at the end of the application.

Jon tested a myriad of biophysical theories until he understood that the odd behavior of the response had little to do with biophysics and kinetics. His decisive observation consisted of analyzing the response of an outside-out patch in a culture dish in which the perfusion had been stopped after the addition of NMDA. When an outside-out patch was made by pulling the pipette away from the cell, it immediately showed the characteristic single-channel activity associated with activation of NMDA receptors. However, if the patch was then lifted toward the surface of the dish, the frequency of the single-channel currents decreased, and then increased if the patch was lowered back toward the bottom of the dish. This was a very strong suggestion that the cells at the bottom of the dish released a factor facilitating the response to NMDA, and that this factor was progressively diluted as one moved away from the bottom. This interpretation was soon confirmed when Jon devised a new system of NMDA application using two parallel tubes and showed that applying NMDA dissolved in fresh culture medium elicited only a very small response. However, if one replaced the fresh culture medium with “conditioned medium” taken after a few hours in contact with the neurons, one observed a large response that did not desensitize and showed no off component.

The fast decay of the response to NMDA applied in slow perfusion or with a U-tube was thus not due to desensitization but to the washing away of the ambient “factor.” The return of this factor, when the application was stopped, explained the off response. And the large responses of Mayer et al. (1984) were likely due to the fact that they used electrophoretic applications of NMDA or glutamate, which did not modify the concentration of the ambient factor. My doubts regarding the technical competence of my sister turned out to be unfounded.

The experiment using the conditioned medium also offered a method for identifying the potentiating factor produced by the neurons. For this identification, we oscillated between a systematic approach of fractionation of the conditioned medium and “fishing expeditions.” The latter approach is not favored by textbooks and grant referees, but it was a way of trying to relieve the frustrations of the fractionation. And it was in one of these unreasonable attempts that Jon decided to test simple amino acids. He prepared two tubes, each containing nine amino acids. At the last minute, and despite the fact that we “knew” that glycine was an inhibitory transmitter, he added a third tube containing glycine. For a reason now forgotten, he applied this compound first and found that it completely mimicked the effects of the conditioned medium (Johnson and Ascher, 1987). Jean-Philippe Pin soon confirmed with high pressure liquid chromatography that glycine was present in the conditioned medium.

The editor of Nature insisted that we add a “physiological hypothesis” to the manuscript, and we suggested that glycine could spillover from glycinergic terminals toward neighboring glutamatergic synapses. In making this suggestion, I had been influenced by the electron micrographs of Yasuko Nakajima showing glycinergic and glutamatergic boutons close to one another on the dendrites of the Mauthner cell. Later I became attached to this idea and spent a lot of time trying to prove it, first in the cerebellum, where glycinergic terminals from some Golgi cells have been described next to the glutamatergic mossy fibers on the granule cell dendrites; then in motoneurons, where the anatomy suggests a situation similar to that of the Mauthner cell. Both sets of experiments were unsuccessful, but the hypothesis is probably true and was clearly validated in at least one example by Ahmadi et al. (2003) in the dorsal horn of the spinal cord. Meanwhile, the discovery of the “glycine site” and the fact that it is also activated by D-serine had attracted a lot of interest in pharmaceutical laboratories, and the site was promoted as crucial in diseases as varied as stroke and schizophrenia. To date, no breakthrough seems to have occurred but this has been the case with all the studies on drugs acting on the NMDA receptors, and it may indicate that these receptors are actually too important and too widespread to constitute a good pharmaceutical target.

Postdocs or Graduate Students?

The Laboratoire de Neurobiologie had been created in a limited space, the ninth floor of the building, and all members of the lab had agreed that, if they felt that they needed to expand, they had to find another institution. For me, it meant that I would not have more than one setup and thus would not take more than one postdoc or one graduate student every year. Choosing postdocs or graduate students was therefore a difficult decision. I took my first graduate student—Alain Marty—soon after my arrival at ENS. My second graduate student was Dominique Chesnoy-Marchais, who was introduced to electrophysiology by Alain Marty during my year in London and with whom I later studied a series of slow inhibitions induced by various transmitters in Aplysia neurons (Ascher and Chesnoy-Marchais, 1982; Chesnoy-Marchais and Ascher, 1982). We were intrigued by the fact that the responses were not independent and seemed to involve a common element. We failed to identify this element, however, which was later shown to be a G-protein (Sasaki and Sato, 1987).

In the following years, I felt that I could not give graduate students all the attention that they needed, and I relied mostly on postdocs or on colleagues from abroad who were on sabbatical. I have already mentioned the first postdocs, Diana Kunze, Tim Neild, Jon Johnson, and Linda Nowak. They were followed by William Sather, who arrived in 1988 and stayed for two years. It was Bill who discovered that if one keeps the suction on while pulling an outside-out patch, the nucleus of the cell often remains at the tip of the pipette, leading to the formation of what we called a “nuclear patch.” This configuration has the basic advantages of an outside-out patch but a much larger surface, allowing for much larger currents. Bill and I used it to analyze the kinetics of NMDA receptors; we were joined by John MacDonald and Graeme Henderson, both on sabbatical leave, and Stéphane Dieudonné, a graduate student (Sather et al., 1990, 1992; Henderson et al., 1990). Another memorable postdoc was Ralf Schneggenburger, who made the very curious observation that the multiple states of NMDA receptor channel openings did not have the same reversal potential. With help from Stéphane Dieudonné, we managed to explain this by a model in which gating is coupled with permeation (Schneggenburger and Ascher, 1997), an idea that Alain Marty and Dominique Chesnoy-Marchais had developed earlier (Marchais and Marty, 1979) but that now gained much greater strength.

In 1992, having been criticized by various committees for not taking enough graduate students, I decided to comply with their recommendations by enrolling not one but two graduate students the same year: Pierre Paoletti and Stéphane Dieudonné. I was violating my own rules, but both turned out to be excellent choices.

I proposed to Pierre Paoletti that we continue the study of internal Cl– regulation, but this objective was soon forgotten when, during manipulations aimed at changing the internal Cl–, we concluded that the effects we observed were due to changes in volume. From there, we went to experiments that showed that NMDA receptors are sensitive to mechanical deformations (Paoletti and Ascher, 1994). We then began a collaboration with Jacques Neyton, a former Gerschenfeld student who had done a postdoc with Chris Miller at Brandeis University and, while there, had acquired a deep understanding of the structures and models of ionic channels. Jacques Neyton had decided that it was time for us to take advantage of site-directed mutagenesis to analyze the NMDA receptors. He rapidly trained himself in molecular biology, brought Xenopus to the lab, and very soon he made us enter the modern era of channel research. Pierre and I, and later Jürgen Kupper, joined him in the experiments that led us to characterize the binding site of internal Mg²⁺, various modulatory sites of external Mg²⁺, and finally the binding site of Zn²⁺ (Paoletti et al., 1995; Kupper et al., 1996; Paoletti et al., 1997). Since that time, Pierre has vigorously developed this line.

When Stéphane Dieudonné entered the lab, he joined us in our attempts at modeling the kinetics of NMDA receptors and was of great help. I would have been happy if he had continued in this direction, but he soon told me that he was more interested in synapses and networks than in channels, and he made a strong case for developing this line of research. I could not resist his arguments, which were those of a true physiologist. He very rapidly learned from Alain Marty and Isabel Llano how to prepare cerebellar slices and went on with this preparation. He has built his group along this line, has recently developed a very original fast scanning two-photon microscope that allows him to combine electrophysiology, imaging, and optogenetics, and he is also applying his mathematical virtuosity to the modeling of networks.

My last postdoc was Mariano Casado. He had become familiar with NMDA receptors during his first postdoc with Juan Lerma in Madrid. He joined me in 1995, and our first series of experiments was a follow-up of the work that I had done with Pierre Paoletti on the mechano-sensitivity of NMDA receptors. We tested the effects on NMDA receptors of molecules (arachidonic acid, lysophospholipids) that are assumed to induce a change in the curvature of the lipid bilayer and to produce a mechanical deformation of the embedded proteins. We did indeed observe effects that were compatible with this hypothesis (Casado and Ascher, 1998). We could have continued the biophysical study of mechano-sensitivity, which is still not understood at the molecular level. But such a search would have been more exciting if we had evidence for this sensitivity’s physiological role. I had tried to show that it was involved in the chemotropic turning of growth cones induced by glutamate (Zheng et al., 1996). This was not successful but opened my views on the possible role of presynaptic NMDA receptors and made me more receptive to Mariano’s suggestion to study presynaptic NMDA receptors. Mariano had been intrigued by the fact that, in the cerebellar granule cells, NMDA receptors containing a particular subunit (NR2C) are very abundant but do not seem to contribute much to the post synaptic currents. He wondered whether they could be presynaptic. The hypothesis is wrong, but it was believable, and Stéphane Dieudonné and I joined Mariano to test it. Soon we were very excited by the observation that, in rats aged 15–20 days, NMDA induced a depression of the synaptic current elicited in Purkinje neurons by stimulating the parallel fibers, and because the Purkinje cells have no NMDA receptors at this age, the effects were best explained by presynaptic NMDA receptors (Casado et al., 2000). It was difficult to convince editors and referees of this interpretation, but we carried on; in the next step, Mariano made me violate my vows about never working on the process known as long-term potentiation (LTP) and long-term depression (LTD). In fact, the last paper that I signed before leaving the ENS was one attributing cerebellar LTD to presynaptic NMDA receptors on the parallel fibers (Casado et al., 2002). After my departure, Mariano continued along this line, and I think that he is close to breaking the last resistance to our initial claim.

Pierre Paoletti, Jacques Neyton, Stéphane Dieudonné, and Mariano Casado remained at the ENS when I left. Although the Laboratoire de Neurobiologie later dissolved into a larger Institut de Biologie, they have helped make this institute particularly noteworthy in the field of neuroscience, in France and abroad.

Creation of the Department of Biology at the Ecole Normale Supérieure

When I arrived at the ENS in 1970, I had fond memories of my student years there, even if I had not enjoyed the dominance of biology by zoologists, botanists, and geologists. By 1970, some biochemistry had been introduced by a small group working on insect pheromones, but molecular biology, cell biology, and physiology were still absent. Much as in the 1950s, the students (the number of which had been substantially increased) were still invited to train in “natural sciences,” and to concentrate on the subjects required to teach biology and geology in high school.

For the first ten years, I had no legal existence. My laboratory was at the ENS, but I taught at the Université Paris 6, which paid my salary. I was not given a key for entering the ENS building at night, the lab had no mailbox, and we had to get our mail through the secretary of the zoology laboratory. Everything changed in 1981, when the ENS got a new director, the mathematician Georges Poitou, who decided that the time had come for renovating the biology department. He set up a committee to analyze the state of affairs. The president of this committee, François Jacob, soon produced a scathing report on the occupation of the various floors and recommended calling for new groups. Then a search committee, presided over by Jean-Pierre Changeux, started recruiting these groups. The biology department was formally created in 1987. Its first director was Pierre Joliot, a professor at the Collège de France whose laboratory was at the nearby Institut de Biologie Physico-chimique. Pierre Joliot was not a former student of the ENS and had always been a severe critic of the “self-satisfaction” and pretense of ENS students and former students. Georges Poitou convinced him that becoming the director of the department was a unique opportunity to correct the defects that he had denounced. In a few years, the building filled itself with a series of small and dynamic groups, most of which were not directed by former ENS students—a novelty! Among these groups there were a significant number of neurobiologists like Patrick Charnay, Alain Prochiantz, and Antoine Triller.

When, in 1991, I was asked to succeed Pierre Joliot, I did not hesitate long. I knew that accepting would not increase my scientific productivity, but I felt that I owed Georges Poitou a debt of gratitude for all that he had done—not only his renovation of the biology department but also his other accomplishments. In 1985, he had succeeded in fusing the old all-male ENS with the “ENS de jeunes filles.” He also introduced the cognitive sciences at the ENS, which were later to become a full department. By the time he died, in 1989, the department of biology had been strikingly transformed. A solid international scientific council had kindly but firmly insisted on reallocating space among the groups and was starting a new wave of recruitments. We had introduced major changes in the curriculum by organizing undergraduate teaching at the local level, allowing the most motivated students from the university to join the students of ENS in programs that involved lab internships, and by “outsourcing” the students’ preparation for the high school teaching certificate (the agrégation).

The physicist Etienne Guyon, who succeeded Georges Poitou as head of the ENS, followed the path that Poitou had charted. He had to deal with the complex attitude of Claude Allègre, who became minister of education and research in 1997. Claude Allègre was ambivalent about the ENS; he recognized that it was an elite institution, but in the socialist lexicon, “elitist” was a derogatory term. He also thought that the ENS was too Parisian, and “decentralization” was the new fashion. I had difficult negotiations with him on the graduate fellowships for the students of ENS. He wanted the students to disperse all over France so as to “irrigate” all French universities. The students, meanwhile, wanted to go to the best labs, many of which were in Paris. Claude Allègre was quite the bully, but in the end, he gave me most of what I had asked for.

Les Saints Pères

By 2003, Jacsue and I were reaching official retirement age. We decided to leave the ENS to join Alain Marty at the Centre Universitaire des Saints Pères of the Université Paris Descartes. Alain Marty had left the ENS in 1994 to join Erwin Neher at the Max Planck Institute in Göttingen. In 2000, he decided to return to France. He knew that his funding would be less comfortable in France than in Germany—although he had not realized that “less” meant one order of magnitude less. He also knew that the Centre des Saints Pères, in which he was offered space, had a checkered history.

The huge building was built in 1953 and has 36,000 m² of labs and lecture halls plus an equivalent surface of extraordinarily wide corridors designed to allow for the rapid evacuation of a few thousand students in a minimum amount of time. The building was destined to host the students applying to the medical school (which number in thousands), as well as research laboratories. In 1958, a new statute, initiated by Robert Debré, introduced the notion that professors teaching in medical schools could become full-time employees with a triple duty (clinical practice, teaching, and research). In 1960, a decree indicated that those satisfying the three requirements would receive a dual salary: one for clinical work, the other for teaching and research. This was a clever way to evade the French law under which the salary is independent of the field of research inside a university; philosophers are paid at the same level as computer scientists, and we have no football coaches. The special statute of medical school professors created jealousy among members of other disciplines but probably limited the flow out of academia of many clinicians.

The new statute encouraged medical school professors to do research, but it implied that the university had to provide them with laboratory space. In Paris, the Centre des Saints Pères was seen as providing this space. However, the center had no place for patients, and the most active researchers soon found that it was more practical for them to do research in the hospitals where they were seeing their patients. After a few years, the center became a strange place where most of the laboratory space was silent but not completely empty (because professors without much research activity jealously held onto the space that they had been allocated). The situation remained stagnant until the mid-1990s, when a group of chemists who had arrived in 1972 decided to transform the building into a proper center for scientific research. They encountered relatively little resistance, and in a few years, the building began taking on a new life. One advantage it had over the ENS was its much larger surface (nearly 10 times more), which meant that Alain Marty was given a reasonably large space. He offered a large room to Jacsue and me.

The main theme of Alain Marty’s lab is the study of cerebellar organization. Initially, I decided to participate in this topic and tried to support the hypothesis that the glycine released by glycinergic neurons could potentiate the NMDA response of a neighboring glutamatergic synapse. The cerebellum offered such a possibility at the convergence between Golgi cells and mossy fibers on the granule cells. I had not succeeded in convincing Stéphane Dieudonné to conduct this experiment, and I was not successful in showing the expected result (although I still think that the hypothesis may be correct). I then met Boris Lamotte d’Incamps, whom I had known as a student at the ENS in the 1970s and who, directed by Daniel Zytnicki, was working on the spinal cord in the neighboring laboratory. I thought that the glycine-NMDA interaction also could be studied in the spinal cord and asked him to introduce me to this difficult preparation. After unsuccessful attempts on the intact spinal cord of newborn rats and mice, we started making slices. Then two papers appeared describing the co-release of ACh and glutamate by the motoneurons at the motoneuron-Renshaw cell synapse (Mentis et al., 2005; Nishimaru et al., 2005). I convinced Boris to join me in the study of this synapse, and we have not left it since then because we are convinced that it is, and will remain for some time, one of the few central nicotinic synapses that can be studied with the same level of refinement as that used for glutamatergic or GABAergic central synapses (Lamotte d’Incamps and Ascher, 2008; Lamotte d’Incamps et al., 2012). We hope to understand the significance of the presence on Renshaw cells of a bewildering variety of nicotinic receptors, as well as the functional role of the co-release of ACh and glutamate by the motoneurons.

Starting a French MD-PhD program

When I arrived at the Saints Pères, the director of the center, Jean-Claude Chottard, was ending his mandate. I had first met Jean-Claude in 1968. He was an exceptional teacher of chemistry, which he taught to medical students at the Saints Pères, but I had also invited him to teach it to the biology students of the ENS. In the early 1970s, he had made an early attempt at improving the training of medical students by adding science courses to their curriculum. (In France, students enter medical school after receiving only one year of basic science courses.) At about the same time, the ENS started recruiting two or three students each year in an embryonic MD-PhD program. Despite the fact that this recruitment was open to students from all French universities, the students prepared at the Saints Pères formed a large fraction of the successful recruits. I had been in charge of the MD-PhD students at the ENS from 1975 to 2003, and it had been an exciting experience because they were extremely bright and motivated. The experience had also been extremely frustrating because many deans of the Parisian medical schools showed indifference, if not hostility, to the students’ efforts to obtain a dual training.

In 2003, Christian Bréchot, the director of Institut National de la Santé et de la Recherche Médicale (INSERM, which is to the CNRS what National Institutes of Health is to National Science Foundation), decided to start a nationwide program reinforcing the scientific background of medical students interested in research. Christian Bréchot had noticed that among the candidates recruited at INSERM for full-time research positions, the proportion of those with a medical degree had fallen from 30 percent in the 1980s to less than 6 percent in 2001. His analysis of this trend suggested that one factor was a lack of science training in the medical curriculum. He asked Jean-Claude Chottard and me to participate in his project, which resembled what we had tried to accomplish with moderate success until then. In the following months, we saw with admiration how he developed his project, negotiated with the deans, and then convinced the Schueller-Bettencourt Foundation to lend financial support. The program, called Ecole de l’Inserm Liliane Bettencourt, has recruited about 20 students a year for the last 11 years, and some of the students who completed the curriculum are now starting their own research. As it happens, many of the students in the program have chosen neuroscience as their major, and I have been accused of letting my own preferences influence the students’ choice of orientation. I usually reply that, if students prefer neuroscience over the other disciplines, it is simply because in addition to having all the interesting aspects of other sciences, it also deals with problems that are of interest to non-scientists. And so it makes for better conversation starters and makes it easier to flirt.

Teaching in France and Abroad

When I left the CNRS for a university position in 1969, my teaching load was three lectures a week. I taught physiology and later biophysics and pharmacology; but with age, I was given the privilege of specializing in neuroscience. I taught large classes and small ones and enjoyed both. I did not mind adding a few other teaching experiences. The most exhilarating ones were the courses at Cold Spring Harbor on techniques in electrophysiology in which I participated for a few years with Jacsue Kehoe and a number of friends. The students were impressive in their motivation, the depth of their questions, and in the speed at which they mastered the techniques we were presenting them. This extraordinarily stimulating environment—plus the beauty of the surroundings—made us feel that we were living in another world. Our children spent the summers with us and enjoyed them immensely. I often think that these summers played a major role in their decision to pursue their studies in the United States.

After I retired, I accepted the invitation of John Nicholls and Jack McMahan to participate in a few of the neurobiology courses that they organize each year in various countries with support from the International Brain Organization (IBRO). I accompanied them to Uganda, Jordan, China, and Cameroon. This was a very interesting experience and was probably the ultimate contrast with the Cold Spring Harbor courses in terms of the working conditions, which were often quite primitive, but similar in terms of the students’ intense engagement.

My memories of teaching, however, are colored more darkly by the period following the arrival of the socialist government in 1981. In 1982, the new government decided to increase the teaching load of all university staff, nearly doubling it. This was based on reports showing that many professors did very little research beyond their three lectures a week. The new rule allowed universities to avoid recruiting new faculty despite the increase in student enrollment. But for those who were doing research, teaching became exhausting and running experiments became difficult. This increased the advantages of those who were full-time investigators in the CNRS or the INSERM. Entering these organisms became the Holy Grail for all the top PhDs, and the universities were unable to recruit the most active researchers.

In addition to this, the government drafted a law that would entrench and amplify what I had long considered a major weakness of our university system, namely the fact that there is no entrance selection for the university. Any student who has obtained a baccalaureate can enroll. This had not been too bad when the baccalaureate was only granted to a small fraction of the high school students but became dramatic when the number of students with a baccalaureate increased enormously. Universities were inundated with students and found themselves unable to react. The best students started abandoning the universities to enter “selective” institutions such as medical schools and engineering school. In the undergraduate courses that I taught, I soon had difficulties introducing the Nernst equation because students did not know or remember what a logarithm was.

For many years, vigorous criticism about the absence of entrance selection at French universities had been made by Laurent Schwartz, who was to become one of my most influential mentors. He was a mathematician who had earned a Fields medal in 1950, and he was famous among the students not only as an extraordinary teacher but also as a political activist. During the Algerian war of independence, his support of a negotiated settlement had made him a target of the Organisation de l’Armée Secrète (OAS), a French terrorist organization; as a student, I had spent a few nights standing guard at his home to prevent a possible bombing. Laurent had been successful in defending Russian mathematicians against persecution and also in reorganizing the science curriculum at the famed Ecole Polytechnique. In other words, this was someone who had succeeded in most of his enterprises. In 1981, he thought that his leftist credentials would give him some political clout. But when he saw that his recommendations were ignored, he started an organization called Qualité de la Science Française, which I joined as one of his lieutenants, and we tried to stop the passage of the new law.

We lost. This was the only battle that Laurent Schwartz ever lost. In the years that followed (until his death in 2002), he would say that he had seen the end of Nazism, the end of apartheid in South Africa, the end of the Berlin Wall, but I would not see the introduction of entrance selection into French universities.”

If I mention this fight here it is because I think that the weakness of our university system darkens the future of neuroscience in France by reducing the number of adequately trained students. The students of the MD–PhD programs are extraordinary, full of questions and curiosity, but very few will actually go into research. The engineering school students are very bright and wonderfully prepared to conduct experiments, but they are discouraged by the difference between the salaries they can expect in academia and those that are offered elsewhere. The students of the Ecoles Normales Supérieures (there are three in France) are well prepared and less afraid of low salaries, but there are too few of them to match the country’s research needs. And in the universities, the students with high potential do not receive the training that they deserve because they are buried in the (average student) majority. Yet we know that the future of neuroscience depends on students who not only have broad experience in biology but who are not afraid of computational modeling, optics, and structural biology—to note only a few techniques requiring significant knowledge of the “hard” sciences.

The Uncertain Future of French Neuroscience

I entered the field of neuroscience in a country still reeling from the war, with very few figures who inspired respect or who could give us advice. Yet once we had defined our own field, we met few obstacles. There was an enthusiasm for the development of science in the country and in the government. New positions opened every year. We felt confident that all those who were deserving and who were imaginative would make it. In addition, a number of the previous system’s defects were progressively corrected. The excessive power of the “mandarins,” the professors at the top of the old system, was severely reduced, if not abolished, after 1968. To start an independent team was difficult, but the development of research centers outside Paris (“decentralization”) offered new opportunities to those in search of independence. There was no system of post-doctoral fellowships, but this forced students to go abroad, learn English, and to discover other ways of organizing research. At the Institut Marey, where I began my research, English was the common language of exchange and of publication, but this was an exception in France. In the early 1960s, attendance at an international meeting was only reimbursed by the CNRS if you promised to deliver your communication in French. Angélique Arvanitaki refused to use the word “ionic channel” because it was an “Anglo-Saxon” expression. Michel Jouvet insisted on publishing his main observations in French. This chauvinism slowly disappeared. This year, a law allowing lectures in English in graduate courses encountered vigorous obstruction in parliament but was finally passed, and this may help France attract more foreign students.

Thus, for many years, I felt that French science was catching up and progressively eliminating the handicaps inherited from the war and from obsolete structures. But more recently, I have begun to feel that the changes we managed to implement were not commensurate with the simultaneous changes in the way that science, and in particular biology, is pursued. I already mentioned the problem of the training of science and medical students. Another problem is that budgets have not kept up with the increase in the cost of research and its tools. In the 1990s, when I joined the scientific boards of a few Max Planck Institutes and read not only the scientific reports but also the financial documents, I was appalled by the difference with our support at ENS, which was considered a privileged institution in France. And finally, there are problems in the way that funding is organized. When I considered bringing some former ENS students back from the United States (such as Catherine Dulac, Emmanuel Mignot, Daphné Bavelier and Alexandre Pouget), I found that French institutions lacked the tools required for such repatriations. We could not offer starting grants, positions for collaborators and postdocs, or decent salaries. Very recently, France introduced competitive individual grants and post-doctoral fellowships, a move that we would have welcomed in prior years. But in a context of restrictions, this has only meant a further and dramatic reduction of the basic recurrent support.

It is probably too early to conclude that France is sliding back. Year after year, we still produce people who are bright and well-trained, and some of them will have the courage to pursue a career in research. Both the CNRS and the INSERM have been stripped of much of their capacity to define their own policies and their long-term strategies, but they have successfully resisted elimination attempts and could well recover their strength. The recent emergence of the European Research Council has raised new hopes. Thus I fluctuate in my predictions. Some mornings, as I roam through the first floor of the Saints Pères looking in vain for a functional elevator, among thousands of students (most of whom have no hope of entering the medical curriculum given their high school record and should have been told so), I decide that we are definitely going downhill; but in the afternoon, a discussion with a bright and enthusiastic student can still trigger optimism. Let us hope this optimism will prove justified.

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Giovanni Berlucchi

BORN:

Pavia, Italy

May 25, 1935

EDUCATION:

Liceo Classico Statale Ugo Foscolo, Pavia, Maturità (1953)

Medical School, University of Pavia, MD (1959)

California Institute of Technology, Postdoctoral Fellowship (1964–1965)

APPOINTMENTS:

University of Pennsylvania (1968)

University of Siena (1974)

University of Pisa (1976)

University of Verona (1983)

HONORS AND AWARDS:

Academia Europaea (1990)

Accademia Nazionale dei Lincei (1992)

Honorary PhD in Psychology, University of Pavia (2007)

After working initially on the neurophysiology of the sleep-wake cycle, Giovanni Berlucchi did pioneering electrophysiological investigations on the corpus callosum and its functional contribution to the interhemispheric transfer of visual information and to the representation of the visual field in the cerebral cortex and the superior colliculus. He was among the first to use reaction times for analyzing hemispheric specializations and interactions in intact and split brain humans. His latest research interests include visual spatial attention and the representation of the body in the brain.

Giovanni Berlucchi

Family and Early Years

A man’s deepest roots are where he has spent the enchanted days of his childhood, usually where he was born. My deepest roots lie in the ancient Lombard city of Pavia, where I was born 78 years ago, on May 25, 1935, and in that part of the province of Pavia that lies to the south of the Po River and is called the Oltrepò Pavese. The hilly part of the Oltrepò is covered with beautiful vineyards that according to archaeological and historical evidence have been used to produce good wines for millennia. My mother was born into a family that had a place of distinction in the history of Oltrepò winemaking. At the beginning of the last century, Luigi Montemartini, a member of the socialist party, a professor of botany at the University of Pavia, and an uncle of my maternal grandmother Serafina, founded an important cantina sociale, a wine cooperative of small landowners of the region. At vintage time, they took their grapes to the cantina, which had the enological expertise, the machinery, and the great barrels necessary for producing large quantities of good quality wine. Luigi Baraldi was the enologist who ran the cantina by organizing and surveying all the winemaking operations and then by distributing the product to wine shops in various northern Italian cities. He was also my grandfather; he had married Serafina Montemartini, and one of their four children (Elsa) was my mother.

I love the Oltrepò for several reasons, two of which are foremost in my mind. First, my enchanted childhood days were spent mostly with my maternal grandparents, in the villages of Montù Beccaria and Montescano (two of the sites of the cantina), from the late 1930s until 1948, the year of my grandfather’s death. I enjoyed the country life enormously—the workings of the vintage and the many friends with whom I could practice our common passion of playing soccer. My grandparents were affectionate, down-to-earth people who enjoyed having children around and making them feel happy and loved. My grandmother Serafina was practically a second mother to me. My other very important reason for loving the Oltrepò is that 53 years ago, I made the smartest and luckiest decision of my life by marrying 19-year-old Maria Luigia (Luisa) Botta from Broni, one of the five towns of the region. As I once truthfully stated on an important public occasion, from our first day together, Luisa has enriched my life immensely by running it with the sweetest and wisest of iron fists.

My father, Carlo Berlucchi, was from Lodi, another Lombard city 30 km east of Pavia. His father, Giovanni, after whom I was named, was an engineer who worked for one of the ceramics factories for which Lodi is known. I did not get to know my grandfather Giovanni because he died of pneumonia in 1922 during the great influenza epidemic. My father was an only child and his mother, Emma Madini, ruled his life with the typical attitude of the reggiora (lady boss), the central figure of the Lombard matriarchy. She had absolute control over the family money and had convinced my father to study medicine rather than philosophy, which he preferred, because she was positive that philosophers always ended up being impecunious. She lived by herself in her house in Lodi until her death at 93. Her beloved companion was a huge Brazilian parrot that she occasionally left free to roam the house or even the street, where its loud vocalizations often demanded the intervention of the city police or even the firemen. At times, Grandmother Emma could be capricious and overbearing, but she had a great sense of humor and self-irony and liked to play with me and tell me funny stories.

My father had started as a medical student in Pavia, where he had been taught histology and pathology by the famous Camillo Golgi. After interrupting his studies for service in World War I, he graduated in 1922 with a degree in medicine from the University of Parma, which then offered remedial courses for veterans. Before and after graduating, my father worked in Parma with Antonio Pensa—a pupil of Golgi’s who was then professor of anatomy—and with the neurologist Luigi Roncoroni—who had been an assistant to the infamous criminologist Cesare Lombroso in Turin. In 1925, my father went back to Pavia to work as an assistant to Ottorino Rossi, another student of Golgi’s who was then chairman of neurology and rector of the university. My mother lived in front of the hotel where the young neurologists took their meals. After a chance meeting on the street, my father fell in love with her at first sight and married her in 1930. Their marriage was a very happy one—blessed by the births of my sister Elena in 1931, myself in 1935, and my sister Maria Luisa in 1940—until my mother developed a severe cardiac valve disease that destroyed her life. She suffered from several embolisms, the last one of which left her in what is now called a vegetative state for over a month; she died at age 50 in 1956. If she had been born 20 years later, the now standard surgical procedure for valve substitution would have allowed her to live a full life, showering her unlimited capacity for love on her husband, children, and grandchildren. It was a tragedy for the whole family, but my father was literally shattered by the loss. Yet eventually he was able to recover by dedicating himself fully to the rest of his family and to his work. He retired at age 70 from the University of Pavia to live until he was almost 95 in a book-filled house in Brunate, a small village on a hill above the city of Como, overlooking the lake. Brunate’s claim for a place in history is justified by a local lady who wet-nursed the infant Alessandro Volta. She was married to an expert builder of anemometers, and an earlier version of a commemorative inscription on a wall adjacent to the village’s church hinted at an improbable connection between Brunate’s air, the nurse’s milk, the husband’s technical skills, and the invention of the electric pile. My wife, Luisa, our children (Filippo and Silvia), and I treasure the memories of the summer days spent in Brunate with my father, my sister Elena, her husband, Alberto Masciocchi, and their children, Laura and Alessandro. My father was such a good and loving grandfather that nowadays not only his grandchildren but also Luisa and I refer to him as Nonno (Grandpa) Carlo. I am deeply and permanently grateful to him for the constant support he gave to me and to my family and for providing such a good model of intellectual and moral values.

As a young man, my father’s research work with Pensa, Roncoroni, and Rossi had been mainly in neurohistology and neurohistopathology. He would have been proud and delighted to see some of the color drawings from his old papers recently reproduced in Cajal’s Butterflies of the Soul (De Felipe, 2010), a book extolling the almost artistic virtues of those who had illustrated the microscopic structure of the nervous system without the benefit of microphotography. Later, he devoted himself to problems of clinical neurology and psychopathology. Between 1936 and 1941, we lived in Parma and then in Padua, where my father was head of neurology. In 1941, he was called back to Pavia by Pensa, who had returned to his alma mater as professor of anatomy and dean of the medical school. As the director of the neurology clinic, my father had the right to live with his family in an apartment on the clinic’s upper floor. During the air raids of World War II, the whole family went to an underground shelter along with the clinic’s inpatients, including those from the psychiatric wards. I remember that sometimes I had to play ball with a very large woman in her fifties who believed she was a three-year-old girl. In the final years of the war, air raids took place almost every night—bombing the bridges on the Po and Ticino Rivers in or near Pavia. On many mornings, it was tough for children like me to have to go to school after a sleepless night in the shelter. One night I sneaked off to my bed instead of going to the shelter. After the end of the air raid, my mother—terrified by my unnoticed disappearance—gave me a well-deserved beating.

Education

I was educated in the public schools of Pavia, where I had some excellent teachers in grammar school and then in junior and senior high school. My senior high school was the liceo classico (humanistic high school) named for the bombastic poet Ugo Foscolo, who had briefly taught at the University of Pavia. The Liceo Foscolo was and is a rather haughty institution where, in accordance with the now almost centenarian public schooling reform of the philosopher Giovanni Gentile, the teaching of the humanities (including Latin and ancient Greek) must take a decided precedence over that of the sciences. For me, a strongly positive feature of the liceo was that it truly made everyone understand that learning requires dedication, time, and effort. In my liceo, effortless learning did not exist. Nor did it exist in the medical school of the University of Pavia, where I enrolled in 1953 and graduated with honors in 1959, after six years of honest toil. In my high school and university days, as a relief from studying, my contemporaries and I enjoyed punting and rowing Venetian style in the slender, elegant, flat-bottomed Pavian boats (barcé) in the blue waters of the Ticino River. In that pre-air-conditioning era, swimming in those clean and fresh waters was the most effective respite against the sultry summers of the Po Valley. A respite, alas, that is no longer available because the most beautiful Italian river has been polluted beyond repair.

Pavia has always been proud of its university, founded in 1361, and its 16th-century Ghislieri and Borromeo university colleges. The university had enjoyed a splendid period as one of the greatest centers of learning in the late 18th century and the beginning of the 19th century. Just to mention a few names, Pavia could then boast among its professors the great anatomist Antonio Scarpa, the founder of experimental biology, Lazzaro Spallanzani, and the inventor of the electric pile, Alessandro Volta. After a period of decadence, the international prestige of the University of Pavia had been at least in part restored by the achievements of Camillo Golgi and his collaborators in the late 19th century—especially by the Nobel Prize in Physiology or Medicine awarded to him in 1906. (In that period of decadence, most of the descendants of Golgi and their colleagues were sadly aware that they could never attain the greatness of their teacher.)

About 10 years before I enrolled in the medical school, Emilio Veratti, Golgi’s pupil and successor to the pathology chair, had publicly expressed his ruthless self-evaluation of his career during his last lecture before retirement. He surprised the students by recounting the parable of the czarina who had lost a precious ring during a grand ball at the czar’s court. The czar had then divided the huge ballroom into a number of sectors equal to the number of gentlemen in attendance, and each gentleman had searched for the ring in the sector assigned to him. Obviously, only one gentleman eventually found the ring, but the czar rightly rewarded all participants because the success of the search was due to the lucky searcher as well as to those who had excluded the presence of the ring in their respective sectors. With this parable, Veratti wanted to convey the moral message that serious science is rewarding by itself even in the absence of major discoveries; but most probably he also felt that finding the metaphorical ring would have been a fairer reward for his competent and conscientious life in research. Ironically, he had found a ring without knowing it, when he had been the first to describe in a masterly way the internal structure of muscle fibers now known as sarcoplasmic reticulum. When, many years later, scientific authorities of the field such as H. Stanley Bennett, Andrew Huxley, and Keith Porter publicly credited him with the discovery, the octogenarian Veratti reacted with his usual modesty and understatement, along with some reservations about the soundness of the judgment of his newly found admirers (Berlucchi, 2002).

During my medical studies, I had a half-baked idea of becoming a clinical neurologist like my father, who encouraged me to start as a student by getting a good training in neurohistology. So I worked as an allievo interno (undergraduate research student) in the Institute of Anatomy headed by Gennaro Palumbi (the successor of the same Antonio Pensa, who in Parma had taught my father, and, as we shall see, the famous neurophysiologist Giuseppe Moruzzi). Pensa had retired years before, but he was still around as the nominal director of a National Research Council center for the study of the nervous system. Although he was well over 80, Pensa still took part in teaching and actually gave me the histology exam and part of the anatomy exam. The scientific atmosphere of the institute was not particularly stimulating, except for the presence of Elio Raviola, an exceptionally bright and enterprising student three years older than myself and now a lifelong friend. He was personally responsible for bringing electron microscopy to Pavia. Unfortunately, the conservative members of the faculty assigned him (correctly but without any vision) to the “dangerous” category of those who tend to rock the boat, and, as a result, he ended up becoming a professor not in Pavia but at Harvard University.

My MD thesis project was to describe the nuclear organization and the connections of the amygdaloid complex in guinea pigs, which I studied with the standard histological methods for the nervous system, including Golgi’s black reaction. In those days, the amygdala was still thought to be mainly an olfactory structure, but I tried to distinguish the cortical nucleus, which receives direct projections from the olfactory tract, from other deeper nuclei with connections hinting at non-olfactory functions. The Anatomy Institute had a good library, including the entire collection of the Journal of Comparative Neurology, where I learned most of my comparative neuroanatomy and the English lexicon of neuroscience. About a year before graduating, I began to think about my future. I was still planning to become a clinical neurologist, and although in those days it was common for aspiring clinicians to do postgraduate research in basic science, I did not want to stay in anatomy. An alternative choice was neurophysiology. The research of the Institute of Physiology in Pavia was of high quality, but the only neurophysiology studied there (by excellent investigators such as Cesare Casella and Virgilio Perri) was restricted to the peripheral nervous system. Because I was interested in the so-called higher nervous functions, Pensa suggested that after graduating I should go to work in Pisa with Giuseppe Moruzzi. Moruzzi was a towering figure in neurophysiology—not only in Italy but in the entire world—because of his discovery with Magoun of the arousal system in the brainstem reticular formation (Moruzzi and Magoun, 1949). Pensa knew Moruzzi well; when he was in Parma, he had trained the young Moruzzi in neurohistology and had helped him publish his first scientific paper (an analysis of Golgi’s neural network in the granular layer of the cerebellum) when he was only 20.

In the spring of 1958, armed with Pensa’s letter of introduction, I approached Moruzzi with much trepidation at a meeting on sleep in Milan. In a calm, matter-of-fact manner he said that after graduating I could work in Pisa in his institute for a couple of years, during which time he and I could decide if I was fit for scientific research because, he explained, not everybody is. In the affirmative case, I could continue working in neurophysiology for another three years, one of which should be spent in a laboratory abroad. When I said that I wanted to become a clinical neurologist, he said that I was young, that I had plenty of time to learn to work with patients, and that five years in basic neurophysiological research could only do me good. Indeed, some of his pupils had become successful clinicians after several years in physiology.

Moruzzi and Pisa

Moruzzi was the first physiologist in Italy to fully devote his research to the nervous system although, for teaching purposes, he kept in touch with developments in all fields of physiology. He was a scientific descendant of the two British fathers of neurophysiology, Charles Sherrington and Edgar Adrian, who had shared the 1932 Nobel Prize in Physiology or Medicine for their studies of neurons (Berlucchi, 2008). Moruzzi’s link to Sherrington was through Mario Camis, the professor of physiology in Parma whom he had joined after Pensa had left for Pavia. Camis had spent a few years in England working with Langley and Barcroft in Cambridge, and then with Sherrington in Liverpool, where he had discovered the phenomenon of occlusion in spinal motor centers. Camis had taught Moruzzi the techniques that had been the staple of Sherrington’s neurophysiology—above all myography—and had also made him accept the Sherringtonian basic concept of the nervous system as an organized aggregate of specialized and selectively interconnected neurons. The link between Adrian and Moruzzi was a direct one. After working in the laboratory of Frédéric Bremer (another pupil of Sherrington) in Brussels, in 1939 Moruzzi had joined Adrian in Cambridge in an experiment providing the first demonstration that the spontaneous activity of single motor cortex neurons could be recorded from their axons in the bulbar pyramidal tract. Their findings implied that the frequency code discovered by Adrian for neuronal communication in peripheral sensory and motor neurons also applied to the highest level of the brain and that, at least in principle, the electroencephalogram (EEG) waves could be correlated with single neuron activities.

After World War II, Moruzzi’s best-known work had been the discovery of the arousing EEG effects of the electrical stimulation of the brainstem reticular formation; he had undertaken this work with Horace Magoun at Chicago’s Northwestern University in 1949. Upon his return to Italy, Moruzzi had founded the most successful Italian neurophysiological school at the University of Pisa, where he had created the material and intellectual conditions for high-quality research and had made further pioneering studies on the physiology of the sleep-wake cycle. Moruzzi had an almost religious concept of scientific research and shared Primo Levi’s belief that loving one’s work is the best approximation to long-lasting happiness in one’s life. On first acquaintance, his shy and rather withdrawn personality might make him seem cold, aloof, and awe inspiring, but everybody who knew him well can attest that he was a warm, caring, generous, altruistic, and altogether noble human being. My debt to him for my personal and scientific formation is so great that I cannot find the words appropriate to describe it.

After graduating in December 1959, I left Pavia at the beginning of 1960 to work in the Institute of Physiology at the University of Pisa, an imposing building located on Via San Zeno in front of a large garden bounded by the medieval walls. I did not know then that Pisa would become my home for more than 20 years, and that I would never return to live permanently in my native town. Pisa is similar in size and structure to Pavia, and like Pavia has some beautiful Romanesque churches—though their style is more ornate than that of the austere Lombard basilicas. As in Pavia, the academic institutions, including the university—in which the great Pisan Galileo had been a lazy student and a mediocre professor—and the Scuola Normale Superiore founded by Napoleon, are among the city’s main cultural and economic resources. I lived for a few months alone in a small hotel near the train station, commuting by train between Pavia and Pisa on weekends in order to be with my fiancé in Broni. Following our wedding in July, Luisa and I set up our home in an apartment not far from the splendid Piazza dei Miracoli and the Leaning Tower. That we were not Pisan was easily revealed by our accents and by our restricted lexicon compared to the torrential verbal fluency of the Tuscans, but we were quickly integrated as bona fide citizens. We spent the happiest years of our lives in Pisa. Our two children were born there, Filippo in 1961 and Silvia in 1966. Bravely combining the chores of housewife and mother with those of a diligent student, Luisa was able to graduate with honors in biology at the University of Pisa and then teach science at junior high schools in or near the city. My research life at the institute, under Moruzzi’s enlightened guidance and in the company of brilliant and friendly contemporaries, could not have been more satisfying. In the summer, the Mediterranean Sea and the beach at Tirrenia, a few kilometers away, were paradise. And above all, we were young and expecting to be masters of our lives.

Research Beginnings

At the institute, after learning some basic experimental procedures, I was assigned to do a project with Piergiorgio Strata, who had just graduated with honors in medicine after working as a student at the institute for six years. Other Italians of my age working in the institute at that time included Emilio Bizzi, Lamberto Maffei, Pier Lorenzo Marchiafava, Andrea Cavaggioni, and a very young Luigi Cervetto, all of whom would become neuroscientists of international reputation. Moruzzi told me that Strata was brilliant and that we would get along well. He was truthful on the first count and foreseeing on the second. I quickly found out that Strata was sharp witted, superbly educated, exquisitely fit for scientific research, and that his verbal speed was astounding. He is from Liguria, the region around Genoa, the inhabitants of which are nationally known for their legendary reluctance to part with their money, called parsimony by Ligurians and stinginess by all others. Although on occasions I still cannot resist the temptation to tease Piergiorgio about the subject, more than 50 years of close friendship allow me to swear that if he is parsimonious, he is also one of the most generous persons I know.

The research task that Moruzzi assigned to Piergiorgio and me was inspired by an old study of Moruzzi himself and by a recent finding of Arnaldo Arduini, Moruzzi’s first student who had followed him from Parma to Pisa to become his historical right arm. In pigeons, Moruzzi had found that each optic lobe contains upper motor neurons for opening the eyelids of the contralateral eye, and he had argued that pigeons can go to sleep with only one eye closed, if the corresponding optic lobe is deprived of facilitatory influences. Some of these influences were known to arise from light stimulation of the retina so that the eyelids of a blinded eye were expected to droop prior to those of the other eye at the beginning of sleep (Moruzzi, 1947). Arduini’s recent work had shown that the spontaneous activity of retinal ganglion cells in the dark had an activating effect on the EEG of the cat (Arduini and Hirao, 1959). Strata and I were to investigate whether the retinal dark discharge had a similar arousing influence in birds. If we could detect an earlier drooping of the eyelids in a blinded eye of birds at the onset of sleep in complete darkness, the effect could be attributed to the absence of a retinal dark discharge, thus providing a behavioral confirmation of Arduini’s EEG findings in cats.

We faced two experimental problems—how to inactivate the retina without producing other damage to the eye and how to observe sleep behavior in the absence of visible light. We chose to work on common owls because of their big eyes and because Piergiorgio had gained some experience in handling them during the preparation of his MD thesis. In the beginning, we planned to inactivate the retina by increasing the intraocular pressure so as to stop the retinal blood flow, but we found that the procedure was successful only if the high intraocular pressure was maintained for several hours. Then Piergiorgio, having seen during his medical studies that ophthalmologists used a photocoagulator for treating retinal detachments, had the idea that we could de-efferent the retina by photocoagulating the head of the optic nerve at the optic papilla. After securing the help of a young collaborative ophthalmologist, Giuseppe Salvi, and the permission from his boss to use the photocoagulator, we had to overcome the obstacles of our ignorance of the avian eye.

It took us some time to find out that, in order to dilate the pupil, you have to use curare rather than atropine because the pupillary constrictor of birds is a striated muscle and that the optic papilla is covered by a vascular structure, the pecten, which protrudes in the posterior chamber of the eye. But eventually Salvi was able to burn pecten and papilla through a curare-dilated pupil, leaving the eye otherwise intact. In a room sealed from light we restrained the owl in a position that would allow it to go to sleep without moving the head, and we “watched” it in the dark with an infrared sniperscope used by American soldiers during World War II for shooting at night. Our instrument was a war surplus that Leopoldo Nicotra, the ever-ingenious head technician of the institute, had bought for us (almost certainly illegally) in the Leghorn flea market. By itself the infrared source of the sniperscope, made visible at the eyepiece by a wavelength multiplier, was completely invisible to our human eyes and most probably also to the only seeing eye of the owl. However, to comply with Moruzzi’s somewhat excessive requirements for complete experimental control, now and then we turned off the sniperscope and took random pictures with flashes too short to cause any physiological reaction within their duration. Thus we observed in several animals the expected palpebral asymmetry and documented it with impressive shots of “winking owls.” Of course, the asymmetry did not depend on an active eye closure such as a wink but rather, as we demonstrated by comparison with an actual blink, on a passive lid drooping in the blinded eye. Moruzzi was happy with our results and published the paper we wrote (Berlucchi and Strata, 1962) in Archives Italiennes de Biologie, the journal that had been founded in 1882 by the Italian physiologist Mosso and had been restarted by Moruzzi in 1956 after its suspension in 1937. Contrary to his modern stance and vision in most things scientific, Moruzzi was somewhat old-fashioned in relation to the reviewing process for Archives. If he felt competent to evaluate a submission, he did not send it out to independent reviewers, even when, as in the case of our owl paper, he could be suspected of being biased because he had inspired and closely followed our study. Because most of the institute’s studies were inspired and followed by Moruzzi, they were usually published in Archives without a regular reviewing process. Regardless, the journal was doing well because—as the most important publication specializing in sleep physiology—it received papers on the subject from important laboratories in Italy and abroad. When we became more experienced, Piergiorgio and I tried to convince Moruzzi that we should be allowed to publish in other international journals to receive independent evaluations of our work. He was not pleased but agreed, with the proviso that we should continue to publish some papers in Archives.

Sleep Studies

During the first 10 years of my research activity, I worked mostly on the physiology of the sleep-wake cycle within the Moruzzi tradition. In 1961, Moruzzi’s right arm (Arduini) was preparing to leave Pisa to assume the physiology chair at the University of Ferrara. Before Arduini left, Strata and I collaborated with him in a study on the degree of spontaneous pyramidal tract activity in free-moving cats during the full sleep-wake cycle (Arduini, Berlucchi, and Strata, 1963). Arduini was a first-class neurophysiologist with many experimental and surgical skills. In the 1950s, he had discovered the hippocampal theta rhythm during arousal with John Green at the University of California in Los Angeles. He was a knowledgeable, level-headed, and generous teacher from whom we learned the technique for chronic electrode implantation and for recording the electroencephalogram, the neck electromyogram, and the electrooculogram to distinguish the different stages of sleep. We recorded the overall pyramidal tract activity with macroelectrodes in the mesencephalon or the medulla as an index of a main cortical output during waking, slow-wave sleep, and fast or paradoxical sleep. The electrode placement was checked at the end of the experiments by Arduini’s wife, Maria Grazia, an accomplished histologist. The main result was that tonic pyramidal activity decreased, as expected, from waking to slow-wave sleep, but in paradoxical sleep was as high as, or higher than, during waking. This was one of the first experimental pieces of evidence for vigorous and sustained activity of the motor cortex in paradoxical sleep, in spite of general muscle relaxation.

Moruzzi’s interest in the phenomenology of sleep prompted a study in which Strata and I collaborated with him and with Giuseppe Salvi, the ophthalmologist who helped us with the retinal photocoagulator. We studied (by direct observation and filming) the movements of the eyes and the changes in the pupil diameter during natural sleep in cats. Piergiorgio brilliantly devised a contact lens with an attached cylinder that kept the eyelids apart without discomfort for the cat, so that we could film the pupil from a close distance in various physiological states. In some cases, the influence of visible light on the pupil was excluded by watching through the infrared sniperscope in the dark or after blinding the eye by photocoagulating the optic papilla. Deserting our puzzled wives, Piergiorgio and I filmed throughout the night, when the absence of the institute’s diurnal din did not disturb the cats’ sleep. We found that the pupil constricted in proportion to the depth of sleep but, during paradoxical sleep, the extremely constricted pupil underwent brief temporary dilations in concert with the bursts of rapid eye movements (Berlucchi, Moruzzi, Salvi, and Strata, 1964). The eye movements in paradoxical sleep, much faster than those observed in humans, were brisk, repetitive, conjugated, and ballistic, making it very unlikely that they served to scan the visual scene of a cat dream. Because pupil dilations during rapid eye movements also occurred after sympathetic denervation of the eye, we attributed them to transient inhibitions of the pupil’s parasympathetic innervation.

The film we eventually put together was really good, and when Piergiorgio showed it at a meeting on the physiology of sleep organized by Michel Jouvet in Lyon in September 1963 (Berlucchi and Strata, 1965), the international audience of sleep specialists was impressed. Moruzzi’s classic distinction between tonic and phasic phenomena of paradoxical sleep, as presented in his Harvey Lecture (Moruzzi, 1963), was partly based on those observations of phasic pupillary dilations on a background of tonic pupilloconstriction. We lent copies of the film to many colleagues, but unfortunately, neither I nor Piergiorgio had the good sense to preserve the original or at least a copy. To my knowledge, a few frames of the entire film used in a video by Allan Hobson are the only survivors in circulation.

In another study, Strata, Lamberto Maffei, and I collaborated with Moruzzi to support his hypothesis of a functional antagonism between the activating mesencephalic and pontine reticular formation and the sleep-inducing structures of the caudal brainstem (Berlucchi, Maffei, Moruzzi, and Strata, 1964). By cooling the floor of the fourth ventricle, we showed that reversible inactivation could produce sleep or arousal in encephale isolé cats depending on which brainstem systems were inactivated. Sleeping encephale isolé cats were aroused by cooling the medullary floor of the fourth ventricle, and encephale cats that were awake were put to sleep by cooling the rostral floor of the fourth ventricle. Although the effects were dramatic, we have always had mixed feelings about this study because it was possible that the medullary cooling stimulated ascending pain pathways, rather than or in addition to inactivating sleep-inducing neurons. Certainly the experiment would not be permissible by today’s ethical standards.

After the completion of these studies, Moruzzi suggested that Strata and I stop working together in order to prove our respective independent research abilities to the scientific community. We were sorry to give up a collaboration that had proven so congenial and fruitful, but we complied with Moruzzi’s advice because we understood that it was offered for our own good. So we went our separate ways, though of course we kept in close contact and continued to exchange information, suggestions, and ideas, as we do by phone or e-mail almost daily today, half a century later.

The next line of research that I pursued had to do with the control of the peripheral auditory input during the sleep-wake cycle of cats. In 1963–64, I collaborated with Moruzzi and Walter Baust, a hard-working and competent German physiologist from the Heidelberg school of Hans Schaefer, one of the discoverers of the muscle end plate potential. In addition to protecting the cochlea from loud sounds, the contraction of the two middle ear muscles—the tensor tympani and the stapedius—can also occur in other physiological conditions. Moruzzi wanted to find out whether the middle ear muscles are specifically used to dampen the auditory input for protecting sleep from disturbing sounds, similar to the way visual inputs are excluded during sleep by closure of the eyelids and pupil constriction. We were to record the auditory input at the cochlea in free-moving cats during waking and the various stages of sleep. One major experimental problem was the variability of the stimulation that occurs because of the changes in the position of the animal’s head within the free field of a sound source with a fixed position in space. We wanted an acoustic stimulus of unvarying intensity throughout the entire sleep-wake cycle of a freely moving cat, and this was provided by an earphone fastened to the cat’s head so that the distance from it and the tympanic membrane was the same regardless of any movement on the part of the cat. The plan was to record the cochlea’s electrophysiological responses to clicks of fixed intensity before and after removing the action of the middle ear muscles. It was then that I made my acquaintance with the wonderful Zeiss binocular surgical microscope, which (after a considerable amount of time and effort on our part and the sacrifice of an equally considerable number of cats from the institute’s stabulary) allowed us to record microphonic and neural responses to clicks at the round window of the cochlea, as well as to cut the tendons of the two tiny middle ear muscles or to stick recording electrodes into the muscles themselves.

Eventually, we were able to show that the amplitude of microphonic and neural responses to clicks of the cochlea were reduced during the stage of sleep with rapid eye movements—particularly in association with the latter movements, but that these reductions disappeared after tenotomizing the middle ear muscles. Accordingly, electromyographic recordings showed that the middle ear muscles contracted synchronously in many physiological conditions, including sleep with rapid eye movements, and their contractions corresponded with and actually caused the reduction in the cochlear response amplitude during paradoxical sleep. Our electroacoustic and electromyographical recordings were really beautiful, and sometime after we published our results (Baust, Berlucchi, and Moruzzi, 1964), we were gratified to read a report from a very important sleep laboratory at Stanford University that described results very similar to ours and that acknowledged the priority of our publication (Dewson, Dement, and Simmons, 1965). Bill Dement, one of the discoverers of paradoxical sleep and an author of the Stanford paper, told Moruzzi, not so light-heartedly, that we had “scooped” them. Because histology was not necessary for our studies, and as a partial compensation for all the cats we had killed while learning to approach the middle ear muscles, I removed the electrodes from a cat that over several days had regaled us with beautiful records, sewed up the skin, and gave her to my mother-in-law, who kept her as a pet for years.

I briefly returned to the auditory system in sleep right after a stay at Caltech (which will be discussed later in this chapter). Giacomo Rizzolatti—another friend who was to become a permanent fixture and influence in my life—John Munson—a student of Bob Doty with superb experimental training in chronic electrophysiological recordings—and I confirmed the role of the middle ear muscles in the control of the auditory input in sleep and studied the central modulation of the transfer of auditory information to the cortex and the cerebellum (Berlucchi, Munson, and Rizzolatti, 1967).

Three studies I did by myself during my time at Caltech also belong in this section because in them I tried to combine my experience with the sleep-wake cycle in the cat with the split-brain studies that Sperry and Myers had started at the University of Chicago and continued at Caltech (Sperry, 1961). I showed that section of the corpus callosum disrupts the fine bilateral symmetry in the EEG but not the synchronous appearance of signs of sleep or arousal in the two hemispheres (Berlucchi, 1966a); that the overall activity of the corpus callosum is low in sleep compared to waking, particularly in paradoxical sleep, except during the bursts of rapid ocular movements (Berlucchi, 1965); and that EEG signs of arousal and waking are still observable in a hemisphere isolated from the rest of the cerebrum (Berlucchi, 1966b). The latter study involved a really difficult surgery, in which I combined a deep midline split with a midbrain hemisection so that the hemisphere on the side of the hemisection was completely disconnected from the brainstem. I think that these were sound pieces of research but not particularly original. The role of the callosum in the bilateral coordination of the EEG had long ago been suggested by Bremer and collaborators, though only in acute preparations. The return of EEG and behavioral manifestations of arousal after destruction of the reticular formation, and its dependence on the hypothalamus, had been demonstrated by Adametz, Batsel, Chow, Villablanca, and others (see Berlucchi, 1970), though my preparation had the advantage of a direct comparison between the EEG of the isolated hemisphere with that of the hemisphere still connected with the brainstem. Finally, my callosal activity findings were very likely due to the fact that I was recording from callosal fibers belonging to large cortical neurons, which Evarts had shown to produce bursts interspersed with periods of complete inactivity during paradoxical sleep (Evarts, 1964). Interest in a reduction or modification of callosal activity during sleep, and particularly during paradoxical sleep, has been resurrected by studies of unihemispheric sleep in aquatic mammals (Mukhametov, 1984) and by recent evidence of a decrease in transcallosal activity in man during awakenings from paradoxical sleep (Bertini et al., 2004). In retrospect, the studies I did at Caltech were most useful to me from a technical point of view because after my previous experience with the middle ear I learned to use the surgical microscope for operating on the brain. It was at Caltech that, under the bright light of the microscope, I learned to expose brain structures such as the corpus callosum, the anterior commissure, the optic chiasm, and the superior colliculi, and to use that ability in many subsequent studies throughout many years.

My Farewell to Sleep Studies

My last experimental effort regarding sleep physiology was connected with a project that Moruzzi had agreed upon—a collaboration with Woodburn (Woody) Heron of McMaster University in Canada. Heron, a pupil of the famous psychologist Donald Hebb and a world authority on the effects of sensory restriction and perceptual isolation, was to spend a sabbatical year in Pisa in 1967. At that time, Moruzzi was trying to obtain evidence for his belief that sleep was necessary for the functional recovery of synapses and circuits that had been used for learning during waking, a hypothesis that he had forcefully put forward at the famous 1964 Vatican conference (Moruzzi, 1965). He wanted to know whether the disconnected hemispheres of split-brain cats would develop different sleep-wake cycles if only one hemisphere was used for learning.

I was to split the optic chiasm and the forebrain commissures in cats that would be deprived of vision in one eye and in the corresponding hemisphere by an opaque contact lens, while the other eye and the corresponding hemisphere were used for various kinds of visual learning and experience. Moruzzi’s expectation was that, at the beginning of sleep, EEG slow waves would appear in the exercised hemisphere sooner than in the deprived hemisphere. Heron’s expectation was the opposite because he had found a slowing of the alpha rhythm in humans submitted to a restricted environmental stimulation. I kept a neutral position and worked hard to prepare the cats. The results were far from clear cut, but if there was a tendency it was in favor of Heron’s expectation. Eventually no publication came out of all that work because Moruzzi noticed, and did not like, some occasional abnormal EEG waves that (not surprisingly) appear in split-brain cats after such a major brain manipulation.

That was a hard period for Moruzzi because of the political unrest that had begun in the Italian universities, with the attendant occupation of classrooms, libraries, and laboratories by students fascinated with the Chinese Cultural Revolution, which was then in full swing. Although it was true that many aspects of the university system were deeply unsatisfactory, the disruption of the institutions and structures of authority advocated by the Maoist revolutionary movements was hardly the solution to the problem. The dogma that all branches of human learning were directly or indirectly ideological in nature undermined the respect for and the trust in science, and even teaching physiology was accused of being influenced by bourgeois and capitalistic prejudices. Moruzzi saw the dangers of the situation, which would tragically degenerate into years of bloody terrorism, and was not afraid to appear at some of the students’ riotous meetings to defend reason, scholarship, and freedom of learning. Usually, he was regarded with respect, if not with sympathy, by most.

For this and other reasons, he did not have much time to devote to our experimental project, which—in spite of Woody’s brave attempts to do quantitative analyses on the EEGs that were acceptable to Moruzzi—eventually collapsed. For me, one compensation for this failure was that Woody and I struck up a very good friendship after surmounting the hurdle of his legendary shyness (he was known for having sneaked out of a classroom where he was supposed to give a seminar because the audience was too big). I learned much from him about many subjects, from Hebbian psychology to American and Canadian politics. Eventually, he participated in the reaction time project that Umiltà, Rizzolatti, and I had started on interhemisperic transmission in humans, and his silent disapproval of my driving style did not keep us from having many interesting discussions while we rode on the autostrada to Bologna to perform the experiments. After going back to Canada, he kept in touch by writing amusing letters about the changes then affecting universities throughout the world, including the then fashionable habit of professors growing long sideburns. Woody died a few years ago, and his former student Doreen Kimura (of dichotic listening fame) wrote affectionately and humorously about him in an autobiographic sketch (Kimura, 2006).

My non-experimental adieu to the field of sleep-wake physiology was a chapter I wrote in English but that was translated into German by my former coworker Walter Baust. He included it in a book that he edited and published in 1970 (Baust, 1970). During my stay at Caltech, I had learned of Strumwasser’s discovery of circadian activities of single neurons in the parieto-visceral ganglion of Aplysia. This led me to suggest that similar pacemaker neurons, endowed with a capability for autonomous activity, but open to exogenous synaptic control from sensory organs and other nervous centers, might engender sleep and waking in mammals. At that time, I was under the influence of Hebb’s and Kleitman’s views of sleep as an endogenous cerebral organization alternative to wakefulness and by Moruzzi’s theoretical and experimental arguments in favor of an active production of sleep by brainstem mechanisms. My chapter was totally neglected in the neuroscientific literature, except for a citation by Moruzzi in his monumental review in Ergebnisse der Physiologie in 1972. Recently, in writing about Moruzzi’s contributions to sleep physiology, my colleague Marina Bentivoglio and her collaborator Gigliola Grassi Zucconi (Bentivoglio and Zucconi, 2011) unearthed my review and concluded that I was the first to postulate the possible importance of pacemaker neurons for the genesis of sleep and waking. Although thankful for their generous evaluation of my old review, I remain skeptical that I was then proposing a particularly new theory; in a commentary at the end of their paper, I pointed out that Kleitman and Hebb had already suggested an endogenous generation of sleep.

Sperry and Caltech

Moruzzi was a strong believer in the idea that working for at least one year in a laboratory abroad was essential for the formation of a young scientist. Accordingly, in the summer of 1963, he started to arrange for Piergiorgio Strata and myself to work in the laboratories of two great scientists: Piergiorgio was to go to Australia to work with John Eccles and I was to go to California to work with Roger Sperry. Neither Eccles nor Sperry had as yet won a Nobel Prize, but those who knew something about brain science had no doubt that sooner or later they would be called to Stockholm, as indeed they were. I knew Eccles personally because in 1961 he attended the meeting of the International Brain Research Organization that Moruzzi organized in Pisa. Many outstanding neuroscientists of the time, including Magoun, Granit, Brazier, Grey Walter, Anokhin, Bremer, Brookhart, Jung, Fessard, Buser, Naquet, and others were present at that conference, and Strata and I and other young members of the institute had to drive them from their hotels to the meeting venue. However I had never heard of Sperry, and Moruzzi directed me to his most important discoveries. These were summarized in a chapter in Stevens’ Handbook of Experimental Psychology (Sperry, 1951) and an article in Scientific American on the formation of brain circuits (Sperry, 1958) plus a review of the effects of sectioning the corpus callosum in cats and macaques (Sperry, 1961). I thus learned, in 1963–64, that Sperry had demolished a pet theory of his two teachers Paul Weiss and Karl Lashley. This was the “blank slate” theory, according to which the developing nervous system starts out as an essentially random network to be shaped into a functionally adaptive structure by use, practice, and elimination of inappropriate connections. In ingenious and deceivingly simple experiments, Sperry had instead shown that in replicating embryogenesis, central nerve regeneration in adult cold-blooded vertebrates rebuilds a preordained pattern of connections that persists even when forced by experimental manipulations to sustain completely maladaptive forms of behavior. Complementary experiments on the effects of peripheral nerve crossing in mammals had led him to conclude that the mammalian nervous system also possesses a high degree of inborn self-organization, prior to and independent of any environmental influence. In accord with Cajal’s largely conjectural chemotropic hypothesis, Sperry’s chemoaffinity hypothesis postulated, on the basis of indirect but convincing experimental evidence, that populations of nerve cells acquire and retain individual chemical identification tags, such that lasting functional synaptic connections are established only among neurons that are selectively matched by inherent chemical affinities.

The other, more recent line of Sperry’s research, which would win him a Nobel Prize, had to do with the functions of the corpus callosum. Sperry had always been in disagreement with Lashley about the role of long intra- and inter-hemispheric connections, which Lashley regarded as mere “skeletal structures” because the evidence then available suggested that they could be cut without causing any major behavioral loss. Instead, Sperry and his collaborators, especially Ronald Myers, had shown by selective lesions and appropriate behavioral tests in cats and macaques that the corpus callosum, far from being a mere mechanical link between the two hemispheres, is the essential route for the exchange of sensory, motor, and higher-order information between the two cerebral hemispheres. But I was most impressed by Sperry’s paper that was published in a book that I found in the rich library of Moruzzi’s Institute of Physiology. Basic Readings in Neuropsychology, edited by R. L. Isaacson (1964), included 16 articles culled from scientific journals. The final paper, entitled “Neurology and the Mind-Brain Problem” and written by Sperry had appeared in American Scientist (Sperry, 1952). Sperry was declaredly influenced by the essay “How to Make Our Ideas Clear” in which the pragmatist philosopher Charles Peirce had argued that “the whole function of thought is to produce habits of action” (Pierce, 1878). Sperry maintained that the core of the cerebral process underlying the perception of an object is neither isomorphic with that object nor in the form of a motor pattern. It is instead premotor or pre-premotor in nature, preparing and adjusting the motor system for selecting among a number of possible reactions to the object itself. This view has long anticipated modern theories according to which perceiving is equivalent to being set to act on the basis of actual or remembered environmental affordances. I still recommend this paper as a gem in the history of ideas about cerebral organization in cognition and behavioral control.

I was thrilled by the possibility of working in Sperry’s lab. Moruzzi wrote to him, and he agreed to accept me as a postdoc provided I obtained an international fellowship from the U.S. Public Health Service. Such fellowships were granted by the National Institutes of Health (NIH) in Bethesda, Maryland, to provide “specially selected and qualified foreign scientists” with research and/or training opportunities in health research laboratories and institutions throughout the United States. On April 1, 1964, I was informed that I had been selected to receive one such fellowship (no April fool, fortunately), and in June, Lee Dubridge (then president of California Institute of Technology in Pasadena) notified me that I had been appointed research fellow in biology for one year, effective September 1, 1964. I knew that Caltech was an outstanding international scientific university, which had grown out of a small technical school mainly due to the efforts of the physicist George Millikan; only later did I read that, according to another of its presidents, Marvin Goldberger, there are no good appointments at Caltech—only superb ones (Goodstein, 1991). I doubt that I am equal to that statement, but certainly I can only define my stay at Caltech as a superb experience in my life.

My wife Luisa, our three-year old son, Filippo, and I were granted visas by the American consulate in Florence and, at the beginning of September 1964, we embarked on an Alitalia flight from Milan Malpensa to the recently renamed John F. Kennedy International Airport. It was our first flight, but in my natural predisposition to fret in anticipation of the challenge that waited for me in the United States, fear of flying was the last of my worries. After a couple of days as very provincial tourists in New York, we went on a tour of laboratories suggested by Moruzzi, which gave me the opportunity to give talks to select audiences (as well as causing me a lot of additional anxiety). In Baltimore, we stayed in the home of Janet and Moise Goldstein—who had previously spent a year in Pisa, and at Johns Hopkins University, I met the legendary physiologist Vernon Mountcastle and my amusing countryman from Genoa Gian Franco Poggio. At NIH, I was a guest of Ed Evarts, in whose laboratory I met Emilio Bizzi, who had come from Pisa via Saint Louis, and a young Bob Wurtz, both of whom were on their way to splendid careers in neuroscience. At Harvard University, I visited the laboratory of David Hubel and Torsten Wiesel, who were already famous for their work on the visual cortex. They impressed me greatly not only for their science but also for their friendly, unassuming manners. Hubel was still interested in the physiology of sleep and was proud that Moruzzi had published his work on single visual cortical neurons during sleep in Archives Italiennes de Biologie. Because of my recent work on the auditory system, I also visited the laboratories of two great men in the field: Bob Galambos at Yale and Hallowell Davis at the Central Institute for the Deaf in St. Louis, both of whom were kind enough to listen to my account of the activity of middle ear muscles in sleep. We then flew from St. Louis to Los Angeles, and Sperry later met us at the Pasadena bus terminal and drove us to a motel near Caltech. He told Luisa that she could rely on the advice of an Italian member of the Caltech wives’ circle, Inuccia Dulbecco, being careful not to mention her former husband, Renato (the future Nobel awardee), because he had just divorced her and moved to La Jolla with a new wife. Inuccia was indeed a great help for our settlement in Pasadena and our familiarization with the local opportunities and ways of living.

My stay at Caltech allowed me a continuous contact with a group of young gifted scientists working under Sperry, including, among others, Chuck Hamilton, Mike Gazzaniga, Emerson Hibbard, Evelyn Lee Teng, and Richard Mark. In addition to Sperry, Caltech’s biology division boasted eminent professors such as Wiersma, van Harreveld, Delbrück, Owen, Sinsheimer, and others, all of whom participated in seminars and informal discussions during which there was always something important to learn. The neurosurgeon Joe Bogen, who had been instrumental in reviving the callosotomy treatment of epilepsy, frequently visited the lab and told me amusing and instructive stories about his hemispherectomized cats. My interactions with Sperry were infrequent but uniquely formative and illuminating. Although I could confirm his reputation for being at times withdrawn, taciturn, and even sullen and grouchy, I was also able to enjoy the moments during which he exhibited his great sense of humor and his propensity for a good laugh. He was always nice and helpful to me, though I was awed and somewhat inhibited by his obvious genius and dry Socratic attitude. I had met American university professors in Italy and had been impressed by their general easy-going, amicable manners. By comparison, Sperry looked to me more like an austere European professor, keeping some distance from his students. Many years later, I heard that when one of his former students—after becoming a full professor in another California university—asked Sperry if as a colleague she could call him Roger, he replied: “Gee, I don’t know, I never called Doctor Lashley Karl.” But even at a distance, he was a superb teacher. He did not particularly like the electrophysiological approach to studying the brain, and he claimed (wrongly, as we now know) that learning does not involve the addiction or subtraction of any actual fiber connection but only physiological (electrical) changes, probably at the synapses. I asked him to coauthor the three papers I completed at Caltech but he refused, possibly because he did not completely trust electrophysiology. Nevertheless, he discussed those papers with me in a profoundly illuminating way and corrected my drafts and greatly improved them. I had learned the importance of clear writing in science from Moruzzi, but I think it was from Sperry and the reading of his papers that I had a direct experience of the closest approximation to perfect scientific writing, along with the distinct feeling that I would never be that good.

In 1964, when I was at Caltech, Sperry had begun to claim that the most important task for the neurosciences is to try and understand the patterns of cerebral organization that underlie the human mind. At the famous Vatican conference of that year, he had caused some commotion in ecclesiastic circles by claiming that if you split the brain you also split the mind (Sperry, 1965). In the following years, he perfected his philosophical conception of an interactionist monism, whereby mind is considered an entity emerging from brain activity that reacts back on the brain without breaking the causal closure of the physical world. I may misrepresent his philosophy here because I must confess that I have never been able to understand it fully. In the late 1980s, Sfera, a beautifully illustrated cultural Italian magazine, asked me to solicit a story from Sperry about the brain and the mind. Sperry suggested that I prepare a draft by combining a description of the classical split-brain experiments with some tentative “consciousness” material that he had sent to me earlier. I prepared the draft in English and submitted it to him with the understanding that I would translate it into Italian after his approval. He approved the draft and added that he trusted that I would appear as joint author because “he could not see himself as authoring alone an article in Italian.” The article eventually appeared with our two names in Sfera magazine (Berlucchi and Sperry, 1990), the elegance of which was much admired by Sperry’s wife, Norma. The final sentence of the article argued that the rejection of the old “mind does not move matter” belief was the most important outcome of split-brain research. On many occasions over the years, I returned briefly to Caltech to talk with my old friend Chuck Hamilton and with other “Sperryists” who had joined the lab after I had left in 1965, especially with Eran and Dahlia Zaidel. If Sperry were around on those occasions, he always told me that as a neurophysiologist I should support his view of consciousness as a main ingredient of brain functioning. He died in 1994 and was commemorated shortly thereafter by many of his former students, friends, and colleagues at a Caltech meeting organized by the psychologist Toni Puente, which I attended with Mitch Glickstein. When I was editor-in-chief of Neuropsychologia, I asked Chuck Hamilton to organize a memorial issue of the journal dedicated to Sperry. The issue appeared in October 1998 with a moving preface by Sperry’s wife, Norma, who wrote: “Roger would have been delighted to see these papers of his former coworkers, surprised by the breadth and quality of their endeavors and in particular gratified that he had passed on a sense of excitement and pleasure in searching for answers to important questions” (Sperry, 1998).

Return to Pisa, Choice of a Career, and the Fortune of Excellent Collaborations

When we returned to Italy, everything looked quite small after our experience with the immensity of the California spaces, from the huge Los Angeles metropolitan area to the High Sierras, from the living Mojave Desert to the wasteland of Death Valley, from the wonderful Yosemite and Sequoia National Parks to the wide beaches of the Pacific Coast. There was one problem, however, that appeared far from small. Clinical neurology no longer attracted me because I wanted to continue to work full time in research. I talked to Moruzzi, and he said that he would be glad to help me pursue an academic career in physiology. I could continue to occupy the National Research Council position that I had before going to the United States until a post at the University of Pisa became available. The problem was thus promptly solved, and we resumed our life in Pisa, with the prospect of a welcome addition to the family. Luisa and I wanted a daughter after our son Filippo, and with her characteristic determination, she delivered Silvia on September 26, 1966.

For a number of years after our return to Pisa, I had the great fortune of collaborating with gifted scientists from Italy and abroad who were attracted to Pisa by the fame of Moruzzi’s institute. I have already mentioned Woody Heron and, briefly, Giacomo Rizzolatti. Giacomo, a medical graduate of Padua, had gone to Pisa on the advice of his mentor Hrayr Terzian, a brilliant clinical neurologist who had spent a couple of years in Moruzzi’s institute in the 1950s (more about him later). While I was in California, Giacomo had already worked with Maffei and Moruzzi in an important study on the modulation of visual input to the cortex during the sleep-wake cycle. During our study in collaboration with Munson, which I have mentioned before, I had had the opportunity to appreciate that Giacomo loved science and culture in general, was extremely well read, and was a keen observer of social and political events in Italy and the world. He had strong and often highly debatable opinions about many subjects and defended them with the same ferocious resolution that he put into his research work. The discovery of the mirror neurons, which has brought him international fame and many well-deserved accolades, is no doubt the best product of that resolution.

Like me, he was interested in the functions of the corpus callosum and wanted to test them electrophysiologically. The occasion for such a study presented itself in the fall of 1966 when Mike Gazzaniga came to Pisa with a postdoctoral fellowship from the U.S. Public Health Service. My deep friendship with Mike started at Caltech in 1964 and continues uninterrupted at this time of writing, in spite of some old disagreements over his responsibilities in his split (no pun intended) with Sperry. Recently, Mitch Glickstein, another great friend from Sperry’s school with whom I share many interests, and I have contributed to the book, The Cognitive Neuroscience of Mind, a tribute to Mike edited by his former students and collaborators. As I wrote in that book, I do not laugh easily, but Mike can make me laugh at will at any time (Glickstein and Berlucchi, 2010). I am sorry that I remember only a few of the million jokes that he used to crack on our way to and from the Caltech cafeteria, where he ate enormous hamburgers at any hour of the day.

My collaboration with Mike and Giacomo focused on a direct electrophysiological identification of the visual information transmitted by the corpus callosum. The behavioral experiments of Myers, Sperry, and others on monocularly trained split-chiasm animals had shown that such transfer occurred through the back part of the corpus callosum. Theoretically, the callosum could either convey a basic visual input to the untrained hemisphere, allowing the parallel formation of memory traces in both hemispheres during learning, or it could convey higher-order visual information encoding a memory trace formed exclusively or predominantly in the trained hemisphere. By recording the responses of single callosal fibers to simple visual stimuli, we could at least learn whether the corpus callosum can transmit basic visual information. Indirect electrophysiological evidence to that effect had been recently published by Whitteridge and coworkers at Oxford University (Choudhury et al., 1965). Using cats as subjects, they had deprived one hemisphere of its direct visual input by cutting its optic tract and had found that it still contained visually responsive neurons in a cortical strip 1–2 mm wide between the primary and secondary visual cortical areas. The receptive fields of the responsive neurons were all in the vicinity of the vertical meridian of the visual field, and their responses were abolished reversibly by cooling the splenium of the corpus callosum, and permanently by cutting it.

Gazzaniga, Rizzolatti, and I decided to use the midpontine pretrigeminal preparation because it does not need pharmacological anesthesia and has an almost continuous “waking” cortical activity. Under microscopic control, we exposed the back part of the corpus callosum by separating the two hemispheres, and we inserted tungsten microelectrodes into it. Various single units that were so isolated responded briskly to static or moving lines presented in their elongated receptive fields, which—in agreement with Whitteridge and coworkers—were invariably located close to or on the vertical meridian of the visual field. The response characteristics of these single units allowed us to assign them to the simple, complex, or hypercomplex classes recently described by Hubel and Wiesel. Thus there was no doubt that the callosum could provide basic visual information to either hemisphere, though from a restricted portion of the visual field.

Although our experimental effort proved successful in a relatively short time, it did not proceed without disturbances. As is usual in this kind of experiment, we monitored neural activity by ear, by transforming action potentials into acoustic clicks. One disturbance that we had to overcome was the tendency of our microelectrodic recording system to pick up music broadcast by local radio stations. Mike was much amused by these nuisances. According to his (most probably embellished) account, on one particular occasion, the loudspeaker blared the Beatles’ song “Yellow Submarine” instead of the rattling sound of action potentials. Giacomo’s prompt and dry reaction was that this is what is transmitted by the corpus callosum. Be that as it may, we eventually were able to collect many beautiful recordings, in spite of other unexpected difficulties. In the fall of 1966, when we were in the middle of our research project, Florence, Pisa, and other Tuscan cities were badly flooded by the Arno River, which had been swollen by an unusually persistent rain fall. There was water at human height in the main streets, the electricity was cut off, and we had to interrupt our experiments and live for a few days in our houses without illumination and heating. Mike and his family had rented Strata’s apartment (at that time, Strata was working in Australia with Eccles) and the flood certainly did not make their stay in Pisa a pleasant one. I was not surprised when Mike announced that he was going back to the United States because he had to immediately take up a position he had been offered at the University of Santa Barbara in California. Fortunately, we had collected sufficient material to make up a reasonable story, so that he was able to present our joint results at the meeting of the Federation of American Societies for Experimental Biology. The abstract that was published in federation proceedings in the spring of 1967 was almost destined to scoop the two best visual neuroscientists of all times, Hubel and Wiesel, who had (completely unbeknownst to us) started to record from the cat corpus callosum more or less at the same time as ourselves. With characteristic fairness, they added the following note to their March 1968 paper in Journal of Neurophysiology (Hubel and Wiesel, 1967): “Since this paper was submitted, Gazzaniga, Berlucchi and Rizzolatti have published a preliminary report on single-unit recording in corpus callosum (Federation Pro., 26: 1864, 1967). Their main findings are in agreement with those reported here.” Our full paper (Berlucchi, Gazzaniga, and Rizzolatti, 1967) was published in Archives Italiennes de Biologie toward the end of 1967.

Galvanized by our success and by the confidence that we could work profitably together, Rizzolatti and I thought that we could demonstrate that the callosal input could not only build up visual receptive fields of neurons in the receiving cortex, as Whitteridge and coworkers had shown, but also interact with the visual input transmitted to them through the geniculo-cortical pathway. We reasoned that, following a splitting of the chiasm and the restriction of the projection of each eye to the ipsilateral hemisphere, binocular receptive fields could be built up in principle by the convergence of a geniculo-cortical visual input from one half-field and a callosal visual input from the other half-field. In split-chiasm cats, we did indeed find binocularly driven neurons in visual areas 17 and 18 whose “callosal” and “geniculo-cortical” receptive fields matched each other not only as to the position occupied at the vertical meridian but also with regard to size and preferred stimulus orientation and movement direction. In brief, the convergence of the callosal input and the geniculo-cortical input appeared to build up homogeneous receptive fields spanning the vertical midline. The laws of optics and the organization of the optic pathways from retina to cortex impose a sharp separation of the projections of the two halves of the visual field onto different hemispheres. The convergence onto common neurons of geniculo-cortical and callosal visual inputs that we had shown could provide the continuity of the cortical visual field map across the interhemispheric gap. We submitted the paper to Science (Berlucchi and Rizzolatti, 1968) where it was accepted and published with few modifications on January 19, 1968. A few weeks later each of us received an identical letter from the Montreal Neurological Institute, dated February 12 and signed in elegant handwriting by the famous neurosurgeon Wilder Penfield. Mine read

Dear Dr. Berlucchi: Many congratulations on the beautiful article which you and Dr. Rizzolatti have written in the January number of Science on “Binocularly Driven Neurons in Visual Cortex of Split-Chiasm Cats.” When I saw it, it stirred a chord of my memory and I turned to an article which two of my associates and I wrote in the April number of the Archives of Neurology and Psychiatry in 1935. . . . In Figure 16, you will see that we hypothecated a crossing tract from the left geniculate ganglion to the right calcarine cortex. Does this correspond to your finding in the cat?. . . Yours sincerely, Wilder Penfield

On one hand, we were amazed and flattered that such a great man could take an interest in our work, and on the other, we were puzzled and preoccupied because we thought that our findings by no means suggested a crossed geniculo-cortical pathway. Our somewhat tongue-in-cheek reply, after profuse words of thanks, stated that

Our findings and those of Choudury et al. and Hubel and Wiesel seem to indicate that a cortico-cortical callosal pathway, rather than a crossed geniculo-cortical connection, is involved. However Glickstein et al. have presented anatomical evidence that a crossed geniculo-cortical pathway, like the one you suggested to account for macular sparing in your patients . . . does indeed exist in the cat. The issue is controversial and requires further investigation.

Jim Sprague and Philadelphia

In 1966–67, James (Jim) Sprague, from the department of anatomy of the University of Pennsylvania, was an illustrious visitor to the Institute at Pisa. He was a longtime friend of Moruzzi and had worked with Magoun at Northwestern University in Chicago shortly after the discovery of the arousal function of the reticular formation. He had done fundamental work with Chambers, Liu, and Stellar—first at Hopkins and then at Penn—on the effects of cerebellar and brainstem lesions on motor, attentive, affective, and adaptive behavior in the cat. His recent work had centered on the visual functions of the superior colliculus, and when he arrived in Pisa, he had just published in Science his now famous paper on the Sprague effect in cats, whereby a hemianopia following an extensive ablation of contralateral visual cortical areas is “cured” by a lesion of the superior colliculus on the intact side (Sprague, 1966). He quickly established an easy-going and constructive personal rapport with Marchiafava, Rizzolatti, and with me, treating us as peers in spite of the difference in academic rank and a two-decade separation in age. He did electrophysiological studies on cortico-tectal relations in awake midpontine cats with Marchiafava and Rizzolatti, while he taught me to train cats in a two-choice visual discrimination apparatus (custom-built in the institute to match the one in use at Penn) with the aim of testing the importance of the superior colliculus in form vision. The view prevalent at the time was that form vision was the job of the visual cortex, whereas the superior colliculus was mainly for oculomotor control and visual orienting. Our approach was to make a large lesion, as complete as possible, in one superior colliculus of cats with a section of the optic chiasm, the corpus callosum, and the anterior and posterior commissures. We knew from Myers’ and Sperry’s findings that, in these split-brain cats, visual pattern discrimination learning proceeds independently in the two hemispheres, such that there is no interhemispheric transfer of discrimination learned with only one eye open. We were thus in the position to compare (in the same animal) the performance in visual learning and memory of a visual system having an intact superior colliculus with that of a visual system without a superior colliculus. I did the brain splitting surgery, for which I had a lot of experience; for the collicular lesion, Jim guided me by watching my actions through a second view-sharing microscope. I performed the collicular ablation after removing the overlying bony tentorium and by aspirating the tectal gray matter until Jim decreed that I had made “a nice crypt” in place of the superior colliculus. For good measure, as often as possible, the lesion was extended into the pretectum. Four of the cats so prepared were tested in Pisa and then flown to Philadelphia for further testing and the final histological control.

In the summer of 1968, I went to Philadelphia on a Fulbright fellowship and was followed after a month by Luisa, the children, and my maternal aunt Liana who taught high school English in Pavia and who took the opportunity to visit the United States. We lived in Merion, a northern Philadelphia suburb, where we rented a nice house belonging to an architecture professor at Penn who was on sabbatical in Bologna. In the lab, it was reassuring to see that the preliminary findings from Pisa were fully confirmed by the Pisan cats themselves and by the additional cats that we prepared and tested at Penn. Jean Levy and the Italian-American Angela DiBerardino were essential contributors to the study with their expert technical help in surgery, training and testing, and histology. In brief, we found that the collicular lesion severely interfered with the learning of visual pattern discriminations but not with the retention of discriminations learned before the collicular lesion. In an extensive monograph published in the Journal of Comparative and Physiological Psychology, we supported the hypothesis that the pretectum and superior colliculus form an important link in the complex neural mechanism for learning to recognize and discriminate visual figures (Berlucchi et al., 1972). Another analysis of the effects of selective cortical ablations showed that, in the cat, the primary visual cortex (the striate cortex, or area 17) is not necessary either for learning or for retention of pattern vision, at least when high acuity is not required. By contrast, pattern vision was severely impaired by lesions of extrastriate areas, and we put forward the hypothesis that a midbrain-pulvinar-cortical pathway reaching these areas independent of the geniculo-cortical pathway could provide the first stage in simple, coarse form perception and discrimination (Sprague et al., 1977). The visual abilities of cats deprived of the primary visual cortex were then studied in detail by Jim with Mark Berkley (Berkley and Sprague, 1979), while I also conducted some studies in which I made select cortical lesions, and Professor Werner von Seelen and his collaborators, first at the University of Mainz and then at the University of Bochum, devised special tests to assess residual visual abilities (Krüger et al., 1986, 1988; Kiefer et al., 1989).

During that stay in Philadelphia and many subsequent ones, Jim and his wife, Dolores, were magnificent hosts to me and to my family. They were in love with Italy and with its geographic, architectural, cultural, and culinary riches, and we tried to reciprocate their hospitality on the occasions of their numerous visits to Pisa and then Verona. As a result, a tradition of reciprocal visiting exchanges between Philadelphia and Italy, initiated in 1966–68, extended through nearly 30 years, with mutual enjoyment and scientific gratification. In Pisa, the Spragues made friends with some of our friends, especially with the plastic surgeon Paolo Santoni and his Swedish wife, Gerd, as well as with Italian and American academics working in the university or the Scuola Normale Superiore. In the summer, the beach at the Lido in Tirrenia was the best place for the Spragues and ourselves to meet and chat with friends, to swim and to enjoy the exquisite fish dishes prepared by the manager of the Lido, Pina Ammannati Giannessi, allegedly a descendant of the family of Galileo’s mother, Giulia Ammannati. I like to remember Jim Sprague as a member of an old generation of gentlemen scientists who knew how to mitigate the natural hubris of the investigator with the dispassionate integrity of the scholar. Contrary to the attitude prevailing today, he was convinced that science can benefit more from cooperation than from competition, and, like Moruzzi, he believed that doing good science is aided by having broad cultural interests apart from science itself. Someone, probably Thomas Kuhn, said that the history of science is written by the winning side. For Jim Sprague, all scientists (barring perhaps a few conceited peacocks) were, or ought to be, on the same side. He died in 2002, and I am grateful to Alan Rosenquist, Larry Palmer, and their colleagues of the Mahoney Institute of Neurological Sciences at the University of Pennsylvania for kindly inviting Luisa and me to Philadelphia in April 2010 on the occasion of the 25th anniversary of the James M. Sprague Lectureship (I had given the sixth Sprague Lecture in 1990). I shared the honor of remembering Jim and his work with two other of his collaborators, Murray Sherman and Guy Orban. I had known Murray in 1965 when he was an undergraduate at Caltech and had re-encountered him in 1968 when he was a PhD student at Penn in the department of anatomy, chaired by Jim Sprague. We share many fond memories.

Collaborations with Other Good Friends in the 1960s and 1970s

Two of the persons who came to work in Pisa in the late 1960s, Carlo Alberto Marzi, a medical graduate from Florence, and Henry (Gus) Buchtel, a psychologist with a PhD from McGill University, became close lifelong friends of mine. Carlo has spent most of his academic career as a physiological psychologist alongside me, first in Pisa and then (after a period in Padua) in the medical school of Verona, where he is presently a full professor of psychology. He and I have many experiences, interests, ideals, and passions in common; his wife, Brigitte, and daughter Tessa are very close to my family; and we all have shared many events (good or bad) over the years. I am sure that Carlo, along with our companion for adventures in Pisa and Verona, Alberto Cangiano, knows my mind better than most, and that I know their minds better than most. Carlo has worked in Oxford with Larry Weiskrantz and Alan Cowey. He is well known for his original contribution to the demonstration of blindsight, based on the influence that visual stimulation of a blind field exerts on the responses to visual stimuli in a normal field, as well as for his work on interhemispheric transfer. Gus left Pisa many years ago to work in Parma, London, Montreal, and finally in Ann Arbor where he works in the departments of psychiatry and psychology at the University of Michigan. In spite of our physical separation from Gus, Carlo and I feel that he is still with us because we have kept in constant contact throughout the years. Of course, e-mail is a great help and so are our yearly encounters at the meetings of the International Neuropsychology Symposium, the Web site of which is under Gus’s very efficient control. Gus brought his deep knowledge of Hebbian and Skinnerian psychology to Pisa, as well as his love for and expertise in experimental control and his mastery of the English language. Moruzzi entrusted him with the correction of the English text of his latest papers. Gus and I share a strong interest in the history of scientific thought in the neurosciences, and I daresay that in 2009 we published the definitive account of the genesis of the term and of the concept of neural plasticity (Berlucchi and Buchtel, 2009). Gus knows and speaks Italian well, and we owe the English translation of the biography of Camillo Golgi by Paolo Mazzarello from Pavia to him and to Aldo Badiani.

Two other close friends who came to work with me in Pisa belonged to emigrant Italian families. Gian Mascetti came from Chile and Franco Lepore came from Canada. They were involved with Buchtel, Marzi, and with me in various behavioral and electrophysiological studies that were partly inspired and coauthored by Jim Sprague. In the 1980s, Gian returned to Italy as a professor of psychology in Padua, where he has done interesting studies on unihemispheric sleep in birds, the research subject of the young Moruzzi. Franco is a professor of psychology at the University of Montreal where he leads a very productive research group studying various aspects of cognitive neuroscience, including hemispheric interaction and specialization.

Antonella Antonini was a PhD student of the Scuola Normale when she joined my laboratory to prepare her thesis. She was a valued presence in the lab because of her sharp mind, collaborative personality, and superior technical abilities, including performing difficult brain surgeries in cats. She was part of the group who followed me from Pisa to Verona, but after her marriage to Alan Stein, whom she had known in Jim Sprague’s department at Penn, she emigrated to the United States, where she proved herself a very gifted scientist working first with Carla Shatz at Stanford and then with Mike Stryker at the University of California at San Francisco.

The research topics that I pursued with Antonella, Buchtel and his former wife Elise, Lepore, Marzi, Mascetti, and Sprague all had to do with various aspects of the organization and functional significance of the cat’s visual pathways, including the callosal connections mediating the interhemispheric transfer of visual discriminations. We showed that, in contrast with the primary visual cortex, where callosal connections are limited to the vertical meridian region, the callosal connections of extrastriate visual areas cover a much larger extent of the visual field because of their wider receptive fields. However, even these wider receptive fields abut the vertical meridian to ensure the continuity of the cortical representation of the visual field across the midline. This has justified the claim that the visual callosal connections obey the so-called midline rule—a notion still debatable but reasonably worthy of support. Our lesion-behavioral studies provided evidence for attributing a primary role in interhemispheric transfer of visual discriminations to the callosal connections of extrastriate areas conveying information from wide visual field areas. Our single unit electrophysiological recordings furnished evidence for a complex interaction between cortex and superior colliculus in the representation of the visual field within and across hemispheres, including participation of the corpus callosum via cortico-tectal pathways. We also studied the abnormalities of this representation in Siamese cats (which, because of a genetic defect, have almost completely crossed visual pathways) and the alterations induced by immobilizing one eye. We used the split chiasm preparation in many experiments, and I always remember the extraordinary feat of Antonella and Franco Lepore when they were able to cut the corpus callosum while maintaining the contact between a cortical neuron and the recording electrode. Thanks to them, I could photograph the response of that neuron to stimulation of both eyes before the callosal section and the loss of the response to stimulation of the contralateral eye following the section (Antonini, Berlucchi, and Lepore, 1983). The thrust of those years of work is summarized in a number of papers and reviews (Berlucchi, 1972; Sprague et al., 1973, 1981; Berlucchi et al., 1978, 1979; Berlucchi and Sprague, 1981; Berlucchi and Marzi, 1982; Berlucchi and Antonini, 1990).

Reaction Time Studies

In 1967, Giacomo Rizzolatti moved to the Institute of Physiology of the University of Parma, which was then headed by Arduini. At that time, Carlo Umiltà, a psychologist from Bologna, who had been encouraged by his professor, Renzo Canestrari, to collaborate with physiologists, was also working at the Parma Institute. Carlo was already a sophisticated experimenter with a solid cultural background. A few years later, after working at the University of Oregon with psychologists of note such as Mike Posner and Steve Keele, he was responsible for bringing a refined experimentalist attitude back to Italy and for training a generation of psychologists interested in the brain. He, Giacomo, and I got together to discuss the possibility of testing the functions of the corpus callosum in humans. I had read somewhere, possibly in a paper in Brain (Efron,1963), that the American psychologist Poffenberger had estimated the interhemispheric transfer time to be about 5–6 msec in a reaction time experiment involving a simple visuomotor task (Poffenberger, 1912). Nowadays you can download Poffenberger’s paper from the Internet as a free pdf, but in 1967, I could not find the volume of Archives of Psychology containing that paper in any library in Italy. My friend Pier Lorenzo Marchiafava from Moruzzi’s institute, who was then on a sabbatical at Yale University with Robert Galambos, lent a crucial hand by air-mailing photocopies of the paper’s 73 pages to Pisa. On the last of them, he had written in large letters: Mi dovrai invitare a cena per almeno una settimana. (You will have to invite me to dinner for at least a week.)

We read that Poffenberger had investigated several factors of simple reaction time to a light stimulus, but the part of special interest to us was that he had found that the right hand is slightly faster than the left to react to a right visual stimulus, and the left hand is slightly faster than the right to react to a left visual stimulus. His interpretation of the finding was that a stimulus lateralized to the right or left visual field is projected through the optic pathways to the contralateral hemisphere. Because the motor pathways are crossed, if the reaction is to be made with the hand on the same side of the visual stimulus, only one hemisphere is needed for the response. If the response is to be made with the hand contralateral to the visual stimulus, the hemisphere in charge of the response is different from the one receiving the visual stimulus. Hence, an interhemispheric transfer is required, and reaction time increases due to added conduction and synaptic delays. Poffenberger had envisaged the callosal connections of the motor cortices as the likely pathway for the transfer, but we thought that the interhemispheric transfer might also occur through the callosal connections of the visual cortex. If so, the transfer should be faster with stimuli projected to visual cortical sites representing the vertical meridian region (which has rich callosal connections) than with stimuli projected to cortical regions representing the far periphery (which have few or no callosal connections). The plan then was to replicate Poffenberger’s study with visual stimuli presented at different eccentricities from the vertical meridian.

We performed the experiment at the University of Bologna’s Institute of Psychology where Umiltà had available a homemade apparatus for visual stimulation and for recording reaction times. We engaged Woody Heron, who had much experience with extrafoveal visual stimulation, and Ray Hyman, a psychologist from Oregon University who was then spending a sabbatical in Bologna, as collaborators. Ray had a deep knowledge of statistics and was already famous in psychology for the Hick-Hyman law of choice reaction time, but soon he would become even more famous for his ability to debunk claims of paranormal or supernatural powers by illusionists such as the then very popular Uri Geller. Performing the experiment on ourselves and on a group of students, we confirmed Poffenberger’s interhemisperic transfer time and found that it did not vary with the stimulus eccentricity. Therefore, we concluded that the callosal connections of the primary visual cortices are unlikely to be involved in the particular type of interhemispheric transfer, which is then best attributed to the callosal connections of other cortical areas.

The idea that one could use simple reaction times to measure interhemispheric latencies appeared repellent to a number of people. When I presented our results at a meeting in 1970 in Oxford, the venerable professor of physiology David Whitteridge, the first discoverer of the link between the callosum and the visual vertical meridian, looked outraged. On the other hand, in 1969 in Australia, Malcolm Jeeves had found that interhemispheric transfer time tested with the Poffenberger paradigm in two subjects with callosal agenesis was more than 10 times longer than in normal controls (Jeeves, 1969). At a 1969 meeting on interhemispheric relations in Smolenice near Bratislava in what was then Czechoslovakia, Rizzolatti and I met Jeeves, who had then become chairman of psychology at Scotland’s University of St. Andrews, and we set up a collaboration that eventually also involved Umiltà’s and Jeeves’ collaborators David Milner and Mick Rugg. The main results on interhemispheric transfer with the Poffenberger’s paradigm in observers with intact brains or partial or total callosotomies have been confirmed over the years in several laboratories, including my own in Pisa and Verona (Milner et al., 1985; Berlucchi et al., 1995; Marzi, 1999).

Measured as a difference in simple reaction times, the Poffenberger effect can be explained by reference to a go-signal conveyed from the visual cortex to the motor cortex along fixed inbuilt connections, with added conduction and synaptic delays when an interhemispheric transfer was required. Rizzolatti, Umiltà, and I began to discuss the possibility of measuring the time for responding to lateralized stimuli that did not merely provide a go signal but that had to be interpreted before deciding to react. That the right and left hemispheres were differently specialized for the recognition of various stimulus categories was well known from classic studies of the effects of unihemispheric lesions and from the recently demonstrated differences in performances of the disconnected hemispheres in split-brain patients (Sperry, Gazzaniga, and Bogen, 1969). There was no doubt that the left hemisphere was dominant for the recognition of verbal material, and there was less-documented but nevertheless convincing evidence that the right hemisphere was dominant for the recognition of faces. We decided to measure choice reaction times to letters and faces presented separately to the two hemispheres, and we found that reaction times to letters were systematically faster with the stimulus in the right compared to the left field and vice versa with face stimuli, independent of the hand used for responding. An obvious interpretation was that the material presented to the non-dominant hemisphere had to be transferred for recognition to the dominant hemisphere, and that this putative interhemispheric transfer was much longer than that connected with the Poffenberger effect and most probably different in kind from it. Subsequent research showed that other interpretations are possible, but this is not the place to deal with this complicated subject.

Our two papers on interhemispheric transfer, one on the Poffenberger effect and the other on the opposite hemispheric superiorities, were published in Brain (Berlucchi et al., 1971; Rizzolatti et al., 1971). They were among the first studies to demonstrate hemispheric interactions and functional asymmetries in normal human observers using simple, inexpensive methods and were received with considerable interest. They contributed, along with a few other pioneering publications, to launching the trend of the so-called divided field studies of hemispheric functions. The trend flourished in the last decades of the last century, filling the pages of various neuropsychological journals, and is not dead yet—even in this era of big and expensive neurotechnology. Of those times, I remember with pleasure and some nostalgia the long hours of heated arguments with Umiltà and Rizzolatti during which each of us learned a lot from the others—although at the same time raising serious doubts about each other’s intellectual competence.

Of the reaction time work done subsequently in Pisa, I remember two studies that have been highly cited: the differentiation of the Poffenberger effect from spatial compatibility effects (Berlucchi et al., 1977) and the influence of unimanual and bimanual responding, and the use of proximal or distal arm muscles, on the Poffenberger effect (Di Stefano et al., 1980). The senior author of the latter paper was Marirosa Di Stefano, a medical graduate from Naples who, after collaborating extensively with Carlo Marzi and me in Pisa, did interesting work on vision in cats with Concetta Morrone and Dave Burr in Australia and in humans and cats with Maryse Lassonde, Franco Lepore, and Maurice Ptito in Canada.

With regard to the collaborations among Pisa, Bologna, and Parma, I also like to remember the demonstration that attention orienting could not explain the opposite hemispheric superiorities for letters and faces found by Rizzolatti, Umiltà, and myself and the analysis of the importance of verbal and non-verbal coding of physically similar stimuli in determining the prevalence of the left or right hemisphere. In addition to Umiltà, Rizzolatti, Marzi, and myself, one student of Umiltà from Bologna, Daniela Brizzolara, participated in the first study (Berlucchi et al., 1974) and two other students of Umiltà (Carlo Franzini and Giovanni Zamboni) and Marcello Camarda (then in Parma with Rizzolatti) participated in the second study (Umiltà et al., 1974). I presented a summary of these results at the Third Study Program in the Neurosciences organized by Frank Schmitt and Fred Worden in Boulder, Colorado (Berlucchi, 1974), where I spent two very pleasant weeks with Luisa and our children. In a subsequent divided field study that was well received by the scientific community, Carlo Marzi and I showed that the left hemisphere may take the lead in recognizing familiar faces by utilizing distinctive characteristics and details (Marzi and Berlucchi, 1977).

From Pisa to Verona

Professor Moruzzi retired in 1980. It was easy to predict that without his enlightened chairmanship, based on a highly idealistic conception of research and scholarship, the Institute of Physiology could never be the same. However, the situation turned out to be even worse than the worst predictions. Efficient academic research and teaching in a large institution comprising small different groups is based on the assumption of mutual trust and on the sharing of values by like-minded scholars. Because the institute’s climate was becoming increasingly bitter and polemical, I did not want to spend my energies on irrational clashes over personal prestige, academic weight, and egotistic demands rather than on scientific research and for the promotion of merit. These completely unneeded clashes had already cost the institute the loss of my close friend and coworker Carlo Marzi, who had moved to the University of Padua as a full professor of physiological psychology. During that troubled period, I benefited from strong support from Alberto Cangiano, another close friend who had been working in Pisa since the late 1960s, and who had built up a group doing original and innovative work on the neuromuscular junction. His thorough analysis of the situation convinced me that we both should leave Pisa for a place where we could create the conditions suitable for our own research work and that of our collaborators.

A convenient solution was offered by Hrayr Terzian, the neurologist who had worked in Pisa with Moruzzi in the 1950s and later in Marseille and Padua. He had made important contributions to basic and clinical neuroscience, including the description with Dalle Ore of a human Klüver and Bucy syndrome with deep amnesia (Terzian and Dalle Ore, 1955). In the late 1960s, the medical faculty of the University of Padua had started a branch in Verona, and Terzian had been appointed chairman of its neurological clinic. The year 1982 saw the separation of the University of Padua from Verona and the inauguration of an independent University of Verona, of which Terzian became the first rector. With his generous help, I moved to the chair of physiology in 1983, soon followed by Cangiano and our collaborators from Pisa—Antonella Antonini, Mario Buffelli, Efrem Pasino, and Giancarlo Tassinari. In 1988, Carlo Marzi moved from the University of Padua to the chair of psychology in the medical faculty of Verona, so that we were able to reconstitute the original research group that we had started in Pisa. Terzian’s pet idea was to create a department of neuroscience comprising basic and clinical disciplines, but unfortunately, he died too soon to see an at least partial realization of his aspiration.

The move from Pisa to Verona was not without costs for my family, and I am most grateful to my wife and children for the good will with which they agreed to leave the city in which they had lived happily for most of their lives. Fortunately, Verona is a beautiful city with many cultural attractions, and it did not take long for us to feel at home there. Although, as I have already said, my deepest roots are elsewhere, I have now lived in Verona longer than in any other city in my life, and I consider it my home. Our son Filippo and his wife Daniela Provasi live in a small town on Lake Garda, but he works as a financial promoter in Verona. Our daughter Silvia and her husband Giacomo Pavesi are both busy neurosurgeons who work and live in Modena, but they keep frequent contacts with their respective families in Verona. Their two children, Elsa and Vittorio, whom Luisa and I adore, were born in Verona and are strongly attached to the city and especially to its soccer team (Hellas). I am sorry for them that Hellas has no chance against my beloved Inter team from Milan.

Research in Verona

In Pisa, while gathering evidence for defending the interpretation of the Poffenberger effect as being due to a simple callosal transfer, we had stumbled on a phenomenon that would occupy us for some time in Verona (Berlucchi, 2006). Believing that a lateralized stimulus always engages the attention of the contralateral hemisphere, with a resulting functional advantage for any response controlled by that hemisphere, Kinsbourne has long regarded the Poffenberger effect as an attentional effect (Kinsbourne, 1975). For him, a left visual stimulus yields a faster response from the left hand than from the right hand, not because a callosal transfer is needed, but because the left stimulus would arouse the right hemisphere more than the left. In Pisa, we tested Kinsbourne’s assumption by presenting a pair of successive peripheral light points, both on the same side or one on the right and the other on the left. The first light point required no response and only informed the subject that the second light point was about to appear with equal probability on the same or the opposite side. The subject’s task was to press a key as fast as possible in response to the second light point. If Kinsbourne was right, the reaction time should be faster with stimuli on the same side because the second stimulus goes to the hemisphere where the attention has been engaged, according to him, by the first stimulus. It turned out instead, and exactly contrary to Kinsbourne’s expectation, that if the two stimuli appeared on the same side, reaction time was considerably longer than if the stimuli appeared on opposite sides. The effect did not interact with the Poffenberger’s effect. I tried to concoct a rather fuzzy attentional hypothesis for the effect we had found, and I discussed it with Michael Posner sometime between 1979 and 1980 when he was visiting Rizzolatti and Umiltà at the University of Parma.

Mike was the right person to consult because he had resurrected the reaction time method for studying attentional effects with great success. We started a correspondence and the following quote is from a letter that he wrote me on July 2, 1980.

When I visited Parma last summer I discussed with you some experiments that you had been running in which inhibition effects related to attention were found. The experiments were rather vague in my mind from the oral report, but during this year I have obtained a similar phenomenon and have been working on understanding its source. If a subject pays attention to a position in space and shifts attention away to a new position, he shows relatively less sensitivity to the position to which he has attended than to the position on the opposite side, or at some other location away from the original source of attention. The effect does not seem to be due to the direction of movement away from the attended area, but rather to inhibition at the attended area. I think this work is most interesting and may be closely related to the phenomenon that you observed.

Mike’s view was that a peripheral visual cue in an empty field summons attention to the cued position, improving efficiency until attention is withdrawn, with a consequent reduction of efficiency. Evidence for this view was provided by an early facilitation of reaction time at the cued position, followed by reaction time (RT) inhibition. I had an opportunity to tell Mike, on another of his visits to Italy, that most often we found inhibition without a preceding facilitation. His answer in a letter of September 24, 1982, was as follows.

It occurred to me before the seminar on attention that your results and our own results might be linked in the way I mentioned briefly in my presentation. In your paradigm, the first stimulus (cue) and the second stimulus (target) are similar and subjects must respond only to the second. Because the subjects are highly trained, they may be able to prevent orienting to the first stimulus, thus preventing any evidence of facilitation while producing a larger inhibition effect than we usually get. This would fit your result and ours together with the additional point that the facilitation effect is more voluntary (under the control of the subject).

Later on, Posner and collaborators (1985) coined the term “inhibition of return,” meaning that once attention has been directed at a location, it is refrained from returning to that location in favor of other potential sources of information. I think that that term disagrees with Posner’s original intuition that inhibition stems from reduced sensitivity rather than from the absence of attention at the cued location; indeed, we showed that reaction time can be increased by previous stimulation at a volitionally attended location (Berlucchi et al., 2000). Probably many of the effects published as instances of inhibition of return, including some from my lab, have little to do with attention, and I tried to expose some of the contradictions of the field in a review a few years ago (Berlucchi, 2006). Although I have recently published a small paper on the so-called inhibition of return with Sonia Mele, a former doctoral student, and Andrea Peru, associate professor of psychology in Florence (Mele et al., 2012), my interest in the topic has almost completely abated. Andrea may perhaps rekindle it when he acts as my favorite sparring partner in discussions on soccer and politics.

My main autobiographical reason for mentioning “inhibition of return” from Verona at some length is that I take pride in the fact that two coauthors of those papers have become international stars in the field of attention, entirely on their own merit (Chelazzi and Corbetta, 2000). One of them is Leonardo Chelazzi, a medical graduate from Florence, who came to work in Verona due to his interest in the higher nervous functions. After doing first-rate work with Bob Desimone at NIH on the neural mechanisms of attention in macaques, Leonardo has developed several original lines of research on the subject—working with monkeys and humans—in Verona, where he is presently a full professor of physiology. The other star in the field of attention is Maurizio Corbetta, a medical laureate from Pavia who worked in Pisa and Verona with Carlo Marzi on blindsight and in Verona with me and with others on spatial attention. After a splendid scientific and clinical career with pioneer contributions to the brain imaging of various cognitive functions, Maurizio went to work with Marcus Raichle at Washington University in Saint Louis where he is now a professor of neurology. Anyone caring about the meritocratic interests of Italian academics and research can only hope that he can return to one of our universities as a professor.

Another field of research in which I was involved in Verona concerns the neural mechanisms of corporeal awareness, as expressed in the ambiguous terms body schema and body image. I owe this interest to Salvatore Aglioti, who graduated in medicine from Pisa and then moved with me to Verona. He did work in clinical neurology with Terzian in Verona and with De Renzi and Faglioni in Modena, and he played an essential part in the studies on spatial attention and interhemispheric transfer in Verona. His collaboration with Mel Goodale in London, Canada, resulted in a now famous experiment showing that visual illusions deceive the eyes but not the hands (Aglioti, et al., 1995). Salvatore is a first-rate researcher and scholar, and I would be proud to be considered even minimally responsible for his development as a scientist. His interest in phenomena and mechanisms of phantom sensations after amputations and mutilations led him to make the important discovery that phantom sensations develop very early after mastectomies, indicating that the removal of a body part unmasks silent functional connections already present in the brain (Aglioti, et al., 1994). These early phenomena precede those attributable to long-term processes of reorganization. The studies we did on his initiative on aspects of bodily awareness and perception in brain damaged patients or in intact observers submitted to transcranial magnetic stimulation are summarized in two reviews that appeared 13 years apart as “The Body in the Brain” and “The Body in the Brain Revisited” (Berlucchi and Aglioti, 1997, 2010). Salvatore is currently a professor of psychology at the Sapienza University in Rome, where he has gathered a very active and successful group of young investigators who explore various areas of the cognitive neurosciences with very original approaches. One of my regrets is that I was unable to obtain a position for him at the University of Verona, but I take consolation in his great success in Rome and in his fast-growing international reputation. He and I share the conviction that if the immanent philosophical problem of knowing ourselves can be solved at all, the solution will have to include knowledge of our brains.

Aglioti was also involved in experiments we did in Verona, Rome, and Ancona on patients with total and partial callosal sections regarding various aspects of interhemispheric communication. We performed the first study ever of gustatory lateralization in a completely callosotomized patient in Verona and inferred from the results that the gustatory pathways from tongue to cortex are bilaterally distributed with a predominance of the uncrossed component (Aglioti et al., 2000). By comparison with intact observers, we also inferred that the corpus callosum equalizes the strength of the crossed and uncrossed components, as previously hypothesized by Pritchard et al. (1999) on the basis of results in patients with unilateral insular cortex lesions. Mike Corballis from Auckland, New Zealand, was then spending a sabbatical in Verona and took part in the research, bringing to it his great expertise with laterality studies and commissurotomized patients. Mike’s stay in Verona enriched us all with his profound knowledge of the human brain and its evolution. I remember with nostalgia his discussions with Alberto Cangiano, Carlo Marzi, and myself at lunch in the medical school cafeteria when he shared with us his vast erudition, spiced with sophisticated humor. Subsequently, we replicated the gustatory split-brain study with our physiological colleagues in Ancona, Mara Fabri and the late Tullio Manzoni, who made it possible for us to study two more partially callosotomized patients from their split-brain population. The additional surprising result was that the posterior rather the anterior callosum was responsible for the suggested equalizing function (Aglioti et al., 2001).

Teaching Activities, Involvement in Scientific Societies, and Awards

In my career, I have consistently regarded research as my real occupation, but I have always accepted, even if sometime grudgingly, forgoing my research to fulfill other obligations toward the university and the national and international scientific community. I do not rank administrative work as a major obligation and shied away from it as often as I decently could. On the contrary, I regarded teaching as a major obligation and have devoted myself to it with enthusiasm, especially when I was younger. Physiology of the nervous system was obviously my favorite teaching subject but throughout my career I have taught courses on most aspects of physiology. Moruzzi had taught me to present physiological facts in light of how they had been discovered, and I have always been fascinated by the history of the search for the mechanisms of the bodily machine, whether neural or otherwise. I taught physiology and physiological psychology in Pisa in the 1960s and early 1970s and physiology at the University of Siena between 1973 and 1976, where I was promoted to full professor. My family remained in Pisa during my years in Siena, and every week I worked three days in Siena and three days in the lab I kept in Pisa. I updated much of my knowledge of physiology on slow trains traveling through the Tuscan countryside, with the advantage that when I lifted the eyes from my books I could see some of the most beautiful landscapes in the world. I was fortunate enough that one of my colleagues in Siena was Giancarlo Carli, who had worked in Pisa and gave me all the help he could, but I was unhappy because I felt that I was not pursuing research work as I should. The teaching load had been made unbearable by granting an unlimited access to medical schools, so that I and my colleagues had to teach and give exams to many hundreds of students several times every year. The mental and physical demands of those efforts and the sheer boredom of repetitious explanations and discussions began to weaken my enthusiasm. When I was able to go back to the University of Pisa, the number of medical students was still unacceptably high, and I remember that for some exam sessions we worked uninterruptedly for several hours every day for a week or more. At the University of Verona, we were blessed by a law that reduced the number of medical students to about 100 per year, but some colleagues responsible for the organization of the courses were obsessed with the idea that the teaching of the basic sciences, including physiology, should be reduced in content and duration to make more space for the clinical disciplines and for practical work in hospital wards. Unlike in my student days, an early contact with fundamental research is no longer regarded as a building experience in the formation of a medical doctor. So after teaching too much, we physiologists ran the risk of teaching too little. Fortunately, the arguments that my colleagues Alberto Cangiano and Carlo Marzi and I put forward in defense of teaching physiology and physiological psychology were at least partially accepted. Now that I am retired, the opportunity for satisfying my residual drive for communicating scientific knowledge is furnished by occasional lectures or seminars to selected and specialized audiences. I am gratified when I meet some middle-aged doctor who tells me that I taught him or her physiology and that they loved my lectures, but I am well aware that those praises may be ascribed to a distorted memory or to an act of personal courtesy.

The papers on hemispheric transmission and on functional hemispheric specialization in normal humans gained me an entrance into some international groups that were forming in those years with the specific aim of dealing with the nervous system, behavior, and psychology. Alan Cowey enrolled me in the European Brain and Behaviour Society founded by Larry Weiskrantz, and I served on one of its first councils with Larry as president and Elizabeth Warrington as secretary. When the European Neuroscience Association (ENA) was founded in the mid 1970s, Konrad Akert, as president of the nominating committee, informed me that I had been elected to represent behavioral neuroscience on the first ENA council alongside the famous neuropsychologist Alexander Luria from Moscow, who disappointingly was never able to attend the council sessions. I would have been thrilled to meet such a legendary figure in neuropsychology. The first ENA council was chaired by János Szentágothai (later replaced by Leslie Iversen) and included Changeux, Hökfelt, Kuypers, Lundberg, Thoenen, de Wied, and myself. I was audacious enough to undertake the organization of the second ENA meeting in Florence in September 1978, at a time when Italy was badly afflicted by political terrorism (the Christian democrat leader Aldo Moro had been assassinated by the Red Brigades just a few months before) and by frequent and unforeseeable strikes of workers in public transportation, the mail, and other essential services. The Fondazione Menarini supported the meeting organization after negotiations with the ENA executive secretary Hugo Zwek and me. I have canceled from my memory most events connected with that meeting because the objective difficulties of its organization, amplified by my constitutional anxiety, cost me a protracted period of suffering. After the meeting, I took pleasure in destroying the enormous mass of paper that I had accumulated (in that pre-electronic communication era) during the meeting’s preparation. I only kept the notes of congratulations that very few kind souls took the trouble to send me after the meeting. Konrad Akert, ever the gentleman, wrote: “Dear Berlucchi, I would like to write to you in my own name and in the name of my collaborators by expressing to you our sincerest thanks for all your efforts you made on behalf of ENA. In our view the meeting has been a great success and certainly has helped a lot in establishing the new society. I hope that you have already recovered from the enormous stress that was put on you before and during the meeting.” Enormous stress indeed!

The support of Brenda Milner and Herbert Jasper got me into the Neuroscience Research Program of Frank Schmitt, and I participated in one of their intensive programs in Boulder, Colorado, and in one or two smaller meetings in Boston and Woods Hole. An invitation by Hans Lukas Teuber helped me join an informal discussion group called International Neuropsychology Symposium. This group, started by the French neurologist Henri Hécaen, had been the crib of neuropsychology, officially born in 1963 as an autonomous discipline with the foundation of the journal Neuropsychologia.

Although I consider myself a neurophysiologist rather than a neuropsychologist, I was on the editorial board of Neuropsychologia for several years and was part of the group of researchers from various disciplinary fields that formed in my country around the charismatic and intellectually catalyzing figure of Ennio De Renzi, a neurologist of international renown and the father of Italian neuropsychology. In 1994, quite unexpectedly, I became Neuropsychologia’s editor-in-chief. After Neuropsychologia’s editorial management by its founder Hecaen and then by his successor, Marc Jeannerod, the journal had passed into the hands of Malcolm Jeeves, the St. Andrews psychologist with whom Umiltà, Rizzolatti, and I had collaborated for years. A sudden illness forced Jeeves to give up many of his commitments including the handling of the journal. He asked me to replace him in that capacity, and after an unfruitful search for other possible and more appropriate candidates, I had to say yes and to commit myself to a difficult five-year job. I had already served as panel editor for journals such as Experimental Brain Research and European Journal of Neuroscience, participating in the foundation of the latter journal with the editor-in-chief Ray Guillery and other colleagues from the ENA, but I had never managed a major journal by myself. Nevertheless, the journal and I survived, though with a cost for my research; altogether I have a positive memory of that experience in which I had the unfailingly wise support of Paul Carton, Elsevier’s senior publisher for neuroscience. In general, I much prefer working as a reviewer to serving as an editor, and nowadays I am still evaluating a fair number of papers for various scientific journals. Immodestly, I believe that reviewing papers is one of the very few things I am really very good at.

Of the awards that I received during my career I will mention the ascription to the Accademia Nazionale dei Lincei and the honorary degree in psychology received from my alma mater, the University of Pavia in 2007. The Accademia, founded in 1603 by Federico Cesi and boasting Galileo as one of its first members, is the most important cultural institution in my country. Its present president, Lamberto Maffei, is a friend from over a half century ago, when as fledgling neurophysiologists in Pisa we started our career under the big wings of Giuseppe Moruzzi. I am involved in the organization of some activities of the Accademia, including scientific meetings and conferences that keep me in contact with the national and international scientific community. The honorary degree from Pavia was a generous gift from the psychologists from that university, Gabriella Bottini and Tomaso Vecchi, who convinced the academic authorities to bestow the honor on me in connection with the inauguration of an undergraduate course in psychology. My dear friend Carlo Marzi did a marvelous job of orchestrating the scientific events connected with the ceremony. The ceremony itself was attended by many who came from Italy and abroad to show their friendship with a gesture of affection, which touched my heart deeply. Carlo, Gabriella, and her husband, Eraldo Paulesu, put together a scientific meeting in which 25 friends who had been fellow travelers in my scientific career presented lectures on their work, flavored with their reminiscences about me (Marzi et al., 2009). The list included Emilio Bizzi, Gus Buchtel, Mike Corballis, Alan Cowey, Ulf Eysel, Richard Frackowiak, Mike Gazzaniga, Mitch Glickstein, Mel Goodale, Mickey Golberg, Charlie Gross, Peter Hoffmann, Marc Jeannerod, Giorgio Innocenti, Franco Lepore, Lamberto Maffei, David Milner, Morris Moscovitch, Elio Raviola, Giacomo Rizzolatti, Wolf Singer, Piergiorgio Strata, Carlo Umiltà, Leslie Ungerleider, and Bob Wurtz. When I read this list today, I am still amazed and moved—as I was then—by the generosity of such important scientific personalities who came to Pavia to show their friendship and esteem for me. And it gives me much sadness to think that two wonderful persons on that list, my long time close friends Alan Cowey and Marc Jeannerod, are no longer with us.

Epilogue

I have no profound thoughts to express or lofty messages to deliver to close this autobiography on a solemn note. I hope I have made it clear that I have been very fortunate to do work that I liked, to have the unstinting support of my family, and to benefit from the affection, friendship, and intellectual stimulation from many people from every walk of life. I also hope that what I have written about them can convey my deeply felt sense of gratitude. I owe my sincere thanks to Larry Squire, the editor of The History of Neuroscience in Autobiography, for deciding that my autobiography could be interesting enough to appear alongside those of the many eminent neuroscientists who have contributed to the publication. I resisted Larry’s invitations for a few years, until his kind prodding convinced my old brain to go back in time and relive and recount some of the experiences of a long life in neuroscience. Memory is known to be fallible and memories can be fabricated, but my old brain believes that what is written here bears a reasonable correspondence to the truth. And my old brain also believes that the completion of an autobiography in neuroscience does not have to coincide with the end of a life in neuroscience, and that there is still a lot of interesting work to look forward to.

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Yuh-Nung Jan

BORN:

Shanghai, China

December 20, 1946

EDUCATION:

National Taiwan University, BS (1967)

California Institute of Technology, PhD (1974)

APPOINTMENTS:

Postdoctoral Research Fellow, California Institute of Technology (1974)

Postdoctoral Research Fellow, Harvard Medical School (1977)

Assistant Professor, University of California, San Francisco (1979)

Investigator, Howard Hughes Medical Institute (1984)

HONORS AND AWARDS (SELECTED):

McKnight Scholar Award (1978–1981)

Elected member, National Academy of Sciences (1996)

Elected member, Academia Sinica, Taiwan (1998)

Distinguished Alumni Award, California Institute of Technology (2006)

Elected member, American Academy of Arts and Sciences (2007)

Javits Neuroscience Investigator Award, National Institute of Neurological Disorders and Stroke, National Institutes of Health (2010)

Seymour Benzer Lecture, Neurobiology of Drosophila meeting, Cold Spring Harbor Lab (2011)

HONORS AND AWARDS SHARED BY LILY JAN AND YUH-NUNG JAN:

W. Alden Spencer Award and Lectureship, Columbia University (1988)

38th Faculty Lecturer Award, University of California, San Francisco (1995)

Harvey Lecture, New York (1998)

The Stephen W. Kuffler Lecture, Harvard Medical School (1999)

K. S. Cole Award, Biophysical Society (2004)

Jan Lab Symposium (2006)

Society of Chinese Bioscientists in America Presidential Award (2006)

Ralph Gerard Prize, Society for Neuroscience (2009)

Edward M. Scolnick Prize in Neuroscience, Massachusetts Institute of Technology (2010)

Albert and Ellen Grass Lecture, Society for Neuroscience (2010)

Wiley Prize in Biomedical Sciences (2011)

Gruber Neuroscience Prize (2012)

Lily Jan

BORN:

Fu-Chow, China

January 20, 1947

EDUCATION:

National Taiwan University, BS (1968)

California Institute of Technology, PhD (1974)

APPOINTMENTS:

Postdoctoral Research Fellow, California Institute of Technology (1974)

Postdoctoral Research Fellow, Harvard Medical School (1977)

Assistant Professor, UCSF (1979)

Investigator, HHMI (1984)

HONORS AND AWARDS (SELCTED):

Alfred P. Sloan Research Fellowship (1977–1979)

Klingenstein Fellowship Award (1983–1986)

Elected member, National Academy of Sciences (1996)

Elected member, Academia Sinica, Taiwan (1998)

Distinguished Alumni Award, California Institute of Technology (2006)

National Institute of Mental Health MERIT Award (2006)

Elected member, American Academy of Arts and Sciences (2007)

HONORS AND AWARDS SHARED BY LILY JAN AND YUH-NUNG JAN:

W. Alden Spencer Award and Lectureship, Columbia University (1988)

38th Faculty Lecturer Award, University of California, San Francisco (1995)

Harvey Lecture, New York (1998)

Stephen W. Kuffler Lecture, Harvard Medical School (1999)

K. S. Cole Award, Biophysical Society (2004)

Jan Lab Symposium (2006)

Society of Chinese Bioscientists in America Presidential Award (2006)

Ralph Gerard Prize, Society for Neuroscience (2009)

Edward M. Scolnick Prize in Neuroscience, Massachusetts Institute of Technology (2010)

Albert and Ellen Grass Lecture, Society for Neuroscience (2010)

Wiley Prize in Biomedical Sciences (2011)

Gruber Neuroscience Prize (2012)

Lily and Yuh-Nung Jan went to Caltech in 1968 after their undergraduate study in physics at National Taiwan University. After two years of graduate study in physics, they switched to biology under the influence of Max Delbrück. They stayed at Caltech for postdoctoral training with Seymour Benzer and then worked in Steve Kuffler’s lab at Harvard Medical School to demonstrate that peptides can function as neurotransmitters. During their postdoctoral training with Seymour Benzer, they began their long-term collaboration. Cloning of the first potassium channel gene Shaker and its mammalian homolog in the Jan lab at University of California, San Francisco (UCSF), followed up with expression cloning of a founding member of the inwardly rectifying potassium channels and the founding member of a novel calcium-activated chloride channel family, has led to molecular and cell biological studies of how these ion channels work and how they contribute to neuronal signaling. In parallel to these ion channel studies, the Jans started their work on neural development at UCSF in order to understand how neurons acquire their specific cell fate and morphology. Their discoveries include atonal—a founding member of the large family of proneural genes that endow cells with neuronal cell fates, and numb—the first cell fate determinant exhibiting asymmetric localization in dividing neural precursor cells. More recently, they have begun unraveling the logic and underlying mechanisms for generating diversity in neuronal morphology (especially dendritic morphology) and learning how such diversity contributes to the wiring of the nervous system.

Yuh-Nung Jan and Lily Jan

Birth

We were born nine days apart. Yuh-Nung’s birthday was listed as December 20, 1946, but that is according to the lunar calendar commonly used then. It corresponds to January 11, 1947, in the Western calendar, which is nine days ahead of Lily’s birthday, January 20, 1947. Because Yuh-Nung was born slightly ahead of his due date, we might have started our embryonic development around the same time.

Family History and Growing Up

Yuh-Nung’s father, Ten-Sun Jan, was from a well-to-do family in Jiangxi Province, China. Originally, Yuh-Nung’s grandfather planned to send his son to the United States to study economics. However, the outbreak of the Sino-Japanese war in 1937 altered the plan. Instead, Yuh-Nung’s father finished college in China and then joined the Nationalist army to resist Japanese invasion. He became an officer during World War II. Yuh-Nung’s mother, Li-Ju Chen, was from Anhui Province and went to the same college as his father. They got married toward the end of the war and moved to Shanghai. Yuh-Nung was born there as their first son.

In 1949, as communists were taking over, Yuh-Nung’s parents got out of mainland China at the last minute and escaped to Taiwan. During the first few years in Taiwan, the family lived in a small rural town of Xinpu in Hsin-Chu County, about 70 km south of Taipei. At the time, Yuh-Nung’s father was still in the military and was stationed in the garrison in the frontline (Quemoy Island). His mother had to work and needed childcare. She persuaded the local elementary school to take in Yuh-Nung as a first-grader on a trial basis even though he was only four and a half years old. Yuh-Nung was able to keep up academically with the older kids in the class, so the school let him continue. Later, after his father left the military and started working for the government, the family moved to Taipei, and Yuh-Nung entered the Jian-Guo High School, which was (and still is) the top high school for boys in Taipei (the counterpart of Lily’s Taipei First Girls’ High School).

Initially, Yuh-Nung was an indifferent student at the Jian-Guo High School. He spent most of his time reading novels, daydreaming, playing sports and the game of go, and so on and paid little attention to schoolwork. He earned barely passable grades. In his junior year, something clicked inside him. Influenced by two superb science teachers (in biology and chemistry) and several academically strong classmates that were his good friends, he became very interested in science, especially physics and chemistry. In the last year of high school, he became very motivated and studied hard in preparation for attending a university to study science.

At the time, the university admission system in Taiwan had some unusual features and was quite different from that in the United States. The students were admitted into a particular university department, so each student had to decide on their major before entering college. There were two ways of being admitted to the university and the department of choice. Each of the 10 or so top high schools throughout Taiwan, including Jian-Guo High School and Taipei First Girls’ High School, could send a few students with the highest grades (the top 1 or 2 percent in those schools) directly to the universities. (Lily was one of those very few.) The vast majority of the students took a common entrance exam for all the universities at the same time. Each student, in a single rank order determined by the results of that exam, was assigned a department in a university based on his or her own priority list; if the slots were filled for the top choice on the list, the department the student would join would be determined collectively by the priority lists and by the entrance exam scores of all high school seniors. At that time, National Taiwan University (NTU) was “the” university among a dozen or so in Taiwan. Acceptance there was very competitive, especially for the most desirable departments—such as physics, medicine, electrical engineering, and chemistry—because they would fill their slots very quickly with the top-scoring students. In this system, except for the few students such as Lily who could bypass the entrance exam because of stellar high school grades, grades had no bearing whatsoever on university admission. It depended entirely on the results of this intense, annual, two-day exam. Yuh-Nung benefited from this system. Despite his so-so grades, he could choose any department he wanted because he did very well on that exam. (His score was among the top 10 out of approximately 30,000 students.) He agonized over his final two choices—the department of physics and the department of medicine at NTU. He could not decide and resorted to a coin toss. The coin toss was for the department of medicine, but he picked the department of physics instead. Eventually, however, he ended up with a career in the school of medicine at University of California, San Francisco (UCSF). That coin toss was “deterministic” after all. Like any traditional Chinese family, Yuh-Nung’s parents cared very much about their kids’ education and future but nevertheless allowed him complete freedom to choose his path. (Several years later, Yuh-Nung’s only sibling, his younger brother, Jonathan, followed his footsteps into the physics department of NTU.)

To go back a bit, Lily was born shortly after the end of World War II in Fu-chow, China. Her parents, Hong-Shu Yeh and Chuan-Hwa Lee, both accountants, brought her to Taiwan as a baby. There, she grew up and was drawn into science while attending Taipei First Girls’ High School, a fairly large school with several dozen students in each of a score of classrooms for the six grades. All students had neatly trimmed short hair that was not allowed to extend past the earlobe, and all wore the unusual uniform of green shirts, black skirts, white socks, and canvas shoes. A subset of students was assigned to Principal Jiang’s “experimental classrooms”—the Kung (fairness), Chung (sincerity), Qing (diligence), and Yi (perseverance) classroom (Ban in Chinese). Lily was in the Qing Ban and studied subjects such as three-dimensional geometry. Lily was fortunate to have a chemistry teacher who offered students opportunities such as reading college level textbooks and working on additional problem sets that he took the time to grade and for which he provided feedback. So, when faced with the choice of three tracks for college entrance, Lily chose the track for math and sciences. When given the opportunity to choose a department, Lily knew very little about the different departments and made her choice more capriciously than by tossing a coin. When told by Lily’s high school classmate of her elder brother’s advice about the two departments not suitable for girls—physics and electrical engineering—Lily then chose the physics department.

Around that time, students in Taiwan were influenced by the awarding of the 1957 Nobel Prize in physics to Tsung Dao Lee and Chen Ning Yang for their theoretical work on nonconservation of parity in weak interactions. Chien-Shiung Wu, the experimental physicist who demonstrated this parity violation, made multiple visits to Taiwan to talk to young students in the 1960s. Lily has vivid memories of Wu’s lectures and her advice to aspiring science students to consider biophysics as an emerging field of interest. Not quite following Wu’s advice, Lily chose to pursue graduate study in theoretical high-energy physics when she was an undergraduate student in the physics department of National Taiwan University (NTU).

National Taiwan University

Yuh-Nung entered the physics department of NTU in 1963, and Lily entered the same department the following year. At that time, it was mostly a teaching rather than a research-oriented department. The research facility and the opportunity to be mentored by top-notch faculty were nowhere near physics department standards for major research universities in the United States (although it is much better now). However, the students were an outstanding group because the department was among the hardest to get in. In general, students were smart and very motivated, and they formed study groups and inspired one another. Although lacking the experience in cutting-edge research, these students did receive a strong foundation in physics and mathematics, which prepared them well for pursuing advanced training, mostly in U.S. graduate schools. Many of our classmates went on to have successful careers in a variety of fields. Perhaps the most notable is Andrew Chi-Chih Yao. Andrew and Yuh-Nung had lived on the same street in Taipei (their families lived three houses apart) since their early teens. They were classmates, friends, and rivals in high school and at the university. Andrew was exceptionally good at mathematics. After earning his PhD in physics, he switched to computer science. He was a professor at Stanford and then at Princeton. In 2000, he received the Turing Award, the highest honor in computer science. In 2004, he moved to China to direct the Institute for Theoretical Computer Science at Tsinghua University in Beijing.

The Hiking Trip to Shitou in the Spring of 1967

Because more than 90 percent of the physics students were male and had mandatory military service the year after college, Lily was with the class one year ahead of hers when applying for graduate school, and she went along for their graduation trip as well. At that time, traveling within the island of Taiwan was still a big deal reserved for special occasions such as the grand field trip celebrating graduation from college. The destination of that year’s graduation trip was Shitou, a beautiful forest recreation area located in the mountainous region of central Taiwan. During that week of train rides and hiking in the mountains, we got to know each other. Yuh-Nung was smitten and began pursuing Lily. Many years later, we participated not only in one special Wu Chien-Shiung Science Camp but also several Wu Ta You Science Camps. The latter were week-long camps organized by Academia Sinica in honor of Wu Ta You, a distinguished physicist who was a former Academia Sinica president and a mentor to Tsung Dao Lee and Chen Ning Yang. For this camp, around a hundred or so bright undergraduates (selected from Taiwan and several countries in Eastern Asia) who were interested in biomedical or physical sciences spent the week with a number of experienced scientists and were exposed, in alternating years, to various areas of modern biology or physics. We participated not only because it was a worthy cause but also for sentimental reasons because the camps were held in Shitou, where we first met.

Graduate School Application

During Lily’s senior year in NTU, Yuh-Nung fulfilled his military service as a communication and electronics officer in the Taiwanese Air Force stationed at an air base about 30 km from Taipei. He got a motorcycle so he could ride to Taipei to see Lily every chance he could sneak out of the base. One of the things we were doing together was applying for graduate school.

Nowadays, one can pursue advanced studies in Taiwan. Back then, one had to go abroad (mostly to the United States). Because we both wanted to do theoretical high-energy physics, Caltech was our dream school. Its physics department had the towering figures of Richard Feynman and Murray Gell-Mann as well as a constellation of stellar theoretical and experimental physicists. In prior years, very few NTU physics students were admitted into the Caltech physics department. As luck would have it, in 1967, the department accepted a student, Wei-Dou Ni, from the NTU physics department in the class one year ahead of Yuh-Nung’s. Wei-Dou performed superbly at Caltech and that undoubtedly helped the subsequent applications of NTU physics students. In 1968, the Caltech physics department accepted three students, Chi-Shin Wang (a brilliant student in Yuh-Nung’s class) and the two of us from NTU; this was unprecedented.

Chi-Shin became a very successful entrepreneur in Silicon Valley. After Caltech, Chi-Shin got a degree in electrical engineering at Stanford. After working for Hewlett Packard for a few years, he started his own company in Silicon Valley. Among his successes were his pioneering commercial applications of the global positioning system (GPS).

Graduate Study at Caltech (1968–1974)

Physics Department (1968–1970)

In September 1968, we arrived in Pasadena from Taipei (see Figure 1). For this first trip overseas, we brought all our belongings in two suitcases that could be carried. Caltech is an academic institution with a superb student to faculty ratio of about four to one and a very small but highly selective student body. In 1968, most of the 750 undergrads and 750 graduate students had nice housing on campus. Yuh-Nung stayed in one of the buildings for male graduate students. However, with no female undergraduate students and only a very few female graduate students, in 1968, the Caltech faculty had just created a graduate women’s house. In the corner house at 293 South Chester Street, Caltech converted seven rooms into bedrooms and there Lily joined six other female graduate students. She stayed in this brand new dorm for three years. To satisfy the fire code for a dorm, which required multiple fire exits for the two upstairs bedrooms, Lily was handed some ropes and told to throw the ropes out of her bedroom window in case of a fire. These ropes were only used once—for a demonstration; somehow nothing ever triggered the fire alarm even with the seven students taking turns cooking dinner every week.

Switch to Biology (1970)

As fellow graduate students in theoretical physics, we became aware of the excitement exuded by biology graduate students we ran into in the dorms and in the small Caltech community. Although we went to Caltech for its great physics department, it happened also to have a fabulous biology division that gave us our first exposure to modern biology. What triggered the switch from physics to biology was a speaker invited by Max Delbrück for the weekly physics seminar in 1970 who introduced the basic concepts of molecular biology and enzymology, hoping to entice physics students to consider doing research in biology. When Yuh-Nung went to talk to Max afterward, Max thought that he wanted to join his lab, and Yuh-Nung thought why not? He returned with a small flowerpot with a stalk of the fungus Phycomyces growing in it and became a graduate student in Max’s lab. Now that Yuh-Nung had joined Max’s lab, Lily thought she would find a different lab for her thesis study, so she knocked on the office doors of the rest of the biology faculty and asked them to please tell her what their research was about. What Lily recalls most vividly was the visit with Jerome Vinograd, an outstanding biophysicist. Instead of telling Lily about his research, he offered the advice that if she wanted to switch from physics to biology, “Don’t try to apply physics to biology; do what Max Delbrück did by becoming a biologist and thinking like a biologist.” When Lily joined Max’s membrane biology subgroup, she began her apprenticeship by painting lipid bilayers for recording the currents generated by carrier molecules and got to work in a smog-free room in the sub-basement of the electrical engineering building. From then on, Max made sure that there was a total separation of Lily’s graduate study from Yuh-Nung’s pursuit of the sensory transduction processes, including the mysterious avoidance response of Phycomyces.

Fig. 1.    Shortly after arrival at Caltech, 1968.

In 1971, we were married. It was the time of the Vietnam War, Woodstock, and general social upheaval in United States. We felt no inclination or obligation to have a traditional wedding, so we chose the simplest ceremony possible. It cost just six dollars to get a marriage license and pay for parking at the Los Angeles courthouse; the mandatory blood tests were free for students. Two witnesses were needed. With foresight, we asked three friends to drive to the courthouse to witness the ceremony (in case one got caught in the Los Angeles traffic). Two made it through the traffic in time to serve as witnesses when a judge married us in his chamber. The next day, we celebrated by camping and hiking at Yosemite. We moved out of the graduate student housing and settled in a little detached cottage on Euclid Street near Caltech. The rent was only $70 a month.

Having gone through the grueling qualifying exams for physics graduate students before switching to biology and then barely passing the placement test on organism biology (so the Caltech biology department did not have to offer this elementary course for the first time to someone utterly unprepared but who somehow turned up in the entering class), we joined fellow biology graduate students in a rebellious challenge to the seven-day, open-book, open-library written exam customarily administered to students at the end of their first year. The faculty patiently worked with our class in multiple meetings to find an alternative qualifying exam format that was mutually agreeable, and they accepted our suggestion that each student write a research proposal and then be tested in an oral exam in which the student would defend his or her own proposal plus a fellow student’s proposal. This original format may have been implemented only for the qualifying exams of our class (students in subsequent years probably thought we were nuts and came up with their own ideas—perhaps more reminiscent of the major and minor proposals).

For this experimental qualifying exam, Lily came up with her own idea for a proposal to localize rhodopsin in photoreceptors and decided to stick to this proposal for her thesis study. At a time when raising antibodies for immunostaining with electron microscopy was a new experimental approach that entailed purification of not only the protein to be used for immunizing the rabbit but also the antibody along with the ferritin or hemocyanin to be conjugated to the antibody, Lily asked Jean Paul Revel, who had just moved from Harvard to Caltech, to join Max Delbrück as her co-mentors. Then she promptly disappeared into either Max’s darkroom in the basement or into Jean Paul’s darkroom in the sub-basement for the dissection of chicken eyes and purification of rhodopsin according to her naïve plan. Yuh-Nung helped out by repeatedly driving Lily to the chicken slaughterhouse to collect chicken heads in a giant ice chest because Lily did not learn to drive until much later. Lily’s fellow graduate students also offered help with their expertise in rabbit immunization. Somehow the rabbit receiving rhodopsin injections could tell Lily was nervous and would thump his hind foot to show his displeasure when he heard her footsteps in the hallway. Most unfortunately, shortly after the last boosting shot of chicken rhodopsin, the rabbit displayed the ultimate displeasure by dying of anaphylactic shock. Despite Jean Paul Revel’s valiant efforts to salvage some usable antibody from this rabbit, all those long hours laboring in the darkroom for the isolation of photoreceptor outer segments from thousands of chicken eyes and the ensuing rhodopsin purification over the course of one year came to naught, at a time when Lily was trying to figure out whether she was cut out for the career path of an experimentalist in biology. The blessing in disguise turned out to be her switch from chicken eyes to cow eyes as the source for rhodopsin; rabbit antibody against cow rhodopsin worked nicely for localizing rhodopsin in mouse photoreceptors—on the densely packed discs within as well as on the plasma membrane (Jan and Revel, 1974).

For Yuh-Nung’s thesis, he worked on two projects concerning sensory transduction processes using the fungus Phycomyces. The sporangiophore of Phycomyces is a giant single cell. It is cylindrical in shape and can reach several cm in length. It was chosen by Max to study sensory responses because it can sense light and gravity. Phycomyces displays a mysterious “avoidance response.” Its growing zone, a segment of the cell several mm long near the tip of the stalk, can sense the presence of any object placed a few mm away and grow away from it. This happens in the darkness, and it does not matter what the object is made of. Yuh-Nung tried hard to figure out what signal is sensed by Phycomyces, and he was able to rule out just about anything he could think of. For a while, he and his coworkers thought that it sensed wind current (Cohen et al., 1975), but that was ruled out several years later. To this day, the nature of this “avoidance response” remains a mystery.

The main part of Yuh-Nung’s thesis was his attempt to begin to understand the molecular mechanism underlying the sensory transduction processes of Phycomyces. Because Phycomyces responds to various stimuli by altering the elongation rate of its cell wall, which is composed of chitin fibers, Yuh-Nung reasoned that the enzyme chitin synthetase could be an important readout. He characterized this enzyme biochemically and indeed showed that blue light regulates the activity of this enzyme (Jan, 1974).

Max Delbrück, Our PhD Thesis Advisor

We were extremely lucky to have Max as our thesis advisor. With his unique combination of intellect, moral integrity, and charisma, Max was a marvelous mentor and a great influence on us during our particularly impressionable stage. One piece of advice from Max was, “Don’t do fashionable science.” Max liked to venture into unchartered research areas and detested entering a field because it was popular or trendy, a trait shared by our other mentors, Seymour Benzer and Steve Kuffler. Of course, venturing into terra incognito carries risks. In Max’s case, his later choice of Phycomyces to understand sensory transduction was not so successful because although Phycomyces has the advantage of being a large single cell that has a rich repertoire of sensory responses, unfortunately, it is an organism not well suited for genetics or biochemistry. However, his earlier choice of phage to study the basis of heredity was a great success that helped launch modern molecular biology.

The virtue of not following the crowd is nicely articulated in this passage from the biography Genius about Richard Feynman (Gleick, 1992):

“It will not do you any harm to think in an original fashion.” Feynman said. He offered a probabilistic argument.

“The odds that your theory will be in fact right, and that the general thing that everybody’s working on will be wrong, is low. But the odds that you, Little Boy Schmidt, will be the guy who figures a thing out, is not smaller. . . . It’s very important that we do not all follow the same fashion. Because it is ninety percent sure that the answer lies over there, where Gell-Mann is working, what happens if it doesn’t?”

“If you give more money to theoretical physics,” he added, “it doesn’t do any good if it just increases the number of guys following the comet head. So it is necessary to increase the amount of variety . . . and the only way to do it is to implore you few guys to take a risk with your lives that you will never be heard of again, and go off in the wild blue yonder and see if you can figure it out.”

Max not only influenced our scientific outlook but also exposed us to many other things that enriched our lives through regular camping trips and through gatherings in Delbrück’s house as part of an extended scientific family—for example, camping under the stars in the desert or reading the works of Samuel Beckett, whose writings Max was very fond of. Max was delighted that the year he was awarded the Nobel Prize in Physiology or Medicine with Luria and Hersey, the literature laureate was Samuel Beckett.

Accepted into Seymour Benzer’s Lab for Postdoc (1974)

In 1973, the thesis work for both of us began to take shape, and it looked like we might get our PhD degrees in another year or so; it was time for us to start figuring out what to do next for postdoctoral training.

One day, Yuh-Nung came upon a paper by Yoshiki Hotta and Seymour Benzer, “Mapping of behavior in Drosophila mosaics” published in Nature (Hotta and Benzer, 1972), in which Hotta and Benzer showed that by making genetic mosaics and constructing embryonic “fate maps” it was possible to locate the anatomical site of abnormalities affecting behavior. It was a very elegant and interesting paper. It got us interested in the ongoing work in Benzer’s lab, and we became very attracted to his approach and to his lab. Benzer was very picky about accepting people into his lab. Fortunately, with some persuasion by Max Delbrück, Seymour accepted us.

We then tried to get postdoctoral fellowships to support our work in Benzer’s lab, with Yuh-Nung proposing to look for learning mutants and Lily proposing to fine-tune mosaic fate mapping of the neural circuitry for visual responses. Unfortunately, the National Institutes of Health (NIH) deemed that neither was worthy of an NIH postdoctoral fellowship so we had to look for less conventional funding sources. Lily somehow got the endorsement of an ophthalmologist from UCLA for her application for a Fight-for-Sight fellowship. For Yuh-Nung, Benzer said: “Why don’t you apply to this Scottish Rite Schizophrenia Research Program fellowship?” because Seymour firmly believed that one could use a fly to study just about any problem in biology including schizophrenia; meanwhile, Yuh-Nung was thinking, “Gee, schizophrenia? Fly? How am I going to pull this off?’ This was back in the era before cloning (BC) and preceding the realization of the remarkable conservation of mechanisms underlying many biological processes. After a while, an idea emerged—there is a fly mutant called tan, which has an abnormal electroretinogram (ERG). It is as if the fly is seeing things and displaying ERG signals when there is nothing to see, and visual hallucination is a hallmark of schizophrenia. Moreover, tan mutants have abnormally low levels of dopamine, and abnormalities in biogenic amines were thought of as a potential cause of schizophrenia.

With a giant leap of faith, Yuh-Nung wrote a proposal including this sentence: “The existence of a link between catecholamine abnormality and a visual defect that is analogous to hallucination in Drosophila mutant tan suggests that it might be used as a model system for schizophrenia.” He sent it in and thought they probably would just laugh at the proposal. To his astonishment, they actually funded his application. His disbelief soon morphed into delusion: “I can’t believe they bought this, imagine what I can do with a less outlandish proposal, maybe I have a future in this business.” Shortly after, the bubble burst when Yuh-Nung attended a small neuroscience meeting. A very prominent neuroscientist saw his nametag and told him: “Ah, I read your proposal. I don’t believe a word of it, but since you are working with Seymour, you’ll do alright.”

Cold Spring Harbor Summer Courses and the Beginning of Our Collaboration (1974)

To prepare for our postdoc in the field of neuroscience, we took one lecture course followed by a lab course in the summer of 1974 at Cold Spring Harbor (CSH) Laboratory, where we had spent the bulk of our summertime as Max’s graduate students, with Yuh-Nung involved in the Phycomyces workshop every summer and Lily doing lab work and taking various summer courses in that secluded idyllic commune for scientists. Little did we know that those summer courses in neuroscience would have such a big impact on our research direction even before we began our postdoctoral study in Seymour’s lab. Seymour’s graduate student Bill Harris was attending the same summer courses with us, and for the one-week break between courses, the three of us visited Woods Hole and also visited Doug Kankel, who did his postdoc with Seymour before joining the Yale faculty. On our way out of Doug’s lab, Bill picked up a bottle of fruit flies and handed it to us, so we could get acquainted with our future experimental animal. That is exactly what we did for the last three days of the lab course.

Although the lecture course was taught by Mike Dennis, Regis Kelly, Carla Shatz, and Eric Frank, all hailing from Harvard’s neurobiology department—the only department in neuroscience at that time—the lab course instructors came from all over the world and included Jac Sue Kehoe and Phillip Ascher (from France) and Enrico Stefani (at that time from Mexico). In that era before the invention of patch-clamp recording, we learned to record from Aplysia neurons and frog muscles. For the last three days of free period left to the students to try whatever they would like, we dug out Drosophila larvae from the mushy food in that old bottle to try out what we had just learned to do with the frog neuromuscular junction, and we enjoyed much encouragement and tutoring from our instructors. It turns out the larval muscles are comparable to frog muscle fibers in diameter but much shorter, so the muscle response to nerve stimulation or iontophoresis of the transmitter glutamate could be readily recorded (with our beginner’s luck) during this lab exercise.

Those CSH summer courses were a fantastic way to learn neurobiology quickly. We not only learned a great deal but also made friends with some great people—our teachers and fellow students. One of our fellow students that we got to know very well was Bob Horvitz. He was on his way to start his postdoc with Sydney Brenner at the medical research council (MRC) Cambridge. He would later make tremendous contributions in developmental biology and especially in programmed cell death, for which he was awarded a Nobel Prize in 2002. Those CSH summer courses were very intense. We worked 16 hours non-stop every day and were exhausted by the end of week two of those three-week-long courses. Bob is the only person we know who took three CSH courses in a row, an early indication that he would have a great career with his tremendous energy and intellect.

Seymour Benzer Lab (1974–1977)

Identifying Shaker as a Likely Potassium Channel Gene

In August 1974, we started in Seymour’s lab. Yuh-Nung began by working on learning and memory as part of the team that did the initial dunce work (Dudai et al., 1976). After spending a few months training flies, we thought that, in order to get to the mechanisms of learning and memory, we needed to develop some functional assay for synaptic transmission, for example with electrophysiology. So, we teamed up to put together an electrophysiology rig in Seymour’s lab in the fall of 1974 to continue what we started in that summer at CSH to characterize larval neuromuscular junction (NMJ) and develop it as an assay for a genetic dissection of synaptic transmission. At that time, the Journal of Physiology was considered the top journal for neurobiology, and it was acceptable for us to take the time and circulate our manuscripts among friends and our CSH summer course instructors until we felt it was ready for the journal. We took pride in publishing our first collaborative work (Jan and Jan, 1976a, b).

Assuming we could go through the recording of a couple of preparations in a few hours, we developed a routine for screening the larvae of behavioral mutants in Seymour’s collection to look for abnormal neuromuscular transmission. Very soon after we started this project, on April 28, 1975, we recorded from a male ShakerKS133 mutant larva and found it displayed an extremely large “unit size” for the excitatory junctional potential in low calcium Ringer—whereas normally each nerve stimulation induced either no response (a failure) or a unit response of the same size as the miniature excitatory junctional potential. Stimulation of the motor nerve of this Shaker mutant generated large responses every time (see Figure 2). In the summer of 1975, the CSH symposium happened to feature the synapse. After Seymour gave a talk and showed our findings based on recordings using a dissecting microscope. Mike Dennis, who taught us in the lecture course the previous summer, offered to teach us to do recordings using a compound microscope with Nomarski optics that would allow us to see the nerve terminals and to do extracellular recordings to test whether the mutant phenotype could be attributed to the nerve or to the muscle of Shaker mutant larvae. We happily made multiple drives to San Francisco. Each time, we stayed for a couple weeks in the Mariana’s guesthouse across the street from the UCSF campus on Parnassus so that we could spend as much time as possible in Mike’s lab in the physiology department. Working closely with Mike, we could see that the Shaker mutant nerve responded to a single stimulation with multiple recurrent action potentials so that calcium iontophoresis several milliseconds after the nerve stimulation could still induce transmitter release and muscle response.

Fig. 2.    First recoding of the abnormally large synaptic potentials (in low calcium ringer) at the larval neuromuscular junction of ShakerKS133 mutants, on April 28, 1975.

At this point, we wrote up a paper with Mike with the conclusion that the abnormality of the Shaker mutant nerve terminal could be a defect in the potassium channel or in the calcium channel and submitted it to Nature. While this paper was under review, we did more experiments and found that the Shaker mutant phenotype could be phenocopied by applying the potassium channel blocker 4-aminopyridine to wild-type larval preparations. When the Nature editor informed us that the reviewers’ comments were favorable but that we needed to shorten our manuscript significantly, we told the editor that with these additional experiments we would have to lengthen our paper instead. So we withdrew it from Nature and submitted our paper to Proceedings of Royal Society because Seymour was just elected as a foreign member, and we thought he would get a kick out of communicating our paper to the Royal Society journal (Jan et al., 1977). Again, the reviewers’ comments were favorable, and this time one reviewer asked the editor to reveal his identity—Sir Bernard Katz—and to pass on a number of follow-up questions that he was curious about. After we did a series of experiments to address these interesting questions, we wrote a long letter to Katz and included those results in that letter. Though we never got around to publishing those studies, we included one set of results in the 1997 review article in Journal of Physiology (Jan and Jan, 1997).

While we worked with Mike Dennis on Shaker mutant recordings, his colleague John Heuser was working very hard next door looking for some physical evidence of exocytosis at the motor nerve ending. Using a fancy machine custom-made at UCSF to strap a frog nerve muscle preparation around a suspended piston, which was triggered to slam onto a cold slab chilled with liquid helium shortly after the delivery of a nerve stimulus, John would recover that flattened frog muscle for freeze fracture and then disappear into the electron microscope room to search for omega-shaped contours at the end plate that had to be very close to the muscle surface to have been frozen immediately on impact with the cold slab. In one of those neighborly chats with Mike and John, we wondered whether the Shaker mutant larvae with prolonged transmitter release could make the task easier to accomplish. When it became evident that the geometry of the larval nerve terminal—a large bouton rather than the nicely elongated end plate of the frog motor nerve ending—was not amenable to freeze fracture, we turned to the alternative approach of treating the frog nerve-muscle preparation with 4-aminopyridine. Indeed, this treatment also prolonged transmitter release from the frog motor nerve endings making it rather easy to capture vesicle fusions using John’s machine (Heuser et al., 1979). Elated with this success, we had a very memorable celebratory dinner outing with John and Mike at the trendy restaurant Café Sports.

Life in the Benzer Lab

The three years we spent in Seymour’s lab were a wonderful experience—tremendously enjoyable and intellectually stimulating. Seymour had a great sense of humor and an immense curiosity. He was a really fun and influential person to be with. He attracted a very talented and somewhat eccentric group of people—fellow postdocs Chip Quinn, Alain Ghysen, Ilan Deak, and Yadin Dudai, and Seymour’s graduate students Bill Harris, Don Ready, and Duncan Byers were there when we joined the group. Several became lifelong friends, especially Alain Ghysen, who had a strong influence on our later scientific direction. Several important lines of research were initiated in Seymour’s lab during that period. For example, Don Ready laid the groundwork for Drosophila eye development (Ready et al., 1976), and Bill Harris discovered the sevenless mutant (Harris et al., 1976), which led to insights about the mechanisms of induction in retinal cell fate specification.

Before we had our first child, toward the end of our stay in Seymour’s lab, we were “owls” with respect to our circadian rhythm. Each weekday, we would get up just before noon and go to Seymour’s cramped lunchroom to eat with the whole group. There were lively and free-flowing conversations and gossip about science, movies, and often food, a favorite subject of Seymour’s. Those lunches could last for hours. Seymour was a good friend of many prominent scientists, and from time to time they joined in those lunches as well. One of the most memorable was the time when Richard Feynman came over from the physics department. He asked us what we were doing with our Drosophila learning studies. In a couple of hours, he managed to think of every clever experiment that had taken several of us months to come up with. His mind was really impressive.

In the afternoon, after those long lunches, we started our daily work or went to seminars/lectures. After dinner, we came back to the lab and often stayed till 2–3 a.m. We could work uninterrupted for six or seven hours and that was when we did most of our experiments. Another night owl was Ed Lewis. He had an even more extreme schedule. He often came back to the lab around midnight and worked till dawn. That was the period when Ed made a breakthrough in his studies of the bithorax complex by using the embryo cuticles to analyze the various chromosome deficiencies and mutants of the bithorax complex; this made it possible to decipher the effect of lethal mutations on body patterning and to expand the analyses beyond previous studies done with adult flies (Lewis, 1978). On several occasions, Ed was very excited by his new findings and wanted to show someone; we were often the only ones around. We got a glimpse of his progress and shared his excitement. Because we were then studying the larval neuromuscular preparation, we even started a little collaboration with Ed to see how the internal tissues might be altered in the bithorax mutants. As with much of Ed’s work, that was never published. Nevertheless, it was a privilege to get to know Ed. Years later, when Ed organized a symposium in honor of Seymour’s 70th birthday in 1991, it was a wonderful opportunity to meet up with Seymour’s old friends and disciples (see Figure 3).

What to Do Next?

Having gone into the field of neurogenetics with the hope that genetics could help with the identification of key genes for neural signaling in much the same way as it did for biosynthetic pathways, we were hopeful that molecular biological approaches being pioneered by David Hogness and colleagues for positional cloning of Drosophila genes might apply to Shaker cloning with the potential of molecular identification of a potassium channel without having to take on the daunting task of purifying potassium channels. However, cloning was in its infancy, and without any training in molecular biology we were not ready to take on such a challenging task. We were wondering what to do next. Mike Dennis had spent some time previously as a postdoc with Steve Kuffler at Harvard Medical School (HMS) and thought that it might be a good idea for us to go there to work with Steve to gain more experience in neurophysiology. At that time, the department of neurobiology at HMS was “the” neurobiology department in the country. Steve was a towering figure in neurobiology, and there were many really outstanding people in that department. Seymour also endorsed this idea because Seymour was a good friend of Steve’s and many other people in that department, and he had a very high regard for them. Around that time, an Ivy League school asked whether we might be interested in applying for a faculty position. We agonized over whether to start applying for faculty jobs or to do a second postdoc at HMS. We spent a long afternoon walking and talking in the beautiful garden of the Huntington Library near Caltech to try to figure out what to do. Finally, we decided that getting additional postdoctoral training with Steve and spending some time in that great department could only benefit us in the long run.

Fig. 3.    Symposium in honor of Seymour Benzer in 1991. Picture left to right are as follows: Ed Lewis, Lily Jan, Norman Horowitz, Rita Levi-Montalcini, Yoshiki Hotta, Yadin Dudai, Sydney Brenner, Francis Crick, Carol Miller, John Abelson, Seymour Benzer, Yuh-Nung Jan, Larry Zipursky, Bob Sinsheimer.

Birth of Emily and the Move to Boston

The last months at Caltech before we moved to Boston were a very hectic time for us. Our daughter Emily was born on August 6, 1977, a couple of weeks ahead of her due date, and we were not quite prepared. On August 5, we were at a group meeting in Seymour’s lab. Lily started feeling contractions and glanced at her watch to time them—they were not exactly spaced with five-minute intervals. As the intervals between contractions got shorter, we were frantically trying to reach the Lamaze instructor for the class we had been taking in preparation for our child’s birth in order to get the course certificate that Yuh-Nung needed in order for him to be allowed in the delivery room to serve as the Lamaze coach. As we were driving to the Kaiser hospital in Hollywood, we were trying to come up with a name for the new baby, one for a boy and one for a girl, because we did not know the sex of the baby. After a long night of labor, a wonderful girl, Emily Huan-Ching Jan, was born early the next morning.

Finally, it was time to leave Pasadena. In September 1977, we packed up and drove across country to Boston with seven-week-old Emily. Pasadena and Caltech were our home for nine years, and we spent our entire twenties there. We had arrived in California very naïve—culturally and scientifically—and we grew up there. Caltech influenced us more than anywhere else. It was a great privilege for us to know the tremendous scientists and human beings Max Delbrück, Seymour Benzer, Ed Lewis, and their wonderful families and many other wonderful people at Caltech. In 2006, we both were given the Distinguished Alumni Award at Caltech, one of our most treasured awards, as if our alma mater was telling us “you kids did all right,” akin to parental approval.

Steve Kuffler’s Lab at Harvard Medical School and Life in Boston and Woods Hole (1977–1979)

Peptidergic Transmission for the Late Slow Excitatory Postsynaptic Potential

In late September 1977, we arrived in Boston to join Steve Kuffler’s lab. We were very fortunate to find a very nice flat near Coolidge Corner in Brookline that was a half-hour walk from the lab. Lily’s mother flew from Pasadena to Boston to live with us and helped take care of Emily during the daytime. We began our new routine of taking shifts to cover the long hours in the lab and to tend to a baby at home in the evening. Lily would set up the bullfrog sympathetic ganglia for recording early in the morning and work together with Yuh-Nung during the day. Yuh-Nung would walk Lily home at dinnertime to relieve her mother of babysitting and then return to the lab to resume the experiments.

At that time, Steve was interested in slow synaptic potentials. Initially, he assigned us to map by electrophysiology the distribution of muscarinic receptors, which mediate the slow excitatory postsynaptic potential that lasts for seconds. It was a useful learning experience but was not that interesting a problem. We became restless after six months and discussed starting a new project with Steve. We were attracted by the mysterious late slow excitatory postsynaptic potential (EPSP) lasting for several minutes. The late slow EPSP, which was initially discovered by Nishi and Koketsu, persisted in the presence of antagonists for nicotinic acetylcholine receptors responsible for the fast EPSP and muscarinic acetylcholine receptors responsible for the slow EPSP. Therefore, some unidentified transmitter other than acetylcholine has to induce the late slow EPSP. With Steve’s blessing, we decided to try to identify the transmitter for the late slow EPSP, a very interesting but highly risky project.

To try to identify this mysterious transmitter, in May 1978, we began to apply all kinds of receptor agonists and antagonists to look for an effect on the late slow EPSP. Besides compounds ordered from Sigma and other companies, we found some small vials of peptides in the freezer that were gifts to Steve from Wylie Vale and Jean Revier at the Salk Institute. Perhaps Steve got these peptides because at the time neuroscientists had begun to suspect that peptides might function as neurotransmitters. To save time, we pooled contents from three vials at a time for a quick survey. One combination produced a moderately encouraging response. Testing them individually identified the culprit as “LHRH.” We then looked up to see what LHRH stood for—lutenizing hormone releasing hormone—and learned about the existence of LHRH analogs as potent agonists and antagonists. When we put those analogs on and observed that the agonist could induce responses that mimic the late slow EPSP, and the potent antagonist could block both the LHRH-induced slow depolarization and the nerve-evoked late slow EPSP, we knew that we were probably on the right track in proposing that an LHRH-like peptide could be the transmitter mediating the late slow EPSP. With the new finding, the obvious next step was to demonstrate that an LHRH-like peptide was indeed present in the presynaptic nerve that innervates the bullfrog sympathetic ganglia and could be released under conditions that could elicit the late slow EPSP. The method of choice was radioimmunoassay, with which we had no experience. We were then told by our colleagues that there was this new postdoc, Tom Jessell, who had just joined Gerry Fishbach’s lab at HMS and who was an expert because he had worked on substance P for his PhD thesis in the UK. We went to see Tom, and he gave us many helpful hints.

Then it was time for the Kuffler lab to make its customary migration to Woods Hole for the summer. Originally, the plan was for Steve and for us to work primarily on the electrophysiology of the late slow EPSP, but we ended up doing mostly radioimmunoassays. Steve’s lab at Woods Hole had great electrophysiology set-ups but hardly any biochemistry equipment. However, Woods Hole was such a communal place that we were able to rely on the kindness of the neighbors to do the necessary experiments.

On the top floor of the Woods Hole lab building with an ocean view on one side, Steve’s lab had windows overlooking the tennis courts on the backside—surely not a coincidence given that Steve was an enthusiastic tennis player. Beyond the tennis courts was the apartment for us, a wonderful arrangement for our daughter and her grandmother to be close by and for us to slip in some tennis during incubation times for radioimmunoassays to detect the LHRH-like peptide in bullfrog sympathetic ganglia and to document the release of the peptide upon nerve stimulation. We had a wonderful three-month stay at Woods Hole and went through the list of criteria that a putative transmitter must satisfy and ticked them off one by one. We also got to celebrate our daughter’s first birthday and go to the beach for swimming and parties at that vibrant and happy community with a long history as the favorite summer retreat for biologists. One of Steve’s visitors was his old friend and coworker Sir Bernard Katz. That was our first chance to meet him. We chatted while pushing Emily in a stroller and watching Steve display his prowess as a tennis player. We were delighted that he remembered reviewing our Shaker manuscript (Jan et al., 1977) and that he liked the paper.

By the time the summer was over and we all moved back to Boston, we had pretty much established that an LHRH-like peptide is the transmitter that mediates the late slow EPSP. It took only about six months since we started the project. It was mostly dumb luck. We wrote up the paper with Steve, and he communicated it to Proceedings of the National Academy of Sciences (PNAS) (Jan et al., 1979). That work most likely helped several schools become interested in us and encouraged us to apply for faculty positions. We felt it was perhaps time for us to get independent positions and to start our own lab.

Although we spent less than two years in Boston, the experience at the HMS was very valuable. The neurobiology department was relatively small but had a very high concentration of terrific neuroscientists. The senior faculty members were Steve and the other founding members of the department, who had all worked with him in their youth—David Hubel, Torsten Wiesel, Ed Furshpan, David Potter, and Ed Kravitz. The junior faculty members were Paul Patterson, Story Landis, Simon Levay, Peter Maclish, Ann Stuart, and John Hildebrand. Each group typically had only a few highly selected postdocs and students. When we arrived in 1977, Lou Reichardt, Carla Shatz, and Josh Sanes had just left. Our contemporaries included among others: Mike Stryker, Bill Harris, Eric Frank, Doju Yoshikami, Larry Marshall, Bob Stickgold, Marge Livingstone, Alison Doupe, Mary Kennedy, Charlie Gilbert, and Terry Sejnowski. It is remarkable how much impact that relatively small group of people has had on neuroscience.

The department then was very tightly knit. Two core activities were especially educational. Because all members of the department could fit into a modest-sized lunchroom, we all had lunch together every day and often had lunch seminars given by visitors. It was a tough crowd. The speakers were constantly interrupted, and there was an element of “who could ask the most critical question” during those seminars. We remembered that during a Christmas party when we were there, “mock awards” were given out at a skit. One was given to the person “who most consistently anticipated the next slide with questioning during those lunch seminars in the previous year.”

One of the best department activities was the “evening meetings.” Every month or two, the department had dinner together, and one group presented their ongoing work. Everyone took those presentations seriously because there was tremendous peer pressure to do well. During those evening meetings, we learned about much of the exciting work going on in the department.

Job Offer at University of California, San Francisco

After a few months of job interviews, we had several nice job offers and one was from UCSF. At that time UCSF was not yet a prominent place (like it is now), and we had better offers in terms of space and start-up funding from more prestigious places. At UCSF, we had to share a faculty teaching equivalent (FTE). The lab space and the setup money were very modest as stated in the job offer letter written by the chair of the physiology department, Fran Ganong, on December 6, 1978: “ Zach Hall and I have combined our resources to provide 1,000 square feet of space.” (That was for two of us.) And then he wrote: “I can also commit $15,000 start-up money for each of you at this time” ($30,000 total). Although a dollar in 1978 is worth about three dollars now, $30,000 is not a lot of start-up money. Nevertheless, we were very attracted to UCSF, especially by the people there. We already knew Mike Dennis and John Heuser from our previous collaborations. Zach Hall was recruited from HMS to UCSF to start the neuroscience program in 1976, and in 1977 and 1978, he recruited Lou Reichardt and Mike Stryker (both star postdocs) from the neurobiology department at HMS. Additionally, several other young faculty were already there including Roger Nicoll, Regis Kelly, Howard Field, Mike Merzenich, and Allan Basbaum. These young faculty members formed a core that soon developed into one of the country’s leading neuroscience programs. Our other job possibilities were also at excellent places, and there is no way to know how things might have turned out if we went to one of those instead. Nevertheless, we felt very fortunate to have decided to come to UCSF to join this group, and this was one of the best decisions we have ever made.

An unexpected benefit of coming to UCSF that we were not aware of initially was that, between 1976 and 1979, in parallel to the developing neuroscience program, a fabulous biochemistry and biophysics department was being greatly enhanced with the recruitments of these few years: Bruce Alberts, Marc Kirschner, Keith Yamamoto, Christine Guthrie, Pat O’Farrell, and Tom Kornberg. Because molecular biology was beginning to revolutionize neuroscience in the early 1980s, we soon began benefiting from having the opportunity to interact with those outstanding molecular biologists and cell biologists.

University of California, San Francisco (1979–present)

Setting Up Our Modest Little Lab

In late June 1979, we drove across the country during the height of the oil crisis, with our daughter a toddler not quite two years old, to start our lab at UCSF on July 1. It took us a couple of months to set up our little lab on the eighth floor of Health Sciences East (HSE) on the Parnassus campus (see Figure 4) and then we started doing experiments.

Fig. 4.    The shared office of the authors’ lab at UCSF in the early 1980s.

Peptide Acting at a Distance

Initially, we continued with our work on peptides as neurotransmitters. We discovered that although the LHRH-like peptide was released together with a classical transmitter, acetylcholine (ACh), from the same nerve terminals that synapse onto the C type neurons in the sympathetic ganglion, the peptide can diffuse over tens of microns to act on their true targets (i.e., nearby B-type neurons with which the LHRH-like peptide containing preganglionic nerve fiber does not form a synapse). So the wiring diagram based on anatomically defined synapses is actually misleading for identifying the real target of the peptide transmitter (Jan and Jan, 1982b; Jan et al., 1980). This is something for the connectome folks to consider.

Starting New Projects: Shaker Cloning and Neural Development Studies (1980)

We might have been recruited to the UCSF faculty as electrophysiologists studying the vertebrate autonomic nervous systems; however, once our peptide work got going, we soon started switching back to studies of the fruit fly Drosophila because of the opportunities offered by new developments in the field. In our youthful exuberance, we initiated two new projects for which we had no relevant expertise whatsoever: neural development and Shaker cloning. Looking back, it seemed rather foolhardy to start such risky projects as beginning assistant professors. Perhaps one reason that we chose to pursue high-risk projects that interested us was because we felt that we had the good will and strong support from our chair, Fran Ganong, and the neuroscience program director, Zach Hall. Indeed, we were tenured rather quickly (in 1983) even though, by that time, our new projects had yielded very little concrete results.

Neural Development

Neural development was a question that had been in the back of our minds for some years. Back in the days when we were in Seymour Benzer’s lab, in one of those long lunch gatherings together with fellow postdocs Alain Ghysen, Ilan Deak, and Yadin Dudai and Seymour’s graduate students Bill Harris, Don Ready, and Duncan Byers, we all unabashedly went to the blackboard in Seymour’s lunchroom to write down the big questions in neuroscience that interested us—a record of those early musings was kept because Seymour took a Polaroid picture of the scribble on the blackboard. How the nervous system forms was one obvious question on the list though it was not clear how one could go about approaching this question.

While in Seymour’s lab, we became very good friends with a fellow postdoc, Alain Ghysen. We thought it would be fun to do some work together at some point. After we set up our little lab at UCSF, Alain and his long-term collaborator Christine Dambly-Chaudiere would come over from their lab in Brussels and work together with us to explore all kinds of crazy ideas for a few weeks at a time every year in the early 1980s. We wanted to work together on something interesting that had not been worked on by any of us already. We chose neural development.

Two papers that appeared around that time suggested an approach to study neural development. The 1980 paper by Nüsslein-Volhard and Wieschaus on “Mutations affecting the segment number and polarity in Drosophila” (Nüsslein-Volhard and Wieschaus, 1980) was inspiring because it revealed the involvement of just a score of genes for the specification of the body plan and demonstrated the power of canvassing the whole genome with comprehensive screens of mutant embryos. Even those “lethal” mutations incompatible with survival can be characterized by examining the cuticle patterns of embryos that may or may not have made it through embryogenesis. The cuticle prep that remained after dissolving away the embryo within retained the body plan signatures for scoring mutations that affect segmentation and polarity but would not work for scoring mutations affecting the nervous system. The hybridoma technology developed by Köhler and Milstein for monoclonal antibody generation (Köhler and Milstein, 1975) offered some hope. Without any knowledge of the molecules involved in neural development, we could simply immunize mice with ground up embryos and screen the monoclonal antibodies based on the staining patterns they yield. That was the plan anyway; and then there were some accidental findings and lucky breaks in this venture.

To get started with monoclonal antibody generation, Sandra Barbel, who was initially planning to join our brand new lab as a technician for a year or two before returning to her graduate study at UC Davis, learned the hybridoma technologies with the helpful advice from Lou Reichardt’s lab. Sandra has remained and is now our lab manager. Yuh-Nung developed a routine of listening to his favorite music while going through hundreds of staining patterns looking for those monoclonal antibodies that appeared to recognize specific cell types or structures, especially ones in the nervous system. This way we began the bootstrap approach of using whatever monoclonal antibodies that emerged from these screens and that could help with the identification of mutant embryos with abnormal distribution of neurons and characterizing those mutants molecularly to end up with more markers for neurons and their precursors that could then be used for additional mutant screens.

Besides the generation and screening for monoclonal antibodies, serendipity smiled several times in our haphazard experiments. Early on, when Yuh-Nung was using horseradish peroxidase (HRP) as a neuronal tracer in the study of the frog autonomic nervous system, he had a vial of antibody against HRP in the refrigerator. Because Lily was doing staining of cryostat sections of fruit flies with antibodies against neuropeptides for no particular reason beyond a simple curiosity, she reached for the vial of secondary antibody and ended up with an amazing staining pattern of the entire nervous system—rather odd and unexpected given the sparse distribution of peptides in the vertebrate nervous system. For the next three days, Lily vehemently argued against Yuh-Nung’s suggestion that she may have made a mistake somewhere, until she repeated the experiment using either the secondary antibody meant for her experiment or the antibody against HRP in the vial on the same shelf. As Yuh-Nung likes to tell the story, because it was Lily’s mistake that led to the surprise finding that antibody against HRP specifically labels Drosophila and grasshopper neuronal membranes, she was the first author of the paper on that study (Jan and Jan, 1982a). While we were going through rounds and rounds of mouse immunization for hybridoma generation, we immunized some mice with HRP for good measure and recovered a monoclonal antibody that prominently marked the germ plasm and germ cells and led Bruce Hay to the molecular characterization of Vasa (Hay et al., 1988). However, this Vasa antibody does not recognize HRP, and we have no explanation other than luck for the way we came up with some of the most useful monoclonal antibodies for our mutant screens.

Even with those neuronal markers, we were still unsure on which part of the nervous system to focus our attention. Around 1985, we finally realized that the larval peripheral nervous system (PNS) is a good assay system for studying neural development. Rolf Bodmer, Alain, Christine, and the two of us worked out an atlas of the larval PNS (Ghysen et al., 1986; Bodmer and Jan, 1987). Then, Alain and Christine made a very critical discovery. They found that mutants of the achaete scute complex (AS-C) displayed a very striking PNS phenotype: one type of sense organ, the external sensory (es) organ, was missing but the chordotonal (cho) organs were not affected (Dambly-Chaudiere and Ghysen, 1987). This was the first, and very nice, example that a mutation can produce a very clear-cut and neuronal type-specific phenotype, which encouraged us to plunge into serious genetic screens for mutants affecting PNS development in 1985. That is how genes like numb and atonal were later discovered.

Shaker Cloning

As we got to know Pat O’Farrell well, we would often stop at the hallway and chat when we ran into one another. One day Pat was all excited about the new development with the P-element, the transposon for the mysterious genetic phenomenon known as hybrid dysgenesis. At the time, Pat was collaborating with Tom Kornberg on the chromosome walk to clone engrailed and was raising the possibility of using P-element insertion mutagenesis as a novel approach to clone Shaker. Pat generously allowed us to do a rotation in his lab to learn about molecular biology. For the next several years, there was close collaboration between Diane Papazian, Bruce Tempel, and Tom Schwarz in our lab and Steve DiNardo and Claude Desplan, who joined Pat’s lab as postdoctoral fellows, to go after the Shaker gene. At a time when there were numerous P-elements in a genome prior to the development of reliable control of movement of these transposons, we settled with the old reliable chromosome walk for cloning Shaker. As the years for this chromosome walking, chromosome sitting (we hit an apparently unclonable region), and chromosome falling off (repetitive sequences doing their trick) dragged on and other interesting biological questions such as cell cycle control in the developing Drosophila embryo beckoned, we were left with our three postdocs Diane, Tom, and Bruce to stick with it to the end.

During the long haul for Shaker cloning and genetic screens for neural development mutants, it was also payback time after having taken so many summer courses at Cold Spring Harbor in our graduate student and postdoc years. We revived the neurobiology of Drosophila course and spent four consecutive summers at Cold Spring Harbor, starting in 1984, the year we were expecting the arrival of our son Max. The apartment building for CSH course instructors was up a gentle slope just about a hundred yards from the lab, a wonderful arrangement for us to be close to our kids even with the traditional long hours for the summer courses. Pat joined us in teaching the course for the first year, and some of our postdocs and students came along to help out as teaching assistants. Some of the summer course students decided to do their postdoctoral research with us later on, as in the case of Ehud (Udi) Isacoff. The scientific nickname Udi can be traced to the first day when he arrived at Cold Spring Harbor for the summer course and, while introducing himself to his roommate Claude and struggling with the French pronunciation of Ehud, he ended up with being stuck with his childhood nickname Udi.

Howard Hughes Medical Institute and the Birth of Max (1984)

The year 1984 was an eventful one. Scientifically, we were at a low point. We had been consistently productive ever since our postdoc days (1974–1982), but from 1983 to 1986 we had a dry spell. Shaker cloning was very difficult. Despite three to four years of hard work, we had nothing to show. Feeling in the dark without knowing what a potassium channel should look like, we could not even tell whether we were on track to clone the first potassium channel gene before everything finally clicked in the end. For the neural development work, we were trying to find our way. We had generated some very useful markers and developed the embryonic PNS as a promising system for genetic dissection of neural development, but we had not yet made any substantial inroad.

During this difficult period, two great events happened to us. One was the birth on November 7, 1984, of our son Max Huang-Wen Jan. We named him Max in honor of our PhD advisor Max Delbrück. Following Chinese tradition, all the kids in Yuh-Nung’s extended family of Emily and Max’s generation share a common given name “Huang,” which means “bright” or “brilliant.” For Emily, her specific Chinese given name is “Ching,” which is an endearing form of “person.” For Max, his specific Chinese given name “Wen” means “literature” or “culture.” With Emily and Max, we are blessed with two wonderful kids, each very talented in a different way.

Another great thing that happened to us was that somehow we were chosen as Howard Hughes Medical Institute (HHMI) investigators. At that time HHMI did not yet have an open competition system, they chose their investigators in a somewhat mysterious way. In 1984, HHMI decided to start supporting neuroscience. They picked five institutes, Harvard Medical School, Columbia, Johns Hopkins Medical School, Salk, and UCSF, and asked these institutions to nominate potential investigators. UCSF decided to choose neuroscience faculty who were relatively young and not yet at the rank of full professor. That meant there was a very small pool of potential candidates. Somehow UCSF picked us even though we were struggling mightily to get our research going. HHMI made a huge difference in our research. We are most grateful for their continued support since July 1, 1984, now more than 29 years and counting.

Breakthroughs in 1987

Shaker Cloning (1987) to Enable Studies of Potassium Channels One at a Time

Finally, after six years of hard work, the project of Shaker cloning came to fruition. One day, Diane saw the S4 sequence with the basic residue arginine or lysine at every third position within an otherwise hydrophobic sequence that could pass as a transmembrane segment, so she knew we probably had the real thing. Over the next few months, Diane, Tom, and Bruce isolated a number of alternatively spliced isoforms of Shaker cDNAs and their fellow postdoc Les Timpe demonstrated functional expression of voltage-gated potassium channels in Xenopus oocytes. The Shaker locus turned out to be quite complex. It is a large gene with several different alternatively spliced transcripts coding for different proteins that form voltage-gated potassium channels with a variety of electrophysiological properties. No wonder it was a beast of a gene for novices like us to tackle. Shortly after that, we were able to clone its mammalian homologue due to high sequence homology. It was gratifying that the fly work could be readily extended to vertebrates. Those results were published in five papers in a nine-month span (Papazian et al., 1987; Tempel et al., 1987; Schwarz et al., 1988; Tempel et al., 1988; Timpe et al., 1988).

The remarkable level of evolutionary conservation of potassium channels became evident right away. It took us six years to clone the Shaker voltage-gated potassium (Kv) channels with the chromosome walk and then just a few months to clone the mammalian homolog of Shaker, Kv1.1. A decade later, the first case for a channelopathy happened to be episodic ataxia type 1 (EA1) due to mutations of Kv1.1, as revealed by physicians and biophysicists in Oregon at the dawning of the decade of the brain (Browne et al., 1994). The physiological role of Kv1.1 in mammalian motor axons, as demonstrated by studies of Kv1.1 knockout mice by Tempel’s lab and Chiu’s lab, is to prevent action potentials from bouncing back from nerve terminals (Smart et al., 1998; Zhou et al., 1998). The recurrent action potential firing after a single stimulation of mouse motor axons is reminiscent of the recurrent action potentials in Shaker mutant larval motor axons we showed in our letter to Katz and later on in two reviews in the Journal of Physiology (Jan and Jan, 1997, 2012). This hyperexcitability is likely the cause of myokymia of EA1 patients, the uncontrollable muscle movements of the limb even after the motor nerve is temporarily isolated via a pressure cuff.

As shown by the studies of Kv1.1 knock-in mutant mice bearing an EA1 mutation by the labs of Jim Maylie and John Adelman, a reduction of Kv1 channel function also causes hyperexcitability of central neurons: Kv1.1 function is important for the cerebellar basket cells to limit action potential propagation into only a subset of the axonal branches; reducing Kv1 channel function allows excessive action potential invasion at axon branch points and compromises the central control of motor activity (Herson et al., 2003). So, hyperexcitability of neurons in the central nervous system is likely the basis of the episodic ataxia of EA1 patients.

As the Kv family grew—with numerous family members cloned by many labs in the channel field, we came to realize and appreciate the tremendous diversity of potassium channels. Looking rather like a quarter of the pore-forming subunit of a sodium channel, Kv channel subunits can form heteromeric channels with properties distinct from homomeric Kv channels, as Udi first demonstrated (Isacoff et al., 1990). Moreover, Morgan Sheng and his fellow postdoc Meei-Ling Tsaur came to the surprise finding that the potassium channels on the axon and dendrites of a neuron have different subunit compositions even though they have similar electrophysiological properties (Sheng et al., 1992). Moreover, the Kv channel expression could change dynamically with neuronal activity (Tsaur et al., 1992).

Later on, we were amazed to realize that, whereas the evolutionarily conserved placement of Kv1 channels in the axon is associated with axon-targeting machineries including conserved features of Kv1 channel subunits (Gu et al., 2003; Gu et al., 2006), the transcripts for Kv1.1 and Kv4.2 are present in dendrites where synaptic regulation of their local translation involves molecules linked to tuberous sclerosis and fragile X syndrome, diseases that greatly increase the risk for epilepsy and autism (Raab-Graham et al., 2006; Lee et al., 2011). The spatial and temporal variations combined with the mix-and-match of Kv channel subunits have the potential for tremendous potassium channel diversity in vivo; studies in our lab and Bruce Tempel’s lab provided the first examples of heteromeric Kv channels in the hippocampus and cerebellum (Sheng et al., 1993; Wang et al., 1993). The opportunity of back-to-back publications coordinated with our colleagues is a pleasure we have enjoyed over a score of years, and these exercises with our lab alumni have been particularly rewarding.

Neurogenesis and Cell Fate Specification: Cut, Numb, and Basic Helix-Loop-Helix Proteins—Daughterless and Atonal (1987–1994)

In 1987, around the time we finally succeeded in cloning Shaker, our neural development work also began to come to fruition. Several of the genes we started studying during that era provided useful insights into how neuronal cell fates are specified: cut, numb, daughterless, and atonal.

One of the first neural developmental genes we studied was cut. Rolf Bodmer and Karen Blochlinger, two postdocs in our lab, discovered that cut functions as a binary switch between es organ and cho organ fate. Cut is normally expressed in es organs but not in cho organs. In cut loss of function mutants, es organs are converted into cho organs (Bodmer et al., 1987). Conversely, ectopic expression of Cut transforms cho organs into es organs (Blochlinger et al., 1991). Karen cloned cut and found that it encodes an unusually large homeodomain containing gene (Blochlinger et al., 1988). Cut is one of the first examples of homeodomain-containing genes that when mutated cause cell fate transformation at the single cell level, as opposed to the homeotic transformation of whole body parts or segments caused by mutations of the bithorax complex or the antennapedia complex. Later on, Wes Gruber discovered that cut has another interesting function in controlling dendrite morphology.

Rolf’s study of cut led to a very nice by-product. He was trying to identify additional cut-like genes by sequence homology and identified another homeodomain-containing gene. It was initially somewhat disappointing because the gene was expressed in developing mesoderm rather than in the nervous system and he named it msh-2 for mesoderm specific homeobox containing gene-2 (Bodmer et al., 1990). Later on in his own lab at the University of Michigan, Rolf discovered that msh-2 is essential for mesoderm development in Drosophila, and he renamed the gene tinman because the mutant lacks heart muscle (Bodmer, 1993). Tinman (the protein encoded by tinman) turns out to be an evolutionarily conserved protein with important roles in mesoderm development in Drosophila and in mammals.

Another informative gene is daughterless (da). In da mutants, the entire PNS is missing. In our lab in 1988, Mike Caudy and Harald Vaessin cloned da and noticed that there is sequence homology between Da (the protein product of da), Myelocytomatosis viral oncogene (Myc), and AS-C. Before we wrote up our paper (Caudy et al., 1988), Lily was at a meeting at MIT and happened to talk to David Baltimore; she learned that their lab had just cloned a gene encoding an immunoglobulin kappa chain binding protein E12/E47, which also has sequence homology with Myc and AS-C. We then sent Baltimore’s lab the Da sequence and it turned out that Da is a homolog of E12/E47. They had the insight to recognize a novel basic helix-loop-helix (bHLH) motif, which is a DNA-binding and protein-dimerization domain, shared by Da, Achaete (Ac), Scute (Sc), MyoD, and Myc (Murre et al., 1989a). Da normally assembles with Ac or Sc to form a heterodimer that binds to DNA and regulates the downstream genes to initiate neural development (Murre et al., 1989b). Da is ubiquitously expressed, whereas Ac or Sc is expressed in discrete clusters of cells that prefigure where the future PNS neurons will form. These findings led Alain and Christine to propose the useful “proneural gene” concept (Ghysen and Dambly-Chaudiere, 1989; Cubas et al., 1991; Skeath and Carroll, 1991).

In parallel to the work on Drosophila neurogenesis, there was substantial progress in understanding vertebrate myogenesis by Harold Weintraub, Eric Olsen, and others. The way that bHLH factors function as genetic switches to initiate Drosophila neurogenesis and vertebrate myogenesis turned out to be remarkably similar (Jan and Jan, 1993; Weintraub, 1993).

Studying the way bHLH factors specify neuronal cell fate led us to approach an interesting issue: How does neuronal type specificity arise during neurogenesis? In AS-C mutants, one type of sensory organs, the cho organs, remain intact. Based on what we knew about how Da and AS-C function to initiate the development of subtypes of PNS neurons, we postulated that there is an as yet unidentified gene X, which most likely also encodes a bHLH protein that can form a heterodimer with Da to initiate cho organ development. Following this hypothesis, we were able to find this missing gene and named it atonal, which is indeed required for the development of cho organs and has all the properties we predicted (Jarman et al., 1993). An unexpected bonus was our finding that atonal is also essential for photoreceptor development in the Drosophila compound eye. We found that atonal is required for the development of the founder photoreceptor R8, which in turn induces the formation of the other photoreceptors of an ommatidium of the compound eye (Jarman et al., 1994). This was a satisfactory finding because it showed that the proneural concept is generally applicable in Drosophila neural development and provided insights about the genesis of neuronal cell type specificity.

Atonal is the founding member of the Atonal family of proneural gene products. Interestingly, the vertebrate homologues are often involved in the specification of neurons involved in vision and hearing—just as in Drosophila (Kanekar et al., 1997; Bermingham et al., 1999; Kay et al., 2001).

Identifying Founding Members of Another Potassium Channel Family (1993–1994) and Searching for Ways Used by Cells to Regulate Channel Number

Although extensive studies of many labs have delineated the extended family lineage of Kv channels and further linked multiple Kv family members to human diseases of various tissues including the brain, heart, and muscle, it also became evident in the early 1990s that certain potassium channels, such as the inwardly rectifying potassium (Kir) channels important for controlling heart rate or insulin release, could not be isolated based on sequence homology to Kv channels. Luckily, that was the time when Yoshihiro Kubo came to our lab for a two-year stint of postdoctoral research, two years after he was recruited as a freshly minted PhD from Tokyo University to join the faculty of the Tokyo Metropolitan Institute.

The circumstances that caused Yoshihiro Kubo to come to our lab in 1991 and Tadashi Uemura to join our development group as a postdoc a few years earlier gave us a glimpse of the remarkable dedication of their mentors. When we and Louis Reichardt became HHMI investigators in 1984 and 1985, HHMI was having some serious discussions with the Internal Revenue Service (IRS) about their status as an institute—rather than a foundation that has to meet the legal requirement of spending down its endowment by a few percent each year. So it was important for HHMI to have all our labs moved to one place to signify the physical presence of an institute at UCSF. Where would they find the space in the very densely populated UCSF buildings for the relocation of HHMI labs? The university hospital was among the first buildings to be built on the UCSF campus in San Francisco in the 1920s, after the 1906 earthquake. Part of it was leased to HHMI. To reconfigure the layout of patient rooms to accommodate lab benches, the remodeling entailed moving the corridor sideways and leaving the pillars in the middle of the lab. In 1986, our lab moved to this newly renovated space. We spent 18 productive years there—until we moved to the new UCSF Mission Bay campus in 2004. At our lab-warming party, Mitsuhiro Yanagida from Kyoto University happened to be visiting UCSF and dropped by to have a drink. Years later—after Tadashi joined our lab, he told us of a highly unusual phone call from his thesis advisor (Yanagida) urging Tadashi to consider doing his postdoc in our lab. We must have done something right at that party though we still do not have the slightest clue what that was. While Tadashi was in our lab, Yoshihiro Kubo’s thesis advisor Tomoyuki Takahashi paid a visit to reminisce about the old times at Harvard’s neurobiology department and to personally endorse the postdoc application of his student Yoshihiro Kubo. As Tadashi came to the lunchroom, Lily cracked an irreverent joke about the rivalry between Tokyo University and Kyoto University, Tadashi and Tomoyuki bowed deeply to each other and exchanged what must have been very formal and respectful greetings in Japanese. All joking aside, it was our great fortune that Tadashi and Yoshihiro followed their mentors’ suggestion to join our lab because their work opened up two significant new directions for the study of asymmetric cell division and Kir channels, respectively.

Using the expression cloning approach originally developed by Shigetada Nakanishi in Japan and our UCSF colleague David Julius while he was a postdoc with Richard Axel at Columbia, Yoshihiro Kubo cloned the inward rectifier IRK1 by first injecting pools of cRNA from a cell line to induce Kir channel expression in Xenopus oocytes and then subdividing the cRNA pools repeatedly until he found a single cDNA clone for IRK1 (Kubo et al., 1993a). Using IRK1 cDNA to probe heart and brain cDNA libraries in parallel, Yoshihiro and his fellow postdoc Eitan Reuveny were looking for G protein-activated inwardly rectifying potassium channels that mediate parasympathetic slowing of the heart and slow inhibition in the brain and ended up with the GIRK1 cDNA from both libraries (Kubo et al., 1993b). Meanwhile, Nathan Dascal was doing a sabbatical in Henry Lester’s lab at Caltech and isolated the same cDNA via expression cloning (Dascal et al., 1993). Together with ROMK1, a weak inwardly rectifying potassium channel isolated by expression cloning in Steve Hebert’s lab (Ho et al., 1993), these founding members made it possible to identify other Kir family members including Kir6.2 that corresponds to the pore-forming subunit of the ATP-sensitive potassium channel that controls insulin release. Whereas the pore-forming Kv channel subunits have six transmembrane segments, the pore-forming Kir channel subunits have just two transmembrane segments, corresponding to S5 and S6 of Kv channel subunits; what is unique with Kv channels is the first four transmembrane segments that form the voltage sensor (Kubo et al., 1993a).

Whereas a number of potassium channels contain auxiliary subunits as well as pore-forming subunits in the Kv or Kir family, the curious arrangement in the ATP-sensitive potassium channel of four Kir6.2 and four SUR1 subunits in the transporter family made Noa Zerangue, a truly gifted neuroscience graduate student, and Blanche Schwappach, the postdoc who was engaged in a close collaboration with Noa, wonder how a cell could count to eight and coax these members of two very old protein families to assemble and form octamers. Having devised a method to detect channel proteins on the cell membrane independent of channel function, to reveal that only octameric channels appear on the cell membrane, they found that channels with fewer than eight subunits are retained in the endoplasmic reticulum (ER) via a novel ER retention signal in Kir6.2 and SUR1 (Zerangue et al., 1999). The idea that channel activity could be powerfully controlled at the level of channel number as well as channel property led their fellow postdoc Zach Ma to identify other novel motifs for traffic regulation such as ER exit (Ma et al., 2001).

Numb and Asymmetric Cell Division (1994–Present)

In our initial screen for genes affecting Drosophila PNS development, one of the genes that caught our attention was numb because of its interesting cell fate phenotype. A sensory bristle is derived from a single precursor that goes through four divisions giving rise to five cells. Each division is asymmetric. In numb mutants, all the divisions become symmetrical resulting in a strange sense organ made of four socket cells. When Tadashi Uemura cloned the gene in our lab, the sequence did not tell us how the gene product Numb might function (Uemura et al., 1989). After Tadashi returned to Japan to become a junior faculty member associated with Masatoshi Takeuchi and to work on cell adhesion molecules, a graduate student (Michelle Rhyu) continued with the project in our lab and discovered that Numb is asymmetrically localized to one pole of the sense organ precursor cell in a crescent shaped cap. Upon cell division, Numb is segregated into one of the two daughter cells to make them different (Rhyu et al., 1994). Numb functions, at least in part, by biasing the Notch signaling between the daughter cells (Rhyu et al., 1994; Frise et al., 1996; Guo et al., 1996). This process is repeated in all the divisions of the sensory bristle linage. Michelle also found that Numb is asymmetrically localized in the neuroblast (NB) divisions.

Numb is the first cell fate determinant identified for asymmetric cell division in the nervous system. It turns out that Numb is just the tip of the iceberg. Soon, we and others began to uncover other cell fate determinants such as Prospero, which is asymmetrically segregated together with Numb, as well as the complex machinery including adaptor proteins Miranda and Partner of Numb that function to localize those determinants asymmetrically during asymmetric cell division (Knoblich et al., 1995; Shen et al., 1997; Lu et al., 1998). In the late 1990s, our main interest gradually shifted to dendrite development. Several lab alumni continued to study asymmetric cell division after they left our lab. (Most notably, Juergen Knoblich has made many important contributions in his own lab in Vienna.) Their studies, concerning how Numb and other cell fate determinants are localized to one of the two daughter cells in order to specify their fates, have provided useful insights about the mechanisms of asymmetric cell division. This is still a very active research area.

Dendrite Morphogenesis (1998–Present)

When one looks at the drawing of neurons by Ramon y Cajal, one cannot help but be impressed by how beautiful those dendrites are. Different types of neurons can have strikingly different dendrite morphology. We have always been fascinated by how different neurons acquire their distinct dendritic morphology. This research subject is not only scientifically interesting but also esthetically pleasing. We were waiting for an opportunity to study this problem. We knew way back in 1987 that a group of Drosophila sensory neurons known as dendritic arborization (da) neurons have beautiful dendrites (Bodmer and Jan, 1987). However, at that time, to visualize the dendrites, Rolf had to dissect the larvae individually and stain them with a neuronal specific antibody. That was too labor intensive for a genetic dissection of dendrite development, so we had to wait until there was a suitable technique. In the early 1990s, Liqun Luo joined our lab. Liqun was the first postdoc in our lab interested in studying neuronal morphogenesis. That was the time when people began to appreciate the important role of the small GTPases Rac/Rho/Cdc42 in regulating actin cytoskeleton in yeast and fibroblast. Liqun was one of the first to discover the interesting function of those small GTPases in morphogenetic events in multicellular organisms, including axon growth, myoblast fusion, and dendritic spine development (Luo et al., 1994; Luo et al., 1996). Liqun left our lab to start his own lab at Stanford in 1996 and has done spectacularly well ever since.

In the late 1990s, with the arrival of green fluorescence protein (GFP) and the Gal4-UAS system, we felt that finally the time was ripe for us to start studying dendrite morphogenesis. Two new postdocs in our lab, Fen-Biao Gao and Jay Brenman, decided to take on this project by using a PNS-specific Gal-4 to drive the expression of GFP in PNS neurons to visualize their morphology in living larvae. This method worked very well and allowed us to start a genetic screen for mutants affecting dendrite morphogenesis (Gao et al., 1999). Although this screen was successful and encouraged us to dive into dendrite morphogenesis, we were limited by treating all the da neurons as if they were a homogenous group. As a result, we would pick up mostly mutations that affected general aspects of dendrite morphogenesis shared by different neuronal types.

In 2001, a new postdoc, Wes Gruber, joined our lab. For his PhD dissertation with Jim Truman at the University of Washington, Wes received superb training in insect neurobiology, which enabled him to recognize that the da neurons could be divided into four classes based on their dendrite morphology (Grueber et al., 2002). This greatly enriched our study, allowing us to gain insights about how different neurons acquire their distinct dendritic morphology (Jan and Jan, 2010). A particularly nice example is Wes’s study of the gene cut that we had studied many years ago. Wes noticed that Cut expression levels exhibit neuronal type specificity: Class III has the highest level of Cut, Class IV has a medium level, Class II has a low level, and Class I has no Cut. By experimentally manipulating the Cut level in different classes of da neurons, Wes demonstrated that the level of Cut regulates the extent of dendritic growth in a class-specific manner. Thus, Cut appears to be a multi-level regulator of class-specific dendrite morphology, and it can exert its function post-mitotically (Grueber et al., 2003).

Further, there are common mechanisms used by all four classes of da neurons to shape their dendritic arbors, for example, repulsion between sister dendrites—so the dendrites can spread out, a phenomenon known as “self avoidance.” There are also neuronal type-specific mechanisms. For example, Class IV, but not Class I, da neuron dendrites exhibit tiling. There are three Class IV da neurons per hemi-segment, and each neuron’s dendritic arbor occupies about one-third of a hemi-segment with very little overlap with its neighbor. This arrangement is known as tiling because it resembles tiles covering the floor. Tiling was first discovered in the mammalian retina, where it is presumably important to ensure complete and non-redundant coverage of receptive fields. We have continued to study the mechanisms of tiling (Emoto et al., 2004; Emoto et al., 2006; Han et al., 2012).

If we label all the dendrites of da neurons, the pattern looks like a complex entangled mess as one would see in any areas of our brain. One important lesson we learned from our study is that this complex pattern of entangled dendrites is actually the superposition of four far simpler patterns, each made by dendrites of neurons of a particular class. Each sub-pattern is quite regular. By figuring out how various mechanisms such as self--avoidance, tiling, and size control help to set up each neuronal type-specific sub-pattern, we can understand how the complex pattern is generated.

By using da neurons, we have gained some insights over the past 10 years about dendrite development including how axons and dendrites are made differently; how a neuron acquires its neuronal type-specific morphology; how the dendrites of different neurons are organized; how the size of a dendritic arbor is controlled; how the pruning, remodeling, and regeneration of dendrites are regulated during development; and how neuronal morphology affects neuronal function (Jan and Jan, 2010). There is much still to be learned, and this subject remains the focus of our ongoing research. More recently, we have also begun to use da neurons to study the molecular mechanisms underlying mechano-sensation, the least understood among the senses (Yan et al., 2013).

Characterizing Members of a Novel Channel Family and Ongoing Studies

Although we pursued a range of projects to study potassium channels one at a time to learn about their physiological functions and their regulation by neuronal activity, we were aware that even in this post-genome sequencing era there are still orphan channels with unresolved molecular identity. One case in point is the calcium-activated chloride channel (CaCC) found in eukaryotes ranging from green algae to man. Molecular identification of CaCC was difficult partly because of its broad distribution. To prevent polyspermia, Xenopus oocytes have robust expression of endogenous CaCC, which provided the electrophysiological readout for the original expression cloning of Gq protein-coupled receptors by Nakanishi and Julius. But this made it impossible to use Xenopus oocytes as the expression system for expression cloning of CaCC. With the generous help and advice of David Julius (early on for cloning IRK1 and years later for cloning CaCC), we searched for an alternative way to attempt expression cloning. Björn Schroeder devoted six years of his postdoctoral research to tackling this problem and resorted to using oocytes of the physiologically polyspermic Axolotl as the expression system for expression cloning of Xenopus CaCC. This led to the finding that TMEM16A and TMEM16B of a family of “transmembrane protein with unknown function” encode CaCC (Schroeder et al., 2008). Using completely different approaches, Oh’s laboratory in Korea and Galiatta’s laboratory in Italy came to the same conclusion that TMEM16A forms CaCC (Caputo et al., 2008; Yang et al., 2008). Before the appearance of these three papers for molecular identification of TMEM16A as CaCC, Jason Rock—who was a graduate student with Brian Harfe—reported their study of TMEM16A knockout mice. This also took place in the summer of 2008 (Rock et al., 2008), thus hastening the in vivo validation of TMEM16A as CaCC.

The TMEM16 family, with 10 members in mammals, turns out to be rather unusual; whereas some family members are anion channels, Huaghe Yang came to the surprise finding that TMEM16F forms a cation channel. As his fellow postdoc Andrew Kim worked on generating the TMEM16F knockout mice, we were surprised to learn that TMEM16F is linked to the Scott syndrome, a bleeding disorder named after a patient; the loss of function mutation of the TMEM16F gene is associated with Ms. Scott’s deficiency in blood coagulation (Suzuki et al., 2010). In collaboration with our UCSF colleague Shaun Coughlin, Huanghe and Andrew found that TMEM16F gives rise to a small-conductance calcium-activated nonselective cation channel in vitro and in vivo, with a crucial role for calcium-activated lipid scrambling in blood cells (Yang et al., 2012). There are likely more unexpected features that will emerge as we revisit the whole range of questions for ion channels—about how ion channels in this new family work and how they modulate neuronal activity to fulfill their physiological roles.

Our Family and Life Outside of the Lab

Compared to our experience with high school and college entrance exams back in Taiwan, our kids had a head start with scrutiny of kindergarten applications that involved observations of the kids and interviews with their parents, which seemed far more nerve-racking for us than our job search. As they went through the same schools, Max played on multiple sports teams while Emily was very much into theater production—so much so that she majored in theater at Brown University before getting another bachelor’s degree (for arts) at California College of the Arts (CCA). She is working on getting her Master’s of Arts from Concordia University in Montreal in 2014. When Max was about to graduate from Princeton University with a major in molecular biology, he became seriously interested in the physician–-scientist career path. Because he had none of the pre-med preparations, he first got his PhD in cancer biology at Stanford and now is on track to get his MD at UCSF in 2015. It has been just wonderful watching both kids grow into thoughtful young adults—“passionate about curiosity, creativity, independence, and the desire to know, understand, and ultimately play some small part in shaping the human condition”—as Emily put it, about the way they grew up, in her Artist Interview for the 2011 World of Threads Festival.

Before our kids left home for college, we rarely went to meetings together (so there was always one of us at home with our kids). Now that our kids are grown-ups and we have an empty nest, we have started traveling together for fun. We have had some wonderful trips in recent years—hiking in the Alps and on the Milford trail in New Zealand, observing animals in the Serengeti, and going to the Galapagos with our kids after they finished their college education. In 2010, we had a wonderful road trip in southern France with our old collaborators Alain and Christine 36 years after we first met Alain in Seymour’s lab. The trip ended with a sublime dinner at Michel Bras, a Michelin three-star restaurant in the middle of nowhere (see Figure 5). In 2011, we took the opportunity presented by a visiting professorship at the Chinese Academy of Sciences and did something we had always wanted to do—see Mt. Everest from the base camp in Tibet.

Fig. 5.    Reunion of old collaborators at Michel Bras in Laguiole, France, on May 19, 2010. Picture from left to right are as follows: Lily Jan, Christine Dambly-Chaudiere, Alain Ghysen and Yuh-Nung Jan.

Some Reflections

We have been extremely lucky in our professional lives. One contributing factor is that, ever since our high school days, we have always been at a top place with a first-rate peer group: NTU, Caltech, HMS, UCSF, and HHMI. Peer pressure is one of the most powerful driving forces. Our peers inspire us. One gets the sense that this is the big league. If you can hold your own there, then you feel that perhaps you can play in the big league, and you have a sense of belonging.

We have been extremely lucky to have had fantastic students and postdocs coming through our lab at UCSF over the past 30 years. To date, more than 135 students and postdocs have come through our lab. Nearly 100 have become professors or group leaders. Some chose nonacademic careers. Many have distinguished themselves. We are very proud of their accomplishments. We learned the philosophy of mentoring from our mentors. When students or postdocs join the lab, the emphasis should be the nurturing and the enhancement of their careers, not ours. If they do well, we will benefit as well because that will attract good people to our lab.

We are also incredibly lucky to have been supported by HHMI for nearly 30 years. HHMI funds people not projects. HHMI investigators do not need to justify what they plan to do. They are free to change research directions as they see fit (as we frequently do). On the other hand, we are all held accountable. There is a rigorous review every five years or so.

Another useful lesson we learned early on from our mentors is the importance of choosing the problem to study. There is a saying (probably by multiple people): “It takes just as much effort to study something relatively trivial; you might as well choose some potentially important problems to work on.”

Finally, there is a passage from Steve Kuffler’s last paper (Kuffler, 1980) that we like very much: “After all, it is ongoing work which makes one go to the laboratory with a feeling of suspense and cautious expectation. Although success is rare, we continue in the spirit expressed by Robert Louis Stevens, that to travel hopefully is better than to arrive.”

References

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Bruce Sherman McEwen

BORN:

Ft. Collins, CO

January 17, 1938

EDUCATION:

University High School, Ann Arbor, MI (1955)

Oberlin College, AB Summa Cum Laude in Chemistry (1959)

Rockefeller University, PhD (1964)

APPOINTMENTS:

United States Public Health Service Postdoctoral Fellow, Institute of Neurobiology, Goteborg, Sweden (1964–1965)

Assistant Professor, Dept. of Zoology, University of Minnesota (Jan.–June, 1966)

Assistant Professor, Rockefeller University (1966–1971); Associate Professor (1971–1973); Associate Professor with tenure (1973–1981); Professor (1981–present)

Alfred E. Mirsky Professor, Head, Harold and Margaret Milliken Hatch Laboratory of Neuroendocrinology (1999–present)

Associate Dean for Graduate and Postgraduate Studies, Rockefeller University, (1985–1991); Dean (1991–1993)

Faculty Chair, Science Outreach Program, Women and Science and Parents and Science Programs, Rockefeller University

HONORS AND AWARDS (SELECTED):

Fellow of American Academy of Arts and Sciences (1994)

MERIT Award, National Institute of Mental Health, 1994 and Jacob Javits Award, National Institute of Neurological and Communicative Disorders and Stroke (1995)

Member, National Academy of Sciences (1997)

Fellow of the New York Academy of Sciences (1998)

Member, Institute of Medicine (1998)

Honorary Sc.D. degree: Oberlin College (2000)

President’s Award, American Psychosomatic Society (2001)

Dale Medal, British Endocrine Society (2001)

Award for Distinguished Scientific Contributions, American Psychological Association (2003)

Honorary Sc.D. degree, University of Michigan (2005)

Karl Spencer Lashley Award, American Philosophical Society (2005)

Pat Goldman Rakic Award, National Association for Research on Schizophrenia and Affective Disorders (2005)

Pasarow Foundation Neuropsychiatry Award (2006)

Segerfalk Award, University of Lund, Sweden (2007)

Gold Medal, Society of Biological Psychiatry (2009)

Ipsen Fondation, Neuroplasticity Prize, shared with Tom Insel and Donald Pfaff (2010)

Edward M. Scolnick Prize in Neuroscience, McGovern Institute for Brain Research, MIT (2011)

Bruce McEwen led the way toward a modern understanding of the interactions among hormones, the brain, and behavior. From his discovery of stress hormone receptors in the brain more than 30 years ago to his more recent studies on the structural and functional brain changes induced by hormones and stress, his work has broadened the scope and altered the definition of neuroendocrinology. His multilevel approach to questions, ranging from the molecule to human behavior, has enhanced the impact of his work and stimulated research in fields as disparate as molecular biology and public policy. He has inspired numerous young scientists to be creative and independent thinkers.

Bruce Sherman McEwen

The Path That Led Me to Neuroscience

When I think of where I am now, I often think of the people who guided me and the serendipitous events that determined my career path. I was born in 1938 in Ft. Collins, Colo., where my dad was an English instructor at what is now Colorado State University. Both my parents grew up in the Chicago area and were among the first of their respective families to go to college—in fact, they met at Park College in Missouri. My dad’s career path as a journalist in San Francisco was diverted by the Great Depression, and he then went on for a PhD in English literature at the University of Michigan and a professorial career there in Ann Arbor, where I grew up. My mother, Esther, studied French and had a passion for art history but, as was the case for many women of that time, her self-defined job was raising my brother, Craig, and me for which we are both grateful! My dad, George, a self-described “frustrated physicist,” introduced Craig and me to crystal radios and other aspects of the world of popular science. He planted the seeds that led me to neuroscience and Craig to sociology and both of us to Oberlin. I sometimes call myself a “molecular sociologist” but I shall return to that later.

After public elementary school in Ann Arbor, I was fortunate to go to junior and senior high school at University High School in Ann Arbor—at that time a practice teaching school for the University of Michigan. Class sizes were small and teachers were excellent; my science teacher, Lawrence Conray, led me, and quite a few classmates, to an interest in the physical sciences. In fact, four of us from the same class went on to Oberlin College and majored in chemistry! In my freshman year at Oberlin, I took a typical class load for possible pre-meds—calculus, general chemistry, German, and English composition. As a sophomore, I needed a break from that so I took a psychology course with Celeste McCollough, a young visual system psychophysiologist (“The McCollough Effect”), who planted the seeds that led me ultimately to behavioral neuroscience. McCollough inspired others, such as Bob Wurtz and Larry Squire, also Oberlin graduates, to careers in what has become the field of neuroscience. I also was inspired at that time by another young professor, Norman Craig, to pursue a major in chemistry. I have seen Norm on campus during recent visits to Oberlin and know he is still going strong!

Summer jobs played a major role in shaping my career path. After several summers as a clerk in a local drug store, including duties as a soda jerk and as a delivery boy (using the owner’s car), I got a job as a hospital orderly at the University Hospital, spending one summer in the recovery room and the next summer divided between surgery and the children’s ward. Because I was on a path toward medical school, the final summer between my junior and senior years at Oberlin was spent as a research student in the University of Michigan’s physiology department and the laboratory of Irving Fritz, a researcher on lipid metabolism. This led to my coauthoring my first paper, which appeared in Science in 1959 (Fritz and McEwen, 1959), on the role of carnitine in facilitating fatty acid oxidation by mitochondria. Irv Fritz, who went on to chair the Banting and Best Department of Medical Research at the University of Toronto, persuaded me to apply to graduate school—not medical school—and suggested the Rockefeller University in New York. I was fortunate to gain admission to “The Rock” and I sometimes think that one of the reasons that, then president Detlev Bronk admitted me was that he had a good friend named McEwen who was president of Hamilton College in upstate New York. (Detlev Bronk was a descendent of the old Dutch family that once had a farm in that part of New York City now known as The Bronx.)

At Rockefeller, my mind was opened to the multiple possibilities within science and to the philosophy that there were no barriers to what one might accomplish. Because of my experience with Irving Fritz, I was fascinated by oxidative metabolism and oxidative phosphorylation by mitochondria, and I joined the laboratory of Alfred Mirsky and Vincent Allfrey, to study the question of how the cell nucleus obtains the adenosine triphosphate (ATP) to make ribonucleic acid (RNA). What I found in my PhD thesis research is that there is another terminal oxidase, most probably in the nuclear envelope, that is less sensitive to carbon monoxide than the cytochome c of the mitochondria (McEwen et al., 1963a,1963b, 1963c, 1964). While working in the Allfrey-Mirsky laboratory, I was imbued with Mirsky’s fascination with environmental control of gene expression and the Waddington concept of epigenetics (Waddington 1942), together with Allfrey’s pioneering work with Mirsky and then by Allfrey by himself on the modification of histones as the start of the current blossoming of what is now called epigenetics (Allfrey, 1977; Moberg, 2012). These have had a powerful effect on my own science, and, indeed, when I returned to Rockefeller in 1966, it was the Mirsky and Allfrey influence that led me to study steroid hormone receptors in the brain.

When I was finishing my PhD thesis, Mirsky suggested that two key areas of the future would be developmental biology and what is now called neuroscience. Perhaps because of the latent influence of Celeste McCollough, I chose neuroscience. I went to Goteborg, Sweden, to work with Holger Hyden, where I began my career in neurobiology focusing on, among other topics, isolation of highly purified brain cell nuclei and also localization in the brain of the S100 protein, a member of the calmodulin family that was thought to be “brain specific.” While in Goteborg, I learned some Swedish to complement the German I had learned at Oberlin; I fell in love with Scandinavia, and especially Sweden, where I have returned many times. By coincidence, because my high school and college friend Alan Hooper was at the University of Minnesota, I found a job there as a junior faculty member of the University of Minnesota’s department of zoology, where I began to study the cockroach nervous system, in vogue at that time because of the work of Graham Hoyle and others. I also was exposed to the Swedish/Norwegian culture of Minnesota and became a fan of Garrison Keillor and the “Prairie Home Companion.”

My stay in Minnesota was to be short-lived, and serendipity intervened. Alfred Mirsky came to Minnesota in March 1966 to give a review but was snowed in for a day. I spent an afternoon with him, and he discovered that I was not particularly happy there. Upon his return to New York, Mirsky arranged for me to come east to interview for a junior faculty position with Neal Miller, who was moving from Yale and needed a “biochemist” to replace David Booth (who had returned to England) for his new laboratory at Rockefeller. I got the job and moved back to Rockefeller in the summer of 1966 and so began my evolution as a “molecular sociologist.”

The Rockefeller environment that I entered in 1966 was much different from the one I left in early 1964 because of the addition not only of Neal Miller but also Carl Pfaffmann (both physiological psychologists), George Miller and William Estes (cognitive psychologists), and Peter Marler and Donald Griffin (animal behaviorists). This constituted the behavioral sciences program that, for a number of years, had a field program in Africa and connections with the New York Zoological Society. Many current leaders in behavioral neuroscience received training in this program. For me, a number of younger colleagues, notably Donald Pfaff and Fernando Nottebohm, created an exciting environment where synthesis and crosstalk began between animal behavior and psychology. A common denominator was the action of hormones, primarily sex hormones (for Pfaff and Nottebohm). Because of Neal Miller’s interest in and development of “behavioral medicine,” the topic of stress and stress hormones was one that I addressed. Our discovery in 1968 of adrenal steroid receptors in the hippocampus opened the path to the eventual realization in the latter part of the 20th century and beginning of the new millennium that circulating hormones of the gonads, adrenal cortex, thyroid gland, and also of the metabolic system affect many—if not most—areas of the brain, including those involved in higher cognitive function (McEwen, 2007). This provides a link, at least in retrospect, to what was in 1966 called cognitive psychology and which now includes not only cognitive neuroscience but also the burgeoning field of social neuroscience. I say this because the circulating hormones are controlled in part by the social environment—and, besides the hypothalamus—they affect the areas of the brain involved in cognitive, social, and emotional processes!

My work on adrenal steroid hormone effects on the hippocampus and other limbic system brain areas attracted the attention of Eliot Stellar and his colleagues at Penn and I was drawn into a fascinating collaboration with Stellar, Alan Epstein, and their younger colleagues, Randall Sakai and Jay Schulkin, Steve Fluharty, Ralph Norgren, and Harvey Grill to study salt appetite and (in my case) the role of mineralocorticoids and glucocorticoids. Stellar (whose Morgan and Stellar Textbook of Physiological Psychology I had used for a course at Oberlin with McCollough) was also a member of a MacArthur Foundation Network on Health and Behavior, together with Judy Rodin at Yale and others from many universities, and he drew me into that network, where I broadened my perspective to include many aspects of translational behavioral science and behavioral medicine. The Health and Behavior Network also was the basis of the subsequent MacArthur Foundation Research Network on Socioeconomic Status (SES) and Health, where many concepts of social neuroscience and behavioral medicine, including allostatic load, helped elucidate how SES “gets under the skin” and affects the health of human populations. It was out of these networks that the notion of “allostatic load” was born and out of which began my involvement in stress effects upon the immune system and in the translational aspect of how stress affects the brain. (Both will be discussed later.) These experiences led to my coauthoring two books for a general audience: The Hostage Brain (1994) with Harold M. Schmeck Jr., who founded the New York Times science section, and The End of Stress As We Know It (2002), with science writer Elizabeth Norton Lasley, that is now available as an e-book and that still fills an important niche in science writing for the public.

My involvement in those networks also led to my current membership in the National Scientific Council on the Developing Child. This last membership has increased my connection to my brother Craig, a professor of sociology and fellow of the Center for the Common Good at Bowdoin College, who studies (among other projects) the social and physical environment in midcoast Maine and relates it to measures of social harmony or discord. Craig and his wife, Maggie, are involved in community organizations that promote better housing and health, including the local United Way, which is lobbying for programs that will improve child development via strengthening the family and home environment. This program is now connected to the National Scientific Council on the Developing Child and to the Peel Region near Toronto, Ontario, another locale with an interest in improving the lot of children.

I should note that, at the beginning of my Rockefeller faculty career and while the hormone-brain story was just beginning, I was involved in several other research areas that relate, at least in part, to the plasticity of the brain. In 1968, Bernice Grafstein and I published the first characterization of the rapid axonal transport of newly synthesized proteins in particulate material in the goldfish optic nerve and followed this with papers characterizing components of that transported material (McEwen and Grafstein, 1968). Second, in the 1970s, David Quartermain and I, together with several colleagues including former student, Efrain Azmitia, published a number of papers demonstrating the reversibility—by a “reminder” procedure—of retrograde amnesia induced by protein synthesis inhibitors and electroconvulsive shock (Quartermain and McEwen, 1970; Quartermain et al., 1970; Randt et al., 1971; Azmitia et al., 1972); these findings cast doubt on the permanence of retrograde amnesia and on the “consolidation” model of passive avoidance (fear) learning but did not go any further at the time. This topic has been reactivated recently in the work on “reconsolidation” of fear conditioning that has taken it well beyond what was envisioned at the time.

Following these reminiscences about where I came from and how I got here, let me launch into some of the scientific substance and further highlight some of the many people who have been part of this along the way.

Hormones and the Brain

Circulating hormones have turned out to be a very effective way to probe brain structure and function, and they have helped to demonstrate the plasticity of the adult, as well as developing, brain not only in relation to the important events in the hypothalamus that regulate reproductive functions and homeostatic regulation but also in relation to higher cognitive processes, as well as emotional regulation and decision making. Here, I will review highlights of this story; I will do this by giving a very brief overview of the history of neuroendocrinology dating back to the work of Geoffrey Harris and to subsequent pioneers in the connections between the brain and the endocrine system via the hypothalamus and the portal blood vessels that carry releasing factors from the hypothalamus to the pituitary gland (Harris, 1948; Meites, 1992).

After the portal blood supply was shown to carry blood from the hypothalamus to the anterior pituitary (Harris, 1948), heroic efforts using hypothalami from slaughterhouse animals led to the isolation and structural identification of peptide releasing factors (Schally et al., 1973; Guillemin, 1978). The feedback regulation of hypothalamic and pituitary hormones implied the existence of receptor mechanisms for gonadal, adrenal, and thyroid hormones. Then the identification of cell nuclear hormone receptors in peripheral tissues (Jensen et al., 1981) using tritiated steroid and iodinated thyroid hormones led to the demonstration by my colleague, Don Pfaff, as well as Walter Stumpf, of similar receptor mechanisms in hypothalamus and pituitary gland (Pfaff and Keiner, 1973; Stumpf and Sar, 1976). For this, it was necessary to use autoradiographic methods because of the discrete nature of these receptor-containing cells; although Richard Zigmond, in his PhD thesis work, used more conventional cell fractionation methods, along with sucrose density gradient centrifugation to demonstrate receptors with molecular sizes such as those in the peripheral tissues (McEwen and Plapinger, 1970; Zigmond and McEwen, 1970; Gerlach and McEwen, 1972; Pfaff and Keiner, 1973).

What about behavior? Before the demonstration of nuclear estrogen and androgen receptors in hypothalamus, some suggested that sex hormones acted indirectly to activate sex behavior (Young, 1961). Yet, the demonstration of binding sites and receptors for estrogens in hypothalamus led to studies using discrete hormone implants as well as to sophisticated neuroanatomical and neurophysiologic methods that demonstrated that sex hormones facilitate sex behavior via receptors in the hypothalamus (Davis et al., 1979; Pfaff, 1980). Yet, in retrospect and even at that time, there were other behaviors and neurological states that were known to be influenced by estrogens involving brain regions besides the hypothalamus, including fine motor control, pain mechanisms, seizure activity, mood, cognitive function and neuroprotection (Bedard et al., 1977; Van Hartesveldt and Joyce, 1986; McEwen et al., 1998; McEwen and Alves, 1999).

But tritiated steroid hormone cell nuclear uptake and retention, as shown by autoradiography, was not all confined to the hypothalamus; although, in the case of sex hormones, the major concentration of such receptors is in the hypothalamic region and amygdala (Pfaff and Keiner, 1973). The big surprise was the discovery of cell nuclear receptor sites for glucocorticoids in the hippocampus not only of rodents but also monkeys, with extension to other species (McEwen et al., 1968; Gerlach and McEwen, 1972; Gerlach et al., 1976). This unexpected finding is a major part of the story, to be elaborated here because it directed us to brain functions above the hypothalamus and, in particular, to the function of the hippocampus— brain region important for memory and other aspects of behavioral regulation (Eichenbaum and Otto, 1992). As it turned out, a further serendipitous finding of estrogen receptors in the hippocampus (Loy et al., 1988) also represented a turning point in our realization that not all steroid hormone actions occur via cell nuclear receptors but rather operate via receptors in other parts of the cell via a variety of signaling pathways (Kelly and Levin, 2001; McEwen and Milner, 2007). This is now recognized to be the case for all classes of steroid hormones, including vitamin D (Huhtakangas et al., 2004), aldosterone (Wehling et al., 1992), androgens (Tabori et al., 2005), as well as estrogens, progestins, and glucocorticoids (to be discussed later in this chapter). Because of the novelty and importance of this realization for many aspects of hormone action on the central nervous system, this is where I shall continue the story, focusing on estrogens and progestins, before returning to the story of glucocorticoids and stress. But first, I shall briefly introduce the evolving concepts of plasticity in the adult brain.

Plasticity of the Adult Brain

Long regarded as a rather static and unchanging organ, except for electro-physiological responsivity—such as long-term potentiation (Bliss and Lomo, 1973)—the brain has gradually been recognized as capable of undergoing rewiring after brain damage (Parnavelas et al., 1974) and as able to grow and change as seen by dendritic branching, angiogenesis, and glial cell proliferation during cumulated experience (Bennett et al., 1964; Greenough and Volkmar, 1973). More specific physiological changes in synaptic connectivity were also recognized in relation to hormone action in the spinal cord (Arnold and Breedlove, 1985) and in environmentally directed plasticity of the adult songbird brain (DeVoogd and Nottebohm, 1981). Seasonally varying neurogenesis in restricted areas of the adult songbird brain is recognized as part of this plasticity (Nottebohm, 2002). Indeed, adult neurogenesis in the adult mammalian brain was initially described (Altman and Das, 1965; Kaplan and Bell, 1983) and then suppressed (Kaplan, 2001), only to be rediscovered in the dentate gyrus of the hippocampus (Gould and McEwen, 1993; Cameron and Gould, 1994) in the context of studies of neuron cell death and in the actions of adrenal steroids and excitatory amino acids in relation to stress. Neurogenesis in the dentate gyrus has gone on to become a huge topic related to effects of stress (Gould et al., 1997), exercise (van Praag et al., 1999), enriched environment (Kempermann et al., 1997), antidepressants (Duman et al., 1997), and learning and memory (Gould et al., 1999).

Studies of stress and sex hormones, which will be elaborated here, have revealed extensive structural remodeling of dendrites and synaptic connections. In my laboratory, these studies were brought about by Elizabeth Gould, who introduced the Golgi technique, along with Heather Cameron, Catherine Woolley, Yoshifume Watanabe, and Ana Maria Magarinos.

Rather than being isolated examples of plasticity in certain brain regions, there are clear indications that many aspects of brain function are subject to structural plasticity involving dendritic branching and debranching, including respiratory and motor control regions, midbrain central gray during exercise training (Nelson et al., 2005; Nelson and Iwamoto, 2006), the nucleus accumbens after repeated sodium depletion causing increased salt appetite and enhanced amphetamine self-administration (Roitman et al., 2002), the nucleus accumbens, hippocampus, and orbitofrontal cortex after morphine, amphetamine, or cocaine administration (Robinson et al., 2001; Robinson et al., 2002; Crombag et al., 2005), and the hippocampus during hibernation (Popov and Bocharova, 1992; Magarinos et al., 2006).

More recently, the notion of developmental critical periods as immutable windows of plasticity have come under some revision with the finding that the effects of monocular deprivation on the visual system can be reversed with the aid of such interventions as fluoxetine treatment during visual stimulation. Such agents may act by increasing levels or activity of a facilitator of plasticity, such as brain derived neurotrophic factor (BDNF) and related growth factors, such as insulin-like growth factor 1 (IGF-1) (Aberg et al., 2000) and fibroblast growth factor 2 (FGF2) (Turner et al., 2011); moreover, other factors such as perineuronal nets and excitatory/inhibitory balance are also involved (Vetencourt et al., 2008; Bavelier et al., 2010). Furthermore, glucocorticoids may play an important role in such plasticity by activating Trk B receptors and by mediating spine synapse turnover (Jeanneteau et al., 2008; Liston and Gan, 2011; Spolidoro et al., 2011). The generalization of this approach is suggested by the efficacy of fluoxetine to enhance neurological signs of recovery from stroke for those doing intensive physical therapy (Chollet et al., 2011).

Sex Hormones, Synapses, Seizures, and Cognitive Function

In the original steroid autoradiography, a few scattered cells in the hippocampus demonstrated strong cell nuclear labeling by ³H estradiol, and these have been identified as inhibitory interneurons (Loy et al., 1988; Nakamura and McEwen, 2005; Ledoux et al., 2009). In spite of the paucity of such labeled cells, there was evidence from seizure studies that the threshold for eliciting seizure activity in the hippocampus was lowest on the day of proestrus when estrogen levels are elevated (Terasawa and Timiras, 1968). Moreover, there were indications that elevated estrogens enhanced memory retention of the type involving the hippocampus (Sherwin, 1988). Using the classical Golgi method, we found that the density of spine synapses, on the principal neurons of the carbonic anhydrase 1 (CA1) region of the hippocampus, show a cyclic variation in the estrous cycle, with peak density occurring on the day of proestrus (Woolley et al., 1990), thus providing a possible structural basis for the lower seizure induction threshold. This work in our lab was led by Catherine Woolley and Nancy Weiland (Weiland, 1992; Woolley et al., 1997), and Woolley has continued this line to new heights of sophistication at Northwestern (Smejkalova and Woolley, 2010; Huang and Woolley, 2012). Because excitatory amino acids are the major neurotransmitter in these neurons and because N-methyl-D-aspartate (NMDA) receptor activity is involved not only in hippocampal memory functions but also in seizure induction, we used a competitive NMDA receptor blocker and discovered that it prevented estradiol-induced spine synapse formation. Thus, estradiol does not work alone in causing this synapse formation; the study of underlying mechanisms is revealing some remarkable new aspects not only of hormone action but also of neuronal plasticity (McEwen et al., 2012).

With Teresa Milner of Weill/Cornell Medical College and Steve Alves in my lab, the paucity of nuclear estrogen receptors in the hippocampus led to our serendipitous finding (using electron microscopic immunocytochemistry that has the resolution to see more than the cell nuclear sites) that epitopes for the classical estrogen receptors can be localized in dendrites, synapses, mitochondria, and glial cell processes (McEwen and Milner, 2007). Concurrently, increasing recognition was being given to the so-called non-genomic actions of estrogens and their signaling pathways (Kelly and Levin, 2001). These non-nuclear sites were shown to bind 125 estradiol using steroid autoradiography at the ultrastructural level, supporting the conclusion that they are estrogen receptors (Milner et al., 2008).

As a side note, there are also androgen receptors with epitopes of the nuclear receptor that are found in the hippocampus in membrane associated locations in dendrites, spines, and glia cell processes (Tabori et al., 2005). Testosterone-induced spine synapses in the male rat hippocampus, even though estradiol does not do so, unless genetic male rats are castrated at birth or treated with aromatase blockers to prevent developmental actions of testosterone (Lewis et al., 1995; Leranth et al., 2003; MacLusky et al., 2006). However, in contrast to the estrogen receptor story, CA1 pyramidal neurons have ample expression of cell nuclear androgen receptors (Kerr et al., 1995; Tabori et al., 2005), although the functional role of these receptors is presently unclear, and like estrogens, androgens have neuroprotective effects (Pike et al., 2008).

Growing out of the recognition of the existence of non-nuclear estrogen receptors and their signaling pathways, the mechanisms implicated in estrogen-induced synapse formation and maturation have turned out to involve interactions among multiple cell types in the hippocampus, as well as multiple signaling pathways. The requirement for NMDA receptor activation is underscored by Catherine Woolley’s finding that one effect of estradiol is to upregulate NMDA receptors (Woolley et al., 1997), and yet it does so via an indirect mechanism involving estrogen modulation of cholinergic activity (Daniel and Dohanich, 2001). Cholinergic modulation of inhibitory interneurons and disinhibition of their input to pyramidal neurons is likely to be involved (Murphy et al., 1998; Rudick et al., 2003).

Although it is unclear how the NMDA receptor activation participates, it may be via the altered ionic environment, in the ability of estradiol to stimulate signaling pathways within dendrites and nascent spines that lead to filapodial extension via actin polymerization (Yuen et al., 2010) and then to local protein synthesis activated by estradiol at the translational level and leading to de novo formation of postsynaptic density 95 (PSD-95), a key anchoring protein of the dendritic spine (Akama and McEwen, 2003; Znamensky et al., 2003). Signaling pathways implicated in these events include LIM kinase and cofilin phosphorylation (Yuen et al., 2010) and PI3 kinase activation (Akama and McEwen, 2003; Znamensky et al., 2003), as well as the Rac/Rho signaling system (Kramar et al., 2009).

Finally, what terminates the estradiol-induced synapse formation? Progesterone treatment after estrogen-induced synapse formation caused rapid (12h) down regulation of spine synapses; moreover, the progesterone receptor antagonist, Ru486, blocked the naturally occurring downregulation of estradiol-induced spines in the estrous cycle (Woolley and McEwen, 1993). But where are the progestin receptors that do this? Because Ru486 is effective, it is very likely that the classical progestin receptor is the mediator as opposed to other G-protein coupled progestin receptors that are not affected by Ru486. Curiously, the classical progestin receptor is not detectable in cell nuclei within the rat hippocampus, but it is expressed in non-nuclear sites in hippocampal neurons, and virtually all of the detectable progestin receptor is estrogen inducible (Parsons et al., 1982; Waters et al., 2008). The mechanism of progesterone action on synapse down regulation presently is unknown.

It is clear that estrogen does other things, such as protecting neurons from excitotoxic damage due to seizures and stroke, as well as Alzheimer’s disease (Henderson and Paganini-Hill, 1994; McCullough et al., 2003). The exact role in this process of cell nuclear estrogen receptors found on inhibitory interneurons is unclear, but one clue is the ability of estrogens to enhance neuropeptide Y (NPY) expression and release because NPY has anti-excitatory actions (Nakamura et al., 2004; Ledoux et al., 2009). Another facet of estrogen neuroprotection is its ability to regulate mitochondrial calcium sequestration, including Bcl-2 translocation (Nilsen and Brinton, 2004).

Investigation of the ability of estrogens to protect against stroke damage, as well as Alzheimer’s and Parkinson’s disease, has uncovered the fact that the brain is capable of locally generating estrogens from androgens and possibly also directly from cholesterol (Hojo et al., 2003); aromatization of androgen precursors is the final step, and knockout of the aromatase enzyme increases ischemic damage even beyond that found after ovariectomy of wild-type mice (McCullough et al., 2003). The brain also appears to have the capacity to locally generate the androgen, dihydrotestosterone, from as yet unknown precursors, independently of the gonads in an animal model in which mild exercise increases neurogenesis in a manner facilitated by those androgens (Okamoto et al., 2012).

Besides the hippocampus, other brain regions demonstrate estrogen-regulated spine synapse formation and turnover, including the prefrontal cortex (Hao et al., 2007) and primary sensory-motor cortex (Chen et al., 2009). Indeed, there is likely to be estrogen-regulated spine synapse turnover in other brain regions. Besides estrogen-induced spine formation, estrogens are implicated in functions in the nigrostriatal system (Xiao and Becker, 1997), brainstem (Milner et al., 2008), and cerebellum (Smith, 1989), suggesting that their effects are widespread in the central nervous system. Moreover, estrogen receptors have been demonstrated in many of these brain regions (Milner et al., 2003).

The nigrostriatal system is particularly interesting because of its role in Parkinson’s disease. The Parkinson’s connection arose with the observation that high-dose estrogen treatment used in the initial contraceptive preparations exacerbated symptoms of Parkinson’s disease in women (Bedard et al., 1977). This was very unexpected for those who believed in the nuclear estrogen receptor story because there are no cell nuclear estrogen receptors in the rodent striatum, and yet tiny unilateral implants of estradiol in the rodent striatum elicited unilateral rotation associated with imbalanced dopaminergic function (Van Hartesveldt and Joyce, 1986). Furthermore, estradiol regulates dopamine release from striatum in a sexually dimorphic manner (Castner et al., 1993). Now, with lower doses of estradiol, there is evidence for neuroprotection in Parkinson’s disease (Leranth et al., 2000; Nakamura et al., 2004).

Finally, aging is known to lead to loss of cognitive acuity, and loss of estrogens after natural or surgical menopause is reported to impair certain aspects of memory, as well as other neurological functions (Halbreich et al., 1995; Sherwin, 2003; Sherwin and Henry, 2008). What happens to estrogen-induced synapse formation? In the female rat, where it is possible to look at animals near the end of their lifespan, there is a loss of the ability of estradiol to induce spine synapses in the hippocampus, along with a loss of the memory-enhancing effects of estradiol (Dumitriu et al., 2010a; Dumitriu et al., 2010b). Recent evidence suggests that this is due, at least in part, to the consequences of long-term estrogen deprivation. Mechanistically, the loss of estrogen effects on spine synapse formation may be explained by an age-related loss of estrogen receptors in dendrites and spines, as well as a loss of the ability of estradiol to stimulate LIM kinase phosphorylation that may be related to actin polymerization and filapodial outgrowth, as described earlier. Further insights into the effects of age come from the rhesus monkey, where estrogen-induced spine synapse formation is detected in the hippocampus and prefrontal cortex (Dumitriu et al., 2010a; Dumitriu et al., 2010b). In these studies by Morrison and colleagues, post-menopausal rhesus monkeys responded to estradiol as far as spine synapse formation, but there is also an age-related and estrogen-independent loss of synapses that can be compensated as far as cognitive function by estrogen treatment. Of great interest is that estrogen shifts the distribution of spine head diameter toward smaller size in both the young and the aged animals. However, aging dramatically reduced the representation of spines with small heads and long necks (Dumitriu et al., 2010a; Dumitriu et al., 2010b). This age-related selective loss of small spines and the partial recovery with estrogen treatment fits in nicely with a developing framework in neurobiology of the essential role that small spines play in learning and memory. Kasai and Harris have recently suggested that thin spines are “learning” spines while big, mushroom-type spines represent “memory” traces (Kasai et al., 2003; Bourne and Harris, 2008). Could age-related loss of cognitive function be related to stress and stress hormone actions? Now we return to the hippocampus and the story of stress and glucocorticoid actions.

Stress, Adrenal Steroids, and the Hippocampus

After the initial discovery of adrenal steroid uptake and retention in the rodent and monkey hippocampus, there were six discoveries that set the agenda for future investigations. The first discovery was the recognition that two classical receptor types, Type 1 or mineralocorticoid receptors (MR) and Type 2 or glucocorticoid receptors (GR), account for the uptake and cell nuclear retention of tritiated corticosterone in the rat and tritiated cortisol in the monkey (Gerlach and McEwen, 1972; Gerlach et al., 1976; Reul and DeKloet, 1985). These receptors coexist in hippocampal neurons of Ammon’s horn and the dentate gyrus, with GR being more scarce in CA3 and MR being more uniform across Ammon’s horn and dentate gyrus (Herman et al., 1989; Sanchez et al., 2000). The MR and GR represent a two-level recognition system for circulating adrenal steroids, with the MR having higher affinity and giving rise to enhanced excitation of hippocampal neurons and the GR having lower affinity and occupancy as glucocorticoid levels rise to the diurnal peak and after stress, with the result that excitation is impaired. In other words, there are inverted U-shaped dose response curves (Diamond et al., 1992; Joels, 2006).

The second discovery was that glucocorticoids exacerbate excitotoxic damage from ischemia and seizures and do so at the higher glucocorticoid levels and through the GR (Sapolsky and Pulsinelli, 1985; Sapolsky, 1992). Along with studies of the aging brain, this led Robert Sapolsky, who did his dissertation in my laboratory, to propose the “glucocorticoid cascade hypothesis” of stress and aging, in which stressful experiences accelerate the aging process and lead, among other consequences, to impaired hippocampal-dependent cognitive function (Sapolsky et al., 1986). Recent evidence suggests that overactivity of excitatory amino acid transmission in the CA3 region of the hippocampus may play a key role (Koh et al., 2010).

The third discovery was that repeated stress causes neurons, particularly those of the CA3 region (but we will see that neurons in the prefrontal cortex and amygdala also change), to shrink their apical dendrites by a mechanism involving not only glucocorticoids but also excitatory amino acid neurotransmission because the shrinkage of dendrites was preventable by an NMDA receptor blocker, as well as a glucocorticoid synthesis blocker, and by drugs such as Dilantin and lithium that stabilize excitatory neuronal activity (Watanabe et al., 1992). In contrast to the damaging actions related to stroke and head trauma, these changes in plasticity are reversible within several weeks of the termination of stress and are reminiscent of the reversible shrinkage and expansion of dendrites in the CA3 region of the hippocampus during hibernation and recovery from torpor in European hamsters and ground squirrels (Popov et al., 1992; Conrad et al., 1999; Magarinos et al., 2006). Mechanistically, besides excitatory amino acids and glucocorticoids (Magarinos and McEwen, 1995), BDNF and tissue plasminogen activator are recognized as modulators of stress-induced remodeling of dendrites and synapses in the hippocampus (Pawlak et al., 2005; Magarinos et al., 2011), as well as in amygdala (see following).

Fourth, Elizabeth Gould and Heather Cameron “rediscovered” neurogenesis in the dentate gyrus of the hippocampus, a phenomenon first described in the 1960s but largely ignored (Cameron et al., 1993; Cameron and Gould, 1996). This has led to a growing body of work on factors that control neurogenesis and the underlying molecular mechanisms. What became evident right away is that stressors of various types can inhibit neurogenesis; indeed, chronic restraint stress over six weeks can actually decrease the number of dentate gyrus neurons and reduce dentate gyrus volume (Pham et al., 2003). Conversely, physical activity increases neurogenesis as does housing rodents in an “enriched environment.” The role of these new neurons in hippocampal function is a matter of ongoing research. Mechanistically, the inhibition of neurogenesis is related to elevated excitatory neurotransmission via NMDA receptors, as well as elevated glucocorticoids (Cameron and Gould, 1996), and endogenous opioids and inflammatory cytokines also play a role (Koo and Duman, 2008). On the positive side, the circulating hormone IGF-1 and the endogenous neurotrophic factor BDNF appear to mediate increased neurogenesis (Aberg et al., 2000; Schmidt and Duman, 2007).

A fifth discovery was the recognition that adrenal steroids have trophic and protective effects at low doses, even if they promote damage at high levels, particularly when combined with the actions of excitatory amino acids. The inverted U-shaped dose/time response curves represent this and apply also to the biphasic effects of adrenal steroids on hippocampal–dependent memory, as well as to molecular and cellular aspects. For example, low levels of adrenal steroids protect dentate gyrus neurons from programmed cell death and also promote dendritic growth and branching of dentate gyrus granule neurons (Gould et al., 1990). Similar effects on dendritic growth and branching have been reported for the prefrontal cortex (Cerqueira et al., 2005). Low levels of adrenal steroids also have protective effects against excitotoxic cell death in neurons and appear to do this by promoting translocation of glucocorticoid receptors to mitochondria along with Bcl2, a process that exists in many cell types (Du et al., 2009a; Du et al., 2009b). Moreover, the ongoing pulsatile secretion of adrenal steroids (Stavreva et al., 2009) is associated with turnover of spine synapses in the brain (Liston and Gan, 2011) that may be responsible for the ability of glucocorticoids to activate the Trk B receptor in a ligand-independent manner (Jeanneteau et al., 2008).

The sixth discovery concerns rapid glucocorticoid actions via a membrane G protein coupled receptor, as yet unidentified, that causes endocannabinoid formation from lipid precursors (Tasker et al., 2006). Among their many effects, endocannabinoids influence the presynaptic release of glutamate and gamma-aminobutyric acid (GABA), as well as acetylcholine and noradrenaline (Hill and McEwen, 2010).

Table 1    Human Hippocampus: Reported Effects on Volume Using Magnetic Resonance Imaging

Smaller volume in

•    Cushing’s disease (Starkman et al., 1999)

•    Diabetes (Gold et al., 2007; Yau et al., 2010)

•    Depression (Sheline et al., 1996; Sheline, 2003)

•    Post-traumatic stress disorder (Gurvits et al., 1996; Gilbertson et al., 2002)

•    Chronic stress (Gianaros et al., 2007) Chronic inflammation (Marsland et al., 2008)

•    Jet lag (Cho, 2001)

•    Lack of exercise (Erickson et al., 2009; Erickson et al., 2011)

•    Low self esteem (Pruessner et al., 2005)

Increased volume

•    Learning (Draganski et al., 2006)

•    Physical fitness (Erickson et al., 2009; Erickson et al., 2011)

Taken together, these findings portray a multi-faceted role for adrenal steroids in hippocampal structure and function in which these hormones operate in concert with other mediators and via direct and indirect genomic, as well as non-genomic, mechanisms involving regulation not only of mitochondrial calcium balance but also of endocannanoid production. Regarding other mediators, it is important to note that metabolic hormones such as insulin, leptin, and ghrelin, along with IGF-1, all have important effects on hippocampal structure and function (McEwen, 2007).

How do these findings in animal models apply to the human hippocampus? Structural and functional imaging has revealed a wide range of phenomena in the human hippocampus suggesting that this brain region is responding, as might be predicted, similarly to the animal model studies (see Table 1). However, the hippocampus is not the only brain region that responds to stress, as we shall now discuss.

Stress and the Amygdala

Whereas chronic restraint stress in rats and mice causes dendrites to shrink and spines to be down regulated in the hippocampus, the basolateral amygdala responds in the opposite direction with increased branching and length of dendrites and increased spine density (Vyas et al., 2002). Accompanying these structural changes, there is increased anxiety-like behavior (Vyas et al., 2003). Even the single traumatic stress of putting a rat into a plastic immobilization cone, such as is used to draw blood from the tail, causes increased anxiety with a 10d delay and an increase in spine density on neurons in basolateral amygdala (BlA) but no increase in dendritic length (Mitra et al., 2005). The increase in dendritic length with chronic stress can be mimicked by a single large dose of glucocorticoids (Mitra and Sapolsky, 2008), although the ability of a single traumatic stressor to cause increased spine density 10d later may involve a different mechanism (Rao et al., 2012). Indeed, a timed mild stressor or elevated glucocorticoids in the drinking water prevent the delayed effects of an acute traumatic stressor to induce anxiety and new spines in BlA neurons 10d later (Rao et al., 2012). These findings are consistent with studies on human post-traumatic stress disorder (PTSD) showing that elevated glucocorticoids during or immediately after a traumatic event blocks PTSD symptoms (Yehuda et al., 1998; Schelling et al., 2004; Zohar et al., 2011).

Although the mechanisms for these changes are not clearly elucidated, BDNF is also involved, and BDNF over expression leads to hypertrophy of dendrites in basolateral amygdala and failure to increase further after chronic stress (Govindarajan et al., 2006). Together with the finding that BDNF under expression impairs the ability of chronic stress to cause dendrites of CA3 hippocampal neurons to shrink after chronic stress, it would appear that BDNF may have a facilitative role in stress-induced remodeling with a floor and a ceiling effect (Magarinos et al., 2011).

At the same time as those changes in basolateral amygdala, tissue plasminogen activator (tPA), which is released from excitatory nerve terminals, also plays a role in the increased anxiety induced by an acute restraint stress (Pawlak et al., 2003) and does so by a mechanism initiated by corticotrophin-releasing hormone receptor stimulation (Matys et al., 2004). These alterations that are dependent on tPA occur in the medial amygdala, which also is involved in the stress-induced anxiety and shows chronic stress-induced reduction in dendritic spines, opposite to those changes in basolateral amygdala (Bennur et al., 2007).

Consistent with the studies on animal models, the human amygdala is hyperactive in chronic anxiety disorders and major depression (Drevets, 2000). Structural imaging has demonstrated increased volume in acute major depression (Frodl et al., 2002), but decreased volume in long-term chronic depression (Sheline et al., 1998). In anxiety disorders, successful cognitive behavior therapy has been associated with a decrease in amygdala volume, implying an increase related to the prior anxiety (Holzel et al., 2009). Clearly, these findings should encourage further work on the plasticity of the human amygdala and on the top-down efficacy of behavioral therapies for anxiety disorders.

Stress and the Prefrontal Cortex

Although the prefrontal cortex never stood out as a target of adrenal steroids, glucocorticoid receptors and some mineralocorticoid receptors are expressed there (Ahima and Harlan, 1990; Ahima et al., 1991). Moreover, the prefrontal cortex (PFC) is implicated in feedback control of hypothalamic-pituitary-adrenal (HPA) activity (Diorio et al., 1993), as well as in downstream control of autonomic nervous system function (Buchanan et al., 2010). The PFC is a very sensitive target of stress in animal models and in humans, as well as being a brain structure that shows sex differences in stress responsiveness and response to estrogens (i.e., a nexus of many aspects discussed in this review concerning sex and stress effects above the hypothalamus). We shall discuss the stress effects first and then devote a separate section to discussing sex differences.

Chronic stress of the same type that causes the changes in the hippocampus and amygdale, discussed earlier, leads to remodeling of neurons in the medial prefrontal cortex (mPFC) and orbitofrontal cortex (OFC). In mPFC (cingulate, prelimbic, and infralimbic regions), layer II/III neurons undergo apical dendritic retraction and reduction of spine density after 21 days of chronic restraint stress (CRS) (Cook and Wellman, 2004; Radley et al., 2004), whereas CRS causes increased dendritic length and complexity in neurons of the OFC (Liston et al., 2006). The behavioral effects of CRS on an attention set shifting task of cognitive flexibility are of similar magnitude to the effects of lesions of the mPFC (Birrell and Brown, 2000). Other measures of cognitive flexibility and decision making also show impairment from chronic stress (Dias-Ferreira et al., 2009). However, the morphological changes caused by CRS are reversible within two to three weeks of stress cessation, at least in young adult rats (Radley et al., 2005; Bloss et al., 2010). In middle-aged and aged (20-month) rats, the dendritic retraction caused by CRS in mPFC neurons is similar in magnitude to that in young adult rats, but it is only partially reversible in middle-aged rats and not at all reversible in old rats within the three-week recovery time frame (Bloss et al., 2010). We are hoping to see if this age-related loss of resilience can be prevented by pharmacological, dietary, and behavior means.

There are several other fascinating features of the stress-induced changes in mPFC neurons. First, they are accompanied by a reduction in spine synapse density, as well as the shape of remaining spines, suggesting that younger spines may be selectively eliminated (Radley et al., 2008). Second, in young rats, the CRS-induced dendritic changes are accompanied by a reduction of D1 dopamine receptors and loss of D1 enhancement of long-term potentiation (LTP) (Goldwater et al., 2009), both of which reappear during the recovery phase; however, the recovery of dendritic length is more proximal to the cell body than the stress-induced loss of distal dendritic material, suggesting that these neurons are somehow “different” from those before chronic stress (Goldwater et al., 2009). Third, in young male rats, the mPFC neurons that lose dendritic material do not project to amygdala, based on retrograde tracing studies, but are most likely projecting to cortical targets (Shansky et al., 2009). Fourth, circadian disruption is also able to cause dendritic shrinkage in the prefrontal cortex along with increasing cognitive rigidity (Karatsoreos et al., 2011).

The human PFC also shows adaptive plasticity that is consistent with the story described here. Medical students, including some studying for the medical board exam and exhibiting different degrees of perceived stress, showed deficits on an attention set shifting task related to their perceived stress score; moreover, a functional connectivity circuit involving the PFC that was defined by activation in the attention set shifting task, showed slower functional connectivity in those students with high levels of perceived stress (Liston et al., 2009). These effects on behavior and functional connectivity disappeared after the students had a vacation! The human PFC is also benefited by physical exercise and cognitive behavioral therapy. Daily moderate aerobic exercise in sedentary adults over a six-month to one-year period increased blood flow measured by fMRI in mPFC and the parietal cortex associated with attention and also improved performance on tasks of executive function (Kramer et al., 1999; Colcombe et al., 2004). Brain volume increases also have been reported from regular physical activity (Colcombe et al., 2006), including increased hippocampal volume, as noted earlier (Erickson et al., 2009; Erickson et al., 2011). Increases in PFC volume have also been reported in a longitudinal study as a result of beneficial cognitive behavioral therapy for chronic fatigue syndrome (de Lange et al., 2008).

Sex Differences and What This Means for the Rest of the Brain

All of the animal model studies of stress effects summarized here were carried out on male rodents. From the first section of this review, we know that sex hormones have their own powerful effects on neuronal structure and function. Thus, it is perhaps not surprising that female rodents do not show the same pattern of neural remodeling after chronic stress as do males. The first realization of this was for the hippocampus, in which the remodeling of CA3 dendrites did not occur in females after CRS, even though all the measures of stress hormones and other factors indicated that the females were experiencing the stress as much as males (Galea et al., 1997). Females and males also differ in the cognitive consequences of repeated stress, with males showing impairment of hippocampal-dependent memory, with females not showing the same impairment (Luine et al., 1994; Bowman et al., 2001; Luine et al., 2007).

In contrast, acute tail shock stress during classical eyeblink conditioning improves performance in males but suppresses it in females (Wood and Shors, 1998) by mechanisms influenced by gonadal hormones in development and in adult life (Wood et al., 2001; Shors and Miesegaes, 2002). However, giving male and female rats control over the shock abolishes the stress effects and the sex differences (Leuner et al., 2004). These findings suggest that sex differences involve brain systems that mediate how males and females interpret stressful stimuli, and that a sense of control is paramount to coping with those stimuli.

More recently, in collaboration with John Morrison, Becca Shansky showed that female rats fail to show the mPFC dendritic remodeling seen in males after CRS in those neurons that do not project to amygdala, but they do show, after CRS, an expansion of the dendritic tree in the subset of neurons that project to the basolateral amygala (Shansky et al., 2010). Moreover, ovariectomy prevented these CRS effects on dendritic length and branching. Furthermore, estradiol treatment of ovariectomized (OVX) females increased spine density in mPFC neurons, irrespective of where they were projecting (Shansky et al., 2010).

Taken together with the fact that estrogen, as well as androgen effects are widespread in the central nervous system, these findings indicate that there are likely to be many more examples of sex x stress interactions related to many brain regions and multiple functions, as well as developmentally programmed sex differences that affect how the brain responds to stress, such as in the locus ceruleus (Bangasser et al., 2010; Bangasser et al., 2011). Clearly, the impact of sex and sex differences has undergone a revolution and much more is to come (Meites, 1992; McEwen and Lasley, 2005; Cahill, 2006; Laje et al., 2007; McEwen, 2009), including insights into X and Y chromosome contributions to brain sex differences (Carruth et al., 2002).

Early Life Stress and Brain Development and Function

Brain development has always fascinated me, but my lab did not work very much on that topic, with the important exception of early gonadal hormone actions and brain sexual differentiation (McEwen 1983; Pfaff and McEwen, 1983). However, Akaysha Tang initiated a collaboration, and Lisa Eiland joined my lab, and these colleagues set us off on some fascinating studies of early life experiences and brain development, in which we are now collaborating with the Huda Akil–Stan Watson laboratory in Ann Arbor.

Akaysha Tang, a faculty member in psychology at the University of New Mexico, spent several short periods in our lab and initiated a long-distance collaboration that also involves Russ Romeo, a former postdoc in my lab and now a faculty member in psychology at Columbia/Barnard. With our input, Akaysha and her lab colleagues have developed the “maternal modulation hypothesis” that emphasizes the role of the mother in providing consistency of maternal care, not just quantity but also the importance for infant cognitive and social, as well as physical, development of exposure to novelty while under consistent maternal care (Akers et al., 2008; Tang et al., 2011; Tang et al., 2012).

Lisa Eiland, an MD neonatalogist at Weill/Medical College of Cornell University and now at Roosevelt Hospital, introduced the maternal separation (MS) model in rats (three hours per day separation from mother rat on postnatal days 2–12) as a model of some of the things that happen to premature neonates in the neonatal intensive care unit (NICU). Her work showed that development of the hippocampus was impaired by MS as was spatial memory in young adults and that chronic stress led to more anxiety in the MS rats (Eiland and McEwen, 2012). These findings have led to collaboration with the Akil-Watson laboratory to compare MS versus non-MS rats with rats from high and low responding (HR and LR) strains developed in Ann Arbor. With the treatment of neonates of all four groups with FGF2 on postnatal day one (based upon the finding that this treatment makes LR rats less anxious and more exploratory than HR rats), we expect that FGF2 will reverse the MS effect (Turner et al., 2011).

Stress and Brain–Body Interactions and Social Neuroscience

So far, I have summarized how useful steroid hormones have been in elucidating mechanisms of adaptive plasticity of the adult and developing brain. Let us now look at a bigger picture, related to how the brain is the master organ of adaptation to a changing external and internal environment and an active and malleable participant in those adaptive changes. Because we are the “Laboratory of Neuroendocrinology,” we deal with the interactions between brain and body, a subject that has matured considerably with progress in endocrinology and neuroscience and with advances in many aspects of physiology and medicine, particularly at the molecular level. As a parallel to laboratory research, I have become involved in applying some of this knowledge to understanding mechanisms of how the social, as well as physical, environment affects human health.

As I said earlier, around 1990 I was recruited into the MacArthur Foundation Health and Behavior Network, an interdisciplinary group of researchers that introduced me to larger questions of how brain, behavior, and physiology interact with each other and with the social environment. After several years, this network was gradually transformed into the MacArthur Foundation Research Network on Socioeconomic Status (SES) and Health (www.macses.ucsf.edu), to address the important and challenging question of how income and education “get under the skin” to produce the linear gradients of health and mortality seen in Western societies, with the higher SES population doing better on the average than the lowest SES, and with the middle SES levels being truly in the middle on an almost linear relationship with high and low SES. This line of research has been summarized nicely in an edited volume (Adler et al. 1999) and PDFs that are available online (“Reaching for a Healthier Life” and “The Biology of Disadvantage” from another edited volume: www.macses.ucsf.edu).

The types of stress and impacts of stressful experiences, as well as choice of lifestyle, are influenced by education, social environment, and access to resources. Based on the idea that the brain is the central organ of stress and adaptation because it perceives what is stressful and controls physiological and behavioral responses that then also influence the brain in ways described earlier, with input from my friend and mentor, Eliot Stellar, and Teresa Seeman of UCLA, we formulated a concept referred to as “allostatic load” that has helped to bridge the gap between biology and biomedicine, health psychology and behavior, and sociology and economics.

Indeed a field of “social neuroscience” (http://s4sn.org/drupal) is beginning to take shape because it recognizes how important the social, as well as physical, environment are in shaping brain function, behavior, and in influencing systemic physiology. A prominent example is the recent publication in the Proceedings of the National Academy of Sciences of the Sackler Colloquium on the “Biological Embedding of Early Social Adversity: From Fruit Flies to Kindergartners,” which was held in the National Academy’s facility on the campus of the University of California, Irvine, in December 2011.

Following is a brief synopsis of the concepts of allostasis and allostatic load (McEwen and Gianaros, 2010; McEwen and Gianaros, 2011). Whereas many physiological parameters, such as blood oxygen and pH, are maintained in a narrow range (homeostasis–essential for life), many other parameters vary in their functionality with time of day and in response to external and internal demands, including those mediators that help the organism adapt. Allostasis, originally created as a concept by Sterling and Eyer (Sterling and Eyer, 1988) and modfied by McEwen and Stellar (McEwen and Stellar, 1993), is the active process of responding to a challenge to the body by triggering chemical mediators of adaptation (HPA, autonomic, metabolic, immune) that operate in a nonlinear network (McEwen, 2006). Allostasis is essential for maintaining homeostasis in the face of challenges or demands imposed by changes in (a) the environment and (b) an individual’s behavioral state that is registered by the brain. Thus, the dynamic mediators of allostasis expressing marked variability facilitate adaptation, whereas the parameters associated with homeostasis do not express comparable variability as a means of promoting adaptation. Allostasis is essential for maintaining homeostasis in the face of external and internal demands that are registered by the brain. Critically, however, this dynamic adaptation has a price, and the cost of this adaptation is called allostatic load—the wear and tear on the body and brain that results from chronic dysregulation (overactivity or inactivity) of mediators of allostasis (McEwen and Stellar, 1993; McEwen, 1998).

The MacArthur experience and the concepts of allostasis and allostatic load set us in an unexpected direction, namely, how the brain and immune system communicate. Arising out of the Health and Behavior Network, the MacArthur Foundation provided grant support for several years to a brain behavior and immunity group that explored topics related to how the stress hormone axis interacts with the immune system (McEwen et al., 1997). This had at least two major consequences. First, Firdaus Dhabhar, a graduate student and now faculty member at Stanford, used this as a catalyst for his PhD thesis work showing, for the first time, that acute stressors enhance acquired immunity, its formation and expression, and do so via the ability of cortisol and adrenalin to promote “trafficking” of immune cells from the blood and from storage organs like the spleen into sites in the body where they are needed to defend against a pathogen or to repair a wound; at the same time, chronic stress has the opposite effect, namely, to suppress immune function (Dhabhar et al., 2012). The latter concept is well known while the enhancement of immune function is surprisingly counterintuitive and is still working its way into biomedical thinking, in large part due to the continuing elegant work of Firdaus Dhabhar, who has shown its applicability in recovery from knee surgery (Rosenberger et al., 2009) and in defending against certain types of immune-sensitive cancers (Dhabhar et al., 2010).

A second major consequence of our foray into the immune system is the study of the immune system of the brain, namely, microglial and brain dendritic cells via the elegant work of Karen Bulloch and her neuroimmune physiology and inflammation program at Rockefeller. Dr. Bulloch, an expert in the thymus and its innervation (Bulloch, 1985) and function of modulators such as calcitonin gene related peptide (CGRP) (Bulloch et al., 1991; Bulloch et al., 1998), was a member of the brain behavior immunity group and transferred her research program to Rockefeller where she shifted her interests, first to study CGRP in relation to brain damage (Bulloch et al., 1997) and then to study microglial cells in the context of aging and inflammation (Sierra et al., 2007) and presently to discover that within the population of “microglia” in the brain is a heterogeneous class of “brain dendritic cells” (Bulloch et al., 2008) that are activated in aging (Kaunzner et al., 2012), after stroke (Felger et al., 2010), and during intranasal viral infections (D’Agostino et al., 2012). It appears that some come in from outside but others are resident in the brain and become activated after insult or with aging, but whether they protect or cause problems remains unclear.

Thus the basic concept of allostasis and allostatic load, whether pertaining to the immune system, the brain, or to other systems of the body, is that the same systems that help the body and brain adapt can also contribute to pathophysiology when overused and out of synchrony with each other (McEwen, 1998). This is so because each regulatory mediator (HPA, autonomic, metabolic, immune) system influences the other mediator systems, directly or indirectly; moreover, each mediator system can have positive and also negative effects (i.e., a U-shaped dose response) depending on level and timing of their activity (McEwen, 2006). There are many implications, but two of them are worth noting here.

First, pharmaceutical agents that enhance or inhibit one mediator system will influence the activity of other mediators, as well as run the risk of tipping the balance on the U-shaped dose curve from good to bad effects (Calabrese, 2008). This is the challenge of drug development for many disorders of modern life, from hypertension to arthritis to metabolic syndrome to depression—to interfere with a process that is either inadequate or overactive but not to the point of either shutting it off completely or of overstimulating it.

This leads to the second point. I have referred to examples of the abilty of physical activity and successful cognitive behavior therapy to change brain structure and function. Indeed, “top-down” interventions such as physical activity, adequate sleep, and postive social interactions, including cognitive therapies, are in some cases a better way to intervene and to help the system of allostasis correct itself and to re-achieve a balance that favors adaptation over pathophysiology (McEwen and Gianaros, 2010, McEwen and Gianaros, 2011). A further example is found in the Experience Corps, in Baltimore, Md., in which elderly volunteers, serving as elementary school teachers’ aides, show benefits to their prefrontal cortical function as well as improved mood and physical health, as a result of participating in this program, which provides positive social interactions, physical activity, and a meaning and purpose in life, as well as benefiting the education of children (Fried et al., 2004; Carlson et al., 2009).

A major contributor to allostatic load and poor mental and physical health over the lifespan is adverse experiences early in life (Anda et al., 2010) that affect brain development and, thereby, alter brain and body health through neuroendocrine, neural and immune mechanisms (Shonkoff et al., 2009). Interventions that improve parent-child interactions at the family level, such as the Nurse-Family Partnership, can have an enormous benefit and have a significant return on investment (Eckenrode et al., 2010) (http://developingchild.harvard.edu/initiatives/council; see also www.dana.org/news/reportonprogress/detail.aspx?id=31362).

Looking Back and Looking Forward

Because I chose to work on hormones, I have been acutely aware over the years of the tendency of neuroscientists to be brain-centric and to largely ignore the influences of the rest of the body via hormones and immune system chemicals, while those interested in endocrinology and internal medicine tend to ignore the brain and its pervasive influence on systemic health. Fortunately, this is changing, and I believe that our work has helped to make this change. For example, it is hard to ignore the fact that the entire brain is a target for sex hormones via genomic and non-genomic mechanisms that affect reacting times, pain sensitivity, mood, and higher cognitive functions, or that the hippocampus is a target not only of stress and sex hormones but also of metabolic hormones such as leptin, insulin, ghrelin, and IGF-1 (McEwen, 2007). Yet, there is still a reluctance to think of a systemic disorder as also a brain disorder. A case in point is Type 2 diabetes that we now know damages the brain, particularly the hippocampus, starting early in life (Yau et al., 2010; Yau et al., 2012) and in adult life and aging (Convit et al, 2003; Gold et al., 2007) with increased risk for dementia later in life (Arvanitakis et al., 2004; Rasgon and Jarvik, 2004).

What our work and that of others on hormone actions has helped to uncover is that the adult brain is much more resilient and adaptable than previously believed, and neural architecture is modifiable. Indeed, adaptive, structural plasticity involves growth and shrinkage of dendritic trees of neurons, turnover of synapses and limited amounts of neurogenesis in the forebrain, especially the dentate gyrus of the hippocampal formation. Stress and sex hormones participate in adaptive structural plasticity in the hippocampus, prefrontal cortex, and amygdala—brain regions involved in memory, decision making, and self-regulatory behaviors such as emotional regulation and impulse control. These hormones exert their effects on brain structural remodeling through classical direct, as well as indirect, genomic mechanisms and also via non-genomic molecular mechanisms; they do so in collaboration with neurotransmitters and other intra- and extracellular mediators. Early life experiences and brain sexual differentiation determine the nature and degree of this plasticity.

Here is what I think is the most important lesson for neuroscience and medicine as we enter the era of “social neuroscience.” Because hormones influence so many aspects of brain structure and function and because hormone secretion is governed by the cognitive and emotional brain acting through the hypothalamus, the role of brain plasticity must be considered in understanding how the social and physical environment “gets under the skin” to affect brain and body resilience and positive aspects of health, on the one hand, and vulnerability to disease, on the other.

Thus some of the lessons, looking forward, can be summarized as follows:

First, the adult brain shows region-specific adaptive plasticity in response to stressful experiences, mediated in part by stress hormones, and this plasticity is also affected by sex hormones, which have their own effects on neuronal structure and function throughout the brain.

Second, steroid hormones act classically via receptors that bind to response elements and act in the cell nucleus, but they also act in other parts of the cell independently of genomic actions or indirectly upon the genome via other signaling processes. In many cases, these non-genomic or indirect genomic actions involve the classical steroid receptor expressed in extra-nuclear sites. In other cases, there are other steroid-responsive receptors (e.g., those which are coupled to G proteins).

Third, steroid hormone actions on structural and functional plasticity of the mature brain involve a convergence of multiple mediators, including neurotransmitters, neurotrophic factors, and signaling molecules, such as tissue plasminogen activator and endocannabinoids.

Fourth, steroid hormone actions on structural and functional plasticity of the mature brain involve collaborations among multiple cell types (e.g., inhibitory interneurons, glial cells, principal neurons) and actions of hormones in multiple cellular compartments (e.g., presynaptic terminals, post-synaptic spines, mitochondria, endoplasmic reticulum, and cell nuclei).

Sex hormones affect the whole nervous system and not just those brain regions involved in reproduction, and they affect multiple neural processes from cognitive function to emotional regulation to motor and sensory processing, as well as vulnerability to damage.

There are developmentally programmed sex differences that affect many of the aforementioned processes.

The brain and body are interconnected and affect each other in multiple ways so that brain and body health and wellness are intertwined, as codified in the allostatic load concept. Ignoring the brain while focusing on body systems invites problems, just as ignoring the body while focusing on the brain creates other problems.

There is resilience in the aftermath of stress, and a healthy brain and body responds to stressors either by actively resisting their actions or by changing and then recovering when the stressor is over. A maladapted brain and body may not spontaneously recover from the stressor or may be adversely and even permanently damaged; early life adversity is a major cause of lifelong physical and mental health disorders.

Finally, the plasticity of the adult, as well as the developing, brain offers opportunities for interventions that are “top down,” that is, involving the activation of brain and body systems by behavioral and cognitive means. These can often be enhanced by pharmaceutical agents; however, these are not a substitute for the top-down intervention.

Acknowledgments

This review is dedicated to current and former postdoctoral fellows and students who, in many cases, catalyzed the research discussed in this review; many of whose names are noted in the text. I am very proud of their accomplishments!

There are many other people to acknowledge over the years such as my PhD mentors, Alfred Mirsky, who introduced me to environmental regulation of gene expression; and Vincent Allfrey, from whom I learned about epigenetics and the role of nuclear proteins; as well as my postdoctoral mentor, Holger Hyden, who introduced me to neurochemical anatomy and the importance of the hippocampus. I am also grateful to my laboratory head when I came back to Rockefeller, Neal Miller, father of behavioral medicine, as well as to Eliot Stellar from the University of Pennsylvania who taught me “collegiality” by example and who introduced me to interdisciplinary research via the MacArthur Network on Health and Behavior; my friend and collaborator over many years, Don Pfaff, with a common interest in steroid receptors and his expertise in the neural circuitry of sex behavior; and my friend and colleague, Fernando Nottebohm, who pioneered work on neural plasticity via his discovery of neurogenesis in the songbird brain.

Essential colleagues for the research described in this review include Teresa Milner, Weill/Cornell; John Morrison, Mt. Sinai School of Medicine; Joe Ledoux, NYU; Sid Strickland, Rockefeller; Sumantra Chattarji, National Centre for Biological Sciences, Bangalore, India; Francis Lee, Weill/Cornell; B. J. Casey, Weill/Cornell; Cecilia Hillard, Medical College of Wisconsin; Akaysha Tang, University of New Mexico; Mary Jeanne Kreek, Rockefeller; Paul Greengard, Rockefeller; and David Allis, Rockefeller. I am grateful for their collegiality.

I also want to gratefully acknowledge the Laboratory of Neuro-endocrinology’s administrative support: Adelaide Acquaviva, Maryse Aubourg, and Halina Korsun are an essential part of the laboratory and deserve warm thanks! Finally, I thank my wife, colleague, and collaborator, Karen Bulloch, PhD, who leads a group that is doing very interesting and important neuroimmune research and who has made many things possible through her wisdom, sense of humor, and caring support.

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Frederick A. Miles

BORN:

Grimsby, England

December 4, 1939

EDUCATION:

University of Leeds, BSc (1962)

University of Sussex, PhD (1971)

APPOINTMENTS:

Schoolmaster, Foxwood School, Leeds, England (1962–1966)

Assistant Lecturer/Lecturer, University of Sussex, England (1966–1971)

Visiting Fellow/Associate/Scientist, Laboratory of Neurophysiology, National Institute of Mental Health, National Institutes of Health (NIH) (1971–1980)

Chief, Section on Oculomotor Control, Laboratory of Sensorimotor Research, National Eye Institute, NIH (1980–2010)

Visiting Distinguished Professor, City University of New York (1987–1988)

HONORS AND AWARDS:

Golden Brain Award of the Minerva Foundation, Berkeley, CA (2000)

Doctor of Science, Honoris Causa, State University of New York (2011)

Frederick A. Miles did his earliest research on the centrifugal innervation of the avian retina and described its effects on the receptive field properties of the retinal ganglion cells. All of his subsequent work has been on primate eye movements. In an early project, he designed optical devices to alter the gain of the rotational vestibulo-ocular reflex and obtained neurophysiological evidence that the underlying changes were occurring in brain-stem pathways. After using a variety of optical techniques to demonstrate other forms of adaptive plasticity, his laboratory went on to discover three independent visually driven ocular reflexes that responded with ultra-short latency: one tracked linear motion and was postulated to work in concert with the translational vestibulo-ocular reflex with which it shared a dependence on the inverse of the viewing distance; the other two reflexes generated vergence eye movements, one in response to binocular disparity and the other in response to radial optic flow. All of these reflexes had special features that would help them to function effectively in a complex 3-D visual world and were critically dependent on the Fourier composition of the stimuli, consistent with early spatiotemporal filtering as in energy models of motion and disparity detection. Later work, using broad-band stimuli, uncovered nonlinearities that were attributed to mutual inhibition between the mechanisms sensing the motion or disparity of the different harmonic components. Two significant outcomes, considered vital for optimal performance: local winner-take-all behavior favoring the most salient harmonic, and global divisive normalization reducing dependence on image size. The local spatiotemporal characteristics of the reflexes of humans strongly resemble those of neurons in the monkey’s striate cortex, suggesting that they provide insights into the processing of visual motion and binocular disparity by the human striate cortex.

Frederick A. Miles

The Early Years

I was born in Grimsby, a fishing port on the east coast of Lincolnshire (England), just after Britain entered World War II. The war and its aftermath were to dominate my early life. We lived in a row house in a working class area of town, and my father was called up for military service in June 1940, when I was six months old. He was small and could drive a car, qualifications that got him into the Royal Armoured Corps as a tank driver. He was taken prisoner in North Africa by Rommel’s Afrika Korps outside Tobruk in early April 1941. After a period in a prisoner of war (POW) camp in Italy, he was transferred to a camp in Upper Silesia. In January 1945, as the Russians were rapidly approaching from the East, his camp—along with many others in the area—was quickly evacuated. The prisoners were force marched westward toward Czechoslovakia. It was a particularly severe winter, and there was no food except what could be scavenged from the mostly deserted towns and villages. Stragglers were shot. One morning, however, the prisoners awoke to find that the guards had left. After a period of indecision, the prisoners split up into small groups and my father’s group (of seven) set out to reach Prague. After various tense encounters, including one with a band of heavily armed Russian women, my father’s group eventually made it to the U.S. Embassy in Prague. Almost immediately, he found himself seated on the floor of a U.S. Army Air Force transport plane flying to Lydd in southern England.

On arriving in England some time in 1945, my father learned that our house in Grimsby had been bombed and that I had been taken in by a couple who lived in the next street. Apparently, on the night of the bombing, I had taken refuge in their outdoor toilet. I have since learned that the bombing started at 1:43 a.m. on June 14, 1943, lasted about an hour, and was the worst of the 37 bombing raids on the town during the war (Smith, 1983). My memories of that night are scant. I recall being in an air-raid shelter in a neighbor’s backyard when suddenly the houses seemed to be engulfed in flames. Soon after, everyone left the shelter. I vaguely remember wandering the local streets but do not recall taking refuge. I did not know that, in addition to the usual incendiary and high explosive bombs, more than 3,000 anti-personnel cluster bombs—commonly called “butterfly bombs”—were dropped on the town that night (Smith, 1983). These butterfly bombs, which were designed to arm only after they had landed and then to explode when disturbed, accounted for many of the 66 deaths in the town that night, but I was unscathed. I do not know where my mother was during the bombing, but it was not unusual for her to leave me on my own, even overnight. I had two sisters—one older and the other younger—who were living with my father’s parents in another part of the town. I do not know why I was not with my sisters.

The couple who had taken me in, Maurice and Olive Pimperton, were in their late forties. An incendiary bomb had gone through their roof, landing on their bed without detonating, and Mr. Pimperton had carried it to the river at the end of the street and thrown it in. The Pimpertons had both left school at the age of 12 to make a living and had a married daughter who lived with them; her husband was in the army and would take part in the Allied invasion of Italy later that year. Mister Pimperton (later, I would call him, “Dad Pim”) worked as a locomotive engineer (“train driver”) for the London and North Eastern Railway, while his wife took care of the home, and their daughter served behind the counter in a local grocery shop. After the bombing, my mother had relocated to a house about half a mile away in a somewhat poorer area near the docks and, after a time, I joined her. The house abutted a sawmill and was infested with rats and cockroaches. My mother’s absences grew more frequent, and I would befriend other children partly in hopes of being invited in for a meal. However, this situation did not last long. It so happened that the Pimperton’s daughter was one of our local air raid wardens, and while on duty one day she saw me on the street. She insisted that I go home with her—apparently, it was clear that I was not being cared for—and I never returned to live with my mother. The Pimpertons raised me as their son, and I became deeply fond of them. I am not aware that my mother made any attempt to take me back, and I long thought that she had completely disappeared from my life. However, she was to make a dramatic, if brief, comeback some years later when I was in college.

The first time that I remember seeing my father was when he stepped off the train at Grimsby Town Railway Station on his return from the war. I do not remember much other than thinking that he was the thinnest person I had ever seen. After his return, my father lived with his parents, along with my two sisters, while I continued to live with the Pimpertons. Not long afterward, my father came to see me at the Pimperton’s home. It was late evening, and I was in bed. Dad Pim woke me and told me that my father wanted to ask me a question—he wanted to know if I would like to go and live with him. Without hesitation, I indicated that I wanted to stay with the Pims. I provided no explanation and none was sought. My father accepted my decision without protest and made no attempt to enlist my sympathy for his predicament, which was even worse than I knew. I was aware that he had been a POW for some years, but I did not know that some time after I moved in with the Pimpertons, my mother had had an illegitimate son who was raised by her sister. (I did not learn that I had a half-brother until I was in college, and I have not seen him for half a century.) My parents soon divorced, and my father married a widow; her husband had been a fisherman who had died when his trawler struck a mine. My father and his new wife later had two daughters, and I would see them occasionally; but I lost contact when I was in my late teens. It was almost half a century before I saw him again, after locating his whereabouts on the Web in 2002; only then did I learn the full extent of his harrowing wartime ordeals.

The Pimpertons always treated me as one of their own. In fact, I was aware that Mam Pim (as I called Mrs. Pimperton) doted on me. Overt displays of affection were not the custom, but I was never in doubt that I was a cherished member of the family. The Pimpertons’ house was small and there were few luxuries; they never had a refrigerator, a car, or a telephone, for example. But they were frugal and resourceful—growing their own vegetables and raising pigs, chickens, and ducks on a nearby allotment—so we always ate well even during the worst of the rationing. Unbeknownst to me, the Pimpertons had wanted to make their adoption of me official, but my father would not agree to it and, much to their disappointment, had insisted that I keep his name, “Miles.” (The irony of this is that my father was to discover much later that “Miles” was not his real name. He too had been adopted, though it was never made official, and only in 1983 did he discover that the name on his birth certificate was actually “Foxon.” Before visiting us in the United States in 2003, when he was age 89, he insisted on changing his name to “Miles” so that his passport would be in the name by which he had been known all of his life.)

When I was five years old, I entered the local primary school (Macaulay Street), which I really enjoyed. I had decided that I wanted to be a doctor but, of course, nobody took me seriously; at that time, I did not even know anyone who had been to a university. There were almost 150 children in my year at school, which was divided into three classes. In 1950, when I was 10 years old, I was one of four children that year who passed the so-called eleven-plus examination and went on to Wintringham Grammar School. The 1944 Education Act had made provision for working-class children like me who “passed the scholarship” to attend grammar schools free of tuition. These schools prepared children for examinations that could eventually allow them to qualify for admission to a university.

Wintringham was the only grammar school in Grimsby, and it was on the other side of town. Neither I nor my friend, Tony Wass, who had also passed the eleven-plus, knew its exact location. Our solution was to cycle into town, find another boy wearing the same uniform, and follow him to the school. From the very beginning, the Pimpertons had always given me complete freedom to come and go as I pleased, and they seemed to assume that I could deal with any eventuality. They knew little of what I was doing at the grammar school but were always very supportive. Many of the pupils there were from middle-class homes, and I generally kept my personal history to myself, in part because it was not usual to talk about wartime experiences and in part because I was ashamed of being adopted. I acquired a lifelong interest in classical music when I was a teenager, thanks largely to an older school friend, David Cressey, who had a record player. We were both besotted with the then-recent recordings of Bach’s “48 Preludes and Fugues” by Rosalyn Tureck and Beethoven’s late quartets by the Budapest String Quartet. David went on to read Greats at Oxford, but I was not a very good student. With a few notable exceptions, I found the teaching at Wintringham uninspired and somehow there were always too many other distractions. Also, I have always preferred to learn from the written—rather than the spoken—word and generally found an hour in the library more informative than an hour in the classroom or lecture hall. Unfortunately for me, good books—especially in science—were in very short supply at the grammar school, and the public library was even worse. (It did not help that both had suffered major bomb damage.) Nonetheless, I managed to gain entry to Leeds University Medical School in 1958. I was 18 years old and simply not mature enough to meet such a challenge.

Medical School

In England at that time, 4.4 percent of the age group went on to a university (Layard, King, and Moser, 1969), and tuition was free. Students like me from working-class homes received grants to cover their accommodation, meals, travel, books, and so forth. One had to be very frugal to make ends meet, but I was used to austerity. Dad Pim was nearing retirement age, and his job did not provide a pension so the Pimpertons were not in a position to help me financially. It was the first time that I had lived away from home and in a large city. The atmospheric pollution was severe, resulting in almost perpetual twilight in winter; visibility could be reduced to a few yards, and all of the older stone buildings downtown, such as the town hall, were completely black from the pollutants. There were also still slums in Leeds at that time, and it had the feel of a hardscrabble northern city. I had been very disappointed with my academic performance in grammar school and was determined to do better at medical school. In my first year, I lived in a series of boardinghouses that had no study facilities, and I relied on the work spaces in the university (Brotherton) library, which was often crowded. Fortunately, the academic load in my first year was very light; and by the start of the second year, when the work load was very heavy, I had my own room and a small desk. The heating in my room was often inadequate but a blanket wrapped around the shoulders helped a lot in winter. Lectures, laboratory classes, and tutorials took up every weekday, as well as Saturdays until 1 p.m. Keeping up with assignments meant working late most evenings and through the weekend, especially because I found many lectures inscrutable and relied heavily on textbooks to learn the material. At first, I was strongly motivated, but gradually I became disenchanted, especially with the emphasis on rote learning, and soon reached the conclusion that I had made a mistake in choosing to study medicine. Without consulting anyone, I secretly decided to quit. But how could I earn a living? I was 20 years old with neither money nor marketable job skills. Transferring to another school at the university was not an option—the system was not flexible enough for that. I did not want to leave the university without a degree, but the prospect of continuing to study medicine for several more years was unthinkable. My salvation came in the form of a bachelor of sciences (BSc) course in physiology, which was offered to a small number of medical students after they had completed pre-clinical medicine (“second MB”) and, importantly for me, it required only one year of study. The purpose of this course was to provide medical students with a more advanced experience of laboratory science and was not meant to be an end in itself. I applied for the course and, in 1961, after completing second MB, I was accepted.

However, a few months before second MB finals, I had learned from my older sister (who had managed to stay in contact despite everything) that our mother, whom I had not seen or heard of for more than a decade, was in a hospital in Grimsby and wanted to see me. My sister explained that our mother was an alcoholic and had collapsed drunk on the street late one winter evening, suffering severe frostbite that had resulted in the amputation of one hand and one foot. With some trepidation, I went to see her in the hospital. I was shocked to see her; she was emaciated, her hair was thin and unkempt, and she was missing some teeth. What remained of her foot was protected from the weight of the bed covers by a cage and the remains of her hand were heavily bandaged. Despite appearances, she was extremely cheerful—even euphoric—and, to my embarrassment, very eager to show off her son to the other patients and nurses. She behaved as though we had a close and loving relationship. Somehow she knew that I was a medical student at Leeds and told me that some years previously she had lived for a time in that city, which was about 75 miles from her hometown of Grimsby. I was amazed to learn that she had served behind the bar in the pub frequented by the medical students! Stranger still, she had lived for a time with an artist there who “painted pictures of dead people at the medical school.” That was the last time I saw my mother. We made no plans to meet again, and she died a few years later. I have no photographs or mementoes of her. Almost certainly, the artist whom she had mentioned was a painter who occasionally lectured the medical students on art. I had recently heard one of his lectures and seen his paintings, including one of a cadaver, in a large retrospective of his work at the Leeds City Art Gallery, which was just a few blocks from the medical school. I recently learned from an assistant curator that the Leeds Art Gallery—as it is now known—has a painting of a cadaver entitled, “Clay,” by a well-known local artist, Jacob Kramer (1892–1962), who had a retrospective at the gallery in 1960. According to his biographer, Kramer lived near the medical school, had friends on the faculty, and frequented the medical students’ pub (Manson, 2006).

I mostly enjoyed the physiology course, especially the opportunity to sit in on faculty research projects. Intellectually though, the highlight was undoubtedly reading the papers of Hodgkin and Huxley: for the first time I realized that science could be wonderfully elegant as well as rigorous and complex. This was a revelation to me—a quantum step in my appreciation of what science could be—and Hodgkin and Huxley’s voltage clamp papers are surely among the supreme achievements in neuroscience.

School Teaching

After obtaining a BSc in animal physiology, I left the medical school with the unrealistic notion that I could earn a living by writing fiction. It was 1962, and a year earlier I had met, and soon married, Jennifer, who was a nurse and the only girlfriend I ever had. At first, we lived on her modest income, but when Jennifer became pregnant, it was evident that I would have to earn a living and put aside “the great novel.” At a friend’s urging, I took a position teaching science at Foxwood School, one of the first purpose-built comprehensive schools in Great Britain, located on a large housing estate in northeast Leeds. At that time, a degree was sufficient qualification to teach in a secondary school. This was a boys’ school, with ages ranging from 11 to 18 years, and catered to all abilities (except boys with very special needs). I found teaching there hugely stimulating but also extremely demanding, requiring long hours preparing classes, setting up the laboratory equipment, and grading papers, in addition to the rather full teaching schedule. Like most of the teachers at the school, I had strong leftist sympathies and was drawn to its egalitarian approach to education, which was in stark contrast to my own elitist grammar school background, and I felt that it was a very successful educational experiment. However, I gradually became overwhelmed by the heavy teaching load and found myself unable to compromise in an acceptable way. Jennifer suggested that I would fare better teaching in a university, an idea I dismissed as completely unrealistic, given that I did not have either a doctorate or publications.

The University of Sussex

But Jennifer persisted and, when I was in my fourth year of teaching at Foxwood, she saw an advertisement in The Times Educational Supplement for a tenure-track faculty position at the University of Sussex, one of several new universities that had opened in Great Britain in the 1960s. The School of Biological Sciences was looking for someone to develop laboratory materials that could be used in the teaching of modern biology in secondary schools—a very unusual position. Jennifer argued that I had the requisite experience, but I was unconvinced and thought it would be a complete waste of time to apply. In those days, one filled in application forms to apply for such a position and, undaunted, Jennifer sent off for the forms. She then cajoled me into filling them in and mailed them. To my surprise, and embarrassment, I was called for interview.

During the interview, I was seated at one end of a long table with faculty members seated on either side and John Maynard Smith (JMS), the dean of the school, at the far end. JMS presided over the interview and started by telling me that the position for which I had applied had already been given to someone else. However, he asked me if I would like to be considered for another position—a tutorial fellowship—that was funded for three years, was not tenure-track, and involved teaching mammalian physiology to the undergraduates. It sounded interesting and I saw little to be lost in allowing myself to be considered—though I was convinced that I had no chance of getting it. JMS asked all the questions and was merciless: Why did you quit medicine? You took a first in physiology, yet you quit that too—why? Why did you choose to teach in a comprehensive school? Why are you now proposing to give up this teaching job? My answers were weak but truthful, along the lines that I had not realized that medicine was not a science, that the physiology degree was undertaken mostly to get an academic qualification, that I liked the egalitarian approach of the comprehensive schools but that I was overwhelmed by the workload. JMS went on to indicate that all faculty at Sussex were expected to do independent research and asked about my research plans. When I indicated that I did not have any, JMS persisted by pointing out that my physiological studies centered mainly on neurophysiology and cardiovascular physiology and, if I were to do research in one of those two areas, which would it be? I indicated that I thought neurophysiology was the more interesting and with that the interview ended abruptly.

I was convinced that the interview had been an unmitigated disaster and returned to Leeds assuming that that was the last I would ever see or hear of the University of Sussex. However, there were a number of things that I did not know about the university and JMS that perhaps worked in my favor. The School of Biological Sciences had opened only a year earlier and had been unable to recruit anyone to teach mammalian physiology—perhaps because there was neither a medical school nor a department of physiology at Sussex. I knew JMS only as a world-renowned theoretician in evolutionary biology and learned only later that he was not enamored of medical schools as centers of learning or research, had started out as an engineer and only later switched to biology, did not have a doctorate, and was politically on the far left. Perhaps this predisposed JMS to be sympathetic to a failed medic with leftist sympathies and unrealistic career goals? In any event, to my surprise and delight, I was offered a position and assigned to the animal behavior group headed by Richard Andrew. Even more remarkable, when I arrived in Sussex, I found that by some clerical error I had been given an assistant lectureship, which was a tenure-track position. I was well aware that others in the school with assistant lectureships had doctorates, publications, and were conducting independent research. When I spoke with JMS about it he denied that there had been any clerical error, and I kept the assistant lectureship. Such things would be unthinkable nowadays. (Even at that time it was extraordinary.) With such great fortune, I surely had a charmed life. I saw this as my chance to make up for all my previous failures and vowed to do everything I could to justify Sussex’s confidence in me. By that time, Jennifer and I had two sons, Richard (born 1962) and Graeme (born 1964), and the move from the northern city of Leeds to the southern rural village of Ringmer in Sussex—10 miles from the university—was a huge change for all of us.

It was 1966. The School of Biological Sciences had opened only the year before so most of the teaching curriculum had still to be decided, and the student teaching laboratories had to be equipped and made operational. I had been assigned an office/laboratory and, because I was the first occupant, I had access to some (rather limited) funds to equip it. But before I could do that I had to come up with a research project. Thomas Collett, who—apart from Richard Andrew—was the only other member of the animal behavior group at that time, was doing single unit recordings in the moth’s visual system and suggested that I might get some ideas from the recent papers of two scientists working in the United States: Hubel and Wiesel. I had never heard of them, and I found their papers exhilarating. After only a few hours in the library, I had decided that I would do single unit recordings in the visual system! I did not have any research experience, and my laboratory was an empty room. Also, I did not have the funding (and the school did not have the facilities) to support research on cats, the preferred animal for visual studies at that time. At this point, Richard Andrew suggested that I work on birds—he was studying self-stimulation in domestic chicks, which he collected each week from the hatchery, and always had a few surplus that he would be happy to make available to me. The problem with this was that I had worked only on mammals—mostly humans and cats—and knew absolutely nothing about the anatomy or physiology of birds. But after a few more hours in the library, I came up with a general plan to adapt the methodology previously used on cats by Hubel and Wiesel (and others) to newly hatched chicks. However, I still did not have a specific project. Once again the library came to my rescue. A recent issue of the Journal of Anatomy contained two papers that described an anatomical projection from a nucleus in the mid-brain of the pigeon, called the isthmo-optic nucleus (ION), to the contralateral retina (McGill, Powell, and Cowan, 1966a, b). This study reported that the ION received a visual projection from the contralateral eye via the tectum that was retinotopically organized and in turn projected back to that same eye, as though part of a closed-loop feedback system. These were anatomical studies, and nothing was known of either the physiology or the function of this centrifugal projection from the ION to the contralateral eye. I thought it would be interesting to characterize the visual receptive field characteristics of the retinal ganglion cells (RGCs) and to find out how they were affected by electrical activation of the centrifugal fibers. I was also interested in the visual receptive field properties of the centrifugal neurons and the effect of lesioning these neurons on the chick’s visual behavior.

There had been few neurophysiological studies on birds at that time so there was no established methodology, and I had never worked on the visual system of any animal. Basic things such as anesthesia of newly hatched chicks had already been worked out by Richard Andrew, but many pilot studies were needed to work out how to prepare the birds for single unit recording. There were many methodological questions: How to apply controlled visual stimuli to characterize visual receptive field properties? How to immobilize the eye while characterizing the visual receptive fields? How to refract the eye so that images were focused on the retina? How to ventilate the paralyzed animal given that they have lungs and air sacs? How to maintain the animal’s body temperature? (The oldest birds I worked on were less than two weeks old and were not able to thermoregulate.) How to monitor the chick’s physiological condition during recording? How to locate the ION, whose dimensions were approximately 0.8×0.3×0.3 mm, especially given that the skull was largely cartilaginous and hence difficult to position accurately in a stereotaxic device (even supposing I had one)? The funds available to equip my office were sufficient to purchase some basic equipment such as an oscilloscope, a Grass stimulator, a pair of Narashige micromanipulators, a Tektronix pre-amplifier for unit recording, and an FM tape recorder for archiving data to allow later quantitative analysis. Fortunately, Thomas Collett was using micropipettes to record unit activity and was happy to allow me to use his equipment to pull microelectrodes. Everything else I would have to construct for myself.

Fortunately, the school had a machine shop and two machinists, who instructed me in the use of the milling machine, lathe, and so forth, and permitted me to fabricate my own equipment. I put together a stable recording platform, a stereotaxic device to hold the chick’s head in place and support the Narashige micromanipulators needed to position the recording micropipettes as well as stimulating electrodes and (later) cooling probes. I also constructed two slide projectors, each equipped with two electromechanical devices—one to operate a shutter to permit precise timing of stimulus onset/offset and the other to move the projected slide at a specified velocity (under feedback control) to apply controlled motion stimuli—and Dove prisms to rotate the images. A back-projection screen with half-silvered mirrors in the two projection paths (to deflect the images onto a plotting table to facilitate the mapping of the visual receptive fields) completed the visual stimulation equipment. I also built a motor-driven microsyringe to provide an intravenous drip of muscle relaxant (at a controlled rate of one-tenth of a milliliter per hour) to immobilize the eyes. Ventilation of the paralyzed bird was provided by flushing air with 5 percent carbon dioxide through the lungs and out through a tube introduced into the abdominal air sac, a technique that had been pioneered on adult chickens by Fedde, Burger, and Kitchell (1963). I also decided to canulate the main artery in the leg and monitor the blood pressure with a half-bridge variable reluctance transducer to monitor the bird’s physiological condition. The chick’s small size meant that all surgery had to be done under a dissecting microscope. Whenever I encountered a problem, there was always the library.

Given that I also had a full teaching load of lectures, tutorials, grading essays, and so forth and was heavily involved in developing the new curriculum and putting together the new teaching laboratories—there were no teaching assistants—it was perhaps not surprising that it took almost two years before I was ready to begin single unit recordings. Toward the end of my first year, I benefitted from yet another clerical error: I received a letter informing me that I had been promoted to a full lectureship, which was a tenured position, even though I had yet to record any data and had no publications. Once more, JMS denied that there had been any error and so I was in the embarrassing position of having a tenured faculty position while many others, who were much better qualified, did not. I still find it hard to understand how this could have happened. It meant that I now had complete freedom to do whatever I wanted with minimal outside interference; and over the next two years, I did a series of experiments on the chick’s visual system.

My first study characterized the visual receptive field properties of the RGCs and indicated that many had on/off excitatory centers and purely inhibitory surrounds. Other RGCs were especially sensitive to motion and showed strong directional selectivity. These experiments were relatively straightforward and served to get me started.

My second study characterized the visual receptive field properties of the centrifugal neurons in the ION, which were identified by antidromic activation of the isthmo-optic tract (IOT) carrying their axons to the contralateral eye. Pilot experiments had established the stereotaxic coordinates of the ION, using electrical stimulation of the optic nerve head in the eye to backfire the neurons in the contralateral ION and using the collision test to establish that the recorded neurons were indeed transmitting impulses toward the eye. However, stereotaxic coordinates alone were not sufficient to identify ION neurons with certainty, and placing the stimulating electrodes on the optic nerve head to backfire the centrifugal neurons compromised vision, ruling out the possibility of examining the visual receptive field properties of the ION neurons. The anatomy indicated that the axons of the centrifugal neurons crossed over to the contralateral side and passed just under the roof of the midbrain. I had found that removing the forebrain allowed excellent visualization of the roof of the midbrain and, remarkably, there was a white band clearly visible with the dissecting microscope, which when electrically activated reliably backfired neurons in the ION that had been previously identified by stimulating the optic nerve head in the contralateral eye. This was a critical methodological breakthrough and meant that I could now leave the contralateral eye intact. After opening the feedback loop (by sectioning the IOT) and identifying individual neurons in the ION (by electrically activating the IOT proximal to the cut), I could now present visual images to the contralateral eye and characterize the receptive field properties of the centrifugal neurons in the ION. This indicated that the receptive fields of the centrifugal neurons were more than an order of magnitude larger than those of the RGCs and were retinotopically organized (in accordance with the anatomical descriptions). The centrifugal neurons were also very sensitive to motion with a strong preference for forward movements through the visual field, dark vertical edges being particularly effective.

In a third study, I opened the feedback loop, again by sectioning the IOT, and recorded the effect of electrical stimulation of the IOT distal to the cut on the activity of the RGCs recorded in the contralateral eye. Activation of the IOT alone did not bring out activity in the generally silent RGCs. Occasionally, activation of the IOT increased the RGC responses to a spot flashed at the field center (as though facilitating the excitatory mechanism) but more commonly this too was without effect. Also, flashing an annulus in the “purely inhibitory surround” of the RGCs was without visible effect with or without stimulation of the IOT. However, when the excitatory field center of the RGC was activated with a spot while the inhibitory surround was activated simultaneously with an annulus so that there was no net excitation, stimulation of the IOT now brought out clear activity in the RGC. I reasoned that the centrifugal input must be suppressing the surround inhibition and thereby uncovering the central excitation, an example of activation by disinhibition.

My fourth study left the feedback loop intact and attempted to demonstrate centrifugal disinhibition using visual—rather than electrical—-activation of the ION neurons. The plan was to first map the receptive field of a RGC and then stimulate it with a large centered spot that encroached on the surround to a sufficient extent that the central excitation was balanced by peripheral inhibition (i.e., there was no net activation). I expected that in such a situation the RGC would be very sensitive to any centrifugal disinhibition, and I proposed to then activate the centrifugal neurons by moving a large vertical dark edge forward through the visual field. I postulated that the dark edge would leave a trail of centrifugal disinhibition in the RGCs in its wake that could then be detected by applying the large-spot stimuli. (Fortunately, most RGCs were minimally responsive to the moving edge alone.) The edge occasionally brought out RGC responses to the large spot but, unfortunately, it was entirely possible that this was due to interactions within the retina and not the result of disinhibition by the centrifugal input. In order to show that the responses to the large spots were due to centrifugal disinhibition, I blocked transmission in the IOT with a cooling probe. To be sure that the cooling probe was effective, I placed stimulating electrodes on the IOT distal to the cooling probe and a recording micropipette in the ION (in addition to the micropipette in the retina), allowing me to show that neurons in the ION could not be backfired from the IOT when the probe was on. I did many experiments but only in four cases did the edge bring out RGC responses to the large spot that could be eliminated by cooling the IOT. The low success rate was unfortunate, but the experimental design was too complicated and too many bits of apparatus had to work to get a positive result.

My fifth and final study on the ION was a collaboration with a graduate student in Richard Andrew’s laboratory, Lesley Rogers. I reasoned that the centrifugal disinhibition of RGCs would have the effect of increasing the excitability of the RGCs and reducing their spatial selectivity, thereby increasing the bird’s ability to detect images (but perhaps degrading its ability to discriminate their physical form). The finding that the centrifugal neurons were activated by vertical dark edges moving forward through the visual field led me to wonder if this meant that the centrifugal neurons were activated by local patches of shadow such as those encountered by the chick while feeding in undergrowth. Perhaps regions of the retina thrown into shadow by the chick’s searching gestures while ground feeding would be subject to centrifugal disinhibition, rendering those regions more sensitive and less selective, and thereby increasing the chance that the chick might detect items of interest in the shadowed areas. Lesley Rogers had been studying the chick’s pecking behavior, including its ability to discriminate food grains from pebbles, and I asked her to look at the performance of chicks with electrolytic lesions of the ION. The study included sham--operated controls, and Lesley did not know which chicks were controls and which had been lesioned. Lesley found that, when the floor was illuminated with a projected checkerboard pattern of light and dark squares, lesioned birds were almost as good as controls in the light squares but performed close to chance levels in the dark squares, consistent with the idea that the centrifugal system assisted the bird’s visual search in shadowed areas. Lesley made a number of other observations on the lesioned birds, but this was the one most relevant to my recordings.

As I began to prepare these data for publication I began to also think about visiting the United States where a lot of exciting neuroscience was being done. At that point (1970), I had visited only one other laboratory—the department of anatomy at Oxford, where all the recent anatomical work on the ION had been carried out—and I had never attended a scientific meeting. Essentially, I was working in complete isolation and relied entirely on the literature for my information—though Richard Andrew and Thomas Collett were always very helpful and remarkably knowledgeable. Richard suggested that I take a year’s leave of absence to visit the United States and this was very appealing to me. Of course, I would have to find my own funding, and the university would have to hire someone to do my teaching. I started to think of new projects and of labs in the United States where I might be able to do them—the idea being to broaden my research experience and bring me into contact with other neuroscientists.

One of the undergraduate courses that Thomas and I had developed together had applied control theory to neural systems, and this had led me to explore the literature on the neural control of eye movements, a field that had applied this approach with considerable success using what was at that time a novel new method: single unit recordings in awake monkeys. This led me to formulate a project involving single unit recordings in the cerebellum of awake monkeys performing saccadic eye movements. I had the idea that the cerebellum might be part of a negative feedback control system that used short-latency inputs from extraocular muscle proprioceptors—recently discovered by Albert Fuchs and Hans Kornhuber—to compensate for variations in orbital viscosity. At that time, one of the pioneering laboratories engaged in single unit recordings in awake, trained monkeys was that of Ed Evarts at the National Institutes of Health (NIH) and I wrote to him, telling him about my research and asking if he could support me to work on this project in his laboratory for one year. At that point, my only publications were a monograph for undergraduates on conduction of the nerve impulse (Miles, 1969) and a short research paper in press in Science that described some effects of electrical stimulation of the IOT on RGCs (Miles, 1970). In any event, Ed wrote back saying that he could not take me because I did not have a doctorate. Richard Andrew immediately suggested that I register as a graduate student at Sussex (with him as my “official” mentor) and submit a thesis based on my chick work. (At that time, course work was not required for a doctorate.) I wrote back to Ed, telling him of my plan to obtain a doctorate, and he indicated that he still would not consider taking me until he had met and spoken directly with me. But Ed also said that this would not be a problem because he was coming to Europe later that year and would be happy to call in at Sussex to interview me. This was remarkably generous of him—he was already eminent whereas I was completely unknown—and he was as good as his word. I showed him my laboratory and my data, and he agreed to take me on as a visiting fellow provided I obtained a doctorate. In a very prescient aside, Richard Andrew opined that Ed probably ran a very tight ship.

And so it came about that I wrote a doctoral thesis, which I defended before two external examiners, Professor Patrick D. Wall from University College, London, and Dr. R. Michael Gaze from the National Institute for Medical Research at Mill Hill. The examination was held in Professor Wall’s office at University College in August 1971 and, only a few days later, I left for the United States to work in Ed Evarts’s laboratory at the NIH. The data from the thesis were subsequently published in a back-to-back sequence of five papers (Miles, 1972a, b, c, d; Rogers and Miles, 1972).

The Move to the NIH

Academic stipends in England were not generous at that time, and it had been a constant struggle to make ends meet. The airline tickets for our journey to the United States represented a major expenditure. In order to keep within the 44-pound baggage allowance, we all wore our winter clothes (though it was August) and stuffed all of our pockets with the smaller items of clothing such as socks and underwear. At the flight check-in they insisted on weighing Richard and Graeme, who were deeply embarrassed at being asked to stand on the scale. We arrived in the United States with a total sum of $300, and within a few days it was almost all gone. Ed Evarts soon realized our predicament and kindly helped out by putting a deposit on an apartment for us. He also came up with some furniture from his basement, as did other scientists at the NIH, such as David Carpenter and Bob Wurtz. However, our predicament soon improved dramatically: Ed had arranged for me to receive a visiting fellowship from the National Institute of Mental Health (NIMH) ($7,000) and, in addition, a Fight for Sight Fellowship ($3,000) that, most importantly, was immediately paid in full. Suddenly, we were in Fat City.

The NIH turned out to be paradise for research—all the facilities one could hope for, no teaching, and no serious administrative responsibilities. Ed Evarts had inherited Wade Marshall’s Laboratory of Neurophysiology in the NIMH a few years earlier and had facilities sufficient for several postdoctoral fellows to each have their own projects. When I arrived, Ed was recording in the motor cortex and Mahlon DeLong was recording in the basal ganglia. Many other postdoctoral fellows came to the lab while I was there including Hiroaki Niki, Jun Tanji, and Peter Strick. All were interested in the neural control of limb movements and used monkeys trained to manipulate a lever. I was interested in activity related to saccadic eye movements and trained monkeys on a visual fixation task using a protocol established by Albert Fuchs and David Robinson at Johns Hopkins and subsequently refined at the NIH by Bob Wurtz. Eye movements were recorded with Ag/AgCl electrodes implanted around the eyes. Everyone was very forthcoming with technical advice, and it was relatively easy to set up my lab. I also went to my first scientific meeting, which was also the very first meeting of the Society for Neuroscience, and there met many of the people who up to that point had been merely names on papers.

I had planned to spend one year in Ed’s lab but, at his urging, I soon extended this to two years. Then, before I had completed my first year at the NIH and while still doing only exploratory recordings, Ed offered me a permanent position. At that time, one had to be a U.S. citizen to take a permanent position at the NIH, and in order to qualify for citizenship, one had to have been a permanent resident in possession of a “green card” for at least five years. A further problem was that my J-1 visa required me to spend two years outside the United States before I could apply for a green card. Ed indicated that he would hold the position for however long it took for me to get U.S. citizenship. On this understanding, I resigned my position at Sussex. I did this with great regret; everyone there had been so kind and helpful, and it was the place where I learned my trade, so to speak.

Plasticity of the Vestibulo-Ocular Reflex

In the meantime, my experiments were not going well. I had great difficulty finding eye-movement-related activity in the vermal cerebellum and switched to recording in the medial vestibular nucleus in the brain stem, a known staging area for eye movements. This work resulted in one short conference paper of little interest, and I began to think of other more substantive projects. One of these concerned the long-term adaptive regulation of the gain of the vestibulo-ocular reflex (VOR). When I had first arrived in Ed’s lab, all of the investigators were at a meeting of the International Union of Physiological Sciences in Munich, and when they returned all had been talking excitedly about Geoffrey Melville Jones’s report that the human VOR could be altered by wearing left-right reversing prism spectacles. At that point, all I knew about the VOR was that it used information from the semicircular canals to help stabilize gaze during head turns by generating compensatory eye movements: when the head turned to the right the VOR rotated the eyes a roughly equal amount to the left. The VOR had been regarded as the very embodiment of a hard-wired reflex that operated open-loop—insofar as the semicircular canals that were ultimately responsible for eliciting the compensatory eye movements received no indication whether those eye movements were of an appropriate magnitude. Melville Jones’s findings clearly suggested that this reflex was subject to long-term visually-mediated calibration.

A trip to the library revealed that Ito (1972) had recently suggested that the floccular lobes of the cerebellum were responsible for the adaptive control of VOR gain. The flocculus was seen as an inhibitory side-loop of the vestibulo-ocular pathway, receiving a mossy-fiber vestibular input and in turn projecting inhibition back onto the vestibular relay neurons in the brain stem via its Purkinje cell (P-cell) output. Brindley, Marr, and Albus had earlier hypothesized that the synapses between the mossy (parallel) fibers and the P-cells in the cerebellar cortex were modifiable and involved in motor learning, and invoked the so-called climbing-fiber input as the shaping influence. Ito was now suggesting that the climbing fibers might convey retinal image slip information to the P-cells in the flocculus to signal VOR gain errors and bring about appropriate changes in the efficacy of the vestibular parallel fiber inputs to the P-cells.

The clear idea here was that the VOR was subject to adaptive gain control, where gain is given by eye rotation/head rotation. One anomaly was that the reversing-prisms used to demonstrate this adaptive capability called for changes in phase rather than gain. Early in 1974, I decided to try the effects of telescopic spectacles, which I thought would present a more direct challenge to the gain of the VOR. I proposed to do this study on monkeys and decided to construct simple ×2 Galilean telescopes that would call for a doubling of the VOR gain; when reversed, they would call for a halving of the gain. I planned to construct the spectacles myself in the NIMH workshop, which I had already used for building other equipment. However, when I placed an order for the lenses, Ed Evarts—who had to approve all such purchases—called me into his office to ask why I needed the lenses. I told him that I was planning to construct a pair of telescopic spectacles for the monkey, but I did not get the opportunity to explain further: Ed became visibly angry and declared that it was “a stupid idea.” I was stunned. I could see that Ed had made up his mind and was not prepared to discuss it. Although I had heard from others that Ed could be difficult, this came as a complete surprise. From that point on our relationship was never the same, though I was to remain in his lab for another six years. A major reason for my staying on after his angry outburst was that soon afterward he spent several months visiting various laboratories in the Soviet Union and left me in charge of the everyday running of his lab in Bethesda. After his departure, I immediately ordered the lenses, constructed the spectacles, and found that, over the course of a few days, monkeys wearing ×2 spectacles showed clear increases in VOR gain and monkeys wearing ×0.5 lenses showed clear decreases. I felt that this was the clearest evidence so far that the VOR was subject to adaptive gain control (often termed, adaptive plasticity). But now I had a problem: I required Ed’s approval before I could submit a manuscript for publication. After agonizing over this for some time with another postdoctoral fellow, Jim Fuller, whom Ed had recently assigned to work with me, we decided to write a preliminary manuscript reporting these findings and simply place it on Ed’s desk where he would surely see it when he returned. On his return, Ed made no immediate mention of the manuscript. One morning soon afterward, however, I entered my lab to find the manuscript on my desk with “approved” written across the title page and “delete” scrawled across a single paragraph inside. After the publication of that manuscript minus the offending paragraph (Miles and Fuller, 1974), telescopic spectacles became the standard technique for studying adaptive gain control of the VOR. Ed and I rarely conversed after that and, amazingly, he left me alone to do as I wished. Even more surprising, unbeknownst to me, Ed had persuaded the NIH to petition for a waiver of the J-1 foreign residence requirement; in 1975, I obtained a green card, giving me permanent resident status without having to spend two years abroad. At times, Ed could be very harsh and authoritarian, but at other times he could be kind and generous. Several years later, Ed confided that he’d been “wrong about those experiments,” but our relationship remained distant.

After Ed had allowed our paper to go forward, I plunged into studying the neurophysiological basis of the long-term adaptive control of VOR gain, with emphasis on determining the locus of the presumed underlying synaptic changes. The semicircular canal afferents were known to receive an efferent innervation from the brain stem and, given my previous experience with a centrifugal system, my initial thought was that these efferents might be mediating the gain adaptation. The recent classical recordings of Fernandez and Goldberg had shown that the canal afferents discharged as though encoding angular head velocity. Accordingly, I decided to examine the impact of changing VOR gain on the sensitivity of canal afferent fibers to sinusoidal angular oscillations of the whole animal about a vertical axis. This involved a statistical evaluation of populations of fibers recorded in the VIIIth nerve in normal and gain-changed monkeys—significant gain changes took many hours, so I did not think it feasible to record the impact of changing the gain on individual afferent fibers. It soon became evident that the VOR gain changes were probably not mediated by the efferents—though it would take quite some time to gather statistically convincing evidence.

Although this was very disappointing, the decision to start by recording in the VIIIth nerve turned out to be most fortuitous. I had recently visited Albert Fuchs’s lab in Seattle and heard about some remarkable observations that he and his graduate student, Stephen Lisberger, had made while recording in the monkey’s flocculus. They had found that the simple spike discharges of many P-cells (reflecting mossy-fiber inputs) modulated in phase with head velocity during angular oscillations about the vertical axis, as though driven by vestibular inputs from the semicircular canals, but only when the animal fixated a visual target that moved with the oscillating chair (i.e., when the monkey’s eyes were roughly stationary in their orbits). Remarkably, there was little or no modulation when the oscillated animal fixated on a stationary target (Lisberger and Fuchs, 1974). Steve and Albert interpreted these findings as supporting Ito’s idea that the flocculus was an inhibitory side-loop of the vestibulo-ocular pathway but offered no explanation as to why the P-cells’ activity modulated only when the monkey fixated on a target that moved with the chair. Of course, this was especially interesting to me because of Ito’s suggestion that the flocculus was the site of the modifiable synapses underlying the adaptive capability of the VOR.

As luck would have it, the microelectrodes that we were lowering into the VIIIth nerve actually passed through the flocculus, and we were soon able to confirm Steve and Albert’s findings. However, the lack of modulation of P-cell simple-spike activity when the animal fixated on a stationary target while being oscillated was puzzling to me—there was no obvious reason for it, and it meant that the flocculus was making little or no contribution to the normal VOR. Almost immediately, Jim Fuller and I found an explanation for this: The simple spike activity of the P-cells also modulated when the stationary monkey tracked a moving target, as though the cells were encoding the velocity of the eyes as well as the velocity of the head. Remarkably, these eye and head signals had the same directional preference (discharges increasing with ipsilateral motion), were of roughly the same strength, and were summed algebraically, which meant that when the oscillating monkey fixated on a stationary target, so that its eye velocity was almost the same but opposite in direction to the head velocity, these two signals canceled one another, hence the lack of observed P-cell modulation. In effect, the P-cells were encoding gaze velocity, which was the velocity of the eyes with respect to the stationary surroundings and was given by the sum of the velocity of the head with respect to the surroundings and the velocity of the eyes with respect to the head.

One of the remarkable things about recording in the flocculus was that gaze velocity was encoded only in the discharges of the output cells—that is, the P-cells—and not in the many mossy fiber inputs to those P-cells, the discharge behavior of which generally resembled that of vestibular afferents (encoding angular head velocity) or oculomotor motoneurons (encoding eye position and eye velocity) or neurons receiving visual inputs (encoding retinal slip velocity). Clearly, the P-cells were synthesizing the gaze velocity signal. Or perhaps they were encoding the velocity of the track target with respect to the surroundings, which would mean they were summing together three signals rather than two: the velocity of the head with respect to the surroundings (“head velocity”), the velocity of the eyes with respect to the head (“eye velocity”), and the velocity of the target with respect to the eyes (“retinal slip velocity”). Note that target velocity is also given by the sum of gaze velocity and retinal slip velocity. Jim Fuller and I published a preliminary report of our findings, proposing that the simple spike discharges of the P-cells in the monkey’s flocculus were effectively encoding target velocity (Miles and Fuller, 1975), and I incorporated this into a signal flow model of the open-loop VOR and the negative feedback ocular pursuit system (Miles, 1976, 1977). In our experiments, the retinal slip velocity was mostly rather small so that a visual contribution to P-cell discharges was generally minor if not negligible (less than 5 percent), and we subsequently came to refer to them as gaze velocity P-cells.

The existence of eye velocity signals in flocculus P-cell discharges complicated our plans to investigate the neurophysiological basis of the adaptive changes in VOR gain; the problem is best appreciated from Figure 1, which shows our signal flow model of the VOR incorporating the gaze velocity P-cells in the flocculus (bounded by the dashed line). We considered the head velocity input to the P-cell to be a vestibular feedforward signal and the eye velocity input to be an efference copy signal in a positive feedback loop. Robinson and others had long incorporated such internal positive feedback loops in their models of the primate ocular pursuit system. The boxes A, B, C, and D in Figure 1 represent the potential gain elements that might mediate the adaptive changes in VOR gain. The gain of the VOR could be increased, for example, by a decrease in the gain of element A (as hypothesized by Ito) and/or by an increase in the gains of elements C, D, or B. We examined the effect of long-term changes in VOR gain on the gaze velocity P-cells in the monkey’s flocculus, evaluating the strength of the head velocity signals carried by the P-cells using Steve and Albert’s paradigm of oscillating the animal while it fixated a target moving with the chair. We also evaluated the strength of the eye velocity signals carried by the P-cells by having the stationary monkey pursue a moving target. Our major finding was that in monkeys with high VOR gain following exposure to ×2 spectacles, the gaze velocity P-cell discharges were significantly more sensitive to head velocity than to eye velocity. In fact, the increase in the sensitivity to head velocity roughly matched the increase in the VOR gain. This meant that during oscillation in the dark, the elevated head velocity signal roughly canceled the now elevated eye velocity signal and P-cell modulation continued to be minor (i.e., the flocculus continued to make only a minor contribution to the VOR in the gain-changed monkey). In the model in Figure 1, such differences in the monkeys with high VOR gain could have resulted from an increase in the gain of elements A and/or C. If the increased sensitivity of the P-cells to head velocity were due solely to an increase in the gain of element A in the flocculus, then this would have operated to decrease VOR gain and it would be necessary to invoke an additional change (increase) in the gain of element D to achieve the necessary increase in the VOR gain. Further, element D, which is in the brain stem, would be properly regarded as the modifiable element subserving the VOR gain increase. We concluded that the modifiable elements mediating the increase in VOR gain were in the brain-stem vestibular pathways, and are represented in Figure 1 by elements C and/or D.

Fig. 1.    Signal flow model of the gaze velocity P-cells in the flocculus.

Our findings were published in a back-to-back sequence of four papers. The first paper described the effects of telescopic spectacles on VOR gain (Miles and Eighmy, 1980). The second described the VIIIth nerve recordings in normal and gain-changed monkeys, essentially reporting no differences (Miles and Braitman, 1980). The third described the discharge characteristics of neurons in the flocculus of normal monkeys (Miles, Fuller, Braitman, and Dow, 1980). The fourth described the discharge characteristics of P-cells in the flocculus of gain-changed monkeys and concluded that the synapses responsible for adaptive gain control were in the brain stem (Miles, Braitman, and Dow, 1980). Data collection had taken several years, and the quantitative data analysis took more than another year—the computers available at that time were quite slow and the quantitative data analysis was very labor intensive. Jim Fuller had left my lab soon after this project began, and I had been joined by another postdoctoral fellow, David Braitman, as well as a visiting scientist, Bruce Dow, both of whom made valuable contributions. Beverley Eighmy worked as a technician in the lab and also helped with some of the data analysis. In the last of the four papers, we ended by pointing out that, during the initial exposure to the telescopic spectacles, the discharges of the gaze velocity P-cells would reflect the VOR gain error and so might be responsible for the induction of the long-term changes in synaptic transmission in brain-stem vestibular pathways that we were convinced mediated the changes in VOR gain. This idea was taken up by Steve Lisberger, who had recently joined me as a postdoctoral fellow. Steve rewarded monkeys for fixating on a small target presented against otherwise dark surroundings while the monkey and the target were moved either in phase or 180 degrees out of phase to mimic the gaze velocity events—and presumably also the P-cell discharge modulation—that normally occur when the monkey first wears minifying or magnifying spectacles. This resulted in “adaptive” changes in the gain of the VOR even though there was no gross retinal image slip, consistent with the hypothesis that the error signal guiding recalibration of the VOR could be the modulation of gaze-velocity P-cell discharge (Miles and Lisberger, 1981a).

Steve also made another interesting finding. In the late 1970s, the visual backup to the VOR was generally studied by placing the stationary subject inside a cylindrical drum that rotated around the subject about a vertical axis. The inside walls of the drum were painted with black and white vertical stripes to provide a powerful visual stimulus. The heavy drum was first brought up to speed in the dark, then the lights were turned on for perhaps a minute and the subject’s eye movements were recorded. These ocular responses consisted of tracking movements in the direction of drum rotation interrupted by resetting saccades, a pattern termed optokinetic nystagmus (OKN). The development of OKN over time had been well described by Cohen, Matsuo, and Raphan (1977) and generally showed two distinct phases that were felt to reflect two distinct mechanisms—an early component (OKNe) with brisk dynamics and a delayed component (OKNd) with sluggish dynamics. Steve found that changes in VOR gain were associated with parallel changes in the magnitude of OKNd, whereas OKNe was unchanged. This finding suggested that the modifiable elements responsible for the VOR gain changes were located between the sites at which these two mechanisms gained access to the final oculomotor pathways (Lisberger, Miles, Optican, and Eighmy, 1981). The clear suggestion was that the variable gain element was shared by the VOR and OKNd. One possible advantage of such a shared arrangement was that the visual and vestibular control systems were synergistic, both working to compensate for rotational disturbances of the observer, and so would benefit from sharing the same coordinate framework and projection pathways. All of our new findings on VOR gain adaptation were summarized and discussed more fully in a review article (Miles and Lisberger, 1981b). Together with another postdoctoral fellow, Lance Optican, who had joined me from Johns Hopkins, we also showed that VOR gain adaptation could be frequency selective (Lisberger, Miles, and Optican, 1983), proposing an adaptive equalizer model of the primate VOR (Miles, Optican, and Lisberger, 1985) and, together with David Zee at Johns Hopkins, showed that bilateral ablation of the flocculus (and ventral paraflocculus) eliminated the adaptive capability of the VOR in monkeys (Lisberger, Miles, and Zee, 1984).

Those were the last projects that I did on the flocculus and plasticity of the VOR, and I never again recorded single units. Already by 1980 I felt that I had expended too much effort on this project—almost six years at that point. My contention that the synaptic modifications responsible for VOR gain adaptation were in the brain-stem vestibular pathways initially met with considerable skepticism. Others have since confirmed most of our findings regarding the changes in flocculus P-cell discharges with long-term changes in VOR gain (Lisberger, Pavelko, Bronte-Stewart, and Stone, 1994), and there is now good evidence for modifiable elements in brain-stem vestibular pathways (Lisberger, 1994; Lisberger, Pavelko, and Broussard, 1994; McElvain, Bagnall, Sakatos, and du Lac, 2010). Interestingly, new data suggest that the neural modifications underlying changes in VOR gain occur initially in the cerebellum but then shift to the brain stem during the subsequent consolidation process that marks an enduring (plastic) change (Kassardjian, Tan, Chung, Heskin, Peterson, and Broussard, 2005; Shutoh, Ohki, Kitazawa, Itohara, and Nagao, 2006).

The transfer of fixation between near and far objects involves changes in vergence eye movements and accommodation, each under separate visual feedback control but known to be cross linked in the brain. In a complete departure from my earlier work, Stuart Judge and I devised what we called laterally-displacing periscopic spectacles to increase or decrease the apparent separation of the two eyes—thereby increasing or decreasing the required amount of vergence per unit change in accommodation—and were able to show that the gains of the neural cross linkages between vergence and accommodation were subject to adaptive regulation (Judge and Miles, 1985).

In 1980, I moved to Bob Wurtz’s new Laboratory of Sensorimotor Research in the National Eye Institute (NEI) intramural program at the NIH and, having recently acquired U.S. citizenship, I was able to take up a permanent position. From my point of view, Bob was the ideal laboratory chief: once appointed you were left alone to get on with it. Bob also attracted a group of unusually talented scientists—including Mickey Goldberg, David L. Robinson, Lance Optican, Bruce Cumming, Ed FitzGibbon, and Okihide Hikosaka—and this made for a very lively intellectual environment. However, Bob’s new lab was in a new building that was still some months away from completion, so I was temporarily without a lab. Stuart Judge had moved to Oxford some months before and kindly invited me to join him there to extend our previous study using rather more refined methodology. The NIH would permit me to work in Oxford for only a few months, so I was obliged to return to Bethesda before completing this study. Because my new lab was still not ready, I completed the study in David Robinson’s lab at Johns Hopkins in early 1981, but it didn’t get published until some years later, after Lance Optican had helped out with the data analysis (Miles, Judge, and Optican, 1987).

The Initial Ocular Following Response

It was now 1981, and for some time I had wanted to explore the visual—rather than vestibular—stabilization of gaze. Because I was now obliged to set up a new lab, this was an opportune time to make the change. The traditional way to study the visual stabilization of the eyes was with an OKN drum, and the assumed adequate stimulus here was simply global retinal slip. Given the complexities of normal visual experience, I did not see how such a crude global system could function in the real world and, working with a new postdoctoral fellow from Japan, Kenji Kawano, we soon discovered that indeed visual stabilization of the eyes was much more complicated than previously assumed. Instead of sitting inside an optokinetic drum, our monkeys faced a large flat screen onto which we back-projected a densely textured image that could be moved with servo-controlled mirror galvanometers. This gave us much more control over the composition of the visual stimulus as well as the onset, direction, and speed of its motion. We immediately found that brief motion ramps (velocity steps lasting 100 ms) elicited tracking movements of the eyes at ultra-short latencies—as short as 50 ms with optimal stimuli. We referred to this initial tracking as the ocular following response (OFR) and were mainly interested in the initial open-loop responses recorded within two reaction times of stimulus onset (100 ms). This meant that the measured responses were very small: the eyes simply cannot move very far in such a short time. In order to get good signal-to-noise, we had to record eye position with very high resolution—this meant using the electromagnetic search coil pioneered by Albert Fuchs and David Robinson—and we also had to average many responses, often more than 100. Fortunately, the initial OFR was very machine-like even though we had neither trained the animals to track the movements nor reinforced them for doing so. That we were dealing with an automatic reflex became clear when the motion stimulus was a one-dimensional sine-wave grating. Remarkably, for a given contrast, latency was solely a function of the temporal frequency (the product of spatial frequency and speed), which specified the rate of change of luminance (in Hz) at any given point on the screen, and this suggested to us that the OFR was triggered by the local changes in luminance. Such direct dependence on the precise physical parameters of the visual stimulus was to become a hallmark of the initial OFR, indicating that it resulted from a rather direct link between the visual and oculomotor systems; although we were recording motor responses, the OFR would turn out to be a valuable source of information on the early cortical processing of the visual motion stimulus. However, our initial studies mostly indicated that the OFR had a number of special features that allowed it to deal with a variety of previously unforeseen real-world visual problems.

In exploring our environment, we use rapid saccadic eye movements to redirect our gaze from one object to another, thereby bringing images of potential interest into the region of the fovea where our vision is most acute. We found that these rapid shifts of gaze had a profound influence on the OFR. Motion applied to the scene in the immediate wake of a (centering) saccade generated a much better OFR than the same motion applied a few hundred milliseconds later. The magnitude of this transient postsaccadic enhancement was dependent on the retinal stimulation during the antecedent saccade, and a saccade-like shift of the visual background alone was sufficient to cause a similar transient enhancement of the OFR to a subsequent motion of that background. Interestingly, this visual enhancement did not show interocular transfer—saccade-like shifts seen by one eye did not enhance the OFR to motion seen by the other eye—indicating that the enhancement was occurring in the early part of the visual pathway, before the inputs from the two eyes converge.

From the functional point of view, this transient postsaccadic enhancement was most opportune because the eyes do not always come to a complete stop immediately after a saccade, often drifting onward or backward for 100 ms or more. These postsaccadic ocular drifts, termed glissades, which undermine retinal image stability and hence compromise visual acuity, occur when the brain fails to program the correct level of innervation to hold the eyes stationary in their newly acquired position. Lance Optican and I had earlier used persistent postsaccadic drifts of the visual background to show that there was a visually mediated adaptive mechanism working to minimize glissades, and we proposed a new pulse-slide-step model of saccadic innervation to explain our findings (Optican and Miles, 1985). Together with David Zee, Lance and I also showed that this adaptive mechanism was disabled by flocculus lesions (Optican, Zee, and Miles, 1986). In operating to stabilize the eyes with respect to the stationary environment, the OFR would work to suppress any residual glissades, and the transient postsaccadic enhancement of the OFR would occur at the very time that ocular stability is most threatened by the glissades. Another important point is that such transient boosts in the gain of a negative-feedback control system avoid the overshoot and oscillation that can occur with prolonged increases in gain.

Partitioning the image on the screen into separate central and peripheral regions using two projection systems (and applying the OFR motion stimuli only when the animal looked at the center) showed that the visual enhancement of the OFR was local. Thus, a saccade-like shift applied to the central (or peripheral) retina enhanced the OFR to a subsequent motion in that same central (or peripheral) region. In contrast, a saccade-like shift applied to the peripheral retina caused a brief powerful suppression of the OFR to concurrent motion in the central retina. This peripheral suppression showed excellent interocular transfer: saccade-like shifts in the peripheral field of one eye suppressed the OFR generated by concurrent motion in the central field of the other eye. This indicated that the suppression must be occurring within the central nervous system (CNS) at a point receiving inputs from both eyes. From the functional point of view, this peripheral suppression would help to prevent the ocular following system from tracking the retinal image motion that occurs when saccadic eye movements sweep the eyes across the visual scene, a form of saccadic suppression. In fact, saccade-like shifts applied only to the center of the visual field actually elicit OFRs (albeit small and transient), whereas such movements applied to the periphery alone or to the whole field do not.

Partitioning the visual scene into separate central and peripheral regions also showed that en masse movement of the visual scene was not the optimal stimulus for the initial OFR. If the center was quite large (20o to 40o across), and the motion was again applied only when the animal looked at the very center, the direction of the OFR was always determined by the direction of the motion in the central region, regardless of the direction of motion in the surround. However, the latter had an anomalous effect on the magnitude of the OFR, which was actually reduced when the motion in the periphery was in the same direction as the motion at the center—en masse motion—and was increased when the motion in the periphery was in the opposite direction to that at the center. This anomalous effect of peripheral motion seemed to suggest that the OFR was optimized for tracking moving objects: a fixated object that suddenly starts moving to the right causes rightward motion of the images in the central retina and results in a rightward OFR so that the image of the stationary background in the peripheral retina would then be seen to move leftward. Note that the central image motion here is due to afference (stimulus motion) whereas the peripheral image motion is due to reafference (observer motion).

The large size of the central area required for this anomalous reafferent effect suggested that, under normal conditions, the objects that would best engage the ocular following system would generally be stationary and nearby, their retinal images moving only because the observer was moving. Thus, the moving observer who attempts to fixate on nearby stationary objects must track them and will experience contrary afferent and reafferent motions in the central and peripheral retinas, respectively, resulting in optimal engagement of the ocular following system. The fact that reafferent motion in the periphery aided rather than impeded the visual tracking of the afferent motion at the center was not due to inversion of the sign of its visual input: motion in the periphery alone generated OFRs that were always in the direction of the seen motion (albeit weak). This led us to suggest a negative feedback tracking system driven by afference from foreground images moving in the central retina and enhanced by reafferent background images moving in the opposite direction in the peripheral retina (motion parallax). We termed this positive reafferent modulation.

The long-term adaptive regulation of VOR gain that I had studied earlier was deemed necessary because the VOR operated open-loop and was therefore very sensitive to fluctuations in internal parameters that might occur as a result of aging, trauma, disease, fatigue, and so forth. However, even closed-loop, negative-feedback mechanisms such as the OFR would have a preferred forward loop gain: if this gain were too high, the OFR would tend to display overshoot and oscillation, and if this gain were too low, the OFR would tend to show undershoot and large steady-state errors. We therefore sought to determine if the gain of the OFR was subject to visually mediated long-term adaptive regulation.

Our adaptation paradigm involved repeated exposure of the monkey to double-ramp motions (“velocity steps”) of the visual scene. Each of these two ramps lasted only 150 ms, and they could differ in either speed (“speed steps”) or direction (“direction steps”) depending on the experiment. The idea was that the first ramp would initiate an OFR and the second would create a consistent error. For example, in a speed step, the second ramp could be faster or slower than the first, simulating under- or over-shoot, respectively. Over a period of hours, simulated undershoots caused gradual increases in the initial OFR, and simulated overshoots caused gradual decreases in the initial OFR. This adaptation was directionally selective so that in a given experiment it was possible to adapt vertical responses independently of horizontal, rightward independently of leftward, and upward independently of downward. Also, to some extent, this adaptation was speed dependent, whereby the initial OFR to high-speed stimuli could be adaptively increased (or decreased) while the initial OFR to low-speed stimuli was being adaptively decreased (or increased). In the direction-step paradigm, the second ramp was directed 90 degrees counterclockwise to the first, so that if the first ramp was rightward, then the second was upward and so on. This paradigm gradually brought out orthogonal responses to our 100-ms test ramps (e.g., the initial OFR to a rightward ramp now included a substantial upward component). Thus, even the direction of the OFR was subject to adaptive regulation. Such versatile adaptive capabilities suggested to us that the OFR was well optimized and that its gain in each of the various directions was tuned to some optimal value.

Kenji Kawano returned to Japan in the summer of 1985 and our various findings on the monkey’s OFR were published soon afterward (Kawano and Miles, 1986; Miles and Kawano, 1986; Miles, Kawano, and Optican, 1986). We concluded that, although the OFR operated as a reflex, it had many special features to deal with problems caused by various incidental factors such as saccades, glissades, and reafference, and its performance was optimized by a very versatile adaptive mechanism. Kenji continued to work on the OFR in monkeys and obtained strong evidence that the initial OFR was mediated by the medial superior temporal (MST) area of the cortex, a region known to be important for the processing of visual motion. Meanwhile, I was joined by a new postdoctoral fellow, Reuven Gellman, and together with a clinical fellow, Jim Carl, we recorded short-latency OFRs in humans, which we found to be very similar to those of monkeys. One particularly interesting finding was that when the initial OFRs to one-dimensional sinewave grating stimuli were normalized with respect to spatial frequency, every one of our subjects showed the same dependence on temporal frequency—bandpass characteristics with a peak at 16 Hz—indicating that temporal frequency rather than speed per se was the limiting factor over the entire range examined. This suggested that, in humans too, the underlying motion detectors were responding to the local changes in luminance (Gellman, Carl, and Miles, 1990).

Two new postdoctoral fellows joined me—Urs Schwarz from Switzerland and Hubert Kimmig from Germany—and we embarked on some new projects. Hubert did a very nice study on the effects of stationary textured backgrounds on the initiation of pursuit eye movements in monkeys (Kimmig, Miles, and Schwarz, 1992), while Urs set about trying to find evidence for a new vestibular response that we later called the translational vestibulo-ocular reflex (TVOR). In 1987–88, I had a year’s leave of absence, which I spent at the City University of New York, working with Josh Wallman at City College. Josh had developed an exciting new model of myopia in the domestic chick, and we did a series of experiments that showed that persistent near viewing in the upper visual field could result in local myopia in that part of the visual field (Miles and Wallman, 1990). I returned to Bethesda in early 1988 and resumed experiments on the hypothesized TVOR with Urs Schwarz.

Translational Disturbances of the Observer and of the Visual Scene

Our finding that the initial OFR was subject to positive reafferent modulation indicated that the OFR had some special features associated with translational—rather than rotational—disturbances of the observer. This led me to think about the optic flow experienced by the observer who undergoes lateral (sideways) translation, and I began to wonder if there was a VOR that compensated for such motion. I knew that the conventional VOR compensated solely for rotations of the head (let us call it the RVOR) and that it relied on inputs from the semicircular canals in the labyrinth, which Goldberg and Fernandez (1975) had shown were selectively sensitive to angular accelerations and insensitive to linear accelerations. However, Goldberg and Fernandez’s paper had also shown that the otolith organs in the labyrinth were selectively sensitive to linear accelerations and insensitive to angular accelerations, and this led me to wonder if the otoliths might support a second VOR that compensated for lateral translations (let us call it the TVOR). A problem here was that lateral translation of the observer causes complex image shear because the nearby objects move across the field of view more rapidly than the distant ones (motion parallax), and a given compensatory eye movement can only eliminate the retinal image motion of objects stationed at a particular viewing distance. Given that primates had frontal vision, vergence eye movements, and stereopsis, it seemed to me that the challenge facing the TVOR during lateral translation would be to stabilize binocular gaze on the depth plane containing the object of regard. To be optimally effective, therefore, the gain of this hypothetical TVOR would have to be inversely proportional to the viewing distance necessitating range-finding information, which I thought might be provided by the vergence angle between the two eyes and/or the accommodative effort used to focus the eyes on the object of regard.

A visit to the library failed to turn up clear evidence for a robust TVOR, and I thought this might have been because in previous studies the subjects had always been translated in darkness without any thought that viewing distance might be important. (Of course, subjects were in darkness to prevent them from using visual tracking.) Urs Schwarz and I recorded vergence and accommodation in stationary, fixating monkeys and found that after the fixation light was turned off—leaving them in darkness—the monkeys often retained the same vergence angle and the same level of accommodation for a few hundred milliseconds, sufficient time for us to translate the whole monkey briefly and record any associated TVOR. Urs and I improvised a linear sled driven by a servo motor from an old turntable and recorded the monkey’s eye movements during brief (200-ms) lateral (sideways) accelerations along the interaural axis. The acceleration was applied only after the monkey had satisfactorily fixated a small target light located at one of several possible viewing distances and the target was extinguished just before the sled began to move, leaving the monkey in total darkness during the translation. We found that sled motion elicited robust compensatory eye movements that were a linear function of the inverse of the prior viewing distance and we attributed these responses to a TVOR. The modulation with viewing distance was less than required, so that the TVOR undercompensated with near viewing and overcompensated with distant viewing, perhaps because the conditions were so impoverished (passive viewing in darkness).

At this point, I recalled our earlier suggestion that the OKNd provided a visual backup to the RVOR and shared the neural pathway containing the gain element responsible for adaptive gain control of the RVOR. It occurred to me that the OFR—with its special sensitivity to motion parallax—might provide a visual backup to the TVOR and, if so, might share its dependence on viewing distance. At the beginning of 1989, a new postdoctoral fellow, Claudio Busettini, joined me from Italy, and together we sought to find out if the OFR was sensitive to the viewing distance. We seated the monkey in a chair mounted on a rail, and this allowed us to adjust the viewing distance to the screen onto which the OFR stimulus was back-projected. Of course, the size and speed of the back-projected image also had to be adjusted so as to preserve a constant motion stimulus on the retina at all viewing distances. Even though the visual motion stimulus was always the same, we found that the amplitude of the initial OFR was inversely proportional to the viewing distance with a sensitivity comparable to that of the TVOR. This led us to propose two visuo-vestibular mechanisms, one dealing with rotational disturbances—the RVOR and OKNd—and the other with translational disturbances—the TVOR and OFR (Miles and Busettini, 1992; Schwarz, Busettini, and Miles, 1989). Using wedge prisms to dissociate the distance cues—vergence and accommodation—we found that neither of these cues alone (nor a linear combination of the two) could account entirely for the dependence on viewing distance of either the TVOR or the OFR. We therefore suggested that the important cue was perceived distance, a rather complex entity that was known to be influenced by many factors.

The data describing the dependence of the TVOR and the OFR on viewing distance were published in two back-to-back papers (Busettini, Miles, and Schwarz, 1991; Schwarz and Miles, 1991). The need for the dependence on viewing distance was clear for the TVOR but less obvious for the OFR, and at first, we assumed that it was perhaps simply tolerated by the OFR as the cost of sharing a pathway and a coordinate framework with the TVOR. However, we had known for some time that the dependence of the OFR on speed showed progressive saturation, and Claudio’s new experiments showed that the saturation level was inversely related to the viewing distance, indicating that the saturation originated upstream of the elements whose gain modulated with viewing distance. This meant that, under normal viewing conditions, this speed saturation would tend to offset the dependence on viewing distance because the retinal slip speeds experienced by the moving observer tend to vary inversely with viewing distance, resulting in greater saturation with nearer viewing.

A later study by Geoffrey Bush, who did a postdoctoral fellowship with me in the early 1990s, showed that the vertical eye movements induced by a brief period of free fall—the vertical TVOR—also had a gain inversely proportional to viewing distance, and these experiments provided an estimate of the response latency that was much shorter than any in the recent literature (Bush and Miles, 1996). These experiments were all done on monkeys, and subsequent studies on humans showed a similar (though weaker) TVOR; dependence on viewing distance was evident in the human OFR only when the visual and vestibular stimuli were interleaved so that, on any given trial, the subject did not know whether he would be moved—-eliciting the TVOR—or the visual image would be moved—eliciting the OFR (Busettini, Miles, Schwarz, and Carl, 1994). It seems that the distance cues used by humans were even more complex and context specific than those used by monkeys.

I had one other postdoctoral fellow in the 1990s, Rich Krauzlis, who worked mostly independently. Rich came from Steve Lisberger’s lab at University of California, San Francisco (UCSF) and was so competent and energetic that he simply forged ahead and managed very well with only minimal help from me. I have real regrets that I did not have more interaction with someone so capable, but, in any event, Rich did a very fine series of experiments on monkeys that dealt with the initiation of pursuit and saccades, including the role of the oculomotor vermis in this process, and he made very elegant use of the gap paradigm (Krauzlis and Miles, 1996a, b, c, d; Krauzlis and Miles, 1998; Krauzlis, Zivotofsky, and Miles, 1999).

The Initial Disparity Vergence Response

Vergence eye movements are used to align both eyes on the same object and so must vary with the viewing distance, nearer viewing requiring greater convergence. It had been known since the classic experiments of Rashbass and Westheimer in the early 1960s that the vergence eye movements responsible for binocular alignment depended in large part on the slight difference in the locations of the images on the two retinas due to the slight difference in the viewpoints of the two eyes (binocular disparity). It had also been suggested that vergence errors were sensed by disparity-selective neurons in the visual cortex: in the usual negative-feedback control models, neurons activated by images nearer than the plane of fixation (crossed disparities) caused increased convergence, and neurons activated by images beyond the plane of fixation (uncrossed disparities) caused decreased convergence.

Claudio Busettini and I found that, without training or reinforcement, small disparity steps applied to large textured patterns elicited consistent, machine-like, vergence eye movements that were always in the appropriate direction for a servomechanism that operates to correct residual vergence errors and, amazingly, had latencies of less than 60 ms in monkeys—less than half that previously reported with small fixation targets. For these experiments, monkeys faced a tangent screen onto which two identical random-dot patterns were back-projected. Orthogonal polarizing filters in the two projection paths together with matching filters in front of the two eyes ensured that each eye saw only one of the two patterns, the positions of which were controlled by mirror galvanometers. At the start of each trial, the two patterns appeared exactly superimposed and then were suddenly separated, creating a horizontal or vertical disparity step that lasted 200 ms before the projected images were blanked. Because the latency of the disparity vergence response (DVR) was similar to that of the OFR, we were concerned that each eye might be tracking the apparent motion that it saw (“monocular OFR”), in which event these vergence responses would not have resulted from the neural processing of the binocular disparity per se.

That this was not the case was evident from three control experiments that all yielded appropriate vergence eye movements at short latency. In the first, the disparate images appeared only after a period of darkness, so there was no motion; in the second, a new pair of (disparate) random-dot patterns was substituted at the time the disparity was applied, so that again there were no motion stimuli; in the third, the whole disparity step was applied to one eye only, yet both eyes contributed to the vergence response—the one not seeing the step moving in the opposite direction to the motion step seen by the other eye. We therefore concluded that it was appropriate to refer to these eye movements as disparity vergence responses.

Like the initial OFR, the initial DVR showed transient postsaccadic enhancement, whereby small disparity steps applied in the immediate wake of a centering saccade yielded vergence eye movements with much higher initial accelerations than did the same steps applied a few hundred milliseconds later. This postsaccadic enhancement of the DVR was like the postsaccadic enhancement of the OFR in also being at least in part due to the visual stimulation associated with the prior saccade. Thus, the DVR was subject to transient visual enhancement when the disparity steps were applied in the wake of conjugate (saccade-like) shifts of the textured pattern. From the functional viewpoint, we argued that this transient postsaccadic enhancement would help speed the binocular realignment of the eyes when gaze was shifted to new depth locations. These first experiments on the short-latency DVR of the monkey were published in 1996 (Busettini, Miles, and Krauzlis, 1996), and a subsequent study uncovered very similar responses in humans at only slightly longer latencies (Busettini, FitzGibbon, and Miles, 2001).

At Oxford, Bruce Cumming and Andrew Parker had made the nice observation that disparity selective neurons in the monkey’s visual cortex were sensitive to the disparity of dense anticorrelated patterns (in which each black dot seen by one eye is matched to a white dot in the other eye), and the associated disparity tuning curves were often inverted compared with those obtained with the more usual correlated patterns (Cumming and Parker, 1997). These inverted tuning curves were consistent with early spatial filtering of the monocular visual inputs prior to their binocular combination as in the disparity-energy model of the complex cells in striate cortex (Ohzawa, DeAngelis, and Freeman, 1990). Importantly, these dense anticorrelated patterns were perceptually rivalrous and lacked consistent depth (Cogan, Lomakin, and Rossi, 1993). Claudio and I were joined by Guillaume Masson from France and, working on monkeys and humans, we were able to show that small disparity steps applied to dense anticorrelated patterns gave rise to inverted (anticompensatory) DVRs (Masson, Busettini, and Miles, 1997). This indicated that the DVR derived its binocular information from an early stage of cortical processing, prior to the level at which depth percepts were elaborated, and relied upon neurons such as those recorded in the monkey’s striate cortex by Cumming and Parker.

The Ocular Following Response: Dependence on Absolute Binocular Disparity

After developing the idea that the OFR worked in synergy with the TVOR to selectively stabilize images in the plane of fixation during lateral (sideways) disturbances of the observer, it occurred to me that, ideally, the OFR should be able to ignore the motion of objects that were nearer or more distant than the object of regard (i.e., ignore moving images that had binocular disparity). This led us to examine the effect of binocular disparity on the initial open-loop OFR. For this, subjects faced a tangent screen onto which two identical random-dot patterns were back-projected. Orthogonal polarizing filters in the two projection paths, together with matching filters in front of the two eyes, ensured that each eye saw only one of the two patterns, the positions of which were controlled by mirror galvanometers. The binocular visual stimulus now used to apply the disparity and elicit the OFR consisted of a horizontal step-ramp. The step was disconjugate (i.e., one eye saw a rightward step and the other a leftward step), serving to immediately position the binocular image of the random-dot patterns in a new depth plane nearer or farther than the screen, hence giving the patterns binocular disparity; the ramp was conjugate (i.e., the two eyes saw motion in the same direction, rightward or leftward, for 200 ms) and served to elicit an OFR. By applying the disparity at the last possible moment—at the start of the OFR stimulus ramp—we were able to avoid significant DVRs until the OFR was well underway. With this approach, binocular disparity attenuated the OFR substantially, just as we had hypothesized.

Claudio, Guillaume, and I published this finding in Nature, citing it as evidence that the OFR responded selectively to images in the plane of fixation with zero binocular disparity (Busettini, Masson, and Miles, 1996). However, two or three years later, after Claudio and Guillaume had left my lab, I realized that the attenuation of the OFR caused by the disparity step probably had nothing to do with its disparity. Embarrassingly, I had forgotten that Kenji Kawano and I had shown some years earlier that a saccade-like shift of the image on the screen caused transient suppression of the OFR to concurrent motion (peripheral suppression). Working with a new postdoctoral fellow, Dongsheng Yang, I soon found that when the disconjugate step in our step-ramp paradigm was replaced with a conjugate one—so that both eyes saw the same rightward or leftward step and hence there was no change in the disparity of the pattern—the OFR elicited by the conjugate ramp was still attenuated. Clearly, a change in disparity was not required, and the attenuation of the OFR by the disparity step in our original experiments had actually been due to peripheral suppression.

I called Claudio and Guillaume to give them the bad news. Fortunately, I also had good news for them. It had occurred to me that applying the disparity and the motion uniformly to the whole screen image effectively simulated the visual experience of a rotating observer who is compensating only partially for the rotation, and who has a vergence error. However, our interest was in the observer who undergoes linear translation in a world with three-dimensional structure and who has visual stabilization mechanisms that utilize binocular disparity to distinguish objects moving in the plane of fixation (afference) from objects moving in other depth planes due to motion parallax (reafference). It occurred to me that the OFR might be much more complex than we had assumed, and that it might require a much more realistic test of our disparity hypothesis necessitating more complicated visual images that simulated afferent and reafferent motion.

Dongsheng and I therefore recorded the initial OFR elicited when the random-dot pattern on the screen was partitioned into horizontal strips that suddenly underwent motion, alternate ones leftward and rightward. Not surprisingly, with alternate strips undergoing conflicting motion, the initial OFR was very weak. However, we thought that if we could apply horizontal disparity selectively to alternate strips, say, to all those with leftward motion, then if our hypothesis were correct those (“reafferent”) strips should lose their influence and the OFR would now be rightward, that is, dominated by the motion in the (“afferent”) strips whose images were still in the plane of fixation. However, we still had the problem of introducing the disparity without eliciting peripheral suppression. In the original experiments, we had applied the step-ramp 50 ms after a centering saccade (to take advantage of postsaccadic enhancement), and Dongsheng and I now found that steps applied during the centering saccade—regardless of whether conjugate or disconjugate—lost almost all of their attenuating effect on the OFR to a conjugate ramp. This meant that we could “hide” the disparity step inside a saccade and thereby avoid peripheral suppression. Thus, in our new experiment, the disparity steps were applied during centering saccades and the conflicting motions commenced 50 ms after the saccades ended (thereby taking advantage of postsaccadic enhancement). The data were exactly in accordance with our hypothesis, indicating that the OFR was sensitive to binocular disparity and strongly favored image motion in the plane of fixation. Furthermore, the OFR used disparity to distinguish afferent from reafferent motion; spatial location (central versus peripheral) was of secondary importance.

Claudio and Guillaume eagerly returned to Bethesda to complete the study, and we included additional experiments in which the conflicting motions commenced at various times after the centering saccade. This showed that the attenuating effect of the disparity was fully developed at the earliest time tested—10 ms after the saccade—too soon to be explained by a shift of attention, for example. The new data from our revised experiments were presented at the Festschrift for Han Collewijn in 2000 and were published the following year (Masson, Busettini, Yang, and Miles, 2001). This whole unfortunate episode indicated that we had seriously underestimated the complexity of our reflex responses.

That the OFR was sensitive to binocular disparity only when applied differentially to regions undergoing conflicting motion and not when applied uniformly to the whole screen image led us to think that the motion detectors driving OFR might be sensitive to relative disparity rather than absolute disparity. Note that absolute disparity refers to the slight differences in the positions of the two retinal images of a given object due to the differing viewpoints of the two eyes, whereas relative disparity refers to the differences in the absolute disparities of different objects within the visual scene due to differences in their distance to the observer. We already knew from the work of Regan, Erkelens, Collewijn, and others that human stereopsis (depth perceived from binocular disparity) was much more sensitive to relative disparity than to absolute. To obtain definitive evidence for relative disparity, it was necessary to show that the disparity tuning in one region of the visual field was dependent on the disparity in another region. Dongsheng Yang and I later used the same partitioned display of alternating strips with conflicting motion and found that the zero absolute disparity at which one set of strips had their maximal impact on OFR was not affected by changing the absolute disparity of the other set of strips with conflicting motion; that is, the responses to the two stimuli were separable. Hence, it was the absolute and not the relative disparity of the motion stimuli that determined their impact on OFR (Yang and Miles, 2003). This meant that the OFR selectively stabilized the retinal images of objects in and around the plane of fixation and so worked in harmony with the DVR, which had long been known to use absolute disparity to bring objects of interest into the plane of fixation.

The Initial Radial Flow Vergence Response

By 1997, there had been many papers in the literature concerned with the optic flow experienced by the moving observer and, in particular, with the radial pattern of flow experienced by the moving observer who looks ahead. The streaming retinal images were seen as a rich source of information about the observer’s rate of progress and direction of heading. It occurred to me that in order to maintain binocular alignment on objects of interest that lie ahead, the moving observer must continuously adjust the vergence angle between the two eyes, and I wondered if, in addition to binocular disparity, the vergence system might also utilize the radial optic flow. I had in mind that briefly presented large-field radial optic flow might elicit short-latency vergence responses. In particular, I wondered if brief centrifugal flow, in which retinal images flowed away from the fovea (simulating the observer’s forward approach) might increase the convergence of the eyes and the reverse pattern of centripetal flow (simulating the observer’s retreat) might decrease the convergence.

For technical reasons, we decided to try single steps of optic flow, using two slide projectors and switching between them so that the subject first saw a stationary random-dot pattern, and this was then suddenly replaced by a second one that was identical except slightly larger (producing a radial-flow step with a focus of expansion at the fovea) or slightly smaller (producing a radial-flow step with a focus of contraction at the fovea). As usual, we applied the simulated flow step in the immediate wake of a centering saccade. Using ourselves and a volunteer as subjects, Claudio, Guillaume, and I found that centrifugal steps resulted in increased convergence and centripetal steps resulted in decreased convergence. Latencies were again ultra-short (about 80 ms). These initial experiments simulated a change in viewing distance and so included size changes as well as radial flow. However, eliminating the change in size was without effect, and size changes applied alone, without radial flow, were ineffective. We felt that these initial vergence eye movements represented a binocular response to the radial pattern of optic flow but were concerned that they might have resulted from monocular tracking, each eye tracking the motion that it saw in the nasal hemifields. For example, with centrifugal flow there would be a net motion vector toward the nose in both nasal hemifields, and if each eye independently tracked that motion, the result would be increased convergence. Masking off different parts of the flow fields seen by each eye indicated that this was not the correct explanation. Thus, the binocular vergence responses to radial-flow steps persisted during monocular viewing and, importantly, also persisted when both nasal hemifields were masked off. In this latter case, each eye actually moved in the opposite direction to the net motion vector that it saw (in its temporal hemifield). We concluded that the vergence responses resulted from a true parsing of the radial flow pattern and so referred to them as radial flow vergence responses (RFVRs).

After we had published our initial study of the RFVR (Busettini, Masson, and Miles, 1997), I realized that as an observer moves forward or backward the vergence angle between her two eyes must change at a rate that is inversely proportional to the square of the viewing distance in order to maintain binocular alignment on the object of regard. This meant that the RFVR might create a problem for an observer moving forward through a visually cluttered environment such as a forest: any convergence resulting from the optic flow created by the nearby trees would be inappropriate if the observer was trying to fixate on something far ahead.

Interestingly, Paige and Tomko (1991) had shown that there was a fore-aft TVOR that operated in complete darkness, working to increase the vergence angle during forward motion and reduce it during backward motion, and they also reported that the magnitude of these vergence responses increased with the vergence angle. (Though whether these TVOR responses were proportional to the square of the vergence angle, as required for full compensation, was not clear because Paige and Tomko had only a limited data set and had not attempted to fit such a function to their data.) However, I now began to wonder if the RFVR might provide a visual backup to this fore-aft TVOR in the same way that we had proposed that the OFR provided visual backup to the lateral TVOR. If so, the RFVR might share a pathway with the fore-aft TVOR and perhaps even share its dependence on viewing distance so that, under normal conditions, the RFVR would be severely attenuated with distant viewing, an effect that would help to reduce the impact of nearby visual clutter when the moving observer looked far ahead.

Dongsheng Yang and I, along with an ophthalmologist at the NEI, Ed FitzGibbon, decided to investigate the possibility that the RFVR was dependent on the viewing distance (or, more particularly, on the vergence angle between the two eyes). Using ourselves and volunteers as subjects, we faced a large tangent screen onto which two identical random-dot patterns were back-projected in exact register. A system of crossed polarizers and matching filters in front of the eyes ensured that each eye saw only one of the patterns, creating a single binocular image in the plane of the screen. These two projected patterns were then slowly separated horizontally, using mirror galvanometers, thereby adjusting the subject’s vergence angle to the desired level for that trial. Once this desired vergence position had been reached, the two patterns were instantly replaced with two new ones that were 4 percent larger (or smaller), so that each eye saw a radial-flow step with a focus of expansion (or contraction) centered on the fovea. Thus, the radial flow steps were always of the same magnitude, but the subject’s vergence angle varied from trial to trial. This revealed that the amplitude of the initial RFVR was proportional to the preexisting vergence angle and, hence, would be inversely proportional to the viewing distance under normal viewing conditions. We argued that this might reflect a shared pathway with the fore-aft TVOR and would help the moving observer to fixate on objects far ahead while passing through a visually cluttered area (Yang, FitzGibbon, and Miles, 1999). It seemed likely that dependence on the vergence angle might represent a good compromise—if the gain of the RFVR were dependent on the square of the vergence angle, it might become unstable with near viewing.

The Disparity Vergence Response: Evidence for True Population Coding in the Medial Superior Temporal Area

The coding of information by the activity of populations of neurons has received considerable attention in recent years. In most cases, the so-called population coding referred to mechanisms whereby the aggregate activity of neurons with broad, overlapping tuning functions could achieve a finer representation of a particular sensory or motor function. However, in the study I am now going to discuss, the population activity conveyed information that was not evident at the level of the individual neurons, analogous to the way that words convey information that is not evident at the level of the individual letters. In this case, the information is an emergent property of the population activity and therefore truly deserving of the description, population coding. The neuronal recordings in question were carried out in Kenji Kawano’s lab in Japan by two of his students, Aya Takemura and Yuka Inoue. I had continued to collaborate with Kenji, regularly visiting his laboratory in Tsukuba, which had been recording the activity in the MST area of the monkey’s cortex associated with the initial OFRs elicited by conjugate velocity steps and the initial DVRs elicited by disparity position steps. For the latter, they constructed disparity tuning curves describing the dependence of the neuronal activity and the associated DVRs on the direction and magnitude of the disparity steps. They used anticorrelated as well as correlated random dot patterns and found that the disparity tuning curves for the DVRs were similar to those that we had described in humans, resembling the derivative of a Gaussian and well fit by Gabor functions. The disparity tuning curves of the single neurons in MST, however, were much more variable.

When Aya had finished recording, she sent the data to me in Bethesda, and we both agreed that it was extremely difficult to classify the neuronal tuning curves rigorously. Lance Optican suggested that we show the data to his postdoctoral fellow, Christian Quaia, a bioengineer from Italy, to see if he could help with this. Christian did a brilliant post hoc analysis of the data. He first fitted each neuron’s disparity tuning curve to the disparity tuning curve for the associated DVR (with gain and offset the only free parameters). The goodness of these fits was then assessed by computing the fraction of the disparity-induced variation accounted for by the fits (r²). This revealed that there were a few neurons with tuning curves that fit the tuning curve for the DVR reasonably well (r²>0.8) with either correlated or anticorrelated stimuli; but none of the neurons had tuning curves that gave good fits with both types of stimuli. Thus, the goodness of the fit depended on the type of stimulus used to generate the DVR, indicating that there were no pure vergence-encoding cells. Most remarkably, however, when Christian took the disparity tuning curves of all of the cells obtained from a given monkey and simply summed them together (without manipulating any weights), the summed activity fit the tuning curve for the DVRs of that same monkey extremely well (r²>0.93). This was true for the unit data obtained with correlated and anticorrelated stimuli.

For the two animals from which most of the data were obtained, the shapes of the disparity tuning curves for the DVRs obtained with correlated stimuli were very similar for the two animals, but the shapes of the disparity tuning curves for the DVRs obtained with anticorrelated stimuli differed significantly for the two animals. These differences in the vergence data obtained with anticorrelated stimuli were such that the summed neural activity from one monkey gave a very poor fit to the vergence data obtained from the other monkey and vice versa (r²<0.35). Thus, the summed neural activity for a given animal matched only the DVRs of that same animal, indicating that the neuronal population data reproduced the idiosyncrasies of the DVRs of the two monkeys.

Christian also used a fuzzy clustering algorithm to rank order the neurons objectively on the basis of the shapes of their tuning curves and, using a genetic algorithm, obtained strong evidence that the encoding of vergence in the population activity depended on contributions from across the entire range of tuning curves found among the disparity-selective cells in MST. Thus, the population code depended crucially on the aggregate activity of a heterogeneous collection of cells. In a subsequent analysis, Christian showed that the summed neuronal discharges also encoded the time course as well as the magnitude and direction of the vergence eye movements, indicating that the summed activity provided a complete description of the vergence motor output. In my view, the paper describing these data (Takemura, Inoue, Kawano, Quaia, and Miles, 2001) is one of the most compelling of all those purporting to describe population coding.

I think that the stimulus set that Aya and Yuka used had a number of features, some novel, that, in retrospect, were crucial for revealing the population coding in the MST area. First, they sought only to identify the possible contributions of the cells, individually and collectively, to one particular well-defined behavior—the DVR. Thus, they ignored the possibility that these cells discharged in relation to other stimuli and/or motor responses. In particular, they did not use an extensive set of stimulus parameters as others have often done in hopes of identifying the stimuli “preferred” by the individual cells. Second, their stimulus set extended well beyond the biologically useful (servo) range. It was the responses to the outlying stimuli that gave the tuning curves their individual shapes, and hence their individual identities. Third, they included stimuli—anticorrelated patterns—that are rarely, if ever, encountered in the real world and that elicit reversed vergence responses with idiosyncratic features. That these subject-specific features of the motor responses were captured by the aggregate neuronal responses helped to persuade us that the population coding had genuine biological significance and was not simply a fortuitous epiphenomenon.

The Need for Better Control of the Visual Stimulus

In 2001, I did an experiment with Guillaume and Dongsheng that was based on some earlier psychophysical findings. Anstis and others had earlier reported that the perceived motion associated with step displacements (phi motion) could be reversed by reversing contrast during the step (reversed phi), and we now showed that the OFRs elicited by small step displacements could also be reversed by reversing the contrast during the step (Masson, Yang, and Miles, 2002). It was generally thought that Anstis’s reversed phi (and, we assumed, our “reversed OFR”) was mediated by dedicated low-level motion detectors that functioned without regard to form or perceptual features. Many computational models of this process had been suggested, and the so-called motion-energy model of Adelson and Bergen (1985) had been particularly influential. In the same way that Hubel and Wiesel had developed the idea that neurons in striate cortex sensed spatial orientation by operating as spatial filters oriented in x-y space and tuned for spatial frequency, Adelson and Bergen (and others) developed the idea that motion was sensed by spatiotemporal filters that were oriented in x-t space and tuned for spatial frequency. Such models were critically sensitive to the Fourier composition of the motion stimulus and responded to the motion energy, which was defined by the luminance modulation. However, it was possible to design moving stimuli that lacked motion energy—being defined not by luminance but by contrast, disparity, or flicker, for example—and so were invisible to these low-level motion sensors. Yet human observers had no problem perceiving the motion of such stimuli. This led to the idea that there were (at least) two motion-sensing systems, variously referred to as “energy-based” versus “feature-based,” “first-order” versus “second-order,” and “Fourier” versus “non-Fourier.”

There was a very extensive psychophysical literature on this topic that had generated lots of interesting ideas about the neural processing of visual motion (and also binocular disparity), and I was keen to explore these ideas using our short-latency eye movements as a probe. I felt that the OFR, RFVR, and DVR could be used to investigate these visual processes objectively and quantitatively but only if we had much better control of the Fourier composition of our visual stimuli. Eventually, in 2003, I decided to drop the slide-projection approach that we had been using up to that point and develop a large-screen video display. Actually, we put together three displays, two in a Wheatstone stereoscope arrangement to provide the dichoptic stimuli required for the DVR and a third, stand-alone screen, directly ahead of the subject for exploring the OFR and the RFVR.

Many technical issues had to be addressed, requiring a detailed knowledge of personal computer (PC) architecture, graphics cards, video monitors, software, and so forth. The complete makeover of the lab took almost a year and involved seemingly endless calibrations and fine adjustments. For the design, construction, and testing, I relied heavily on my two coworkers, Boris Sheliga, who was a scientist from Russia, and Ed FitzGibbon, who was an ophthalmologist in the NEI. Our new setup was designed for human subjects only and allowed us to specify the harmonic composition of our visual stimuli in exquisite spatiotemporal detail. It was to make the final years of my research (2004–10) among the most interesting and productive of my career. Boris was a crucial part of all of this, taking care of the day-to-day running of the laboratory—including writing all of the software needed to generate the stimuli and to collect and analyze the data—and we worked very closely together right up to the time of my retirement.

Evidence for Energy-Based Sensing Mechanisms

The idea for the first experiment with our new approach came from reading Adelson and Bergen’s lovely review. They had mentioned an apparent motion stimulus that I will refer to as the missing fundamental (mf) stimulus, which consisted of a square-wave grating that lacked the fundamental (see Figure 2A). When seen through a fixed window and moved smoothly, the mf stimulus was perceived to move in the direction of motion—nothing surprising about that—but when moved in discrete, quarter-wavelength steps, then it was generally perceived to move in the opposite direction to its actual motion. The explanation offered was that the first-order motion detectors responsible for the perception here were not sensing the motion of the raw images (or their features) but rather a spatially filtered version of the images, so that the perceived motion depended critically on the Fourier composition of the spatial stimulus. In the frequency domain, a pure square wave is composed entirely of the odd harmonics—first, third, fifth, seventh, and so on—with progressively decreasing amplitudes such that the third, fifth, seventh, and so on have amplitudes that are one-third, one-fifth, one-seventh, and so on, that of the first (i.e., the amplitude of the ith harmonic is proportional to 1/i). The mf stimulus lacked the first harmonic and so was composed entirely of the remaining odd harmonics, with the third having the lowest spatial frequency and the largest amplitude. This meant that when the mf stimulus grating stepped one-quarter of its wavelength, the largest Fourier component, the third harmonic, stepped three-quarters of its wavelength in the forward direction. However, a three-quarter-wavelength forward step of a sine wave is exactly equivalent to a one-quarter-wavelength backward step and, because the brain gives greatest weight to the nearest neighbor image matches (spatial aliasing), the perceived motion was invariably in the backward direction. In fact, with one-quarter-wavelength steps of the mf stimulus, all of the 4n–1 harmonics (where n is an integer), such as the third, seventh, eleventh, and so on, shift in the backward direction, whereas all of the 4n+1 harmonics, such as the fifth, ninth, thirteenth, and so on, shift in the forward direction, and the most prominent harmonic—the third—generally dominates the motion percept. (I will come up with a more complete explanation for that later in this chapter.)

Fig. 2.    Sample patterns used to generate optic flow. (A) A pattern of vertical bars for which the horizontal luminance modulation is that of a square wave lacking the fundamental; arrows indicate a quarter-wavelength rightward displacement of the pattern, which generates a leftward OFR. (B) A pattern of concentric circles for which the radial luminance modulation is that of a square wave lacking the fundamental; arrows indicate a quarter-wavelength radial expansion of the pattern, which generates an RFVR that decreases convergence. (C) A radial pattern for which the angular luminance modulation is that of a 3f5f grating pattern; arrows indicate a quarter-wavelength clockwise step of the pattern that results in the 3f component undergoing a counterclockwise step one-quarter of its wavelength and the 5f component undergoing a clockwise step one-quarter of its wavelength.

The important point was that the direction of perceived motion was determined by the principal Fourier component rather than the overall pattern. We found that the initial OFR elicited by quarter-wavelength steps applied to an mf stimulus such as that seen in Figure 2A had the usual ultra-short latency and was invariably in the opposite direction to the motion of the pattern. In fact, the initial OFR here was almost identical to that elicited when the same quarter-wavelength steps were applied to a pure sine-wave grating whose spatial frequency and contrast matched that of the third harmonic (Sheliga, Chen, FitzGibbon, and Miles, 2005). As with the reversed OFR seen earlier with the reversed phi stimulus, the reversed OFR seen with the mf stimulus was consistent with the idea that the underlying motion detectors were energy-based rather than feature-based.

Soon afterward, we recorded the DVR elicited in human subjects when binocular disparities were applied to mf gratings using our new dichoptic viewing arrangement in which each eye saw its own video monitor through a 45-degree mirror (Sheliga, FitzGibbon, and Miles, 2006). The mf patterns (again like those in Figure 2A) were identical at the two eyes except for a phase difference (i.e., binocular disparity) of one-quarter-wavelength, and this elicited a robust DVR with the usual ultra-short latency, that was always in the opposite direction to the disparity applied to the overall pattern (i.e., in the direction of the disparity of the principal Fourier component, the third harmonic). Thus, with an uncrossed disparity, for example, the DVR showed increased convergence, which as far as the overall pattern was concerned was anticompensatory. Like the anticompensatory DVR seen earlier with anticorrelated patterns, these new anticompensatory data supported the idea that the earliest DVR was a response to the disparity energy in the stimulus. While the RFVR and the OFR generated very different kinds of motor response and were elicited by completely different global patterns of optic flow, it seemed likely that both relied on the same low-level local motion detectors. We therefore sought to elicit RFVRs in human subjects by applying quarter–wavelength radial steps to concentric circular patterns where the radial luminance modulation was that of a square wave lacking the fundamental (see Figure 2B). While the overall pattern and the 4n+1 harmonics (where n = integer) underwent radial expansion (or contraction), the 4n−1 harmonics—including the principal Fourier component, the third harmonic—underwent the opposite radial motion. The radial motion commenced only after the subject had fixated on the center of the pattern so that the optic flow was centered on the fovea (i.e., centrifugal or centripetal optic flow pattern). For these experiments, we were joined by Yasushi Kodaka from Kenji Kawano’s laboratory in Japan. We found that, as with the initial OFR, the initial RFVR was always in accordance with the motion of the third harmonic, consistent once more with mediation by motion detectors that were responding to the local motion energy (Kodaka, Sheliga, FitzGibbon, and Miles, 2007).

Nonlinear Interactions with Opponent Motion: Winner-Take-All

We were somewhat puzzled as to why the responses to the mf stimulus were always so completely dominated by the third harmonic, and it was not until we manipulated the contrasts of the individual harmonics that we understood what was going on. When the contrast of the third harmonic of the mf stimulus was selectively reduced below that of the next most prominent harmonic—the fifth, which moves in the opposite (forward) direction—then the OFR reversed direction and the third harmonic effectively lost all of its influence as the OFR was now dominated by the fifth harmonic. It was as though the principal Fourier component was actually suppressing the responses to the weaker competing harmonics and thereby dominating the OFR in a winner-take-all (WTA) fashion.

To examine this idea more carefully, we simplified things by using only two of the competing harmonics of the mf stimulus—the third and fifth—creating what we called a “3f5f pattern.” When this 3f5f pattern underwent quarter-wavelength steps, there was opponent motion; the 3f component stepped backward one-quarter of its wavelength and the 5f component stepped forward one-quarter of its wavelength. (To further simplify the paradigm, we carefully selected a fundamental wavelength whose third and fifth harmonics were of equal efficacy when of equal contrast and presented singly.) These 3f5f stimuli indicated that the critical factor determining the OFR was the ratio of the contrasts of the two harmonics; when of similar contrast, both harmonics were effective and canceled one another so that the OFR was minimal, but when the two harmonics differed in contrast by more than about an octave (i.e., contrast ratio >2 or <0.5) then the one with the higher contrast completely dominated the OFR and the one with the lower contrast lost all of its influence: WTA (Sheliga, Kodaka, FitzGibbon, and Miles, 2006). This meant that the response to one grating was not independent of the response to the second grating (i.e., the system was nonlinear). Like others before us, we attributed such nonlinear interactions to mutual inhibition between the mechanisms sensing the motion of the competing harmonics. Amazingly, the nonlinear dependence on the contrast ratio was fully described (mean r²>0.99) by a simple contrast-weighted-average model with only two free parameters.

Broadband and dual-grating stimuli had clearly uncovered significant nonlinearities in the visual information processing that could not have been seen with a single sine-wave stimulus. We felt that these nonlinear interactions favoring the component with the higher contrast also made functional sense: they would help to maintain binocular alignment selectively on the objects in the plane of regard because the retinal images of those objects would tend to be better focused—and hence tend to have higher contrasts—than the retinal images of objects in other depth planes. (To a first approximation, image blur operates like a low-pass spatial frequency filter.)

When 3f5f stimuli were used to elicit the DVR and the RFVR, these too displayed nonlinear interactions and generally showed WTA behavior (Kodaka, Sheliga, FitzGibbon, and Miles, 2007; Sheliga, FitzGibbon, and Miles, 2007). Once more, a difference in contrast of an octave or more was sufficient for the harmonic of higher contrast to dominate the RFVR and the vertical DVR, but it required more than a fourfold difference in contrast before the horizontal DVR displayed WTA behavior. Again, we attributed the nonlinear dependence on the contrast ratio to mutual inhibition between the detectors sensing the 3f and the 5f components, but this inhibitory coupling was clearly much weaker for the horizontal DVR. We are not sure why this is so. One might think that the mutual inhibition would have to be very powerful to be biologically useful, but if it were too strong, then the system would be very sensitive to even small differences in contrast, rendering it unstable and overly sensitive to noise. Presumably, the strength of the inhibitory cross coupling is a compromise between the need for a clear winner and the need for noise immunity. Having a visual tracking mechanism operate initially to stabilize the most prominent harmonic might be more useful to the observer than having it respond to the average motion when no particular image is singled out for stabilization.

I was very interested in the spatial extent of the mutual inhibition postulated to be responsible for the WTA behavior and wanted to know what would happen if the competing harmonics did not occupy the same location (i.e., were not overlapping). But how could we separate the harmonics spatially if we had to use large-field stimuli to get our reflex mechanisms to respond? This led me to challenge our long-held belief that large-field stimuli were necessary to elicit our short-latency ocular responses and, to our amazement, we found that the horizontal OFR elicited by a vertical striped grating that occupied the full screen (30o high, 45o wide) was no greater than by a grating of the same contrast and spatial frequency that occupied only a narrow horizontal strip (1o high, 45o wide) at the screen center (Sheliga, FitzGibbon, and Miles, 2008a). Clearly, large-field stimuli were not necessary, and we soon found that the horizontal OFR elicited by horizontal 3f5f gratings still displayed clear WTA behavior when the pattern occupied only a narrow horizontal strip. Even more importantly, when the 3f and the 5f harmonics were restricted to separate horizontal strips, a vertical gap of one degree between them was sufficient to completely eliminate the nonlinear dependence of the OFR on their contrast ratio, and the OFR now approximated a simple vector sum of the responses to each grating strip alone. Thus, the nonlinear interactions responsible for the WTA outcome with the OFR were strictly local, indicating that the postulated inhibitory connections did not extend much beyond the (vertical) spatial confines of the visual stimuli.

Nonlinear Interactions with Component Motion: Global Normalization and Local Winner Take All

The OFR operates as a negative-feedback control system, and Kenji Kawano and I had shown some years earlier that it is subject to long-term, adaptive gain control, consistent with the idea that its gain is tuned to some optimal value. If an increase in the areal extent of the motion stimulus were to increase the visual input signal driving the OFR, it would have the same effect as raising the forward loop gain, potentially destabilizing the system. Ideally, the responses of an ocular tracking mechanism should be relatively insensitive to the spatial extent of the moving images. Such insensitivity to the size of the driving stimulus would require some sort of divisive normalization, a nonlinear process that has often been described in visual cortical neurons and attributed to mutual inhibition.

After we realized that a single narrow strip of grating was sufficient to elicit robust OFRs, we were keen to examine its spatial summation properties. For this, we used a vertical stripe pattern (sinusoidal grating) that was partitioned into a number of horizontal strips each one-degree high and always equally spaced vertically (Sheliga, FitzGibbon, and Miles, 2008a). A single centered strip (covering 3.3 percent of the full screen) always elicited robust OFRs, and three strips (10 percent coverage) were sufficient to elicit the maximum OFR. Increasing the number of strips to 15 (50 percent coverage) had little impact—that is, responses had leveled off—and further increasing the coverage to 100 percent (full-screen image) actually decreased the OFR so that it was now often less than that elicited with only one strip. Thus, over a fivefold range (10–50 percent coverage), the initial horizontal OFR was independent of the total area of the stimulus. In this experiment, the gratings always had the same contrast, and in a second experiment, the contrast of the gratings could be fixed at one of four levels. The OFR showed essentially the same pattern of dependence on the number of strips (i.e., on the screen coverage) at any given contrast, but, significantly, the lower the contrast, the lower the magnitude at which the response leveled off. This indicated that the leveling off was not due simply to the passive achievement of some intrinsic upper limit in the magnitude of the tracking eye movement or the underlying motion signals (“ceiling effect”). Rather, this insensitivity to size over a fivefold range was seen as the result of an active process—divisive normalization—similar to that described by others in cortical neurons and attributed to global inhibition.

There were no competing motions in these last experiments: the motion all came from a vertical striped grating composed of a single sinusoid, albeit one broken up into separate horizontal strips that all moved together. In another study (Sheliga, Kodaka, FitzGibbon, and Miles, 2006), we used a vertical stripe grating pattern that consisted of two sine waves equivalent to the third and seventh harmonics of the mf stimulus, creating what we called a “3f7f pattern,” which occupied the whole screen. Because both are 4n−1 harmonics, with quarter-wavelength horizontal displacements of the 3f7f pattern, both harmonics underwent quarter-wavelength shifts in the same (backward) direction, here termed component motion. Again, when of similar contrast, both harmonics were effective; but when their contrasts differed by more than an octave, then the one with the higher contrast became dominant and the one with the lower contrast became ineffective: WTA. Thus, the WTA interaction between competing harmonics also applied to motion stimuli that shared the same direction and differed only in spatial frequency and speed.

In a subsequent study (Sheliga, FitzGibbon, and Miles, 2008b), the vertical striped pattern was composed of 3f and 7f gratings that were each confined to separate horizontal strips only one to two degrees high, and a robust WTA interaction was still apparent when the two gratings overlapped. However, unlike the situation with the 3f and 5f strips, when the 3f and 7f strips were separated by a vertical gap of up to eight degrees (the largest separation possible), the OFR was still less than the linear sum of the responses to each grating alone. We postulated that there were two nonlinear interactions operating here—local mutual inhibition resulting in WTA behavior and global divisive inhibition resulting in normalization. Interestingly, motion stimuli with responses totally suppressed by coextensive opponent motion of higher contrast were rendered invisible to normalization, indicating that the local interactions responsible for the WTA behavior here were occurring at an earlier stage of neural processing than the global interactions responsible for the normalization.

Temporal Dynamics

A two-frame movie consisting of a single quarter-wavelength step applied to a sine-wave grating pattern occupying the whole screen was sufficient to generate robust, though transient, OFR, and introducing an inter-stimulus interval (ISI) of 10–200 ms (during which the screen was gray with the same mean luminance) reversed the direction of the initial OFR (Sheliga, Chen, FitzGibbon, and Miles, 2006). This reversal was reminiscent of the oft-reported reversal of perceived motion by brief ISIs, which had been attributed to the temporal dynamics of the early visual pathway and, in particular, to the negative phase of the well-known biphasic temporal impulse response function of the human visual system, reflecting the band-pass characteristics of its modulation transfer function. Interestingly, the RFVR could also be elicited with single radial steps, and brief ISIs resulted in reversal of the vergence response (Kodaka, Sheliga, FitzGibbon, and Miles, 2007).

These experiments with ISIs were all done under photopic luminance conditions and it has long been known that changing to scotopic conditions changes the human modulation transfer function from band-pass to low-pass in the frequency domain and from biphasic to monophasic in the time domain. We therefore repeated our experiments on the OFR in the dark-adapted subject using patterns with extremely low luminance. The changes were dramatic. I was the first subject and during the experiment protested that we were wasting our time because I was not able to perceive either the dim stimulus pattern or its motion. Fortunately, my colleagues insisted on finishing the experiment: The OFRs to quarter-wavelength steps in these dim conditions had longer latencies but were by far the largest that we had ever recorded, with an amplitude and duration that were eight times greater than those we usually recorded in normal light-adapted conditions (Sheliga, Chen, FitzGibbon, and Miles, 2006). Perhaps the rod-driven OFR is not subject to divisive normalization? Under these scotopic conditions, reversal of the OFR occurred only with longer ISIs and was very weak, reasonably consistent with the human psychophysics.

The Torsional Ocular Following Response

On a whim, I decided to see if a motion stimulus that rotated the retinal image around the line of sight (“circular optic flow”) would elicit torsional eye tracking at short latency, even though it involved a motion that would normally be associated with rotational disturbances of the observer (in contrast with all of our other motion stimuli, which would normally be associated with translational disturbances of the observer). For this, we replaced our usual search coils with the ingenious figure-eight search coils that Han Collewijn’s laboratory had designed especially for recording torsional eye rotations (Collewijn, Van der Steen, Ferman, and Jansen, 1985), and we redesigned all of our visual stimuli so that the subject now always saw images rotating around the lines of sight, that is, circling around the fovea (Sheliga, FitzGibbon, and Miles, 2009). An initial experiment using random-dot patterns soon revealed that, indeed, there were robust torsional responses, though with latencies approximately 15 ms longer than for the usual OFR.

With 3f5f circular gratings arranged like the spokes of a wheel (see Figure 2C) as well as 3f7f circular gratings, the torsional eye movements elicited by quarter-wavelength steps of angular rotation showed a clear dependence on the motion of the two Fourier components rather than on the motion of the overall features, again consistent with mediation by spatio-temporal filters sensitive to motion energy, and showed a highly nonlinear dependence on the relative contrast of the two gratings that resulted in WTA behavior when their contrasts differed by more than an octave. Thus, the neural mechanisms sensing the two overlapping rotational motions were negatively cross-coupled as though subject to mutual inhibition, regardless of whether those motions were in the same or in the opposite direction. When the 3f and the 5f circular gratings were each reduced to a single annulus of the same radial thickness (3°), WTA behavior was evident only when the two overlapped (same radius) and not when they were separated (different radius), that is, the nonlinear interactions were local. These various stimulus dependencies were, in all essentials, like those we had previously seen with the horizontal and vertical OFR and could even be described by the same mathematical functions, often with very similar parameter values. Accordingly, we referred to these initial torsional eye movements as the tOFR. However, there was one major surprise: The tOFR showed much weaker spatial normalization than the horizontal OFR, and Boris Sheliga discovered that this had a very interesting consequence. Using a circular grating consisting of a one-dimensional sinusoid partitioned into a number of equally spaced concentric annuli all of the same radial width (that could be 0.5°, 1°, or 1.5°) and same contrast (that could range from 2 percent to 32 percent), Boris found that the latency and the magnitude of the tOFR were well described by single monotonic functions if plotted against the product of the total area of the annuli and the square of their Michelson contrast (A*C²). It was as though the onset and magnitude of the tOFR were determined simply by the total motion energy in the stimulus! Boris also reanalyzed our old horizontal and vertical OFR data and found that, when plotted against A*C², a single monotonic function sufficed to describe the latency but not the magnitude. The latter was inevitable, given that the OFR was subject to such powerful spatial normalization whereby responses failed to grow with fivefold increases in stimulus area. Thus, the global organization of the tOFR provided some new insights into the distribution of the mutual inhibition thought to underlie the divisive normalization of the OFR: these inhibitory connections extend horizontally and vertically, but not circularly around the fovea.

The Disparity Vergence Response: Independent Sensing of First- and Second-Order Disparity

Based on the initial DVRs recorded when disparities were applied to anticorrelated random-dot patterns, mf stimuli, and 3f5f stimuli, we had concluded that the earliest vergence was a response to the disparity energy in the stimulus. However, there is substantial evidence for stereopsis when disparity is applied to binocular stimuli that lack first-order energy because they are defined not by luminance but by a second-order characteristic such as contrast. In what was to be my last project, Holger Rambold (a postdoctoral fellow from Germany), Boris Sheliga, and I recorded the initial DVRs elicited by disparity stimuli in the form of one-dimensional sinusoidal gratings with a binocular phase difference of one-quarter-wavelength, created by luminance modulation (LM) and/or contrast modulation (CM) of a dynamic noise carrier that was uncorrelated at the two eyes (see Figure 3A–C). We showed that gratings defined by CM at both eyes (Figure 3E) elicited robust DVRs that worked to reduce the quarter-wavelength disparity (i.e., gave greatest weight to the nearest neighbor matches). One problem here that had to be taken care of was that compressive nonlinearities early in the visual pathway were known to result in first-order distortion products that can render even pure second-order stimuli—such as the CM stimuli—visible to first-order (energy-based) detectors. However, we were able to show that disparity stimuli defined by CM at both eyes still elicited robust DVRs—although at slightly longer latency (∼ 20 ms)—even after such early first-order distortion products had been nulled by adding in-phase LM at both eyes, consistent with mediation by cortical mechanisms selectively sensitive to disparities defined by the second-order CM. Hybrid first- and second-order disparity stimuli—in which one eye saw a grating defined by LM and the other saw a grating defined by CM with a binocular phase difference of one-quarter-wavelength (Figure 3F)—generated only weak DVRs that were always in the “wrong” direction and had the ultra-short latencies associated with first-order DVRs, consistent with mediation by first-order distortion products associated with the CM stimulus. In fact, these (reversed) DVRs could be eliminated entirely by adding a small amount of in-phase LM to the CM stimulus that was exactly equivalent in magnitude to the first-order distortion products seen earlier. Various controls indicated that the failure of the hybrid LM and CM stimulus to elicit DVRs after nulling any first-order distortion products was also not due to differences in the amplitude, spatial phase or timing of the inputs from the two eyes, leading to the conclusion that the cortical detectors sensing disparities defined by first-order LM and second-order CM must be independent. These findings were published in my last paper (Rambold, Sheliga, and Miles, 2010). Of course, the methodology in this study could also be used to look for OFRs and RFVRs to second-order stimuli defined by contrast.

Fig. 3.    Sample disparity stimuli. (A–C) One-dimensional sinusoidal gratings created from a dynamic binary noise pattern (A), by luminance modulation (B), and contrast modulation (C); the upper plots show sample cross-sections of the luminance and the lower panels show the patterns as seen by the observer. (D–F) Patterns as seen by the observer when disparity stimuli in the form of one-dimensional sinusoidal gratings with a quarter-wavelength binocular phase difference were created by luminance modulation at the two eyes (D), contrast modulation at the two eyes (E), and luminance modulation at one eye and contrast modulation at the other eye (F). (LE, left eye. RE, right eye.) Such beautiful patterns would not be out of place in an art gallery. From Rambold, H.A., Sheliga, B.M., and Miles, F.A. (2010). Evidence from vergence eye movements that disparities defined by luminance and contrast are sensed by independent mechanisms. Journal of Vision, 10(14): 31, 1–34. With permission.

Epilogue

The emphasis in this memoir has been on my research—mostly what I did and how I came to do it—with little about my private life except during the early years before I entered science. Some will find it too detailed, but it seemed the only way to capture the full flavor. Always one hoped that the ideas would be novel, the methodology would be rigorous—perhaps even elegant—and the data would be decisive. Of course, things often fell short of that, and looking back, I think the last phase of my research perhaps came closest, when the turnover of ideas was satisfyingly rapid and everything was completely quantitative. During this period, I found it especially pleasing that, almost always, stimulus dependencies could be modeled with simple mathematical expressions that had only one or two free parameters and yet described at least 95 percent (often, 99 percent) of the stimulus-induced variance. This is so rare in neuroscience. It was also deeply satisfying that many of the local spatiotemporal characteristics were so like those of neurons in the monkey’s striate cortex; it was as though we were probing the neural processing in the human striate cortex, even though we were actually recording only motor responses. Almost by chance, we had happened upon a beautiful way to study the human visual system. Perhaps an important factor here was that, at any given moment, there could be only one eye movement, and our reflex responses were the culmination of a prodigious amount of neural processing that represented the nervous system’s best initial estimate of what was in the subject’s best interests. I thought that alone made them deserving of close study.

I retired in 2010 after almost 40 years at the NIH. I had had the ideal situation—a well-equipped laboratory, a steady stream of talented and highly motivated coworkers, no teaching, and minimal administrative duties. It was rare for me to have more than one or two postdoctoral fellows at a time, allowing me to spend most days working with them in the lab rather than administering a group from an office. I always felt that close contact with the raw data was imperative if the many potential pitfalls in research were to be avoided. Even so, constant vigilance—and numerous controls—were always needed if one wanted to lay claim to a genuine advance. In my last year or so in the lab, I began to notice that I could not always recall the details of a given experiment and would have to check with my colleague: I was no longer a reliable source of information, and retirement was the only option. But I was well satisfied. I had had a good run, and it was time to turn to other things: family, friends, reading, travel, opera, concerts, art exhibitions, theatre, the outdoors, and so on and so forth.

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Peter M. Milner

BORN:

Silkstone Common, Yorkshire, UK

June 13, 1919

EDUCATION:

Leeds University, U.K. B.Sc. (Engineering) (1941)

McGill University, Montreal, Canada, Ph.D. (1954)

APPOINTMENTS:

Scientific Officer. U.K. Ministry of Supply (1941)

McGill University (1955)

HONORS AND AWARDS:

Emeritus Professor, McGill University (1991)

Canadian Psychological Society Gold Medal for Distinguished Lifetime Contributions to Canadian Psychology

Peter Milner’s first degree was in communication engineering, and he worked (during World War II) on the development of radar and nuclear energy. In 1947, as a result of reading Hebb’s Organization of Behavior, he switched careers and trained as a neuropsychologist. In 1953, James Olds and Peter Milner, working at McGill University in the laboratory of Donald Hebb, found that electrical stimulation of a region rostral to the hypothalamus of the rat brain caused the rat to behave as if it had been rewarded. For several decades after the publication of this finding, many groups, including Peter Milner and his students, investigated the nature of this phenomenon.

Peter M. Milner

History

I was born in 1919, the first child of David William Milner, a research chemist, and Edith Anne Marshall, an ex-schoolteacher, who everyone called Nance. My paternal grandfather had a corner grocery store near Leeds, where my father grew up. I heard that my great-grandfather Milner was a butler who ran the household for one of the gentry in North Yorkshire. Going back even further, to the eighteenth century, rumor among my paternal relatives has it that Joseph Priestley, the Unitarian minister who discovered oxygen and carbon dioxide, was an ancestor of ours. The daughter of one of my father’s cousins, Dr. Thelma Rowell, who was a professor of psychology at the University of California at Berkeley for many years, heard the same story from her family. My belief in the rumor increased when I found that, amongst his many accomplishments, Priestley was a pioneer of neuropsychology. In 1775, he wrote a book entitled Hartley’s Theory of the Human Mind, on the Principle of the Association of Ideas; with Essays Relating to the Subject of It. Hartley’s theory was that sensations and ideas are the result of brain cell vibrations. In the introduction to his book, Priestley writes, “It will stagger some persons that so much of the business of thinking should be made to depend upon mere matter, as the doctrine of vibrations supposes…. But I do not know that this supposition need give any concern, except to those who maintain that a future life depends on the immateriality of the human soul.”

My mother was a daughter of John Marshall and Elizabeth Mountain. In his younger days, John was an auctioneer and ran a pub in Boro’bridge, a North Yorkshire market town. Elizabeth did not consider a pub to be a suitable environment in which to raise daughters; so when my mother and her sisters began to appear, the family moved to a farm in the nearby village of Roecliffe. My grandparents still lived there when I was young, and a highlight of our visits, as far as I was concerned, was being met at Boro’bridge railway station (long gone) by my grandfather with his pony and pony cart. My mother was raised on the farm with her brother and two sisters. Her intelligence impressed the local parson, and he encouraged her to attend Teachers Training College in Ripon.

My father also trained as a teacher and because he did well in his science courses, he was persuaded to study for a bachelor’s of science degree at Leeds University. This was a stroke of luck because when World War I started, shortly after he graduated, my father was sent to work in the laboratory of an explosives factory instead of to the trenches. After the war, he was employed as chief chemist of a company that processed the by-products of the conversion of coal into coke. He never became a schoolteacher, though at one period he taught an evening class in organic chemistry at Barnsley Technical College.

Early Years

Until I was about five, we lived in a small village in south Yorkshire, close to Barnsley. Our house had no gas or electricity, I needed a school, and my father’s lab was in a suburb on the other side of Barnsley, so we moved into the town. I was enrolled in the infants’ section of St. Mary’s School and, after a couple of years, was promoted to St. Mary’s Elementary School for Boys. Henceforth, as was the almost universal custom in England at the time, I was not distracted at school by the proximity of students of the opposite sex. Indeed, at the secondary level, my grammar school and the girls’ high school were in different parts of town. Even when I reached the university, there were no female students in my engineering courses (though I believe that was not due to any official policy). Both my parents were trained teachers, so elementary school was only a minor part of my early education. My mother taught me how to read and write and tried, without success, to teach me how to play the piano. My father answered most of my questions about what things were for and how they worked. I also got further scientific information from regular installments of Arthur Mee’s Children’s Encyclopedia. In general knowledge, I was way ahead of most of my classmates.

My father liked making things; he fitted the Barnsley house with an electric doorbell powered by a homemade Leclenché cell, the wet forerunner of the zinc–carbon dry battery. He also built wireless sets. He gave me discarded components to play with, and I built pretend sets. Later, as I learned how receivers operated and I inherited functional components, I built sets that worked. When I was about ten or eleven, I built my first (unlicensed) transmitter that I, and no doubt our neighbors, could hear on our home wireless sets. I also built shortwave receivers and hoped one day to have an amateur transmitter’s license. Rebuilding my sets, and finding new stations, took up a good deal of my time during secondary school. One of my teachers told me I could go far if I were not so lazy, but my apparent laziness was really an addiction to my hobby. After tea (the evening meal in Yorkshire), I rushed through my homework and stole time to scan shortwave radio bands for distant transmitters.

Television was not a problem; it did not exist. It is true that, as early as 1929, John Logie Baird and the BBC tested broadcasts of ultra-low definition TV, using the regular medium-wave transmitters after normal hours, but it could hardly be called entertainment. One of my father’s former assistants, Ernest Woodcock, had a friend who built a television receiver, and I once saw it working. A beam of light passed through a Kerr cell, where its intensity was modulated by the radio signal. A small square of the modulated light was scanned by viewing it through holes punched in a rapidly rotating disk. The image was about the size of a postage stamp and was accompanied by a strong smell of toxic nitrobenzene from the Kerr cell. An amazing technical achievement perhaps but not something anyone might be tempted to stare at all evening.

When I was about 13, we moved to a semidetached house in a suburb near my father’s lab. The adjoining house was occupied by our friends the Copleys. Their son, Ronald, and I both liked to listen to late night music. This was long before the days of bedside clock radios. I had a homemade wireless set in my bedroom, but Ron had no such luxury. Our bedrooms were adjacent, so it was easy to sling a wire between the two windows to pipe the music to his room. My innovation was that I incorporated a relay into the receiver to switch it off when the transmitter closed down, usually around midnight. This gadget allowed me to fall asleep or, if I was awake, obviated the need for me to switch it off. As it turned out, these extracurricular activities were not a complete waste of time. They may have saved my life, just as my father’s chemistry degree may have saved his, and they undoubtedly enhanced my quality of life a few years later.

Higher Education

In my grammar school, after four years of general education, students intending to pursue postsecondary education continued to the sixth form for a two-year program specializing in either science or humanities. I, of course, chose science and because I wanted to go to university became more focused. It was not all science, however; German was compulsory. Mr. Noot our teacher, Dutch I believe, had spent the previous summer in Germany. He was favorably impressed by the changes there since Adolf Hitler took over, but he met only skepticism in school.

My favorite periods at school were the science labs. Our physics teacher, Mr. Cottingham, spent his spare time designing teaching tools, amongst which was a multipurpose overhead projector. As well as projecting the usual transparencies, it could, with a glass dish of water, equipped with electrically driven paddles for generating ripples, project wave interference patterns and other wave phenomena onto a screen for class demonstrations. Cottingham also constructed an oscilloscope, using a loudspeaker unit and a mirror drum. I, and some other sixth-form students, accompanied him to a Science Masters’ Association Conference in Manchester to show off these toys.

This formative period of my life lay between World War I and World War II. I was born after the armistice that halted the fighting in WWII, but before the signing of the Treaty of Versailles, which formally ended the war. In 1933, in my third year of grammar school, Hitler took over a demoralized Germany with promises to restore territory and prestige lost in World War I. Canon Dick Sheppard thought that it might defuse the situation to demonstrate the strength of the anti-war feeling in Britain, so he organized a Peace Pledge renouncing war. One or two of my teachers, in subjects such as geography and history, were pacifist Quakers who recruited students, including me, to go door-to-door getting signatures for the Pledge. It received great support, of course, and probably gave much encouragement to Hitler, who had just sent his tanks with impunity into the Saar, a border region demilitarized by the Versailles Treaty.

In 1936, the Spaniards overwhelmingly elected a socialist-leaning government, triggering a revolt by some army officers, including General Franco. His army consisted mainly of troops airlifted from the Spanish colony of Morocco by the German air force, augmented by German and Italian “volunteers” from the two fascist powers in Europe. The Germans in particular used the ensuing Spanish civil war to rehearse the blitzkrieg techniques they were to use with such effect a few years later. Thanks to Picasso’s painting, their destruction of Guernica, a Basque town that was carpet-bombed continuously for three hours on a market day, is still remembered. By the time I graduated from grammar school in 1937, only incurable optimists were dreaming of peace. For most of us, it was just a question of what could be done to stop the fascists and how soon.

Job Hunting

I must have thought better of becoming a ship’s radio officer at about this time. I attended an open day at Leeds University and found some of the demonstrations in the electrical engineering department very interesting. Before the results of my final exam for the Higher School Certificate were posted in July, my father may have had doubts about my getting into university, so I had an interview for a job in the Post Office telephone service. Before satellites and submarine cables, transatlantic and other intercontinental telephone services had to bounce shortwave radio signals from the unreliable ionized layers of the atmosphere to overcome the curvature of the Earth, so I might have found a job related to my hobby. My father and I also consulted the chairman of the electrical engineering department at Leeds University, and he strongly recommended that I apply to Metropolitan-Vickers for admission to their probationary college apprenticeship program. Metropolitan-Vickers (Met-Vicks), which started out with the name British Westinghouse around the turn of the century, was a large engineering firm located in Trafford Park, near Manchester. Their most visible activity was building power stations, but they also had a research lab that interested me. Each year they enrolled a few prospective engineering students in their probationary apprentice program. The apprentices spent a month or two in different departments of the factory—such as the foundry, the turbine-assembly shop, and so on—learning what went on there. The candidates were supposed to return to Met-Vicks as fully fledged college apprentices after they graduated, with a good chance of subsequent employment. The Great Depression was still going on, so getting a job was a serious consideration.

Metropolitan-Vickers

I made the short list of applicants invited to Manchester for an interview and, after a rather intimidating day in luxurious surroundings, I passed muster and became a probationary college apprentice (PCA), earning the princely sum of 17 shillings and 6 pence (about $4.40 US in those days) per 48-hour week. The work was pretty strenuous, but during term time we were given Thursdays off to attend classes at Manchester Tech. I lived in a boardinghouse in Stretford with a couple of other apprentices, Struan Robertson (of Scottish-American background from Shanghai, whose father was an oil man) and Torfinn Oftedahl (a college apprentice from Norway). Recently, I read Torfinn’s obituary in the Washington Post and discovered that he had entered the Norwegian diplomatic service in 1938; after 17 years in Washington, he was appointed as Norwegian ambassador in turn to Austria, Czechoslovakia, Canada, and Romania. In 1989, he died at the age of 80 in Baddek, Nova Scotia, so he must have liked his spell in Canada. Our Stretford landlady was an excellent cook and housekeeper, whose invalid husband had fallen victim to mustard gas during the war. She served substantial evening meals, so I was able to economize with a light salad for lunch in the Met-Vicks refectory. Thus did I acquire the habit of eating my main meal in the evening. My fellow apprentices came from all parts of the UK, and a few, such as Struan and Torfinn, were from abroad. My year at Met-Vicks was my introduction to people with relatively sophisticated backgrounds.

We apprentices were circulated through a variety of workshops, usually for a month or two in each. I remember only a few of the places I worked; one was the assembly shop where they were putting the finishing touches to a turbine that may have been destined for Durban. I spent two months in the iron foundry, the first month helping to feed the furnace where the iron was melted, the second on the casting floor. In the machine shop, I helped to mill some small turbine blades. Probably the only reason that I still remember the job is that it was rumored that the blades were for an experimental gas turbine. A few years later fighter planes powered by jet engines began to appear.

During my time at Met-Vicks, the factory was visited by a team of efficiency experts conducting a “time and motion” study. They watched people work and recommended ways in which time and effort could be saved. Of course, building a power station is not the same as assembling a car or a washing machine, but some of the jobs at Met-Vicks were repetitive. The exercise was not popular with the workers, but I thought the approach had some merit and it probably influenced the way I plan some of my activities.

Leeds University

The first year in engineering at Leeds University was quite general; my specialty, communication engineering, was taught in later years. Math was mostly a repetition of the calculus, matrix algebra, analytical geometry, and so on that I had learned at school, relearned at Manchester Tech, and have spent the rest of my life forgetting. The dean of engineering was a heat engine man, so we received a thorough grounding in that. Possibly inspired by the rumor about the turbine blades that I milled at Met-Vicks, another student and I tried to apply theory that was well established for steam turbines to the design of hot air turbines, but I do not remember that it aroused much excitement among the faculty.

By the end of the school year, the war in Spain was over, with General Franco in control and the rest of Europe was waiting for Hitler’s next move. I landed a summer job with the British Broadcasting Corporation (BBC)—a month at the Moorside Edge transmitter and another month at the other side of the microphones. The BBC had two 50-kilowatt medium-wave (about 300- to 600-meter) transmitters serving the north of England. They were located at a fairly isolated spot in the Pennines, the chain of highlands between Yorkshire and Lancashire. In 1939, the engineers—most of them ex-Navy men, were adjusting the frequency controls so that several BBC transmitters in different parts of the country could transmit on very nearly the same frequency. This made the signals difficult or impossible to use for navigation. Shelters and other preparations for air raids were also underway.

The daily routine at the transmitters was rigidly adhered to, and there was little for us summer students to do except in emergencies, such as a burned out transmitter valve, so I was looking forward to my month at the Manchester studios, which started in the middle of August. In fact, because I was assigned to outside broadcasts, I spent the first couple of weeks at various seaside resorts hauling and connecting sound equipment to broadcast music and variety shows. The next week I was due to move to the studios, but on Friday, Hitler invaded Poland and I was told that, in the likely event of Britain declaring war on Germany, I would not be allowed on the premises because I did not have a security clearance. Two days later, on Sunday morning, Neville Chamberlain announced the declaration of war, and my summer job was over. My parents came to take me back to Barnsley in the car. Nobody knew when the air raids would start, so a complete blackout was enforced, and we drove home over the Pennines with no lights of any sort. It was a scary ride. There were still a few weeks before term started, so Ron Copley and I volunteered to help a local farmer with his harvest.

Engineering was considered an essential occupation by the War Ministry, and engineering students were allowed to complete their degrees before being drafted. We were, however, expected to join the Officer Training Corps (OTC). We were given uniforms and drilled once or twice a week, trained in the use of Enfield (World War I) rifles, and taught to disassemble, clean, and reassemble (but never fire) Bren light machine guns. Our degree program was also accelerated by eliminating the 1940 summer vacation.

Germany overran half of Poland very quickly and the USSR took advantage of the situation by grabbing the other half. Poland’s allies decided against making a suicidal attempt to evict them. During the winter, all was quiet on the Western Front: the “phony” war. The Royal Air Force dropped propaganda leaflets on Germany; the Luftwaffe refrained from dropping bombs, or anything else, on England or France. Then in April 1940, Germany launched a surprise attack on Norway, a neutral country.

During World War I, the German Navy was bottled up in the Baltic Sea; this time they wanted Norway’s Atlantic ports to avoid a repetition of the problem. I found out some years later that the Germans also wished to take over the heavy water plant at Vemork. This hydroelectric plant was the only source of substantial quantities of heavy water before the war, and Germany had imported a lot of it. The few people familiar with nuclear research at the time guessed that it was destined for research on nuclear energy and, eventually, bombs. The invasion should have ensured continuous access for the Germans, but in fact, because most Norwegians did not take kindly to the German presence, a large quantity of the heavy water went missing (much of it turned up eventually in Canada), and sabotage of the plant was so persistent that it was dismantled and taken to Germany, where it was never reassembled.

The success of the seaborne invasion under the nose of the British Navy was demoralizing, especially because it considerably increased the threat of submarine attacks on transatlantic shipping. But we had hardly taken it in before things took a more serious turn for the worse. Early in May, around exam time, a large and highly effective German army pushed through the Netherlands and Belgium, bypassing the strong defenses of the Maginot Line along the French border, and routed the French, Belgian, and British forces that were curiously ill-prepared for blitzkrieg tactics. The French collapsed, and the British raced the Germans to Dunkirk; in early June, thanks to thousands of small boats, 300,000 British troops escaped to England, leaving most of their equipment and supplies behind.

We all thought the Germans would not be long following them. Those of us in the university OTC were issued rifles and spent our nights guarding factories and sensitive areas in Leeds against possible parachute landings. Curiously, I do not remember that I ever considered the fact that someone with a World War I–era rifle that he had fired only a few times would not stand much chance against a squad of well-trained commandos with automatic weapons. The whole thing felt very unreal, and in fact it was. The invasion never came. Hitler wanted to get control of the air first. He never got it, largely because the Germans underestimated the effectiveness of the British radar. In the attempt, Hitler lost a very large number of his bombers and their crews, and he decided Russia was a better bet; meanwhile, I started my third-year courses. In the communications classes, we learned about the design of transformers, amplifiers, telephone lines, and filters for a variety of functions.

It was not part of a formal course, but in our spare time two fellow students and I used the electronics lab to investigate and exploit a little-known property of the pentode valve. The early electron tubes had three electrodes: a hot cathode to emit electrons, a positively charged anode—to which the negatively charged electrons were attracted—and an interposed wire grid the voltage of which determined the electron flow. When the grid was at the same voltage as the cathode, it did not interfere with the flow of electrons to the anode, bringing the anode voltage to a minimum. A negative voltage on the grid reduced the flow of electrons and allowed the anode to go more positive. The grid and anode voltages thus go in opposite directions; an oscillator requires amplification without reversal of phase.

Pentodes have a second grid, held at a positive voltage, to eliminate capacity feedback between the anode and grid one, and a third grid usually held at the same voltage as the cathode, to catch electrons that might bounce off or be knocked from the anode onto the second grid. If this third grid is made negative, it reduces the current reaching the anode, but the repelled electrons go instead to the positively charged screen grid, reducing its voltage. Thus the voltage on the second grid goes in the same direction as that of the third grid. We used this characteristic to make an oscillator and discovered that the frequency of oscillation so produced could be varied by changing the voltage on the normal control grid (grid number one) of the pentode. By connecting that grid to the time base voltage from an oscilloscope, the frequency of the oscillator may be made to vary as a function of the horizontal position of the oscilloscope spot, so that the response of any circuit to a range of frequencies could be visualized on the screen. This application was the one that we emphasized in a paper we published in the Leeds University Engineering Society Journal (Burrell, Milner, Russell 1941), my first journal article.

Before the war, I had become interested in ultra shortwave radio and, possibly because of the pentode work, it occurred to me that at extremely high frequencies the time it takes an electron to travel from the grid of a normal triode to the anode could result in amplification with no phase reversal at extremely high frequencies. For example, if it takes a bunch of electrons 0.0005 microseconds to fly from the grid to the plate of a valve, and part of the resulting drop in plate voltage is transmitted at the speed of light from the plate to the grid by capacity coupling, this negative voltage on the grid would cut off the flow of electrons, causing the anode and—by capacitive coupling—the grid to go positive and release another bunch of electrons. This process would recur every 0.001 microseconds, generating an oscillation at one gigahertz, corresponding to a wavelength of about 30 cm. I may have looked thoughtfully at various types of valves, wondering whether they were oscillating in the microwave range, but I had no way of detecting such oscillations, even less of modifying the structure of the valve. Thus it remained a theoretical concept.

After the war started, I was told that if I wanted a choice of military service I should volunteer before I was called up, so I volunteered for the Royal Air Force (RAF). My enlistment was put on hold because of my engineering degree courses, but I expected to hear from the military when I graduated. At Leeds University in the spring of 1941, Cedric Burrell and I were the only students graduating first class in electrical engineering (but Cedric got his only after an oral exam). After the results were announced, a representative of the Ministry of Supply visited the department, and Cedric and I were invited to Cambridge for interviews for positions in a radar research and development establishment. (It was called radio direction finding [RDF]; at the time, the name radar had not yet been coined.)

We were interviewed in Cambridge by the novelist C. P. Snow, who was also a physicist and fellow of Christ’s College, and by John Cockroft, another Cambridge physicist, who, with Ernest Walton at the Cavendish Laboratory, had bombarded lithium with high-velocity hydrogen ions to achieve the first transmutation of one element into another that did not involve naturally radioactive material. (A lithium nucleus absorbs a proton and disintegrates into two helium nuclei.) In 1941, when he interviewed us, Cockroft was the director of the Air Defense Experimental Establishment (ADEE) of the Ministry of Supply. I do not remember much about the interview, but I do remember that my idea of using the time of flight of electrons to generate centimeter radio waves came up and Cockroft asked me if I had ever heard of the klystron. I later discovered that an electron tube working on that principle had been developed at Stanford University in 1939.

Air Defense Establishment

Cedric and I were appointed experimental officers in the Ministry of Supply and told to present ourselves at ADEE, near Christchurch on the south coast. The ADEE had been set up during World War I to develop means to locate nocturnal intruding aircraft by sound, in order to guide searchlights. The intruders could then be tracked visually and attacked by anti-aircraft fire. Increasing speed and numbers of enemy planes made acoustic detection almost useless, but the discovery that aircraft reflect radio waves provided a method of detecting them above clouds and at much greater distances, allowing time for fighter aircraft to reach operational height. It also held out the promise of providing a non-visual method of aiming anti-aircraft guns. But to achieve sufficient accuracy, very short radio waves were required; ideally less than a meter. A new laboratory for radio direction finding was built adjacent to a small airport at Somerford, a suburb of Christchurch, and ADEE moved to the site early in the war. Soon after Cedric and I arrived, the name was changed to the Air Defense Research and Development Establishment (ADRDE).

The surroundings were very attractive, close to the beach (unfortunately inaccessible) and not far from the New Forest. I was happy to be there, but a day or two later I learned that I would be going to Birmingham to work on transmitter valves. I expect this was the result of my discussion with Cockroft about klystrons. Fortunately, the workings of government departments are unfathomable, and the transfer never materialized. Possibly some bureaucrat was told that the newly developed cavity magnetron was excellent for centimeter wavelengths and no more research was needed. Cedric was assigned to a group working on centimeter-wave measurements. I was put in charge of developing a simulator for the new 10-cm Mark III radar that could be used to test the efficacy of different ways of displaying the returning pulses to the operators and to evaluate methods of steering the antenna. The simulator could later be used to train operators.

I worked on the equipment under the direction of Edward Shire, a physicist from King’s College, Cambridge. My first design was an electronic circuit that simulated the changes in azimuth and elevation of an aircraft flying within range of the radar, but Shire did not like it. He argued that electronic devices were not robust enough for army use; he wanted something mechanical. We finished up with a massive steel contraption a couple of meters or more long in which a block, representing the target plane, was drawn along a metal track. As it moved, it turned a potentiometer to give a voltage corresponding to the changing azimuth of the simulated target. The operator turned a handle coupled to another potentiometer in an attempt to keep it in step with that turned by the simulated target. The operator had a display showing the error (i.e., the difference between the voltages from target and operator potentiometers). Equalizing the two signals sounds as if it would be easy, but in the real equipment the operator had to control the position of a large parabolic dish antenna perched on the roof of the cabin and exposed to the wind. Moreover, the strength of the reflections from the aircraft varied from pulse to pulse, due to the interplay of reflections from different parts of the fuselage as the plane moved, so there was a lot of “jitter” on the pulse display.

A motor-driven antenna controlled by the operator would need less effort, but the accuracy would suffer. When the operator notices an error and adjusts the speed of the antenna drive, overshoot almost always occurs. Trying to correct the overshoot is then likely to cause an overshoot in the opposite direction—an outcome called “hunting.” Hunting can be minimized by linking a direct control of the antenna position with the velocity control. A motor turns the antenna to track the target, and the operator turns a handle that simultaneously corrects errors directly and makes slight compensatory adjustments of the speed of the motor drive. Our task was to find the best ratio of direct drive to motor speed control. This was not an area of expertise for engineers or physicists, but there was an operations research group in Cambridge that evaluated military equipment and procedures; Shire applied to them for help.

In due course, a young Cambridge psychology graduate named Brenda Langford arrived from her previous job of giving tests of sensory conflict to prospective air force pilots to decide whether they should go to bombers or fighters. She was well-versed in statistics and experimental methodology. She organized appropriate subjects and made suggestions as to what modifications of the simulator/trainer would be worth trying. Her main problem was that our prototype was not built with frequent modifications in mind, and I was kept busy changing displays and controls. As far as the jittery display was concerned, it was eventually determined that it was better to leave it alone and let the operators do the averaging in their heads. The pairs of pulses that had to be equalized were displayed side by side on a cathode ray screen. The operators then tried to keep the appearance of the two pulses as similar as possible.

In February 1942, British commandos raided a German radar station across the English Channel and brought back some important components and one of the German technicians. The significance of the fact that ADRDE was located on the south coast of England just across the channel from this event did not escape the War Office, and by April, our establishment had been moved lock, stock, and barrel to Malvern, near the Welsh border. ADRDE set up shop in a compound originally built to accommodate a government ministry, should London ever have to be evacuated. The compound was self-contained with barracks-style living quarters for unmarried staff—three to a room and common showers and washrooms for the men, somewhat less Spartan for women, with only two to a room.

Brenda continued to work on the operator interface, with technical contributions from me on occasions. My main job at the time was to develop a more sophisticated trainer, based on more realistic target trajectories recorded on film or tape. It was never finished. Anti-bomber artillery did not have a very high priority during the build-up for the invasion of Europe, and I never found out how useful our 10-cm Mark III proved to be against aircraft. According to Google, it was used to locate mortars during the invasion of France. Although the Mark III probably came too late to bring down many bombers, we learned a lot from it. It was the first radar to incorporate the new cavity magnetron; in fact, it was originally designed to work with a klystron, but the cavity magnetron was better.

In June 1944, the Germans started to launch their V1s (unmanned flying bombs) from the French coast against southern England. The V1, or buzz bomb as we usually called it, had a simple ram-jet engine and could fly faster than all but the latest jet fighters. After flying a preset distance (measured roughly by a propeller), its nose turned down. It was intended to dive to the ground under power but in the nose-down position, the fuel failed to flow to the combustion chamber, providing a brief warning period of silence before impact. I was assigned a new job, which involved plotting the paths of these bombs in the hope that they could be traced back to the launching sites, which could then be attacked. I spent a week or two at a radar station on the south coast, near Beachy Head, making measurements. Unfortunately, it turned out that multiple launching sites were hidden underground. Bombing proved futile, and the sites were destroyed only when the advancing Allied troops reached them.

Two years after Hitler turned eastward for Germany’s next lightning invasion, he was in deep trouble in the USSR. Furthermore, his failure to take advantage of the disorganization in Britain in 1940 allowed a build-up of Allied forces and air power on his doorstep. With the Allied landings in Normandy in June, the end seemed to be approaching. Things also seemed to be winding down at ADRDE. Our director, John Cockroft, was away in the United States for long periods, and it seemed clear that further developments in radar would be too late to affect the course of our war. The war in the Pacific was another matter.

Tube Alloys

In the autumn of 1944, someone in the director’s office asked me if I had any objection to going abroad for a year or two. I was not very keen on the idea, but I never refused new experiences in those days. My guess was that it would be to somewhere in the Far East such as Burma, where I had heard that they were having trouble using radar among the mountains. A few weeks later, after being sworn to secrecy, I learned that I would be going to Canada to work on atomic energy. In 1938, less than a year before the outbreak of war, two German scientists, Hahn and Strassmann, had reported that atoms of uranium broke up into lighter elements when bombarded by neutrons. That uranium reacted in a peculiar fashion to neutron bombardment had been known for some time, but Hahn and Strassmann—with some help from Lisa Meitner, a former colleague—identified the cause. Because the total mass of the fragments is less than the mass of the original uranium, it was clear from Einstein’s famous formula E = MC² that an enormous amount of energy must be released during the reaction. The implications of this discovery received surprisingly little publicity. In fact, I had never heard anything about the phenomenon before I learned I would be working on the attempt to harness this energy.

The project in which I had agreed to participate was code-named “Tube Alloys,” a joint British-Canadian enterprise. The British government was, of course, aware of the U.S. Manhattan Project, but it did not have the resources to prepare for the invasion of Europe and to develop nuclear weapons, or energy, at the same time. However, there were mobile resources in Britain, scientists who were no longer needed to develop armaments. With an eye to future commercial demand for atomic energy, it was decided to send a crew to Canada to learn the ropes and to form the nucleus for a post-war research establishment in Britain. I heard that our director, John Cockroft, was to become the head of this Canadian project, which explained his frequent absences. I was happy that Canada was the destination of the move, but there was a serious flaw in the arrangements; spouses were allowed to accompany the appointees but girlfriends received no mention, and I had a girlfriend.

Several factors had conspired to deprive me of much female company during my youth. The upshot was that my job at Christchurch was the first time I encountered a number of women of about my age. I had a few dates with Shire’s blond assistant but then she told me she was engaged and stopped seeing me. I was upset and assumed that my role had probably been to light a fire under the more fortunate suitor, a very good catch as I learned. This diversion into my love life may seem irrelevant to a history of neuroscience, but the sequel certainly is not. When Brenda Langford came to help us compare different settings of the machine/operator interface of my simulator, she rapidly became a dominant influence in my life. I was in some awe of her; she had an excellent Cambridge degree and was very competent in her work. We had a good friendly relationship, but I did not feel very competitive, especially after my recent bad experience. The establishment was overrun by brilliant Cambridge physicists so I did not think she would be interested in an engineer from Leeds. What I did not know was that somehow Brenda, the psychologist, had discovered that my vocabulary was slightly better than hers, tilting the playing field. She sensed that I might need some encouragement and gave me some. By the next summer, we were very close. There did appear to be a simple solution to the Canada problem, but I was not sure what Brenda would think of it. I was under the impression that she was looking forward to starting a new job in Cambridge after the war. Nevertheless, when we discussed the idea she seemed happy with it, so we got a special license, took it to the registry office, and were married in time to make the travel arrangements. We scrounged some stout wooden boxes that had contained radar parts and filled them with our books, which had to go to Birmingham for censorship and were shipped separately. In late October 1944, we boarded the Queen Elizabeth (then almost new) in Glasgow, along with war wounded and war brides. The North Atlantic was rough, and the zigzag course did not help. Brenda did not eat much on the journey, which seemed much shorter than I expected. We were supposed to land in New York, but for some reason we disembarked in Boston. I remember being very charmed by the first words I heard on American soil from an American. The customs inspector told the lady ahead of me, “Don’t try to rush me ma’am. I got low blood pressure.” Not in accordance with my stereotype.

Our small group of scientists was taken to the Copley Plaza Hotel, through streets that seemed to us flooded with light, though they told us that it was their blackout. We had not seen such sights for five years. And there was planked steak for dinner. Boston was a good place to have landed because we had friends in the radiation lab of the Massachusetts Institute of Technology who had spent some time at ADRDE working on proximity fuses for anti-aircraft shells. One of our friends managed to get clearance for us to tour the lab. Another lent us some dollars. We had been allowed to take no more than five pounds sterling (about $25 U.S.) out of England, and there were no such things as credit cards. I had a hard time paying him back because, to my surprise, sending money from Canada to the United States required a lot of red tape. After a couple of days of luxury, we took the train to Montreal; just as we crossed the border, it started to snow. It was November 5, Guy Fawkes Day.

When I arrived, the Tube Alloys group occupied one wing of the University of Montreal’s new building, which was still incomplete. I knew little of the history of the group except that it had originally consisted of some European scientists at the Collège de France in Paris, who had fled to England with precious heavy water and then moved to Canada for greater security. The significance of the heavy water derives from the fact that less than 1 percent of natural uranium consists of the isotope (U235) that is fissile, and the neutrons released during fission are too energetic to be captured by enough fissile atoms to maintain a chain reaction. They need to be slowed down before too many escape, and heavy water is an ideal moderator. I learned later that in 1940, one month before the Germans invaded Norway, a large consignment of heavy water was acquired from the Norwegian source by the Collège de France group. In May, when the Germans invaded France, the group—with their heavy water—escaped to England and later went to Canada, where they established a base in Montreal near McGill University. The group later became associated with the National Research Council of Canada and moved to more spacious quarters at the University of Montreal.

Tube Alloys had settled on building a heavy water moderated “pile” in a sparsely populated area that was easily accessible and that had a source of cooling water. Chalk River, about 150 km up the Ottawa River from Ottawa, was a favored location. Chalk River was hardly a town; it was just a watering stop on the Canadian Pacific Railway line through northern Ontario. The Trans-Canada Highway ran parallel to the river and the railway at that point, and there was plenty of water in the Ottawa River for cooling. Once settled in Montreal, my first proper job was to see how quickly scale would build up on cooling pipes in the river. This entailed a number of trips to the vicinity of Chalk River. My memory of how I went about measuring the scaling is cloudy, but I do remember that one technique I tried involved nuclear magnetic resonance, a phenomenon that I had just read about. (Isidor Rabi received a Nobel Prize for its discovery in 1944.) This was a bizarre thing to try, and I can only assume I did so because I wanted to play around with nuclear resonance. I hoped to use it to measure the amount of scale without having to keep removing the test pipe from the river, but of course, I could not get it to work. I think I eventually just passed hot water through the submerged pipe and measured its temperature drop—the assumption being that it would lose less heat as scale formed. The scaling turned out to be negligible. Another of my jobs was to build an apparatus to measure the effect of an intense neutron flux on the mechanical properties of various materials used in the construction of the reactor. I was proud of the apparatus I built, but I left before the reactor managed to produce any neutrons, so I never found out how well it worked with “hot” samples.

In the meantime, Brenda, having ascertained that the psychology department of McGill University was in hibernation, found a job teaching comparative psychology (in French) at the University of Montreal, which at that time was a Catholic institution run by Dominican priests (Milner B, 1998). Brenda liked languages. She not only enjoyed French literature, but when she was working at ADRDE in Malvern, she found someone to teach her conversational French. This was in the middle of a war, when there was little chance that she would find herself in France and with no inkling that fluency in French might soon be essential for her job. After the privations of wartime life in England, life was much more comfortable in Montreal. But I think we both suffered some culture shock and began to look forward to the end of what we had been told would be about an 18-month mission. The war in Europe ended the next spring and in August, to the horror of many of us in the nuclear energy business, we heard that Japan had been attacked without warning by atom bombs. By the next month, the war was over. Work on the Chalk River site continued, of course, and I continued to work on my apparatus for measuring elasticity ultrasonically. Brenda and I moved to an apartment in Westmount and bought furniture. By the spring of 1946, the labs at the Chalk River site and the new residential village, Deep River, several miles upstream, were declared adequate and all the scientists and their equipment were transported there. Unfortunately, the nuclear reactor, which I believe was the first heavy-water moderated “pile,” was still far from being operational. All of us who were waiting for high levels of neutron flux had to find other things to do. In my case, I worked on part of the safety system that turned the pile off if the cooling water temperature rose too high. But I had a good deal of spare time, during which I read some of Brenda’s psychology books and learned to type.

Brenda stayed in Montreal to finish the course she was teaching and when she finally came to Deep River in the summer, she hated the place. It was deliberately chosen to be isolated so that if the pile got out of control, not too many innocent bystanders would be affected. Pastimes were pretty much limited to lying on the beach, boating, flirting, and listening to music. People brought their phonograph records to the Staff Hotel on Sunday evenings to give concerts. Though her father had been the Manchester Guardian music critic, and her mother a singer, Brenda has always been quite unable to recognize a tune or process any aspect of music other than its rhythm. She had been teaching at the University of Montreal for more than a year and was thoroughly enjoying it, so her visits to Deep River were short and infrequent that summer. There was good train service to Montreal, however, and I would often spend the weekend there.

McGill Psychology

Meanwhile, McGill’s psychology department was beginning to come alive again. The ailing absentee chairman died and was eventually succeeded by Robert MacLeod, a well-organized experimental psychologist who had spent the war in army intelligence. He set about establishing a laboratory and collecting a new department. He was an excellent teacher of traditional psychology, and Brenda was able to arrange her lectures so that she could attend a graduate seminar he gave. Like most English academics of that era, she did not have any post-graduate degree. Two of MacLeod’s recruits, Donald Hebb and George Ferguson, arrived on the scene the next year, 1947. Both were raised in Nova Scotia, both attended Dalhousie University—Hebb in the 1920s, Ferguson about ten years later. As an undergraduate, Hebb did well in science, but because he was set on becoming a novelist, he majored in philosophy and English. After graduating, he went back to his old school as a teacher, hoping to write a novel in his spare time. That did not happen, however; so after a few years, he returned to academic work and received a master’s degree in psychology from McGill and a PhD from Harvard with Karl Lashley, the most important American physiological psychologist of the time. Then, after a fellowship with the neurosurgeon Wilder Penfield at the Montreal Neurological Institute, he spent some time teaching psychology at Queens University in Ontario. Next followed a five-year fellowship in Florida, with Karl Lashley again, studying chimpanzee emotion, after which he was invited to McGill by MacLeod. Ferguson had obtained an excellent degree in Latin at Dalhousie, earning a scholarship to Edinburgh, where he was granted a PhD in psychology. He spent the war in the army, developing tests for soldiers, and was then recruited by MacLeod to teach statistics at McGill. The next year, MacLeod moved to Cornell University, and Hebb took over as chairman of the McGill psychology department.

Hebb must have really liked teaching because, until he retired, every new graduate student had to attend his weekly seminar, and every psychology undergraduate had to take his elementary course, which most years occupied at least two of the largest classrooms linked by video. He had a good fund of chimpanzee anecdotes. His graduate seminars were as much concerned with communication as with research. Timing of student presentations and pronunciation were carefully monitored, and Hebb’s stopwatch and pencil-tapping were legendary. When he came to McGill, Hebb brought the manuscript of a book titled The Organization of Behavior. It was not published until 1949, but he used the manuscript in a graduate seminar that Brenda attended. Oliver Zangwill, her supervisor at Cambridge, studied patients with brain lesions so Brenda already knew something about the role of the brain in behavior, the theme of Hebb’s book. She found Hebb’s seminars exciting and sent me some extracts from his manuscript. I became particularly interested in Hebb’s speculations about the circuitry of the brain.

This situation unfolded at a critical time for me. The British government was now prepared to enter the business of nuclear energy and offered research positions to the pioneers they had sent to Canada. I had the alternative of becoming a Canadian and continuing at Chalk River with the Canadian National Research Council or going back to England. The situation in Britain was not at all attractive. Two or three years after the war, food and fuel were still in short supply and were rationed. Many towns were still suffering from the results of enemy bombing. On the other hand, I had no desire to spend the rest of my life in Chalk River as an engineering physicist. Hebb’s manuscript suggested another more radical alternative; I could try to persuade Hebb to let me pursue the brain–behavior relationship with his supervision. I think I had an idealistic impression that professors sat around concocting and publishing theories that students would then take to the lab and test. So in the spring of 1947, on one of my visits to Montreal, I arranged to meet Hebb and asked him if it would be possible for me to do graduate work with him. After checking my qualifications, he told me I would have to take some psychology and physiology courses in a qualifying year. If I passed, he would take me on as a graduate student. I was lucky that the department was still small and somewhat disorganized, and that Hebb was new to the job of chairman. A few years later, there would have been much more red tape; the chairman would have had to consult his executive committee before accepting a graduate student, for example.

One of the regular visitors to the nuclear site at Chalk River was John Stuart Foster of the McGill physics department. He was in charge of the McGill Radiation Laboratory where a large synchro-cyclotron was being assembled, so the next thing I did was to visit him and ask if any part-time help was needed. There was a job for me; it was to build an ion source. Foster had the specifications used in the synchro-cyclotron built by Ernest Lawrence at the University of California, Berkeley, but they were for a hot-cathode source, which did not work well in our machine. I converted it to a cold–cathode source, which was an improvement. I also had to design and construct a transformer to deliver pulses to the source, which sent me back to my Leeds textbooks. The rest of the time I took courses in psychology, physiology, and statistics. One of Hebb’s graduate students, Herb Lansdell, taught me how to operate on a rat brain. At the end of the year, my exam results apparently satisfied Hebb, and I was accepted into the graduate program.

Graduate Student

I became an acknowledged graduate student in the fall of 1948. This qualified me for a job as an assistant, which in my case involved getting to the lab at the crack of dawn and cleaning out the dog cages. I also had to decide on an experiment for my master’s of science thesis. Hebb had settled in as chairman and renewed his contacts with people at the Montreal Neurological Institute (Neuro) with whom he had worked during his fellowship, 10 years earlier. Probably because of my background, he suggested that I follow up on Penfield’s use of electrical stimulation of the cortex or perhaps record cortical electrical activity. Accordingly, he sent me to the Neuro to learn how to implant cortical electrodes in dogs. (Hebb used dogs for much of his animal research.) In human patients, Penfield was able to interfere with speech by electrical stimulation of the cortical speech areas. I started to look for stimulation-produced interference of learned behavior in the dog but gave up due to technical difficulties. Dogs are less tolerant of being wired-up than rats. Also, the cortical electrodes either fell out or got infected. It became obvious that I could not finish the experiment within the allotted time, so I looked for something that required no surgery and used rats.

In his book and lectures, Hebb suggested that animals must learn what food is good for them. I decided to test this hypothesis for my master’s research. I deprived weanling rats of potassium, and then gave them a choice between dilute potassium chloride and magnesium sulphate solutions. The results were clear; the deprived rats immediately chose the potassium salt much more often than did the undeprived controls, making it improbable that the preference depended on a beneficial aftereffect of its consumption. Some learning was observed, however. After the preference trials, rats of the deprived group were fed the control diet for six days and given unrestricted access to the potassium salt. In subsequent preference trials, they showed an even greater preference for the potassium solution than they had done in their earlier, deprived trials. This suggests that the reinforcing effect of the potassium on the deprived rats established a long-lasting liking for the taste of potassium salt that became independent of deprivation. I was intrigued by the implications for motivation of this finding. The master’s thesis was accepted in the fall of 1950, and I advanced to the PhD. Some of the experiment was repeated later by one of my students (Milner and Zucker, 1965).

As mentioned earlier, Hebb still had links with the Montreal Neurological Institute. He knew many of the staff and sent several of his graduate students to participate in their seminars. Francis McNaughton taught us human brain anatomy (we made models using colored Plasticine), and Herbert Jasper discussed recent information about the brainstem and other neurophysiological findings. Jasper was a man of wide interests extending from philosophy through biochemistry to electronic engineering. He was a pioneer of electroencephalography (EEG) and, with Carmichael, published the first U.S. paper on the relation of the EEG to the level of arousal. His use of the EEG to localize epileptic foci played a vital role in Wilder Penfield’s surgical treatment of epilepsy. When I attended his seminar, Jasper had recently discovered that electrical stimulation in part of the brainstem of anesthetized cats produces cortical activity resembling that of an alert cat. The next year, Moruzzi and Magoun (1949) localized the effect to the brainstem reticular system. The relation of the reticular system to sleep, waking, and arousal was a subject of much investigation during the late 1940s, and we heard a great deal about it during the seminars. Seth Sharpless, a philosophy student from the University of Chicago and fellow graduate student, who like me was attracted to McGill by Hebb’s Organization of Behavior, did his doctoral research on sleep and wakefulness in Jasper’s lab (Sharpless and Jasper 1956).

Seth and I spent a lot of time discussing Hebb’s cell-assembly theory. Like his mentor Lashley, Hebb was good at identifying problems but handicapped in their solution by the primitive state of neuroscience. In his book, Hebb refers to the problem of motor equivalence, the ability of animals to reach a goal in different ways depending on circumstances. Although the main emphasis of the Organization of Behavior is on the visual system, Hebb argues strongly in favor of better understanding the motor system. Sperry (1952) wrote an article in which he pointed out that the sensory systems evolved to enhance the effectiveness of the motor system, further focusing my interest on response mechanisms.

In most learning situations, the goal is the source of a reward; therefore, an association with the goal is also an association with the reward system. Seth and I speculated that there must be a component of the reward system that goes to the motor system and attempts to find a learned intention to approach the goal and, if successful, to boost it until the responses become overt. We called this facilitator the “go” pathway. I recently discovered the following sentence in the “theory” section of my master’s thesis: “The alternative seems to imply that there are separate structures, or overall patterns of cerebral activity, subserving pleasure sensations, or the facilitation of some general concept of approach” (Milner 1950). Apparently, I had already been thinking along these lines before starting my doctoral research. The behavior of a rat at the choice-point of a T-maze provides a simple illustration of the proposed reward feedback mechanism. Before training, the choice-point responses are random, but, if a hungry rat finds food after turning left, it soon acquires an association between the neural intention to make a left turn and a neural representation of food. Food is rewarding to a hungry rat, so its association with an intention to make a left turn must trigger the reward system, amplifying the intention until the rat actually makes a left turn. The reticular arousal system we were hearing about from Jasper sounded as if it might be a promising candidate for our postulated “go-system.”

My doctoral research involved subcortical electrical stimulation of rats, and some of the rats had electrodes in the reticular pathway. Seth and I decided to use these rats to test the notion that stimulating their reticular activating systems could influence their behavior in a maze. We found that it did but not in the way we had hoped. The only clear outcome was that almost all the rats responded as if they had been punished by the stimulation. They avoided the places where it had occurred. Electrical stimulation of sensory pathways is usually aversive so it was not too surprising to find that nuclei receiving sensory input respond in the same way. We abandoned the experiment for the time being, and I went back to my official thesis research, which was investigating the neural mechanism for estimating short time intervals. I was intrigued by the way estimates of the passage of time seemed to depend on attention. On the evidence of the “watched pot never boils” phenomenon, I guessed that attention speeded up a neural clock, making an objectively short time interval seem longer. I thought it might be possible to exert some control over time estimation in rats by stimulating their arousal systems. I used shock-avoidance conditioning in a shuttle box to measure the ability of the rats to estimate time. (Thinking about it now, it was probably not a good idea to use foot shock to train rats for an arousal experiment.) The rats learned to avoid shock by jumping the shuttle box partition at about 12-second intervals; when they were shuttling regularly, the shocks were turned off and the effect of stimulating the arousal system observed.

The research that was reported in my thesis was hardly more than a pilot study. Only about 20 rats completed the trials, and their electrodes were distributed widely through the brainstem. The duration, frequency, and voltage of the brain stimulation were also scattered. Brief stimulation caused a statistically significant, but unexpected, slowing of response rate in almost all the subjects. Continuous low-level stimulation during the animal’s responding caused a significant rate increase in the group of rats that had the most posterior electrodes, but most of the others continued to be slowed by the stimulation. The best part of my thesis was the introduction, which was a very exhaustive review of the reticular arousal system.

Reward

Obviously, the doctoral study should at least have been followed up by a more systematic investigation of the caudal mid-brain tegmentum, but fate stepped in. One day in the fall of 1953, Hebb brought a young man to my lab and introduced him as James Olds, a new “postdoc” from the Harvard Department of Social Relations. In spite of his provenance, he was interested in motivation and learning. He had just written a paper on Tolman’s sign-Gestalt theory and, influenced by Hebb’s Organization of Behavior, he wished to develop a neural version of the theory. He had obtained a post-doctoral fellowship to do so with Hebb. Jim had no experience with animals or the brain, so Hebb asked me to show him the ropes. I do not know whether Hebb knew at the time about my experiments and speculations concerning the reticular activating system and motivation.

I gave Jim a rat brain atlas and told him to learn some neuro-anatomy. By the end of the week, he knew the rat’s brain map better than I did. Next, we tackled electrode implantations. After my bad experience with infections in dogs, I had adopted an electrode design used in monkeys by José Delgado at Yale. Two insulated, stainless steel wires were glued together and, using a stereotaxic instrument, inserted into the target area through a small hole drilled in the skull. The electrode was then fixed to the skull with dental cement. When the cement had hardened, the electrode was released from the stereotaxic instrument and the emerging wires were passed under the scalp, brought out through the back of the neck, and provided with a small socket.

I showed Jim this technique and watched as he practiced. After a few days, he felt ready to perform an implantation on his own, intending to put the electrode into the reticular activating system. He probably chose that target because it was the system that everyone was interested in at that time. He may also have been talking to Seth, who was somewhat reluctant to accept the negative results of our earlier attempts to guide rats to a target by stimulating the reticular activating system. Although our experiment consistently yielded negative results, most of the subjects were still alive, so we did not know precisely where their electrodes were located.

When Jim’s rat had recovered from the operation, he tested it. As it wandered about on a bench top, Jim stimulated it using a handheld switch. He noticed that after a bout of stimulation the rat sniffed around the region where it had occurred and would return there if displaced. Jim got very excited and told Seth and me that the rat was being rewarded by the stimulation. We, who had stimulated that region before, were somewhat skeptical. I told Jim we would believe it if the rat would work for stimulation in a Skinner box. The McGill psychology department may have been the only one in North America at that time that did not possess a Skinner box, so I had to build one. The rat passed the Skinner box test rapidly and convincingly. I next tried to replicate the effect, using the coordinates that Jim said he was using, but without success. We then began to have doubts about the location of the electrode. The Donner Building, where our lab was located, was mostly occupied by the department of experimental surgery. They had an X-ray machine, and we persuaded the operator to X-ray the rat’s head. It was immediately obvious that the electrode had not gone where it was supposed to go. Its tip appeared to be in the vicinity of the septal area. We guessed that the dental cement had not completely set when Jim bent the external part of the electrode back to go under the scalp, forcing the business end to move in a rostral direction. Unfortunately, by the time we reluctantly sacrificed the rat, its brain had become too infected for autopsy. After we had more self-stimulating rats, we recognized that the rat’s behavior had been similar to that of rats with electrodes in or near the nucleus accumbens or the medial forebrain bundle.

The next priority was to obtain enough data for an acceptable paper as quickly as possible. Jim was a very energetic and efficient person, and he knew this was a big deal. He planned to collect data from many rats, so he designed a battery of Skinner boxes with large floor level “levers” that the rat could hardly help stepping on. This raised the unrewarded operant level high enough for it to be possible to measure aversive as well as rewarding stimulation. He also designed electrodes that were easier to implant. He had been reading Hess et al. (1953), who inserted electrodes into the brains of cats, mounting them on a small platform screwed to the skull. Jim designed electrodes embedded in small, rectangular plastic blocks that could be secured to the skull with jeweler’s screws. In some rats, Jim left the skull around the electrode open, and to my astonishment, they did not get infected. Hank Macintosh, the chairman of the physiology department, heard about this and remembered a story that, in colonial days, people who had been scalped in the Indian wars often developed infections and died. But then a French surgeon started to bore small holes in their skulls and the fluid that oozed out spread over the bone, coagulated, and protected it from infection.

A reporter for the Montreal Star, D. Macfarlane, routinely roamed the McGill campus, and Hebb steered him in our direction. As a result, the Star for March 13, 1954, had a front-page banner headline “McGill Opens Vast New Research Field with Brain ‘Pleasure Area’ Discovery” and in slightly smaller print “It May Prove Key to Human Behaviour” and “Anglo-American Achievement Has Fantastic Possibilities.” It must have been a quiet day for news because the story was copied around the world. Jim and I thought some of the report was a bit over the top; in any case, it was unorthodox to have the work evaluated by a newspaper reporter before it was submitted to a journal and peer reviewed so we sent a letter to the Star to that effect. Nevertheless when our paper, “Positive Reinforcement Produced by Electrical Stimulation of Septal Area and Other Regions of Rat Brain,” was eventually published in December (Olds and Milner 1954), it certainly boosted Hebb’s efforts to persuade psychologists to take the brain seriously.

At the time, I doubt whether there were many other psychologists who had tried unsuccessfully to find a brain system that facilitated goal-directed responses, so fate must have had a good time sending us someone to show us how to do it. Fate chose the right person to send; it would be difficult to imagine anyone better qualified for tackling the awesome task of thoroughly investigating the phenomenon. Most of the valuable early research on the anatomy and pharmacology of the reward system was carried out by Jim and Marianne (Nickie), his wife. I was as excited by the discovery as Jim but could not completely abandon my thesis research.

After confirmation of the reward effect, one of the first questions to be studied was the relation between brain stimulation reward and more conventional rewards, such as food. Hebb gave Jim a graduate student, Rolphe Morrison, who investigated the effect of food deprivation on self–stimulation and the effect of self-stimulation on feeding (Morrison 1955). Jim and Nickie worked all-out, mapping the brain for reward and punishment sites (Olds 1956; Olds and Olds 1963). They left McGill in 1955 and were given every resource to continue their investigation of the reward system at the Brain Research Institute of the University of California, Los Angeles. In 1957, Jim was appointed assistant professor at the University of Michigan. I returned to my research, finished my doctoral thesis as best I could, and it was accepted. Hebb then treated me rather as Lashley had treated him, appointing me as a sort of postdoc and giving me some teaching to do. I also became an IBM consultant.

Artificial Intelligence

I was working in the field of nuclear energy when I first read Hebb’s account of the cell assembly in the copy of his manuscript that Brenda sent to me in Chalk River. My previous impression of physiological psychology had been that it was a piecemeal attempt to discover the function of the brain by studying the effects of different brain lesions in animals and human patients. Hebb’s synthetic model, which used the properties of neural elements in an attempt to explain function, appealed to me as being more like other sciences, though adequate knowledge about neurons was still lacking. I thought Hebb’s model was a step in the right direction, but my work with nuclear reactors alerted me to a serious flaw in the basic component of his model, the cell assembly.

Nuclear reactors depend on a chain reaction, and I recognized the cell assembly as a neural version. In Hebb’s model, when a cortical neuron fires, it delivers excitatory stimulation to similar neurons with which it synapses. As a result, some of those neurons fire (especially any that are being facilitated by sensory input) and randomly excite other cortical neurons. In a nuclear reactor, when an atom of uranium 235 absorbs a neutron and undergoes fission, it sprays neutrons at random. Some of them penetrate neighboring atoms of uranium 235, causing them to undergo fission and to emit further bursts of neutrons. Chain reactions such as this are fundamentally unstable; if the fission of one atom causes an average of more than one other atom to undergo fission, you very soon have a bomb. But if an average of less than one fission is triggered, the action fizzles out. To deliver controlled energy, the average fission must result in exactly one new fission. Fortunately, there is a slight reduction in efficiency as the neutron flux increases, reducing the probability of neutron capture. Small fluctuations, therefore, do not start an avalanche. Unfortunately for Hebb’s hypothetical cell assembly, however, a small increase in firing of cortical neurons, as might be caused by increased sensory input, would result in increased synaptic summation, leading to a further increase in cortical firing. Hebb’s learning rule, which also increases the number of other neurons fired by the average cortical neuron, would exacerbate the problem. Without inhibition, the classical cell assembly would grow exponentially until every cortical neuron fires full time.

One way to avoid this outcome would be for cortical neurons to inhibit each other via inhibitory neurons. An increase in cortical firing would then turn off some cortical neurons but never enough of them to stop cortical firing altogether, for that would also eliminate the inhibition. Hebb avoided the use of inhibition; it was incompatible with the prevailing idea of electrical transmission of neural activity and was deemed to be impossible by influential neuro-physiologists. Chemical neuro-transmission was demonstrated at about the time Hebb’s book went to press (Eccles 1953). Another problem I had with Hebb’s account of the cell assembly concerned the way one cell assembly was supposed to become associated with other assemblies. It was not clear why, if two assemblies were active at the same time, they did not combine into a bigger cell assembly, so that eventually the cortex would be just one giant cell assembly. I suggested that cortical neurons that received synaptic input from an active assembly, but did not fire because of simultaneous inhibition, might start to fire when a new assembly starts up, thus becoming incorporated into the new assembly and forming a link between the two assemblies.

My decision to do graduate work at McGill was influenced by a desire to follow up on the ideas I had to bring Hebb’s model more up to date. I thought Hebb might want to be involved, but he considered the running of a very understaffed department, with lectures all day and seminars in the evening, more urgent than fiddling with his book, which was enjoying far greater success than he expected. He was kind enough to comment on a paper I wrote introducing inhibition into the cell assembly model, so the paper, titled “The Cell Assembly: Mark II,” was eventually published (Milner 1957).

Nat Rochester, who helped to design IBM’s digital computer 701, the first digital computer to be made available commercially, thought Hebb’s cell assembly might be used to make his computer think for itself. He and his group at the Poughkeepsie lab of IBM had tried to adapt the cell assembly for the task and had encountered the predicted instability. They cured this by weakening inactive synapses whenever active synapses were strengthened, but repeated identical sensory input still did not generate cell assemblies, so Rochester consulted Hebb. Hebb sent him to me, so presumably he accepted my tinkering with his model. I told Nat about inhibition and gave him a draft of the Mark II paper. He then made some rather drastic changes to his “Conceptor” model, and eventually was able to obtain cell assemblies. (Rochester et al. 1956). They still could not get them to associate with each other, however, even when they moved to a later model computer, which was bigger (with a RAM of just over two whole kilobytes!) and allowed them to model a (very slow) cortex of 512 neurons. I visited Poughkeepsie a few times to observe progress but was unable to help. I thought more work had to be done on the neural model. During this period as an IBM consultant, I was invited to a meeting of computer scientists and information theorists at Dartmouth College. Most of the time I had no idea what they were talking about, but the Dartmouth Conference is now considered to be the birthplace of artificial intelligence. Due to criticism from some IBM shareholders, who thought artificial intelligence was a waste of research funds, Nat’s program was abandoned shortly afterward.

Lecturing

The next year, 1956, I was appointed assistant professor to replace Haldor Rosvold, who had left to start an animal behavior division at the National Institutes of Health in Bethesda. I took over his physiological psychology course, which in the next year or two occupied much of my time. The textbook I inherited was not entirely suited to my plans for the course, so I supplemented it with printed lecture notes. I subsequently updated and added to the notes and, after a few years, they were collected in book form and sold by the McGill bookstore. Several publishers then invited me to turn them into a textbook, which I started to do.

By this time, in the early 1960s, I had plenty of distractions. I was still trying to extend Hebb’s brain model. In March 1959, I presented a theoretical paper in a current trends in psychology series at the University of Pittsburgh (Milner 1961a) and a somewhat different paper later in the same year, at a conference on self-organizing systems in Chicago (Milner 1960). I was a research associate of the Carnegie Institute in Washington from 1960 to 1964, site-visiting labs in the United States and Europe where research on brain modeling was being carried out. From 1963 to 1967, I was a consultant for the Rand Corporation and spent the summer of 1963 helping design the “brain” of a robot vehicle that may have been intended for the moon or some planet. Between 1963 and 1973, I spent a number of years on the granting agencies for the National Research Council of Canada and the U.S. National Institute of Mental Health. Reading the applications was a lot of work but it kept me up to date on the latest trends in physiological psychology, and I enjoyed meeting all the famous psychologists. During the school year, I gave the usual undergraduate lectures, graduate seminars, organized research, and wrote papers and grant applications; progress on the textbook was slow.

It was eventually published in 1970, and for a few years, it dominated the market. It was translated into several languages, including Portuguese, Italian, and Russian. I like to think its popularity was partly because the factual material was spiced with snatches of speculation. As it aged, I was under considerable pressure from the publisher and others to prepare a second edition, but I write slowly and neuroscience progressed very fast. After a couple of years, I stopped trying to keep up and went back to supplementary lecture notes. Some of my students are dispersed all over the world, teaching and doing research.

Research

I chose to do graduate work at McGill with the idea of developing Hebb’s theoretical model, but after I completed my PhD and Hebb appointed me to a research position, brain-stimulation reward was the obvious topic for me to take up. Jim and Nickie Olds had, by then, completed a monumental mapping of reward and aversive stimulation sites in the rat brain, and after the publication of the first stages of that study in 1954, research on the phenomenon was quickly taken up by other groups. There were many avenues to explore. The original mapping revealed that the sites had different properties. Some required little or no practice; the rat pressed the lever enthusiastically within seconds of the first accidental press. Other sites needed several hours of stimulation before the rat responded spontaneously. It was also found that rats would not bar-press for less than a train of at least four or five pulses of current, no matter what their strength. The effect apparently required temporal summation. Most rats, even those that appeared most vigorous once started, ignored the lever the next day when they were returned to the Skinner box; they still needed to be “primed” before they would return to the lever. It was also noticed that rats terminated the stimulation after a few seconds when given control over its duration. They soon learned to turn off the stimulating current if it were turned on by an experimenter. Apparently, stimulation rapidly becomes aversive. Perhaps it is aversive from its onset, but as soon as the current train ends, the rat seems compelled to turn it on again.

Mapping reward sites does not demand accurate measurement of the intensity of reward, but as the emphasis turned to other characteristics of the system, several researchers found that rate of bar-pressing, or speed of running down an alley, were not reliable measures of reward strength. Increasing the stimulating current beyond a certain level reduces rates of response, but in a choice experiment, the rats nevertheless choose the source of higher current. In an effort to circumvent this measurement problem, I designed a stimulator with feedback that automatically adjusted the current to maintain a constant response rate. The current was then a relative measure of reward. Deutsch (1964) thought that self-stimulation must involve two neural circuits, one for drive and the other for reinforcement, and tried to distinguish them by measuring the refractory periods of the neurons involved. I tried to identify the participating neurons by plotting strength-duration curves, varying pulse duration and noting the change in current to maintain constant rate of pressing.

These, and other experiments conducted by the many groups working on self-stimulation problems during the decades after its discovery, indicated that the medial forebrain bundle was important for reward, but that it consisted of many different paths. The physiological measurements suggested that the path stimulated during self-stimulation consisted of thin myelinated fibers. Pharmacological tests implicate dopamine, which uses unmyelinated fibers. The myelinated path descends to the midbrain nuclei and the dopamine path goes in the opposite direction, to the basal ganglia. Attempts to clarify the functioning of the reward and reinforcement systems continued for many years and were reviewed in detail (Milner 1991). More than 75 of these papers were published by my students from McGill or by their students.

Problem-Solving

When I began to study psychology, the major theories were mainly concerned with visual perception and learning. Reading Hebb (1949) and Sperry (1952) made me realize that the motor system, the source of overt behavior, was relatively neglected. Lecturing and writing a textbook also made me aware that understanding behavior requires knowing how the whole brain works. What goes on in the chicken’s brain before it crosses the road is a fundamental neuropsychological question.

By analogy with the sensory system, it seemed that the motor cortex should be a storage place for action engrams. Established theories, based on Pavlovian reflexes, held that a response engram was selected by external sensory input, but that certainly was not true most of the time. People do not enter a room in daylight and turn the light on because they happen to see a switch. In the dark, you may try to find a light switch even if there is no light switch in sight. Most of the time, the action is selected by a need. Conventional learning theory might have attributed the choice of potassium solution by the deprived rats of my master’s research to some sensory characteristic such as its smell, ignoring the fact that the characteristic had no effect on rats that did not need potassium. The problem was to find out how need selected a behavior that ensured satisfaction.

One hypothesis was that a state of need, either innately or through learning, facilitates motor engrams for reaching a satisfier. These motor engrams then facilitate the sensory engrams of objects they have found useful in performing their responses. If any of the helpful stimuli are present, their engrams receive facilitation from both need and the environment, strongly activating them to inform the motor system about the location, size, and so on of the needed object. This was roughly the model that Seth Sharpless and I had in mind when we did the failed reticular-formation stimulation experiment. When Jim Olds appeared on the scene, I discovered that his reading of Tolman (1932) and Meehl and McCorquodale (1951), Tolman’s interpreters, had led him to a somewhat similar model, though expressed in less neural terms.

During the 1930s, psychologists dealt with learning mostly in terms of Pavlovian conditioning. The conditioned stimulus was usually auditory or, sometimes, a light; it could vary in intensity, but the neural response was much the same from trial to trial. When psychologists began training animals to respond to visual stimuli, however, it was no longer possible to assume a simple relationship between the stimulus and the neural response. The visual stimulus from an object has many degrees of freedom: location, size, color, and so on. Attention or relative position of the observer and the stimulus can profoundly change the neural activity elicited by the stimulus. For some time, learning theorists continued to assume that responses become associated with what they called the stimulus, ignoring the fact that the association must often be transferred from one neural version of the visual stimulus to a completely different one. For example, a large triangle does not stimulate the same retinal receptors as a smaller triangle, but a rat trained to approach one for food will also approach the other.

Theorists who worried about this problem thought that the brain could somehow convert the different neural activities into engrams with common properties that could be associated with the rewarded response. Köhler (1940), who was a Gestalt psychologist, suggested that equivalent stimuli might evoke similar electric fields in the cortex. Lashley (1942) postulated that a shape gives rise to similar brain wave interference patterns, no matter what its size, orientation, or retinal location. No evidence supported these rather vague suggestions. I first learned about this problem from Hebb’s monograph (1949), where he cites convincing evidence that eye movements are important for perception and proposed that they enable stimulus-equivalence learning in infancy. He postulated that cell assemblies (engrams) for a shape are sequential, such as the sounds and letters in the engrams for words, consisting of a series of visual traces separated by eye movement traces. Thus, after a lot of experience, a large number of closely associated cell assemblies would represent all neural versions of a shape. I had my doubts about this theory, partly because complete learning of a new shape would be very slow, even for adults, and the peculiar perceptual difficulties of anyone who had not yet learned all possible versions of the stimulus would be obvious and widespread.

These tentative suggestions from some of the brightest neuropsychologists of their time underlined the need for more research. Relevant experiments had to await the introduction of micro-electrodes capable of recording the activity of single cortical neurons. Hubel and Wiesel (1959) performed such experiments, though their relevance to the stimulus-equivalence problem was not fully appreciated at the time. This may have been because the advent of affordable digital computers had led some theorists (e.g., Minsky and Papert 1969; Rosenblatt 1958, 1962) to believe that an algorithm could be found to account for stimulus-equivalence. I like puzzles, so I thought about this problem from time to time but never got far beyond the criticism of existing theories. In 1971, my textbook was safely launched, and I was due a sabbatical year. I heard that some interesting experiments on the neural mechanisms of vision were underway in Cambridge University, so I went there. The physiological studies of vision were not very enlightening from the stimulus-equivalence viewpoint. But I looked again at the Hubel and Wiesel experiments, and it occurred to me that they might have a key to the solution. I was sure that others must have had the same idea, but I had seen no mention of it. Hubel and Wiesel describe two classes of neuron in the primary visual cortex (V1), simple and complex. A simple cell responds to the sum of inputs originating from a line of retinal receptors; complex cells respond to visual stimulation from any of a group of parallel lines. It was assumed that the complex cells respond to synaptic input from any one of a group of simple cells fired by parallel lines. In other words, the key to generalization was convergence. If a complex cell responds to parallel lines in only a part of the visual field, a number of such complex cells fired by lines in different small fields could converge on another complex cell, causing it to respond to lines in a larger field. Cells fired by the convergence of outputs from two complex cells representing lines of different orientation would detect angles. I also worked out neural circuits to calculate length ratios of lines, making it possible to generalize size differences. Objects can thus be recognized whatever their size and location, but if we want to make a response to them, these generalized engrams are useless because they do not tell us where the objects are; their origins are hidden by repeated convergences. Only retinal receptors provide completely reliable information about the location of a visual stimulus in relation to the body, and the only way to access this information is by selectively amplifying it with top-down attention from the engram of the relevant object.

How is that particular engram chosen as the target of attention? This is a question that I had already addressed when dealing with need and motivation. An experienced animal will already have learned that the target engram represents a satisfier of the current need. Water, for example, rapidly becomes attractive to a thirsty animal. The attraction to water is shared with objects frequently present at the time. This means that the cortical engrams for water, and any associated stimuli, receive input from the need for water. Henceforth, thirst facilitates water engrams, even when no water is around; but if water is present, the engram receives facilitation from both the need and water, so it fires vigorously. The aroused activity travels back along a reverse path to the eye and increases activity in the receptors receiving light from water and objects related to water. When the output of the visual receptors is selectively intensified in this way by the top-down attention, it is intensified in all the neural representations of the object in the ventro-lateral visual recognition path, and to the motor system via the dorsal visual pathway, which is separate from the recognition path. (The dorsal visual path found by Ungerleider and Mishkin [1982] was unknown when I wrote my first account of this theory [Milner 1974], but there is a direct path from the retina to the superior colliculus to keep the eye focused on, and directed toward, the attended object. I suggested that it might also convey the location of the desired object to the rest of the motor system.)

I thought that I had found a neural model of the stimulus-equivalence phenomenon that was at least plausible. I published my version of the model (Milner 1974), but it aroused little interest. Probably the few psychologists who were aware of the problem assumed that it had been dealt with by Lashley or Hebb. I thought that if I wrote a computer program based on the model, it might attract more attention. Before Windows arrived to complicate things, I could still write C-programs, and I succeeded in writing a program that could name a figure (up to pentagons) at every location and orientation the program could accommodate. It could also answer questions as to whether a particular figure was present, even if it was part of a larger figure (e.g., a triangle in a rectangle with a diagonal). I put it on my Web site but never published it. I still have a copy of the program, but modern processors do not recognize the code. These days, when practically every camera or mobile phone has face locating capability, I can only conclude that the mechanism of visual stimulus-equivalence is no longer a mystery.

Lashley (1951) was also puzzled by the memory for serial order—an ability essential for most learned responses, especially speaking and writing. Lashley said it was “both the most important and the most neglected problem of cerebral psychology.” I tried to provide an answer in 1961 with a paper, “A Neural Mechanism for the Immediate Recall of Sequences,” which turned out not to work because I made some bad guesses about synaptic change. I made what I think was a more plausible attempt to explain it many years later, when I was writing The Autonomous Brain (Milner 1999). One difficulty is that the trace of the first member of a series is presumably the one that has become most weak by the time the series must be recalled. My solution was to work with fading inhibitory synapses that suppress active traces. The problem is of prime importance for language neuropsychologists, an ingenious group whose work l have not been following closely, so possibly they have discovered a better solution by now.

After I retired from teaching, I indulged my devotion to puzzles in my spare time by polishing some of my speculations and assembling them in a book, The Autonomous Brain, published in 1999 (the fiftieth anniversary of Hebb’s book). It is basically my attempt to provide Hebb’s theory with a more up-to-date nervous system, the goal I set myself when I chose to study with Hebb about a half century earlier. That task is by no means complete, but it provided me with a sort of closure.

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Fernando Nottebohm

BORN:

Buenos Aires, Argentina

November 10, 1940

EDUCATION:

University of California, Berkeley, BA in Zoology (1962)

University of California, Berkeley, PhD in Zoology (1966)

APPOINTMENTS:

Assistant Professor, Rockefeller University (1967)

Associate Professor, Rockefeller University (1971)

Professor, Rockefeller University (1976)

Director, Rockefeller University’s Field Research Center for Ethology and Ecology (1981)

HONORS AND AWARDS:

American Academy of Arts and Sciences (1982)

National Academy of Sciences (1988)

American Philosophical Society (1991)

Charles A. Dana Award (1992)

Fondation Ipsen Neuronal Plasticity Prize (1999)

Lewis S. Rosenstiel Award (2004)

Benjamin Franklin Medal in Life Sciences (2006)

The Mortimer D. Sackler, MD, Prize for Distinguished Achievement in Developmental Psychobiology (2011)

Fernando Nottebohm is a pioneer in the study of the neurobiology of vocal learning in birds and was the first to describe their forebrain’s song system and some of its salient features: sexual dimorphism, seasonal changes in size, hormonal sensitivity, and the relation between its volume and song-learning potential. The work of Nottebohm and his colleagues also provided the first incontrovertible evidence that new neurons continued to be added to the adult brain of a warm-blooded vertebrate, where they were born by division of radial cells. Most surprising, perhaps, was the evidence that many of these neurons were ephemeral, being added at times of peak memory load, lasting for a few weeks or months, and then disappearing. He saw this turnover of neurons as a process of self-rejuvenation that enabled new learning to occur. His findings challenged some well-established dogmas.

Fernando Nottebohm

Growing Up in the Pampas

I was born in Buenos Aires in 1940, a second-generation Argentine. My father was Guillermo Oscar Nottebohm, my mother Amelia Grant Menzies. My father’s family came from Germany, Belgium, and Holland, my mother’s from Scotland.

No one was very religious at home, except for my sister Florencia, who went to a convent school and every Sunday herded her three younger brothers to church. My mother did not come with us, and when I asked her why, she said that she communicated with God directly. So did my dad. I gave up religion at age 16.

Animals fascinated me, and I was able to observe them and to enjoy them at my family’s ranch, Estancia La Maya, in southeastern Cordoba province. I spent much time there when not at school. La Maya was northwest of Buenos Aires, an eight-hour trip by train. In pampas country, with an average rainfall of some 900 mm, its park and meadows seemed always replete with birds, which I spied with my binoculars. I grew familiar with their habits, sounds, and nests; I knew where to find them and was immensely happy in their company. Of course, there were other attractions to ranch life. My older brother, Guillermo, and I rode every day with the gauchos and enjoyed working with cattle, but I always kept an eye open for birds and what they did. My favorite author was William Henry Hudson, born in the pampas south of Buenos Aires in 1841, the son of American settlers at a time when Indian incursions were still much feared. As a boy and a young man, Hudson was an observer of nature. He left for England at age 33 never to return. Many years later, he wrote a wonderful book, Far Away and Long Ago (1918), in which he told about his youthful adventures among birds. When I was in my early teens, that book represented all I wanted to be—an able observer of nature and a writer. Unfortunately, by the 1950s, the pampas had changed a lot; they no longer were the enchanted world that Hudson knew. Now agriculture was prevalent. Fortunately, my father was much fonder of cattle than of crops, and so at La Maya as much land was devoted to pastures as to crops, and this rotation protected the rich soil as well as the wildlife. Now, 60 years later, pesticides and herbicides squeeze greater profits from the land, but many of the birds are gone, even some that were very common before, such as tinamous and the burrowing owls.

Determinism or Free Will?

I had my first “scientific” insight at age 17, influenced, I suppose, by things I read, but I experienced it as if I had worked it out on my own. I took it as a given that the mind was inside the head and part of the normal function of the brain and therefore had all the attributes of matter. How did matter behave? I reasoned that if substance “A” was defined by its properties, then, under any set of conditions, the outcome of its interactions with other substances would always be the same. Apply that to all kinds of matter and all the combinations in which it occurs, brain included, and the result was determinism. Things happened, and the outcome was either predictable or, due to chance events, unpredictable. Either way, there was little room for freedom of choice, and therefore little room for sin. This insight did not change my ways but made me wonder at the paradox of “free will” and the reliability of our mind as a witness to ourselves. What to make of consciousness and the feeling it gave us of being in charge? I have been fond of paradoxes ever since.

School

My formal schooling took place in Buenos Aires; I attended the Escuela Argentina Modelo for grade school and the Colegio Nacional de Buenos Aires for high school. Both were all-boys schools, the Colegio the best one in Argentina. Teachers there were also professors at the University of Buenos Aires and very knowledgeable, but they worked through a set curriculum that was meant to inform, rather than encourage discussion or original thinking. This curriculum included six years of Latin, three years of French, and three years of German or English. I chose German because I had learned English at home. Periodically, I grew tired of school and on lovely days, hopped on a train to Tigre, at the edge of the Parana Delta, just an hour away. There I would settle into a canoe and, with a picnic and binoculars, paddle into the rivers and marshes of the delta. Sometimes I took a book, so that I could read as the canoe rested among the reeds or on a quiet bank. Such sweet truancy! I would be back home for supper. My parents knew of these little excursions. Because I did well at school, they did not interfere with the way I managed my time.

In my last year in high school, I had to decide what to be when I grew up. I had several interests. One of them was politics. Argentina’s dictator, Peron, had been ousted by the army in 1955, after 12 years of what I remember as a mix of fascism, populism, cronyism, intimidation, and plain thievery, though many of the poor regarded Peron as an idol. It now seemed as if democratic institutions might flourish and that the country might experience a renaissance. A couple of years after Peron’s departure, I went with a friend to observe the meeting of a constitutional assembly. This assembly would be the doorway to Argentina’s democratic future. Ever the naturalist, I brought with me a pair of binoculars so that from the balcony I could observe the politicians close up. After witnessing endless maneuvers, posturing, and delays during which nothing at all was accomplished, I tired and returned home much disappointed. I lacked the patience and stomach for politics.

The Magnet of the Big Unknowns

My curiosity was drawn more strongly to the big unknowns—the origin of the world, of life, of humans, of consciousness and mind, and I was, of course, much drawn by my love of nature and, in particular, birds. I admired the work of Charles Darwin and had become acquainted with that of Karl von Frisch, who described the dance language of bees. I also had read a great book on the history of philosophy by Will Durant and a book on cosmology. Nothing, I decided, would please me more than to spend the rest of my life delving into these matters and studying nature. I asked my father to send me to Oxford or Cambridge, but he thought this was a weak plan. Scientists in Argentina, he explained, were very poorly paid, philosophers even a rarer breed, and neither occupation would land me a job with which I could support a family. Moreover, at that time, university positions were often assigned on the basis of politics, not merit, which made a career in science doubly risky. I remember my father repeatedly asking, “Do you want to be a bohemian?” I was not sure what a bohemian was but from the face he put on when he asked, I decided I probably did not want to be one.

Become a Rancher?

My father offered a compromise. He suggested I go to the United States to learn the latest about farming and ranching and then return to Argentina and work with him and help him manage the family lands. This would secure my income, and on weekends I still could lose myself among the birds I loved. I agreed to this plan. It coupled the adventure of going abroad and sampling new intellectual horizons with the reward of a safe return. I was very close to my mother, father, and siblings, and so my studies abroad would entail only a temporary separation.

In January 1959, two months after my 18th birthday, I flew to Miami. It was my first time on an airplane. I fell desperately in love with one of the stewardesses, a girl from Chile, but she left the plane in Lima. In Miami, I boarded a Greyhound bus that would take me to Lincoln and the school of agriculture of the University of Nebraska. When I arrived there, Lincoln was deep in snow. My friend Fernando Lagos, a fellow Argentine and agronomy student was waiting for me, and I settled in. Lagos and I became close friends.

The school of agriculture organized a rodeo each spring for university students, and I signed up to ride a bull and a bronco. The bull was a shaggy Scottish highlander with broad horns. The bronco was a huge, white, and very ill-tempered horse named Tombstone. I had to ride both animals bareback and did well with the bull, even earned a prize, but the bronco ride was brief. After the ride, the bull circled back, rammed its head on my buttocks, and tossed me into the air. That was my most interesting day at the School of Agriculture.

I stayed in Nebraska a full year. During that summer, I worked as a hired hand at a ranch near Valentine, in sandhill country. I milked cows, put up hay, painted barns, built fences, and rounded up cattle. On Sundays, I spied on nature, and in the evenings, I read. I realized that summer that I was not cut for either farming or ranching. I loved the outdoors but was not interested in cattle, corn, or hogs. My mind was on other things and so, when I returned to Lincoln in the fall, I went directly to the library and looked at the catalogues of some of the best universities, searching for the blend of courses that would help me get to where I wanted to go. I was accepted at the University of California at Berkeley and allowed to transfer into the zoology department as a sophomore. Despite this change in course, I was glad that I had entered the United States through the Midwest because there I encountered many of the values that made the country great; I found the people hard working, sensible, polite, generous, and warm. I realized, as had my father, that my choice would have lasting consequences, for it was then that, like W. H. Hudson, I veered away from Argentina. Toward the end of his life, Hudson wrote to his brother, who stayed in Argentina, that he had often wondered how things might have gone if he had never left the enchanted land of his youth. In England, Hudson became a naturalist of renown, but he treasured most the years he spent among the birds of the pampas. When, later, I was asked by young Argentines for advice on studying abroad, I recommended that they do so but only if their interests were so deep that to forgo them would feel like torture; otherwise, they should not desert family, friends, language, and land. Once trained abroad and imprinted with standards of excellence, fair play, and opportunity, it is difficult to return to the setting where one started. Moreover, he who leaves early has no godfathers that will pave his return. I never received a job offer from Argentina—not once.

Berkeley and Peter Marler

In January 1960, I drove from Lincoln to Berkeley, with a stop at the Grand Canyon, and immediately fell in love with my new destination—the Spanish accents of the buildings, the broad sunny lawns, the palms and eucalyptus trees, and the many flowering plants. I loved the blend of people and cultures and the palpable ferment and diversity of ideas, though I missed the beauty and charm of the Argentine girls and felt clumsy with a language that was not my own. I would spend two and a half years as an undergraduate in Berkeley and another two and a half for my PhD; those were among my happiest days.

I enrolled in the zoology department and that first semester I met Peter Marler, who taught Zoology IB. Marler was an Englishman with one PhD in botany and one in zoology. He had arrived from Cambridge a few years earlier, and he was a master lecturer. He paced in front of the class as he told us about the evolution of vertebrates, his voice lowered, his eyes fixed on an imaginary horizon, his brows working up and down. At times, his posture and movement would evoke the animals that roamed the land millions of years ago. I remember his conspiratorial tone as he introduced the first mammal, a small, furtive thing that was no match for the lumbering dinosaurs of the day; yet it was smarter, the improbable hero in a struggle for dominance that would unfold over millions of years. That was the kind of grand drama I wanted to learn about. It was difficult not to be inspired and want to learn more. I was glued to every word of Marler’s and realized that I had finally found what I wanted to be.

Marler had trained as an ethologist under Professor William H. Thorpe of Cambridge University, who was the first to use the sound spectrograph to describe vocal learning in a songbird, the chaffinch (Fringilla coelebs) (Thorpe, 1958). The sound spectrograph turned sounds into a visual display that showed how loudness and frequency changed over time. Thorpe (1958) used this instrument to do a detailed analysis of how song was learned. Marler had, as part of his thesis, described the geographic distribution of chaffinch song dialects in Scotland. He had also noted how chaffinch song differed in various Atlantic islands and how these differences were related to the relative richness or paucity of the local avifauna. Marler suggested that when many different species communicated vocally, the channel for each would be narrower, promoting the use of signals that were more distinct and less variable. In California, Marler was testing Thorpe’s insights and those from his own chaffinch work, using a common California songbird, the white-crowned sparrow, Zonotrichia leucophrys, which also had song dialects (Marler and Tamura, 1964). I learned from Marler to go for the broadest, simplest questions, and to articulate the findings so they never sounded like dogma. His insights were “suggestions” of how things might be, and they were worded so that further data could modify them without loss of face. Marler built on the insights from his chaffinch and white-crowned work using still other songbirds. Taken together, his field and laboratory observations on song learning led him to propose the existence of an innate “instinct to learn” that determined the what, when, and how of learning. This view departed radically from that of B. F. Skinner, a Harvard psychologist who taught that, with proper reinforcement, animals could be made to perform even very unnatural behaviors. Of course, these two outlooks were not mutually exclusive, for although one emphasized the limitations or guidance built into a natural learning program, the other one focused on the power of conditioning to modify behavior. These ideas interested me a lot. Just as earlier I had wondered about the reliability of our mind as a witness to ourselves, now I wondered how often we were held back by limitations built into our ability to know. Was our world restricted by unsuspected programs in our minds?

Until Marler’s appearance on the scene, the field of animal communication had been full of anecdotes but light on basic science. Marler suggested broad rules that were based on the physics of sound transmission, the properties of binaural sound perception, the relation between sender and receiver, and the nature of the behavioral and environmental context. For example, his approach suggested that sounds used in communication would differ physically depending on whether they must conceal or reveal the position of the emitter. Moreover, from the context of a signal and the response of the receiver, he inferred what kind of information was conveyed. His approach was fresh, didactic, and compelling. It stressed field observations, comparative studies, and laboratory experimentation, and its principles could be applied to all sensory modalities and all groups of animals, whether invertebrates, amphibians, fish, primates, or birds. Marler was also enthusiastic regarding field experiments.

In later years, Marler spent equal amounts of time studying vocal communication in birds and primates, including a stay with Jane Goodall in Kenya studying vocal behavior in free-ranging chimpanzees. Marler’s students studied the vocal behavior of diverse primates throughout the world, reflecting Marler’s intense desire to come to grips with the conditions that might have led to vocal learning and the emergence of language in humans. It will be clear from my description of the man I encountered teaching Zoology IB that this was an extraordinarily lucky break—I had found someone that walked on water.

During my undergraduate years at Berkeley, I tried to put together a curriculum that acquainted me with many levels of biological thinking, such as ethology (Peter Marler), ecology (Frank Pitelka), anthropology (Sherwood Washburn), comparative psychology (Mark Rosenzweig), behavioral endocrinology (Frank Beach), marine biology (Donald Abbott), comparative anatomy (Wilbur Quay), embryology (Richard Eakin), comparative physiology (Paola Timiras and Walter Freeman), neurophysiology (Donald Wilson), biochemistry (Melvin Calvin), cell biology (Max Alfert), genetics (Kurt Stern), and human neuroanatomy (Marian Diamond). This was a rich fare, later supplemented in graduate school by courses in philosophy of science (Paul Feyerabend) and history of science. During those years, I also enjoyed taking courses in German and in German literature that allowed me to explore aspects of the mind that went beyond the factual description and objectivity of science. I remember, in particular, my thrill at reading Kafka. However, and to my lasting chagrin, I did not take courses in the then-young field of molecular biology, something that I would now put high on my agenda. With this notable exception, I felt I had brought together many of the lines of expertise that I would need to think about matters that interested me.

During the last year of their undergraduate studies, students in the zoology department at Berkeley could take an “honors course” consisting of research in a chosen laboratory. I chose Marler’s lab for this, and my project was to work on the biology of sound production by the syrinx. There was already literature on this topic. Marler was very supportive, and I put together a transparent pressure chamber that mimicked the pressurized inter-clavicular airsac that surrounds the syrinx in birds. The syrinx and trachea of a rooster were placed inside this chamber and connected in such a way that air could flow from the bronchi past the sound generating membranes of the syrinx and out the trachea. I was able to manipulate the flow of moist air, the configuration of the syrinx, and the pressure in the air space surrounding the syrinx. The crowning touch, suggested by Marler, was to use a stroboscopic light while sound was produced to see at what frequency the membranes of the syrinx would seem to stand still. That was the fundamental frequency of the sound produced.

I received my bachelor of science degree in June 1962, three and a half years after my arrival in Lincoln, Nebraska. At Marler’s invitation, I joined his laboratory as a doctoral student. The invitation was conveyed by Mark Konishi, who was then close to finishing his doctoral work with Marler and with whom I had developed a close friendship (both of us enjoyed skiing). I answered that same day. I could not think of a better opportunity to further advance my interests, and I had no alternative plans. I was still keen on all the big questions about origins that I have mentioned earlier. I hoped that, by focusing on vocal learning, I would eventually be able to find my way back to these issues, though I did not know how this might come about, if at all.

I Find the Girl I Love

In the summer of 1963, I met a lovely Argentine girl, Marta Seeber, who was finishing high school in San Francisco. Not only was she beautiful but loved animals and nature and had a great sense of humor. Half a year later we were married in Buenos Aires, and I entered the happiest period of my life. Marta was from then on an invaluable partner in many of my scientific adventures. Her thinking was clear and incisive, and she was superb at editing what I tried to put down on paper. I later learned of studies that showed that most immigrants to the United States marry others born not more than 10 miles away from their own birth site. In a figurative sense, it is like salmon going back to their home stream, but in this case, while staying abroad. Porteños, as the people from Buenos Aires are called, have a strong “dialect” and perhaps this common dialect influenced our choice. It is a phenomenon that others have studied in birds.

We rented an apartment at 2727 Hearst Avenue, on the road up to the Lawrence Radiation Laboratory. We saw President Kennedy from our doorstep when, during a visit to the university, he was driven up the hill to visit the cyclotron. It was a marvelous time in the United States—a time full of hope and promise, and the young people (and in particular university students) felt very much a part of it, inspired by a president that, I believe, most of us loved. Less than a year later, President Kennedy was dead.

Left Hypoglossal Dominance

Marler spent the 1964–1965 academic year studying primates in Africa, and I spent the year as a guest in the laboratory of W. H. Thorpe in Cambridge. During that year, I set out to test a suggestion advanced by Konishi (1965). He had noticed that if a white-crowned sparrow was deafened after it had mastered its learned song, this song would be retained with great accuracy; he wondered how this was achieved. Might proprioceptive feedback play a role? I tested this idea by denervating the syrinx. Denervation would debase the sound produced, but would the altered pattern remain stable? If yes, this would suggest that the learned motor program was no longer dependent on feedback. If the answer was no, this would suggest that, as motor output and associated auditory and proprioceptive feedback were altered, stability broke down. These experiments would be conducted with hearing and deaf individuals. In retrospect, it was a complicated experiment, and results could be difficult to interpret. Yet, I did it, and the outcome was totally unexpected—a classical example of looking for A and finding B.

During my year in Thorpe’s sub-department of animal behavior, I had just one room to myself. It held my desk, my surgery, and all of my birds. The morning after I did my first bilateral syringeal denervation, I unlocked the room, flipped the lights on, and walked in. The operated chaffinch was on a perch and looking well but upon my arrival got agitated and started to hop from perch to perch and breathe ever more laboriously, producing a sharp wheezing sound; then it fell to the floor of the cage and died. The same fate awaited my second bilateral denervation and then, bearing in mind what I had seen in my earlier pressure chamber experiments, I understood. The walls of the syrinx are soft, and as air flows by, they are drawn into the lumen of the bronchi, like lips, creating a narrow aperture through which air must flow; air streaming past a narrow aperture creates turbulence and, in birds, the periodicity (or not) of this turbulence accounts for the quality of the sounds we hear. These sounds are modulated by the syringeal muscles that set the size and shape of the aperture past which air flows, and by abdominal muscles, acting on the abdominal air sacs, that set the pressure head of the outflowing air. I inferred that during inspiration the role of the syringeal muscles must be to maintain the syringeal lumen fully open so that inspired air flows unhindered. Otherwise, the walls collapse (Bernoulli effect), with accompanying wheezing, a phenomenon that to some extent must also occur during expiration. In this light, the syringeal muscles have a dual role: (1) enablers of air flow and (2) voice production. When I entered the room, the birds were alarmed, then became agitated—breathing harder—and this led to asphyxia.

I wondered how to avoid this unwanted outcome. Perhaps unilateral denervation would still yield a useful result, and that is where I got lucky. For no particular reason, I denervated the left syringeal half in a number of chaffinches and, in all, song was severely modified. Then, one day, I denervated the right syringeal half: the song was unaltered. Fearing I had made a mistake, I repeated the operation a second time in the same bird and still no effect, and then a third time, now sectioning the three roots of the hypoglossal nerve that provide the innervation to the right side of the trachea and syrinx, and still no effect. Suddenly, I understood: I had discovered song handedness—left hypoglossal dominance for the production of learned song. I repeated the same operation in many more chaffinches (Nottebohm, 1971, 1972) and, later, in canaries (Nottebohm and Nottebohm, 1976), always with the same result. If anything, left hypoglossal dominance was, in my birds, more robust than handedness in humans because I never found a right-handed chaffinch or canary. I noticed, too, that when nerve section was not followed by regrowth, it was just the muscles of the denervated side that atrophied, becoming very thin and colorless. I carefully inspected the syrinx and could find no reason why one side would be dominant for the production of learned song. The two syringeal halves were mirror images of each other. The only difference was that the muscles on the left side were somewhat heavier than their right counterparts, but this I attributed to differential use. Intriguingly, in a majority of chaffinches and, later, canaries, the right syringeal half was not totally silent but contributed a few high frequency sounds, so that one could imagine a division of labor with one side producing low frequencies, the other high frequencies. Yet, when the dominant left syringeal half was denervated in juvenile chaffinches before the onset of singing, then the right intact side developed accurate imitations of external models so that—a bit like the hands of humans—both sides were, at the onset, equipotential and each could on its own do the entire song. The exception was that unilaterally denervated birds could not copy harmonically unrelated simultaneous sounds. In canaries, I found that this potential for dominance reversal persisted into adulthood, perhaps because canaries are able to learn a new song every year. The discovery of singing handedness and its reversal (Nottebohm, 1971, 1972a, 1977; Nottebohm and Nottebohm, 1976; Nottebohm et al., 1979) had not been predicted and came as a surprise. I have known, since, that all true discoveries come as surprises.

Field Work

Even as I explored the topic of song handedness, there was a part of me that also wanted to study the biology of vocal learning in the field—dialects in the rufous-collared sparrow, Zonotrichia capensis, and vocal imitation in wild parrots, Amazona amazonica. I pursued that work from 1966 through 1974, including two years spent in and out of the jungles of Trinidad, together with my wife. During those years, I learned a lot about field biology but did not come across an issue that, in my view, was basic and ripe for cracking. Eventually, I realized that I would not be effective in both lab and field and gave up field work after publishing some of my observations (Nottebohm, 1969b, 1972b, 1975, 1976; Nottebohm and Selander, 1972; Handford and Nottebohm, 1976).

The Song System

In birds, I had found a learned vocal skill produced by a single, specialized organ that showed handedness similar to that in humans. What next? Would these birds also show hemispheric dominance for the production of learned song? To address this question, I had to smoke out the brain pathways responsible for the acquisition and production of learned song. Harvey Karten suggested, correctly, that I first make an atlas of the canary brain. For this, I teamed up with Christiana Leonard, whom I knew from Berkeley. She was now a wonderful neuroanatomist in the laboratory of Carl Pfaffmann at Rockefeller, and she had a great technician, Tegner Stokes, with whom I did much of the actual work. Once the atlas was done (Stokes et al., 1974), we identified the medullary motor neurons that innervated the muscles of syrinx and trachea. We then placed lesions around the known forebrain auditory projection of birds, Field L, hoping to find a site that, when lesioned, affected song—perhaps an avian equivalent of Broca’s area in humans. We found such a site (Nottebohm et al., 1976) and called it the hyperstriatum ventrale, pars caudale (HVC); but this was an error because HVC was really part of what then was called the neostriatum and now is known as the nidopallium. Because the abbreviation HVC was already established in the literature, I decided to stick with it and have it stand for “high vocal center.” Some find this use of English and the assigning of a function unorthodox and so, when referring to HVC, they add “abbreviation used as a noun” in brackets. I find this silly and confusing. There are precedents for using English and functional terms in brain anatomy (e.g., “optic tectum” and “olfactory bulb”), so why not “high vocal center”? The high vocal role of HVC is supported by connectivity, physiology, and behavior. Much research from several laboratories has shown that this anatomically discrete nucleus is, indeed, the headwaters of the “song system” (See Figs. 1 and 2).

The 1976 report showed that HVC projects to two other discrete anatomical nuclei, the “robust” nucleus of the archopallium (RA), which in turn projects to the hypoglossal motorneurons that innervate the muscles of the trachea and syrinx (nXIIts), and Area X, that we now know is part of the basal ganglia. Interestingly, much as HVC-RA-nXIIts provides the backbone of the descending pathway for the production of learned song (1976), HVC also receives input from the auditory forebrain, as first described by Kelley and Nottebohm (1979) and subsequently in greater detail by Vates et al. (1996) and Mello et al. (1998). Katz and Gurney (1981) provided the first neurophysiological evidence that HVC receives auditory input. HVC’s pre-motor and auditory profile is reminiscent of Broca’s area in humans.

The existence of discrete forebrain nuclei that controlled a specific learned skill seemed contrary to the findings of Karl Lashley (1950), whose lesion work in rats had suggested that the impairment of maze performance was proportional to the amount of cortex destroyed and not dependent on lesion of any one particular site. Perhaps these very different outcomes had to do with the fact that song is a learned motor skill produced by a special purpose organ, the syrinx. By contrast, running a maze—though a motor activity—is not much of a motor “skill,” and it does not depend on a specialized organ for maze running.

Fig. 1.    The song system can be imagined as consisting of four modules. Module #1 is in the brain stem and shared by vocal learners as well as by non-vocal learners. Module #2 is a telencephalic module that tells module #1 what to do. Module #3 starts from module #2 and then returns to it; it is necessary for vocal learning but not for production of learned song. Modules #2 and #3 are very well developed in vocal learners, less so or absent in non-learners. Module #4 is the ascending auditory pathway that conveys information about the sounds to be imitated and auditory feedback about the sounds produced. From Nottebohm, 1993.

Fig. 2.    Schematic diagram of the nuclei and connections of modules #2 and #3 and their relation to modules #1 and #4. All the connections shown are ipsilateral, and each right and left brain half duplicates the anatomy of the other side. Abbreviations: HVC, high vocal center; RA, robust nucleus of archipallium; X, area X of basal ganglia; lMAN, lateral part of the magnocellular nucleus of the anterior nidopallium; DLM, medial portion of dorsolateral thalamic nuclus; nXII, tracheosyringeal part of the hypoglossal nucleus; Field L, auditory nidopallium. The color code for the four modules of the song system is the same for both figures. From Nottebohm, 1993.

Hemispheric Dominance and Its Reversal

My interest in vocal learning had led to the accidental discovery of syringeal “handedness.” I was a “lefty” as a child but was schooled to become right-handed. I still draw with the left and can write with either hand. Handedness interested me and so I took to the readings of not just Paul Broca but also Hans-Lukas Teuber and Norman Geschwind and many others concerned with such matters. It was now time to look for handedness in the central song system. In the absence of a corpus callosum, most of the song system’s forebrain circuitry is ipsilateral as are its descending pathways. The left HVC, for example, controls the performance of the left RA and of the left syringeal half. In adult canaries, lesions to the left HVC have a much more devastating effect than those of the right one, and the quality of song following such a left lesion is reminiscent of the highly variable subsong of juveniles. Yet, seven months later, this same canary has learned to produce a new, normal song, this time under right side control; the new song is silenced if the right tracheosyringeal nerve is cut, evidence that dominance had flipped from one side to the other (Nottebohm, 1977). By then, I felt that the 1976 publication on “Central Control of Song in the Canary” had planted the germinal seed of a new field, the neurobiology of vocal learning, which nicely complemented the ethological work of Thorpe and Marler.

Two Pathways—One to Learn, One to Know

In 1976, I did not understand the significance of the projection from HVC to Area X, nor did I realize that, though embedded in what then was called “Lobus parolfactorius,” it was really part of the avian basal ganglia. Lesions to Area X in adult canaries did not alter song (Nottebohm et al., 1976). In 1984, a key study by Sarah Bottjer and Arthur P. Arnold showed that though an intact Area X was not necessary for the production of learned song, it was necessary for song learning. The importance of this observation became apparent when the circuit connections of Area X became fully understood. We knew that HVC projected to Area X (1976) and that the lateral nucleus magnocellularis of the anterior neostriatum (LMAN) projected to RA (Nottebohm et al., 1982), Then, in 1987, Okuhata and Saito (1987), working in Japan, reported that Area X projected to nucleus DLM of the thalamus and that DLM projected to LMAN. This connectivity, also shown in Figure 1, was confirmed by Bottjer et al. in 1989. By then, we realized that the song system included two forebrain circuits, an “anterior” one (HVC→Area X→DLM→LMAN→RA) necessary for vocal learning and a “posterior” one (HVC→RA) necessary for the production of learned song. Once a song has been learned, it is HVC that “knows” and executes the pattern. All the nuclei of these two pathways are anatomically discrete. HVC is at the headwaters of both these circuits, and RA provides the common exit point from forebrain to brainstem (Figure 1). The arrangement described here seems to be general among songbirds.

Vocal Variability Is Necessary for Vocal Learning

In 1991, Constance Scharff and I looked more closely at how the “anterior” pathway contributed to vocal learning and suggested it had two roles:(1) as an information channel necessary for learning and (2) as a modulator of plasticity necessary for learning. These two roles seemed to be differently represented in Area X and LMAN. Although early lesions of Area X yielded results reminiscent of early deafening, with the bird producing in adulthood variable, abnormal song, early LMAN lesions resulted the day after in a drastic reduction in note diversity and variability, with no further changes. The idea that LMAN played a crucial role in fostering circuit plasticity necessary for learning was not farfetched because the same RA neurons that received input from HVC also received input from LMAN (Canady et al., 1988); moreover, these cells projected to the motor neurons that innervated the syrinx. However, the neurophysiological nature of the relation between LMAN and RA was not understood until the laboratories of Michael Fee at MIT (Ölveczky et al., 2005; Aronov et al., 2008; Andalman and Fee, 2009) and Brainard and Doupe at University of California, San Francisco (UCSF) (Brainard and Doupe, 2000; Kao et al., 2005) showed how this worked. In a nutshell, Fee calls LMAN a “noise generator” whose input to RA promotes the vocal variability that is necessary for learning. This “noisy” input is not totally random because, given access to auditory feedback, it helps shape motor signals crafted by the HVC-RA axis. Intriguingly, the same LMAN neurons that project to RA also send a collateral back to Area X (Vates and Nottebohm, 1995), but the consequences and system’s logic of this feedback are not yet understood.

Ontogeny and Origins of Vocal Learning

My work has always been driven by immediate questions as well as by deeper and more speculative ones, and the origins of vocal learning falls into the latter category. It is easy to imagine how some traits evolved, but in other cases, the sequence is not obvious. How did modification of a non-learning vocal system—as inferred to exist in chickens (Konishi, 1963) and doves (Nottebohm and Nottebohm, 1971)—lead to the emergence of auditorily guided vocal learning? This, to me, remains a fascinating question. It was a standard approach among students of human evolution to state that “language” (which was not separated from “vocal learning”) arose in humans as societies became more complex and there was a need to convey more information. I thought we might be able to do better with birds. Take the case of the chaffinch. The earlier a male chaffinch is deafened, the more rudimentary the song it produces in adulthood, suggesting that the interaction between hearing and motor output starts well before the imitation of a specific model (Nottebohm, 1968). Next, a careful analysis of vocal ontogeny suggests that the food-begging calls of juvenile chaffinches give rise to two distinct sounds that occur in subsong, the “chirp” and the “rattle” (subsong being the babbling stage of birds before external models are incorporated). Modification of these two subsong components then seems to give rise to all the sounds of adult song. I suggested that in this manner each stage in vocal ontogeny provides auditory and motor cues and guidance for the next one, culminating in the imitation of an external model (Nottebohm, 1972a). Such self-assembly need not be very different from the way organs put themselves together, but the key difference is, of course, the role of auditory feedback.

Direct evidence that hearing was important for the early, pre-imitation stages came many years later from work that Wan-Chun Liu did with chipping sparrows. Chipping sparrow males learn their song by imitation, but females do not sing. In these birds, the food begging calls of juveniles are much more variable in males than in females and, as I had surmised in the chaffinch, in this case too, they transition into subsong. Importantly, whereas early deafening affects the food-begging calls of male chipping sparrows, it does not affect those of females. In males, but not in females, food begging seems to be part of a vocal learning program that depends on intact hearing and is guided by hearing (Liu et al., 2009).

The observations on chipping sparrows were of interest in another way. We used immediate early gene (IEG) expression to identify which of the song nuclei were active during food begging (Jarvis and Nottebohm, 1997), and there was only one, RA, in which a rise in IEG expression was driven by food begging. Intriguingly, lesions of RA did not stop food begging in males but just made them as stereotyped as in females (Liu et al., 2009). These observations suggest that hearing-dependent vocal variability is an early and necessary event in the ontogeny of vocal learning, and therefore, perhaps, also in its evolution. Might juveniles that disguise their vocal identity through increased vocal variability be fed more frequently by their parents? If so, the origins of vocal learning may be rooted not in the need to communicate more information, but in the need to obfuscate and misinform. Does this sound like a human ploy?

It is perhaps no accident that the most recent publication from my laboratory focuses on the song pathways of a passeriform (same order as the song learning oscines), the Eastern Phoebe, Sayornis phoebe. Phoebe song develops normally in deaf individuals yet goes through a protracted ontogeny suggestive of a role for practice. These birds have a rudimentary RA-like region in their forebrain but, apparently, no HVC, LMAN, or Area X, or at least none that can be easily recognized. These observations remind us of how difficult it is to imagine how the song system or language evolved, with each stage offering a selective advantage (Liu et al., 2013).

Brain Sexual Dimorphism

Neuroscientists had never before had anything as anatomically discrete as the song system responsible for the acquisition and production of a narrowly defined, learned, communicatory behavior; nor had we had before the neural substrate for a learned behavior that was particularly well developed in males and less so or not at all in females. Perhaps because of this lack of precedent, none of us had predicted or expected that the song system would be sexually dimorphic. Indeed, when Stokes, Leonard, and I produced our atlas of the canary brain we used males and females interchangeably, on the assumption that gender would not matter.

Eventually, our eyes told our brain otherwise. Arthur P. Arnold and I noticed independently, he in zebra finches and I in canaries, that the song system showed marked sexual dimorphism, and this was the first example of gross sexual dimorphism in the vertebrae brain. This discovery was unexpected because until then the brains of male and female vertebrates had been thought to be much the same, with hormones and experience accounting for differences in performance.

Male canaries sing much more than females, and their song is much more complex; female zebra finches, Taeniopygia guttata, do not sing at all. Arnold (who was my first PhD student) and I found that HVC and some other song nuclei were several-fold larger in males than in females. The extreme case was in the zebra finch, in which some of the song nuclei are vestigial in females (Nottebohm and Arnold, 1976). Earlier observations had shown that many song nuclei have receptors for androgen (Arnold et al., 1976) and estrogen, which then raised the issue of whether the dimorphisms we observed could be altered by hormonal treatment. Mark Gurney, in Konishi’s laboratory, showed that female zebra finches treated with estradiol during their first month after hatching developed a male song system. In adult female canaries, testosterone treatment doubled the size of some song nuclei and induced male-like song. As this happened, the dendrites of one class of RA neurons doubled in length and formed many new synapses (DeVoogd and Nottebohm, 1981a; Canady et al., 1988). This hormone–dependent plasticity in the adult brain was as novel as the dimorphism itself.

Seasonality

Once I realized the potent effect that gonadal hormones could have on the morphology of the adult brain, I wondered how the male canary brain fared under seasonally changing hormone levels. I compared the size of song nuclei in males soon after they finished their breeding season with that of others in full breeding condition. The result was astounding. HVC was twice as large in the spring as in late summer, after breeding ended (Nottebohm, 1981b). The effect was also present but less strong in nucleus RA.

Brain Space for Learning

The year 1981 was a good one for me. It was then, too, that I made another simple and satisfying observation. The size of nucleus HVC was related to the complexity of the song repertoire. Taking advantage of the very clear anatomical boundaries of this nucleus, it was possible to estimate its volume rather closely. There was no systematic difference between right and left HVC—in itself a puzzle—but HVC volume was a good predictor of learning potential. Canaries with a relatively simple song, defined by number of different song syllables, might have a large or small HVC, but birds with the more complex songs always had large HVCs (Nottebohm et al., 1979). This correlation has held when comparing populations of a same songbird species (Canady et al., 1984), and others have shown it holds across species comparisons. Apparently brain space for learned song is at a premium.

Two Dogmas

In the early 1980s, the neurosciences harbored two prevailing beliefs. The first one was that the number of neurons in the brain of adult, warm-blooded vertebrates was reached soon after birth, an idea that went back to the classical work of Santiago Ramon y Cajal. Neuron numbers could decrease in adulthood, as in neural degenerative disorders, but no new ones could be added. The other, much more recent but equally widespread belief was that learning occurred at the level of synapses and could be explained by changes in synapse efficacy and numbers. Because synapses could change in number and in efficiency even in adulthood, many thought these changes could account for all changes in behavior. In computer terms, the hardware was provided by an existing population of neurons and their projections—the circuits of the brain—and the software was provided by malleable synapses.

Science is supposed to be the province of hard facts, yet I have been often surprised by how few hard facts there are. What we see in brain slices is determined by how the tissue is harvested and fixed, by the protocols used for different stains, by what the animal had been doing before it was killed, and so on. What we see might be an artifact that bears little relevance to what is in the living brain of an animal leading a natural life. What we do not see might not be there or might be there but be invisible. In short, science is replete with “observations” that, upon closer scrutiny, turn out to be interpretations and inferences, which leaves enormous room for error.

One day I pondered about anatomical seasonality in HVC and RA. Was it really a case of growth and retraction of dendrites and synapses, much like leaves that grew in the spring and were shed in the fall? Was this a good metaphor? Why was it that the seasonal changes were more marked in HVC than in RA? And why assume that these changes occurred in a constant set of neurons? Was it possible that neurons came and went and that the players in HVC were not always the same? I could not resist sharing these thoughts with Marta. Can you imagine, I mused, how this would set everything on its head? She liked this line of thinking a lot, for she favored bold science. We talked about it and laughed; it all seemed so improbable.

I also shared these thoughts with one of the young members of my laboratory, Steve Goldman, a very bright MD–PhD student; we talked about how to test for the possibility that new neurons were added and subtracted from HVC. He volunteered to do the work with help from my technician, Sue Kasparian, and begged me not to talk to others about this project. He was afraid that people would think we were ignorant, or worse, stupid. They used a method for birth-dating cells that was well established among embryologists. It relied on tritiated thymidine that was injected systemically and found its way into cells where it became incorporated into newly synthesized DNA. The tritium was an unstable isotope of hydrogen with an extra electron. As tritium reverted to a more stable form, it gave off a pulse of energy that oxidized a silver grain in an overlying photographic emulsion. This technique is called autoradiography. The principle behind autoradiography had been used by clinicians treating cancer; if enough radioactively labeled thymidine was concentrated by the nuclei of dividing cells, the energy it gave off would fragment existing DNA and kill the cells. However, this required high doses that also killed other, non-cancerous dividing cells and did not kill cancerous cells that at the time were not dividing, so this approach had been given up as a cancer treatment.

Adult Neurogenesis

We thought our chance of finding new neurons in the adult brain would be maximal in adult female canaries treated with testosterone, in which, as explained earlier, HVC volume doubled over a period of a few weeks. Some of our birds were treated with testosterone and some were not, and they were killed at various intervals after receiving the tritiated thymidine injections. The results were most rewarding. Birds allowed to survive 14 or more days showed, in cresyl violet-stained material, many labeled cells with relatively large and clear nuclei, which looked like neurons. “Label” was the appearance of a least five exposed silver grains over the nucleus; many cells had many more, making the nucleus of these cells look like a sliver of cucumber with pepper grains on top. Birds killed two days after tritiated thymidine treatment had no labeled neurons, yet showed many labeled cells on the ventricular wall immediately above HVC. We suggested that this was where the new neurons were born and that they then migrated from there into HVC. Our observations seemed to exclude the possibility that existing neurons gave rise to new ones by dividing in situ.

This story became Steven Goldman’s thesis work. By the time we got our results, we also became aware that we were not the first to use radioactively labeled thymidine to look for neurogenesis in the adult brain. Joseph Altman had used this very same approach and published observations in which he reported that neurons born in adulthood were added to the granule layer of the dentate gyrus of the hippocampus, to the olfactory bulb, and to cortex. Altman had published his observations between 1962 and 1970, but they had not gained wide acceptance—Ramon y Cajal’s dogma persisted. There were good reasons for this. First of all he had, like us, used stains that were not selective for neurons; second, he did not try to discriminate between a label that may have been incorporated during DNA repair and a label incorporated during the S-phase preceding mitosis; third, he did not systematically pursue the possible origin of the new neurons. These uncertainties proved sufficient for the rest of the field to adopt a wait and see attitude.

Steve Goldman and I were a bit crestfallen that we had not been first to plant our flag in this new field. At the same time, it was true for Altman as for us that the evidence for adult neurogenesis remained open to challenge. I asked Pasko Rakic, an experienced developmental neuroanatomist from Yale, to be the outside member of Goldman’s thesis committee. I knew that Rakic was very opposed to Altman’s claims of adult neurogenesis and so expected that he would be a stern evaluator of our work. Pasko looked at our slides, went over our protocols, and pronounced the data real, if yet not conclusive, for the very same reasons that he and others had found Altman’s data not conclusive. It was our good luck that Viktor Hamburger, from Washington University, heard about our work; he invited me to St Louis to lecture, and I brought some of our slides. He, like Pasko, felt the data were real and of interest and suggested we submit them for publication in the Proceedings of the National Academy of Sciences (Goldman and Nottebohm, 1983), which was a tremendous help.

Testing Beyond Reasonable Doubt

Steve Goldman then went on to finish the medical part of his training at neighboring Cornell Medical School; I decided to focus on all the pieces of data that were still missing and that would test, beyond reasonable doubt, whether adult neurogenesis was or was not a real phenomenon in the brain of adult, warm-blooded vertebrates. I use the latter wording because work by others had already shown that in fish—the body, brain, and eye of which continue to grow after sexual maturity—new neurons are added to the brain and spinal cord as the whole animal becomes larger.

After Steve left, Sue Kasparian and I did an inventory of where in the brains of adult male canaries new neurons (i.e., tritiated thymidine-labeled cells that looked like neurons in cresyl violet stain) occurred. We found them in great numbers through most of the forebrain but not in the cerebellum, thalamus, diencephalon, or medulla. This was not without interest because the forebrain is usually credited with the processing of perceptual information and with the planning, acquisition, and execution of complex behaviors and learning.

A Heroic Experiment

We needed irrefutable evidence that the cells we called “new neurons” were neurons and were new. I knew that if I gave adult male canaries injections of tritiated thymidine at eight-hour intervals for two weeks and killed them one month later, 10 percent of HVC “neurons” (i.e., cells that looked neuron-like with the cresyl violet stain) were labeled. I satisfied myself that this label was likely proof of birth by comparing the amount of label per cell with that seen in other cell types known to continue to proliferate in adulthood, such as endothelial cells and glia.

I then teamed up with John Paton, an excellent and painstakingly careful neurophysiologist who had trained with Bob Capranica at Cornell. We argued that if one were to record randomly from neurons in HVC, one in 10 would have been born during the previous four to six weeks. What we needed was to use a hollow glass electrode with a very slender tip, so that it could penetrate a neuron without killing it. This hollow electrode was filled with horseradish peroxidase that could be extruded into the neuron after recording from it so that later, as the tissue was harvested, that individual neuron could be recovered.

We applied this approach to adult male canaries that had received tritiated thymidine for two weeks one month earlier. We knew, from the work of Katz and Gurney, Konishi, and Margoliash that many neurons in HVC responded to sound, so we gathered data as follows. As the electrode advanced through HVC, its entry into a neuron was revealed by a change in resting potential; this neuron might show further changes in electric current in response to sound playbacks. The cell was filled with horseradish peroxidase and harvested later in 100-um thick sections that allowed a fairly good characterization of the cell’s anatomy—soma, dendrites, dendritic spines, and axon. Then, this thick section was thin sliced, yielding sections that were only 6-micra thick, which were then incubated for autoradiography. These various steps proved extraordinarily laborious and at each step many things could go wrong. After 12 months of full dedication to this project, Paton had full sets of information from 77 neurons. Seven of these—the uncanny 10 percent we had hoped for—had a fine array of exposed silver grains over their nucleus, and of these, three had responded to sound. This experiment provided, for the first time, firm evidence that cells born in an adult warm-blooded brain became neurons and that at least some connected to existing circuits so that, in fact, they were working neurons. It was this publication, which came out in Science in 1984 that, I believe, changed the thinking of many—so that now, adult neurogenesis loomed like a real possibility. As Eric Kandel commented to me years later, it was a sea change in thinking.

Hope for a New Neurology

That same year, at the behest of Jane and Peter Pattison’s Institute for Child Development Research, I organized a conference on “Hope for a New Neurology” at the Waldorf Astoria hotel in New York. The title for the conference undoubtedly struck some as hyperbole, but I felt it was justified. Clearly, neurons were born in the brain of adult, warm-blooded vertebrates and, in our material at least, they could find their way and establish connections. Our findings, I felt, added credence to Altman’s claims. All around, this seemed like a most hopeful moment for a field such as neurology. My friend Fred Plum, head of neurology at Cornell Medical School, had confided to me that often times the best advice for patients with brain damage was, “Get a good nurse and, if you are religious, pray.” We now might have the beginning of something better. Shirley Bayer lectured at that meeting about her evidence for neuronal addition to the adult hippocampus of rodents, while Joseph Altman, her husband, by then retired, sat in the audience. Pasko Rakic spoke about his search for adult neurogenesis in the brain of juvenile and adult macaques. That search produced no positive evidence, and Rakic was still of the opinion that the phenomenon did not apply to primates and was not relevant to humans; he was not even convinced that it occurred in mice. In my opinion, what mattered was the conceptual breakthrough. We now knew for sure that the adult brain had not lost the potential to give birth to new neurons and to recruit them into existing circuits. The 100-year-old dogma had sprung a leak.

Soon after that conference, I went to see Jerome Posner, head of neurology at Sloan Kettering Memorial Hospital in New York. That hospital specialized in treating cancer patients, of which quite a few had a very limited life expectancy. I asked him if it might be possible, with patient consent, to give some a low dose of tritiated thymidine and then to look for labeled neurons in their brains after they died. I reasoned that, if this could be done with patients of a diversity of ages and other backgrounds, we might see if the human brain ever recruited new neurons as my canaries did. Posner was interested but a few weeks later told me that his ethics board had vetoed the project on the grounds that someone might accuse the hospital of conflict of interest. Subsequently, a study using terminal patients was done in Sweden, and it revealed the addition of new neurons to the adult human hippocampus. More of this work needs to be done.

New Neuron Origin and Migration

Next on my agenda was to identify the cell type that, in my canaries, gave rise to new neurons and how they migrated from birth site to work site. The initial work with Steve Goldman suggested that they were born in the ventricular zone (VZ) facing the forebrain’s lateral ventricle, but this was tentative and details were missing. I was lucky, again, that the right person to build on this initial observation was in my laboratory, Arturo Alvarez-Buylla, a doctoral student from Mexico. A little bit earlier, a postdoctoral fellow in my lab, Daniel Buskirk, made a remarkable observation. Dan had been searching for monoclonal antibodies that might help us recognize cells or stages of cells that would help us visualize the choreography of adult neurogenesis. One day he came with a slide that showed what he feared might be an artifact and wanted to know my opinion. The slide showed a cresyl violet-stained section through the adult canary forebrain with many antibody-positive gold-brown fibers streaming through fit. The fibers emanated from small cells on the surface of the lateral ventricle. I almost jumped out of my skin. “Dan,” I said, “we are looking at radial glia in [the] adult brain!” Embryologists had, of course, long been aware of the importance of radial glia during brain development, when they were thought to guide the migration of neurons. In mammals, these radial glia disappeared before the end of embryogeny. Now, we had radial glia in the forebrain of adult canaries. Follow-up work by Alvarez-Buylla showed that the antibody that displayed these cells was selective to vimentin (Alvarez-Buylla et al., 1987).

Two experiments followed soon thereafter. The first one combined the use of tritiated thymidine and the anti-vimentin antibody; its purpose was to visualize the relation between newly born cells and radial fibers. This experiment was conducted in the forebrain of canaries anterior to HVC. One day after treatment with tritiated thymidine, there were lots of labeled cells in the lateral wall (ventricular zone) of the lateral ventricle. Starting three days later, small, elongated cells with radioactively labeled nuclei could be seen immediately next to the ventricular zone (VZ), and then at longer survivals, further and further away from the VZ; the cells were, in their great majority, closely apposed to vimentin-positive fibers. By the end of the second week, the small, fusiform cells had reached most corners of the forebrain; their numbers peaked by day 20; after that, they declined, although those of labeled neurons increased. At its peak, on day 40, the cohort of labeled neurons was just one-third the peak number of labeled fusiform cells. We drew four inferences: (1) the small cells moving away from the VZ were young migrating neurons; (2) their migration was guided by the fibers of radial cells; (3) as the small, elongated cells reached their destination, they differentiated into adult neurons; and (4) only a fraction of the young neurons produced was still present 40 days later (i.e., there was, such as during embryogeny, an overproduction of new neurons in the adult brain) (Alvarez-Buylla and Nottebohm, 1988).

Neuronal Stem Cells

Follow-up work showed that, one hour after tritiated thymidine, 80 percent of VZ cells labeled with thymidine were positive for vimentin, and many of these cells gave rise to vimentin positive fibers. The number of silver grains over these vimentin positive cells fell by half when the material was collected one day after thymidine treatment. This study suggested that the principal dividing cell type in the VZ was the radial glia, which, we suggested, played two roles in adult neurogenesis: (1) they acted as neuronal stem cells; and (2) they guided neuronal migration. Because of this dual role, we decided to call them “radial cells” rather than lump them together with other glial cell types (Alvarez-Buylla and Nottebohm, 1988).

Taken together, my laboratory had established beyond reasonable doubt that neurons continued to be produced in the adult forebrain, had shown where they were produced, had revealed the identity of the neuronal stem cells, had shown how the new neurons migrated, and had provided evidence that at least some of them joined existing circuits.

In the years that followed, I focused on understanding why adult neurogenesis occurred in the first place. What was its context and significance? Initially, the temptation was to assume that it had to do just with seasonal changes in song, but clearly the phenomenon was broader than this because new neurons were added to many parts of the adult canary forebrain. Yet nucleus HVC stood out as an excellent place to unravel the significance of the phenomenon because we knew so much about its anatomy, circuitry, and function.

Do the Same New Neurons Encode and Decode Learned Song?

Many new neurons are added to canary HVC between the ages of one and eight months, when sexual maturity is achieved. We knew that the majority of song syllables that male canaries use during their first breeding season appeared between post-hatching days 60 and 120, when young canaries make the transition from the highly variable “subsong” to the more structured, but still variable, “plastic song” (Nottebohm et al., 1986). Perhaps new neurons in juveniles provided malleable circuitry for vocal learning. However, new neurons were still added at eight months when males were ready to breed and their song was stereotyped. What to make of this? Though I have emphasized that HVC plays a key role in the production of learned song, HVC neurons also respond to sound (Katz and Gurney, 1981). This response then propagates down the descending motor pathway, so that even the hypoglossal motor neurons innervating the syrinx respond to song playbacks, with different parts of the hypoglossal nucleus responding selectively to playbacks of different syllables (Williams and Nottebohm, 1985). Alvin Liberman and colleagues (1967), working on sound perception in humans, had suggested in their “motor theory of speech perception” that phonetic decoding required an understanding of how speech sounds were produced. Heather Williams and I interpreted our findings as supportive of a “motor theory for song perception in birds.” Perhaps HVC’s RA-projecting neurons play a role not just in song production but also in song perception, a view endorsed as well by Margoliash and Konishi (1985) and Margoliash (1986); and this role may differ between the two hemispheres (Cynx et al., 1992).

The motor theory of song perception—and its implication for the role of the HVC→RA neurons fitted well with the work that George Ojemann had done in humans. Ojemann was a neurosurgeon working on epilepsy. It was important for him to map speech cortical areas before surgery so that he could avoid unnecessary disturbance of areas important for speech perception or production. He showed that cortical stimulation of infero-frontal sites in the hemisphere dominant for speech that interfered with sequential orofacial movements also interfered with phonetic decoding; under such conditions, patients were not able to discriminate between “aba” and “apa” (Ojemann and Mateer, 1979). The evidence for this seeming convergence of perception and production suggested that I had, by a very indirect route, returned to one of the big issues that so intrigued me as a youngster—the issue of “consciousness”—that the words we spoke, thought, and heard were all, perhaps, part of the same, elusive, conscious “self” and perhaps even vested in the same cells and circuits.

Windows for Recruitment and Survival

During the next 20 years, many studies from my lab focused on the relation between vocal learning and the recruitment of new HVC neurons. To my surprise, new HVC neurons were added to the HVC of adult male canaries during every month of the year, but seasonal differences in numbers could be as high as sixfold. Peak neuronal recruitment occurred in late summer and early fall and again in late winter, right before the onset of the breeding season (Kirn et al., 1994). These were times when the birds added, modified, and replaced many song syllables (Nottebohm et al., 1986). Intriguingly, the peaks in new neuron recruitment were preceded by peaks of cell death. The dying cells were identified as shriveled or fragmented dark staining nuclei (“pycnotic”) that looked very different from the round, pale nuclei normally seen in tissue stained with cresyl violet. Of course, we did not know whether the pycnotic nuclei were those of neurons; but we suspected they were part of a process of neuronal replacement in adult male canaries. Eventually, we obtained direct evidence about the survivorship curves of neurons added to the adult canary HVC at various times of year (Kirn et al., 1991, 1999; Kirn and Nottebohm, 1993; Nottebohm et al., 1994; Alvarez-Borda et al., 2004)

Neurophysiology Characterizes the Modus Operandi of HVC→RA Neurons

A majority of the new neurons added to the HVC of adult male canaries could be backfilled from RA. Years later, in a study that used zebra finches, Michale Fee from MIT showed that, as these birds sang, individual HVC→RA neurons fired during a 6-msec window with each neuron firing always at the same time during delivery of the song motif; different HVC→RA neurons fired at different times (Hahnloser et al, 2000). Fee has argued that the firing of these neurons, like a metronomic device, determines successive instants of song. Or, to put it differently, the learned pattern is encoded by the order of firing of the HVC→RA neurons and by the connections they form in RA, where David Vicario had shown that the muscles of the songbird vocal tract are represented. Such a modus operandi solves the age-old problem of “who” tells the brain what to do. In our canaries, the “conductor” function apparently shifts from one set of HVC→RA neurons to the next every 6 msecs. As this happens, the instructions delivered to the “musicians” in the RA “orchestra pit” are updated every 6 msecs and in this manner, plus any feedback loops that may occur, the song plays itself. Interestingly, these HVC→RA neurons are the neurons replaced when canaries discard old songs and acquire new ones; the neurons acquired in the spring disappear much sooner than neurons born in late summer, most of which are still around eight months later when the new breeding season starts (Kirn et al., 1991; Kirn and Nottebohm, 1993; Nottebohm et al., 1994). That is what one would predict if the new neurons that learn the new song in late summer–early fall are the ones that sing it the following spring.

Use Them or Lose Them

People sometimes forget that when you count new neurons of a particular birth date you do not count the number produced, but the number that is still around. That is why I prefer neuronal “recruitment” to neuronal “production.” We seldom know how many new neurons were produced. Testosterone treatment of adult female canaries does not alter the number of new HVC neurons produced but markedly affects their survival (Rasika et al., 1994). Similarly, the number of new neurons counted in the HVC of adult male canaries killed 38 days after birth-marker (bromodeoxiuridine) treatment differs markedly depending on whether the birds were or were not allowed to sing from day 30 to day 38. Singing interdiction occurred by waving a hand every time a bird started to sing. The birds allowed to sing from day 31 to day 38 had 40 percent more bromodeoxyuridine-labeled neurons in HVC (Li et al. 2000). The same study showed that singing upregulated the expression of brain derived neurotrophic factor (BDNF) in HVC— the more the singing, the greater the level of expression—and that most of this upregulation occurred in HVC→RA neurons. Earlier work had shown that the testosterone-dependent survival of new HVC neurons in female canaries was mediated by a heightened expression of BDNF in HVC; direct infusion of BDNF at a site adjacent to the HVC of adult female canaries promoted the survival of new HVC neurons (Rasika et al., 1999). Thus, not only is there a temporal relation between new neuron addition and the learning of new song (Kirn et al., 1994) but the act of singing itself and the attendant hormonal changes promote the survival of these new neurons—the ones we count.

In addition, work done in zebra finches suggests that the act of imitating a song model also regulates new neuron recruitment. Zebra finch males exposed to adult song master their imitation of the model between post-hatching days 45 and 90; by 90 days, their song is stable. Their recruitment of new HVC neurons drops sharply after day 65. However, juveniles prevented from hearing or seeing an adult male have no model to imitate, and their song remains very variable. In these birds, a greater number of new HVC neurons continue to be recruited until 150 days of age. Apparently, having imitated a song diminishes the recruitment of new HVC neurons in juveniles (Wilbrecht et al., 2006). Neuronal learning may peak at a particular neuronal age; learning programs may take this into account so that neurons of the right age are available.

Ephemeral Neurons

Studies with other songbirds confirmed what 20 years of work had revealed in the canary song system—that neuronal recruitment peaks at times of peak memory load. My favorite one was done with free-ranging chickadees, Parus atricapillus, a common forest bird in the northeastern United States, and conducted by a very hard working and talented Israeli scientist, Anat Barnea. Chickadees hide many food items in late summer and early fall, one item per hiding place, to be retrieved later during the cold winter months. Adult chickadees also recruit many new neurons into their hippocampus, and this recruitment also peaks in late summer to early fall. Most of the new neurons live for a period of six to ten weeks, and then gradually disappear. Intriguingly, this recruitment of new neurons is twice as high in rostral as in caudal hippocampus, suggesting different rates of memory turnover. It also is twice as high in free-ranging chickadees as it is in chickadees of the same age and population kept in a large outdoor aviary (Barnea and Nottebohm, 1994). To me, this was a reminder of the very different workloads placed on the brain of free and captive individuals. Those just studying the brains of laboratory-housed animals may be missing something.

Another study, using adult zebra finches, showed that the rate of neuronal recruitment in caudal nidopallium (NC), a part of the forebrain that processes auditory and visual information, doubles when males or females are placed in a novel and more complex social setting. In that case, it was the caudal reaches of NC that showed greater recruitment and turnover; in this case, too, the majority of the new cells were ephemeral (Lipkind et al., 2002; Barnea et al., 2006; Barkan et al., 2007; Adar et al., 2008). In all cases reviewed up to this point, peaks in neuronal recruitment coincided with peaks in information load—new song learning, food caching peaks, peaks in complexity/novelty of social stimulation, or peaks in expected learning needs (delayed song imitation in juveniles kept as isolates).

Why Replace Neurons?

An earlier heading referred to two dogmas. The first one stated that neurons were not born in the CNS of adult, warm-blooded vertebrates. Joseph Altman valiantly challenged that dogma, but his evidence was not compelling. The songbird studies challenged it too and proved beyond reasonable doubt that new neurons continued to be added, many of them to be replaced again and again, a new concept in brain function.

The second dogma states that learning is explainable by changes in the number and efficacy of synapses—synapses are the learning software. Plenty of evidence supports this idea. But if all learning takes place at synapses, and they retain full plasticity, why replace neurons in the adult, healthy brain? Neuronal production and replacement in the adult brain suggests there is a limitation in the synapse hypothesis. I estimate that in my songbirds, using the song system as the norm, some 5 percent of the brain’s neuronal classes continue to be produced, and some have been shown to fall into the “replaceable” category. These neurons presumably occur at junctions in existing circuits where synaptic plasticity does not suffice to provide the full flexibility needed. The evidence available suggests that this phenomenon is much more common in birds than in the laboratory mammals studied so far. Why? My suspicion is that this has to do with two avian conditions: light weight and long life. Perhaps birds, despite their relatively large brains, must economize on brain costs. It might be energetically cheaper to replace brain cells, and the memories they hold, than to carry around all the memory space that will ever be needed and a lifelong store of experience. Still, why replace cells at all? My suggestion is that the very plasticity of synapses challenges the permanence of memories. For true memory stability, at least at the temperature and metabolic rate of birds, the secure solution may be to lock information in place by irreversible changes in gene expression. This “lock” would take the form of “freezing” all synapses in a neuron (input and output) at the settings when learning occurred. These changes may provide memory stability but at the price of blocking future learning—hence the neuron replacement solution and my suggestion that in some circuits the neuron, not the synapse, may be the unit of learning. I have not tested this idea. Undoubtedly, someone else will settle this point.

Doubt Everything

Some years after I finished my canary work, a splendid doctoral student from England, Clare Walton, joined my laboratory and made an observation in zebra finches that reminded me of the difference between facts and inferences and how careful one must be about generalizations. As mentioned earlier, zebra finches learn their song only once, before they reach sexual maturity at approximately 90 days of age. The song mastered by then is the one that male zebra finches sing for the rest of their life, which in captivity can extend for up to 10 years. However, there is a kind of song learning that continues after day 90 because, if young adult males are deafened soon after mastery of their song, it deteriorates over a period of two to three weeks as if the motor pattern were completely forgotten. Yet, if deafening occurs when the bird is older than two years, then deterioration is so slow as to take more than a year (Lombardino and Nottebohm, 2000). We do not know how this “engrainment” of the learned pattern comes about, but Walton’s observations may be relevant.

Zebra finches are not seasonal, and the size of their HVC does not change after sexual maturity. I had assumed from this fact that their population of HVC neurons was stable. I was wrong. Clare Walton discovered that the population of HVC neurons in zebra finches doubles during the first year after sexual maturity, and this happens without gross changes in HVC volume or, for that matter, song. During that year, the HVC→RA neurons become smaller and more closely packed. Neuronal addition continues to occur in future years, though at a decreasing pace. At no time after sexual maturity did Clare find any evidence of culling of existing HVC→RA neurons, regardless of their date of birth. Thus, in these birds, adult neurogenesis leads to a net gain in neuron numbers. It is possible that the new neurons are connected like their older peers, strengthening the stereotypy of the learned song, which could explain why as time goes by song becomes more resistant to deafening. But the significance of this doubling in neuron numbers must remain speculative. Do female zebra finches place so much stock on male song stereotypy that this extra addition of neurons is worth the investment? Or could it be that the new neurons in the HVC of the intensely sociable adult zebra finches play no role in song production but instead serve to better perceive, recognize, and memorize the sounds of others? Perhaps the new neurons serve both purposes. We do not know; but Clare’s observations (Walton et al., 2012) are a reminder of the benefits of having a broad, comparative database before drawing general conclusions. To this day, we have no direct evidence of the role served by neurons born in the adult songbird brain.

The Story Ends

I have told my story. It started in the pampas with a love for birds, nature, and the big questions, then it focused on one—the biology of vocal learning. How had this wonderful trait come to be, and how did the brain manage it? It was a big question, and I have not answered it, but I have learned that simple questions sometimes behave like fireworks—they fragment, and the constellation of new questions is even more beautiful than the previous single one, each glowing in the nightly sky of our ignorance. It is the way of science.

Looking back, I wonder if my style of doing science was the best one. I tried to move fast, leapfrogging ahead. I hoped that others would follow and fill in the gaps. That did not always happen. Yet, it was a style I enjoyed. Discoveries seemed to be waiting around each corner.

In my early twenties, the airplane that flew me from the United States to Argentina and back would spend many hours high above the Matto Grosso and its meandering rivers—so much to see, so little known. I had read as a child that somewhere in all that greenery, near the Rio das Mortes, Colonel Fawcett, the British explorer, had disappeared. It was the land of headhunters. Much of the Matto Grosso is gone now, but a wilderness is still out there, beyond where our mind can reach. How enormously thrilling! We need so much to have them both—the known and the unknown.

Acknowledgments

Those that read my story will realize I am a very lucky man. I had loving parents that encouraged me and supported me. I ran into a wonderful man, Peter Marler, and learned from him and his student and friend, Mark Konishi. I got a splendid job at Rockefeller University, where all my time was my own and was well supported. I was in the United States in the golden era of American science. During 32 years, I had a generous partner in the National Institutes of Mental Health. I received further and timely help from two private individuals, Howard Phipps and Herbert Singer. Through it all, I had the wonderful encouragement, stimulation, and hands-on help of my wife, Marta, and of her elegant, inquisitive and playful mind. Ever the triple-tasker, she also gave us two magnificent children, Lawrence and Olivia, and a lovely home. At Rockefeller, I enjoyed a fabulous group of young people that as doctoral students and post-doctoral fellows brought to my laboratory their talents, enthusiasm, and trust. But the greatest acknowledgment goes to the beautiful birds I studied. They charmed me as a child and gave me their secrets. I have been a very lucky man.

Selected Bibliography

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Alvarez-Borda, B, B Haripal, and F Nottebohm. 2004. Timing of BDNF exposure affects life expectancy of new neurons. Proc. Natl. Acad. Sci. USA 101(11):3957–61.

Alvarez-Buylla, A, DR Buskirk, and F Nottebohm. 1987. Monoclonal antibody reveals radial glia in adult avian brain. J. Comp. Neurol. 264:159–70.

Alvarez-Buylla, A, JR Kirn, and F Nottebohm. 1990. Birth of projection neurons in adult avian brain may be related to perceptual or motor learning. Science 249:1444–46.

Alvarez-Buylla, A, C-Y Ling, and F Nottebohm. 1992. High vocal center growth and its relation to neurogenesis, neuronal replacement and song acquisition in juvenile canaries. J. Neurobiology 23:396–406.

Alvarez-Buylla, A and F Nottebohm. 1988. Migration of young neurons in adult avian brain. Nature 335:353–54.

Alvarez-Buylla, A, M Theelen, and F Nottebohm. 1988. Birth of projection neurons in the higher vocal center of the canary forebrain before, during and after song learning. Proc. Natl. Acad. Sci. USA 85:8722–26.

Alvarez-Buylla, A, M Theelen, and F Nottebohm. 1988. Mapping of radial glia and of a new cell type in adult canary brain. J. Neurosci. 8:2707–12.

Alvarez-Buylla, A, M Theelen, and F Nottebohm. 1990. Proliferation “hot spots” in adult avian ventricular zone reveal radial cell division. Neuron. 5:101–9.

Andalman, AS, and MS Fee. 2009. A basal ganglia-forebrain circuit in the songbird biases motor output to avoid vocal errors. Proc. Natl. Acad. Sci. 106:12518–23.

Arnold, AP, F Nottebohm, and DW Pfaff. 1976. Hormone concentrating cells in vocal control and other areas of the brain of the Zebra finch, Poephila guttata. J.Comp. Neurol. 165:487–512.

Aronov, D, AS Andalman, and MS Fee. 2008. A specialized forebrain circuit for vocal babbling in the juvenile songbird. Science 320:630–34.

Barkan, S, A Ayali, F Nottebohm, and A Barnea. 2007. Neuronal recruitment in adult zebra finch brain during a reproductive cycle. Developmental Neurobiology 67(6):687–701.

Barnea, A, A Mishal, and F Nottebohm. 2006. Social and spatial changes induce multiple survival regimes for new neurons in two regions of the adult brain: an anatomical representation of time? Behavioural Brain Research 167(1):63–74.

Barnea, A and F Nottebohm. 1994. Seasonal recruitment of new neurons in the hippocampus of adult, free-ranging black-capped chickadees. Proc. Natl. Acad. Sci. USA 91:11217–21.

Barnea, A and F Nottebohm. 1995. Patterns of food storing by black-capped chickadees suggest a mnemonic hypothesis. Animal Behav. 49:1161–76.

Barnea, A and F Nottebohm. 1996. Recruitment and replacement of hippocampal neurons in young and adult chickadees: an addition to the theory of hippocampal learning. Proc. Natl. Acad. Sci. USA 93:714–18.

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Burd, GD and F Nottebohm. 1985. Ultrastructural characterization of synaptic terminals formed on newly-generated neurons in a song control nucleus of the adult canary forebrain. J. Comp. Neurol. 240:143–52.

Canady, RA, GD Burd, TD DeVoogd, and F Nottebohm. 1988. Effect of testosterone on input received by an identified neuron type of the canary song system: a Golgi/EM/degeneration study. J. Neurosci. 8:3770–84.

Canady, RA, DE Kroodsma, and F. Nottebohm. 1984. Population differences in complexity of a learned skill are correlated with brain space involved. Proc. Natl. Acad. Sci. USA 81:6232–34.

Cynx, J and F Nottebohm. 1992. The role of gender, season, and familiarity in discrimination of conspecific song by zebra finches (Taeniopygia guttata). Proc. Natl. Acad. Sci. USA 89:1368–71.

Cynx, J and F Nottebohm. 1992. Testosterone facilitates conspecific song discrimination in castrated zebra finches (Taeniopygia guttata). Proc. Natl. Acad. Sci. USA 89:1376–78.

Cynx, J, H Williams, and F Nottebohm. 1990. Timbre discrimination in zebra finch, Taeniopygia guttata, song syllables. J. Comp. Psychol. 104:303–8.

Cynx, J, H Williams, and F Nottebohm. 1992. Hemispheric differences in avian song discrimination. Proc. Natl. Acad. Sci. USA 89:1372–75.

DeVoogd. TJ, B. Nixdorf, and F. Nottebohm. 1985. Synaptogenesis and changes in synaptic morphology related to acquisition of a new behavior. Brain Res. 329:304–8.

DeVoogd, TJ and F. Nottebohm. 1981a. Gonadal hormones induce dendritic growth in the adult brain. Science 214:202–4.

DeVoogd, TJ and F. Nottebohm. 1981b. Sex differences in dendritic morphology of a song control nucleus in the canary: a quantitative Golgi study. J. Comp. Neurol. 196:309–16.

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Jarvis, ED and F Nottebohm. 1997. Motor-driven gene expression. Proc. Natl Acad. Sci. USA 94:4097–102.

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Kirn, J, B O’Loughlin, S Kasparian, and F Nottebohm. 1994. Cell death and neuronal recruitment in the high vocal center of adult male canaries are temporally related to changes in song. Proc. Natl. Acad. Sci. USA 19:7844–48.

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Lipkind, D, F Nottebohm, R Rado, and A Barnea. 2002 Social change affects the survival of new neurons in the forebrain of adult songbirds. Behavioural Brain Research 133:31–43.

Liu, W-C, TJ Gardner, and F Nottebohm. 2004. Juvenile zebra finches can use multiple strategies to learn the same song. Proc. Natl. Acad. Sci. USA 101(52):18177–82.

Liu W-C, W Kazuhiro, E Jarvis, and F Nottebohm. 2013. Rudimentary substrates for vocal learning in a suboscine. Nature Communications 4, doi:10.1038/ncomms3082.

Liu, W-C. and F Nottebohm. 2005. Variable rate of singing and variable song duration are associated with high immediate early gene expression in two anterior forebrain song nuclei. Proc. Natl. Acad. Sci. USA 102(30):10724–29.

Liu, W-C and F Nottebohm. 2007. A learning program that ensures prompt and versatile vocal imitation. Proc. Natl. Acad. Sci. USA 104(51):20398–403.

Liu WC, K Wada, and F Nottebohm. 2009. Variable food begging calls are harbingers of vocal learning. PLoS ONE 4(6):e5929. doi:10.1371/journal.pone.0005929.

Liu, WC, K Wada, ED Jarvis, and F Nottebohm. 2013. Rudimentary substrates for vocal learning in a suboscine. Nature Communications 4: 2082/doi:10.1038/ncomms3082.

Lombardino, AJ and F Nottebohm. 2000. Age of deafening affects the stability of learned song in adult male zebra finches. J. Neuroscience 20(13):5054–64.

Margoliash, D. 1986. A preference for autogenous song by auditory neurons in a song system nucleus of the white-crowned sparrow. J. Neurosci. 6:1643–61.

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Marler P and M Tamura. 1964. Culturally transmitted patterns of vocal behavior in sparrows. Science 146:1483–86.

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Nottebohm, F. 1968. Auditory experience and song development in the chaffinch, Fringilla coelebs. Ibis 110:549–68.

Nottebohm, F. 1969a. The “critical period” for song learning. Ibis 111:386–87.

Nottebohm, F. 1969b. The song of the chingolo, Zonotrichia capensis, in Argentina: description and evaluation of a system of dialects. Condor 71:299–315.

Nottebohm, F. 1970. Ontogeny of bird song. Science 167:950–56.

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Nottebohm, F. 1976. Phonation in the orange-winged Amazon parrot, Amazona amazonica. J. Comp. Physiol. 108:157–70.

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Wilbrecht, L, T Petersen, and F Nottebohm. 2002. Bilateral LMAN lesions cancel differences in HVC neuronal recruitment induced by unilateral syringeal denervation. J. Comp. Physiol. A.188:909–15.

Wilbrecht L, H Williams, N Gangadhar, and F Nottebohm. 2006. High levels of new neuron addition persist when the sensitive period for song learning is experimentally prolonged. J. Neurosci. 26(36):9135–41.

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Tomaso A. Poggio

BORN:

Genova, Italy

September 11, 1947

EDUCATION:

University of Genoa, PhD in Physics, Summa cum laude (1971)

APPOINTMENTS:

Wissenschaftlicher Assistant, Max Planck Institut für Biologische Kybernetik, Tubingen, Germany (1978)

Associate Professor (with tenure), Department of Psychology and Artificial Intelligence Laboratory, Massachusetts Institute of Technology (1981)

Uncas and Helen Whitaker Chair, Department of Brain & Cognitive Sciences, Massachusetts Institute of Technology (1988)

Eugene McDermott Professor, Department of Brain and Cognitive Sciences, Computer Science and Artificial Intelligence Laboratory and McGovern Institute for Brain Research, Massachusetts Institute of Technology (2002)

HONORS AND AWARDS (SELECTED):

Otto-Hahn-Medaille of the Max Planck Society (1979)

Member, Neurosciences Research Program (1979)

Columbus Prize of the Istituto Internazionale delle Comunicazioni Genoa, Italy (1982)

Corporate Fellow, Thinking Machines Corporation (1984)

Founding Fellow, American Association of Artificial Intelligence (1990)

Fellow, American Academy of Arts and Sciences (1997)

Foreign Member, Istituto Lombardo dell’Accademia di Scienze e Lettere (1998)

Laurea Honoris Causa in Ingegneria Informatica, Bicentenario dell’Invezione

della Pila, Pavia, Italia, March (2000)

Gabor Award, International Neural Network Society (2003)

Okawa Prize (2009)

Fellow, American Association for the Advancement of Science (2009)

Tomaso Poggio began his career in collaboration with Werner Reichardt quantitatively characterizing the visuomotor control system in the fly. With David Marr, he introduced the seminal idea of levels of analysis in computational neuroscience. He introduced regularization as a mathematical framework to approach the ill-posed problems of vision and—more importantly—the key problem of learning from data. He has contributed to the early development of the theory of learning—in particular introducing the mathematics of radial basis functions (RBF)—and has supervised learning in reproducing kernel Hilbert spaces (RKHSs) and stability. In the last decade, he has developed an influential quantitative model of visual recognition in the visual cortex, recently extended in a theory of sensory perception. He is one of the most cited computational scientists with contributions ranging from the biophysical and behavioral studies of the visual system to the computational analyses of vision and learning in humans and machines.

Tomaso A. Poggio

Brains, Minds, and Machines

Most neuroscientists these days study the brain to understand its disorders. Of course, this is important—and is funded by the National Institutes of Health (NIH)—but from this point of view, the Year of the Brain and the present Brain Initiative are not very different from the Year of the Heart and the Colon Initiative. Instead, I am interested in the brain because it generates what philosophers call the mind and what we call intelligence. Thus, this is the autobiography of a hybrid neuroscientist and computer scientist working to understand mind and intelligence in brains and computers.

Early Years in Europe

Childhood in Genova

I was born in Genova (Genoa), a harbor city in Liguria with a long history stretching back to Roman times. Genoa was one of the four Repubbliche Marinare that dominated the Mediterranean Sea between 1100 and 1400, and the city was at war with Venice for several centuries. Marco Polo’s Il Milione was written while he was in a prison in Genoa after being captured in one of the many naval battles between Genoa and Venice. “La Via Nuova” in Genoa is the best fully preserved Renaissance street in Europe. (Unfortunately it was later renamed Via Garibaldi with the typical bad taste of the Risorgimento.) It was a new street in 1500 at the core of what was a real estate development—probably one of the first in history—by Andrea Doria. La Via Nuova is just outside the old medieval center, which is probably the largest in Europe and which grew around the original Roman castrum. Genoa was the place where bonds were invented and used by Genoa bankers to finance various kings of Europe and their wars. Genoa is also the place where marine insurance has what are probably the world’s oldest records. At the Banco of San Giorgio, where many of the old documents are kept, you will find that, in 1300, insuring the transportation of merchandise from Genova to Barcelona was equivalent to what it is today, despite all the pirates who then infested the Mediterranean. During my childhood in the 1950s, Genova was recovering from the destruction of the war; it was an industrial city with a busy harbor and nearby oil refineries. Minor oil spills made their way to the rocks on the beaches in the Riviera and were a regular annoyance of summer swims.

My father owned a textile industry in the outskirts of Genova and a marine supply magazine in the vicoli of the old city, next to San Matteo, the family church of the famous Genoa family—Doria. My maternal grandfather was an entrepreneur who started multiple industries in Italy, Argentina, and Brazil. His company in Genoa, Olio Moro, produced and distributed olive oil and tuna cans. We have no ancestors in academia on either side of the family, though my grandfather, Tommaso Moro, improbably claimed Thomas Moore as a distant relative. At the time when I began reading books about mathematics and physics, my grand father advised me to not waste too much time in study. Eventually, I built model airplanes and somewhat dangerous rockets in the big garden of his old country house in Quarto. Despite his opinion of my studies, I have surely inherited my curiosity from him. He had traveled a great deal in Europe and especially in South America.

Absent scholarly traditions were replaced by various encyclopedias, among them the Enciclopedia Treccani, an Italian version of the Encyclopedia Britannica, which became my main source of information. Through these volumes I developed a fascination with physics, especially the theory of relativity. Einstein was my main hero. The question of what made him such a genius became the focus of my curiosity. This early curiosity developed into a burning interest in intelligence—how we could improve it, how the brain works, and how to make intelligent machines that could solve the scientific problems that excited me, such as the possibility of time travel.

At about the same time, I read the short story “Flowers for Algernon,” which had just come out. It is a story about the eponymous Algernon, a laboratory mouse that had undergone brain surgery intended to increase his intelligence. The story is told in a series of progress reports written by Charlie Gordon, the first human test subject for the surgery and a moron. The mouse and the moron become progressively smarter and then their intelligence degenerated. I thought that this was the ultimate human tragedy: achieving genius-level intelligence and understanding exactly what was happening while slowly becoming stupid again.

School—Jesuit Arecco

Later, I had the opportunity to study with exceptional teachers, not only for Greek and Latin, but also for mathematics and physics. The Arecco was a Jesuit school in Genova, which I attended from age six to eighteen—elementary school up to la maturità classica. Most school hours were devoted to Latin, Greek, and Italian literature every day except Wednesday and Saturday. The time spent on math, physics, and biology was only two hours a week for each, but the quality of the science and math teachers (Padre Vergnano and Padre Spessa, both Jesuits who were also teaching at the University of Genoa) made up for the scarcity of time.

I read Plato in his original words, enjoyed the easy translations from Caesar’s De Bello Gallico and compared them to the Asterix cartoons, wrote essays on the Divina Commedia, and absolutely loved Kant. Sports were also very important. There was some soccer at school but much more tennis. Later, sailing at the yacht club absorbed my time and my dreams. The yacht club site was the oldest in Italy and, of course, of English origin and tradition. It was tucked between the big ships at the entrance of the commercial harbor, and I managed to capsize in front of big oil tankers more than once. The Genoa that I remember seeing from the windows of my house was really the port, with the big ships waiting beyond the dam. I remember scrutinizing the weather to see what it would be like for that day’s regatta. Sailing became my passion during those years. My father, who had driven racecars in his youth and had held some world’s record for speed, introduced us to sailing to prevent us from being stricken with his racecar passion, which he deemed to be too dangerous. I went boating with my yacht club friends and with my brother. We were the crew of our Flying Junior and later of a 470, an Olympic class. We often won regattas, though I remember how badly we lost an Italian championship in the Bay of Naples despite being the pre-race favorites. Since my teenage years I have never believed more than 50 percent of what I read in the newspapers. The critical experience was reading reports of sailing races, in which I competed, in the sports section of the main newspaper in Genova, Il Secolo XIX: I knew exactly what had happened in critical moments of the race while the reporter was on the beach or on a far-away jury boat!

Physics at the University of Genoa

I passed the maturità, the Italian baccalaureate, with pretty good grades, especially in philosophy, and managed to enthrall my examiner with some far-fetched discussions of the relationship between Kant and Popper. I am still curious about what that idea was because I certainly cannot reproduce it. After a summer traveling to Spain and England, I decided to enroll in the physics program at the University of Genoa. I did not want to be an entrepreneur or a politician or a bureaucrat. I was interested in information (which at the time meant electrical engineering), and I was interested in the brain (which meant biology). But engineering looked boring and the biology department was just ancient zoology. Molecular biology had not yet arrived in Genoa. In retrospect, I think physics was the right choice. Physics in Italy had good teachers and a long tradition of excellence: one of my teachers had been a student of Enrico Fermi. Physics was and still is a broad introduction to applied mathematics and many deep and useful scientific tools.

After one year of physics, I became fascinated by mathematics. Professor Pucci and his assistant, Talenti, almost convinced me to switch from physics to mathematics. Toward the end of my studies, four years later, I had to make up my mind. I decided on Antonio Borsellino as an advisor, who was a particle physicist converted to biophysics. During my final years, Borsellino invited me to attend a biophysics conference that he had organized in Erice, Sicily, a magic village on a mountain near Trapani, where—according to mythology—Venus was born. Artificial membranes, lipid bylayers in particular, were the main topic of the conference. This was too close to biochemistry for me, so for my doctoral thesis I decided to work on coherent optics and the potential to store and process information this way. Dennis Gabor of Imperial College had just won the Nobel Prize in Physics for his invention of holography. Antonio took me to see Gabor, whom he knew, in his retirement house on the coast near Rome. Despite such august contacts, my thesis did not amount to much, partly because I was still in the regime of the old Italian laurea. Very little time was available for thesis work. My laurea in physics was recognized officially as a European-wide PhD in Germany, but it was certainly less arduous than a PhD today. My thesis, however, included one chapter that established a formal correspondence between the mathematics of holography and the mathematics of correlation. The correlation model had been proposed a decade earlier by another friend of Antonio Borsellino, Werner Reichardt, founder and director of the Max Planck Institute für Biologische Kybernetik in Tübingen, Germany. Antonio told me to apply for a European Molecular Biology Organization (EMBO) fellowship and to visit Werner Reichardt and his new institute. The fellowship was awarded, and I went to visit Tübingen for two weeks to meet Werner.

Tübingen and the Max Planck Institute

Arriving in Tübingen and at the Max Planck Institute was discovering a paradise of science. There were roses around the institute and a gardener taking care of them. Werner’s house had a beautiful view and a beautiful garden. Germany at the time was rich and socially fair. The gardener, who also was the jack-of-all-trades at the institute, had a Mercedes, produced in nearby Stuttgart, that was larger than Werner’s, the institute director. The institute and its roses mesmerized me. And of course, I was impressed by Werner, the person to whom I most owe my scientific career.

Werner Reichardt was born in 1924 in Berlin. During his school years, he worked in the laboratory of Hans Heinrich Hollmann, one of the pioneers in the electronics of the day.

At the beginning of World War II, Werner was assigned to work on radio projects in the air force. He was 19 years old when both of his parents were killed in an air attack on Berlin. He became a member of a resistance group and was arrested by the Gestapo; condemned to be executed, he was able to escape from jail. In postwar Berlin, Werner managed to set up a radio repair shop, and with Hollmann’s help, continue his studies. He obtained his master’s degree and his PhD at the Technische Universitat in Berlin. From 1952 to 1955, Werner was a research assistant at the Fritz-Haber-Institut of the Max-Planck-Gesellschaft in Berlin, where he had among his teachers and advisors Max von Laue, who had received a Nobel Prize for Physics in 1914, and Emst Ruska, who was later (1986) awarded the Nobel Prize for the development of the electron microscope.

In the 1950s, Werner began working with Bernhardt Hassenstein on the experiments and the theory of motion perception in the beetle. They had met during the war when Werner was on duty in a radio station monitoring the state of the ionosphere. Werner the physicist had met Berhard Hassenstein the future biologist, who had a similar radio station assignment. Those two kids (they were 20 years old or less) decided then that they would someday start a novel institute in physics and biology. This was clearly a critical meeting for their mutual futures.

Because of their 1952 paper on the beetle, Max Delbrück offered Werner a postdoctoral position at the California Institute of Technology (Caltech) and convinced him to work as a physicist in biology. At about the same time (in 1954), Jim Watson and Niels Jerne were also postdocs with Delbrück. Werner made an adventurous coast-to-coast automobile trip with Jerne at the end of his postdoctoral period that was punctuated by car breakdowns and impromptu lectures at local colleges to help pay for gas and repairs. They offered a package of two lectures: one on horses, on which Niels Jerne had done his experiments on the clonal theory of immunology (for which he received a Nobel Prize), and one on beetles, the experimental subjects of Werner’s theory of the optomotor response. Shortly afterward, in 1958, Werner became head, together with Bernhardt Hassenstein and Hans Wenking, of the Forschungsgruppe Kybernetik within the Max-Planck-Institut für Biologie in Tübingen. In the meantime, offers by Caltech, Massachusetts Institute of Technology (MIT), and Bell Labs triggered a counteroffer by the Max-Planck-Gesellschaft in 1960 that Werner accepted; in 1963, he started his own department in the Max-Planck-Institut für Biologie. In 1968, this department became, with the nomination of three other directors: V. Braitenberg, K. Goetz, and K. Kirschfeld, the Max-Planck-Institut für Biologische Kybernetik. For the new institute, Werner chose a system for studying visual information processing that was neither too simple nor too complex. The fly’s brain, with its 10⁶ neurons, is halfway on a logarithmic scale between unicellular organisms and man.

My EMBO-sponsored two-week visit at the institute took place a couple of years after the institute was founded (1968), when the building was still very new and partly unfinished. At the end of the two weeks, Werner offered me a one-year position as Wissenschaftliche Assistant. I accepted immediately. Arriving in Tübingen in September 1971, I stayed in the GastHaus for the first three months and then rented an apartment with a fellow researcher from Wales (Brian Rosser) in Walhauser Ost, a 10-minute walk to the institute, though I had a red Mini Morris station wagon of my mother’s. I started working with Werner and Leo Heimburger, who was Werner’s technician in charge of the quantitative torquemeter-based behavioral experiments with flies.

In June 1972, I was married in Genova in the ancient San Siro di Struppa. The original church was built in the fourth century; the actual building is new, dating from the twelfth century. My wife, Barbara Venturini Guerrini, joined me in Tübingen in what became a great journey together. She helped me more than anything or anybody else not only in life but also in my scientific career. The initial two-week visit to the Max Planck Institute stretched first to two years and then to ten years. It was a very happy period of our life together.

The Grand United States Tour

In the fall of 1973, after almost two years of work in the institute, Werner invited me to join him on a scientific trip to the United States. It turned out to be a dream tour for this (then) 26-year-old. In retrospect, Werner made a point of introducing me to many of his scientific connections. In New York, we stayed at the guesthouse of Rockefeller University and met with Haldan Hartline and Floyd Ratliff, who established the concept of lateral inhibition in limulus. We visited Gerry Edelman, who was just beginning to think of switching to neuroscience. I was incredibly impressed by Gerry and his broad knowledge of art and music. By chance, we bumped into Marc Kac the mathematician (“Can one hear the shape of a drum?”) in the Rockefeller faculty club. At Columbia, we visited Eric Kandel, whom I already knew because of a talk he gave in Tübingen. In Boston, at Harvard Medical School, we met with David Hubel (I forget whether Torsten was also there), and, at MIT, we met with Lucas Teuber, Walther Rosenblith, and Frank Schmitt, who had then stepped down from the chairmanship of the biology department. Frank was very good friends with Werner, and somehow I was then invited to a meeting organized by the Neuroscience Research Program (NRP) that was to take place in fifteen days. Two weeks later, I was again flying to the United States, this time alone. At the NRP workshop, I met a good part of the remaining neuroscience community of Boston including Emilio Bizzi, Peter Schiller, John Dowling, Whitman Richards, and Walle Nauta.

I met David Marr for the first time in 1973 when I went to chat with Marvin Minsky at the artificial intelligence (AI) lab. Boston was wet, foreign, and dark. David came out of his office in the “playroom” and we exchanged a few words. His name was known to me, of course, because of his cerebellum paper, which was highly praised by many VIPs in the biological sciences. David also attended the NRP meeting in Boston. We had both been invited at the last moment and were not scheduled to speak. David sat quietly the whole time, listening to what people were saying about psychophysics and physiology. John Dowling joked with David about his red Mustang. Back at the AI lab, a scientific conversation took place about the ideas on the retina David was then developing. I had been asked by Werner Reichardt and Antonio Borsellino to invite David to give a series of lectures at the spring course on biophysics in Erice, Sicily. I was happy that he accepted immediately, and so our next meeting was already arranged.

Erice, Sicily

Erice is a beautiful old village on top of a mountain overlooking the Mediterranean Sea. For two weeks in 1974, the participants of the spring course on biophysics gathered together mornings and afternoons. Among them were Mike Fuortes, David Hubel, Bela Julesz, John Szentagothai, Sir John Eccles, and Michael Arbib. At lunch and dinner, we divided into small groups to explore the five restaurants of Erice, all above average for scientists. We also made several expeditions to the various beaches down the hill. I was impressed and obviously pleased by the interest and the respect David had for my lectures and my comments. David’s approach to science was by far the most unconventional and for me the most interesting. We discussed our ideas at length while dining and lying on the beach.

The Fly Visual System: A Visuo-Motor Control System—Fixation and Chasing Behavior

During the time I collaborated with Werner (1971–1981), the behavioral and physiological work on the fly’s visual system led to experiments, theories, and models at three levels of integrative neuroscience: the phenomenological theory of flight behavior, the algorithms for detection of motion and relative motion, and the underlying neural circuitry. I will briefly describe each one.

Werner had discovered that flies fixate; in other words, they fly toward small dark objects. He had developed a sophisticated flight simulator in which a flying fly is held fixed while its torque, measured by a very sensitive device developed by his longtime friend and colleague Karl Goetz, controlled the visual environment, thereby simulating free flight. In this way, it was possible to experimentally study and quantify the fixation behavior. Reichardt also developed a model of the visual fixation behavior, which was extended in joint work in 1971–75 into a quantitative description capable of accounting for the main features of fixation, tracking, and chasing in flies. The equations, derived from the experiments in the stationary setup, could predict the free-flight trajectory of one fly chasing another! Gadi Geiger, a dear friend of ours whom I met the first day I was in Tübingen, showed that the theory could also predict correctly a Kindof Mueller-Lyer illusion in flies, judging from the fixation behavior induced by the Mueller-Lyer figures!

Motion Detection: Algorithm and Circuits

Early on, long before I arrived in Tübingen, Werner had worked out the properties of motion detection in the beetle with B. Hassenstein and D. Varjú. This early work is his best-known scientific contribution. The optomotor response of the beetle Cholorphanus is the animal’s tendency to follow the movement of the visual surround to compensate for it. The beetle was glued to a rod so it could not move its body, head, or eyes relative to the surround but could express its behavior by rotating a “Y-maze globe” under its feet. The rules of the optomotor behavior are summarized in a precise, quantitative way by the correlation model, by now known as the Hassenstein-Reichardt model or simply as the Reichardt detector. The strict mathematical treatment of this model led to many counterintuitive predictions, which were, one by one, verified experimentally. The model holds up in many species and in many types of neurons. The influence of the Hassenstein-Reichardt model can hardly be overestimated. It inspired work on motion vision in many animals, including humans. Thus, the model set the standard for how researchers thought about visual motion detection and how they designed experiments.

In a more general sense, the Hassenstein-Reichardt model introduced mathematical techniques and quantitative modeling to biology. Visual stimuli were presented to the beetle Chlorophanus, held by its back in a fixed position while climbing on the grass-like ribs of y-maze globe. The frequency of left/right choices revealed its intended turns. Thus, it was shown that the beetle’s motion detector requires at least two input sensors looking into slightly different areas of the visual field. These sensors are excited in sequence by pattern edges moving by. If one input signal is delayed relative to the other, the two signals become synchronous for the “preferred direction” of pattern motion and strongly asynchronous in the opposite direction. Multiplication of the two signals and time averaging of the result yields a direction-specific motion signal regardless of the polarity of the change of brightness achieved by a moving object. This process corresponds formally to an autocorrelation of the input signal—hence the name “correlation-type motion detector.” This work describes the algorithm for motion used by the beetle and other insects such as the fly and also by primates. I was recently at a Janelia farm meeting (in 2013) in which several talks suggested that new genetic and connectomics methods are finally about to identify which neurons are the Reichardt detectors, including the site of the multiplication and of the subtraction.

Relative Motion Detection: Algorithm and Circuits

In 1974, Reichardt discovered that flies use motion discontinuities in the visual surround to distinguish objects from the background. Flies turn toward a single, randomly textured stripe in front of an equally textured background but only if it moves relative to the ground. Part of our theoretical and experimental work between 1974 and 1978 was devoted to characterizing the properties of the algorithm used by the fly’s visual system to detect relative motion in a way similar to what Werner had done 35 years earlier for motion detection. The interplay of experiments and theory led to a class of model that could be characterized as a form of nonlinear lateral inhibition between motion detectors. Together with Klaus and Werner, we derived a skeleton model of the necessary neural circuitry and refined it further through quantitative experiments. It is a lateral inhibition network that finds and enhances discontinuities in the motion field, such as the discontinuities generated by an object moving relative to the background. Starting with the pioneering work of K. Hausen and of the late R. Hengstenberg, it became possible to record from several of the neurons that correspond to boxes in our original model. Thus, the original model and experiments led to a series of remarkable physiological experiments, which were broadly consistent with the outline of the model, while revealing its precise anatomical and biophysical features. This work took the problem of motion discontinuities to another level, describing the neural circuitry and the biophysical mechanisms. The close interplay between behavioral analysis, theory, and neurophysiology guided this work very efficiently and led to a profound understanding of these perceptual processes, very much as Reichardt had suggested way back in 1965.

Cambridge, Massachusetts—Levels Framework

In 1976, I came to the AI lab at MIT for a period of three months to work with David Marr and to clear my head so I could decide what to do next. For the first week or so, I was left relatively alone, free to play with Macsyma and LISP. I spoke about the fly visual system at David’s vision seminar. It went well. After the lecture, we had a beer together in Harvard Square. David was very happy about my lecture. His enthusiasm and his praise were contagious. I felt great and alive!

While at lunch together at the MIT cafeteria, David and I were still trying to define the nature of our approaches to the problem of the brain. Our views were already very near and converged rapidly. I told David the philosophy of the approach I had been following in my work with Werner. We discussed it at length and finally I suggested that we write a paper together that the Neuroscience Research Program (NRP—the influential program founded at MIT by Frank Schmitt) had asked me to write. The resulting paper eventually became an important part of Marr’s book entitled Vision (Marr, 2010, reissued). The “levels of understanding” manifesto has been mentioned as one of the most enduring constructs of 20th-century cognitive science and computational neuroscience (Wilems, 2011). The argument in our paper and in Marr’s book is that complex systems, such as a computer and the brain, should be understood at several levels. Here, let me list just three levels: the hardware, algorithms, and computation. Our paper and David’s Vision book emphasize that explanations at different levels are largely independent of each other: a software engineer does not need to know the hardware in any great detail. The message was important at the time, 30 years ago. The study of the problems to be solved, and of the associated computations, is relevant in its own right and is needed for a full understanding of the brain. As I have argued more recently, I think that it is now time to emphasize the connections between these levels, and to extend the range of levels, if we want to make progress in computational neuroscience.

To elaborate, let me recount the background of the argument. Our 1977 paper was the original “manifesto” on our computational approach to the brain. We started from an argument described in a paper by Reichardt and Poggio (1976) on the visual system of the fly, where we distinguished three levels: single cells and circuits, algorithms, and behavior (of the organism). David insisted, correctly, on replacing the behavior level with the level of computation and computational analysis. This was important for defining the approach of computational neuroscience. But one key aspect of the original argument in Reichardt and Poggio (1976) almost disappeared in the process. We had stressed that one ought to study the brain at different levels of organization, from the behavior of a whole animal to the signal flow (i.e. the algorithms and the circuits and single cells). In particular, we expressed our belief, which Werner had written about even earlier, that (a) insights gained on higher levels help to ask the right questions and to do experiments in the right way on lower levels, and (b) it is necessary to study the nervous systems at all levels simultaneously. From this perspective, the importance of coupling experimental and theoretical work in the neurosciences is clear; without close interaction with experiments, theory is very likely to be sterile.

I believe that David would agree that it is time to look again at the levels of understanding framework, now emphasizing the connections between levels and their synergies. In particular, I believe that neuroscience can help computational theory and even computer science as suggested by recent models of the visual cortex, which are leading to interesting approaches in computer vision. In 1979, when David wrote Vision, our belief was that computational theories might be of use to neuroscientists. The rise of computational neuroscience during the last several years confirms this notion. Moreover, the table is now turning. In the near future, neuroscience may well provide new ideas and approaches to artificial intelligence.

Cambridge, Massachusetts—Stereopsis

As time went on, I developed a deeper understanding of David’s work on vision. In retrospect, it took a lot of time. Really new ways of thinking cannot be appreciated easily. A thousand different facets must be communicated with the magic of a language and a fascinating style. David’s early papers on vision have these rare properties. A good way to understand something new is to criticize it, playing the role of devil’s advocate. In doing this with David, I found myself at some point defending recurrent networks. David formulated the challenge of solving stereopsis in his way. He explained it in terms of his analysis of the computational problem of stereopsis—which cells had to be excited and which ones had to be uninhibited. On a paper napkin at the MIT cafeteria, I wrote down the obvious equations for the recurrent network. I claimed that it would be very easy to prove its convergence; Liapunov-like functions constructed from conditional expectations were what I had in mind. Back at the lab the same evening, after a dinner at the Greek restaurant in Central Square, David programmed the recurrent algorithm, which seemed to work well in one dimension. The day after, the two-dimensional version of the algorithm showed encouraging signs of liking the stereograms constructed by Béla Julesz. One week later, when I had finally understood David’s computational analysis, I also realized that an analysis of the convergence of the algorithm was going to be very difficult. All general standard methods failed. When I told David that I had to turn to a last resort, a probabilistic approach, the teasing began. The teasing became even more intense when I had to write a program to compute the result of the probabilistic analysis.

In the meantime, our creative collaboration was exciting, despite the headaches from the convergence problem. We began working closely together. It was a fantastic experience. David was very sharp; he had clear ideas about almost everything, and they were usually right. I slowly discovered other facets of him. He was passionate about music, Italian opera for instance. I heard him improvising a few times on the piano. He played with ease and emotion. I was impressed. I had to wait another year, however, before hearing him play his true instrument, the clarinet.

During those three months in Boston, I often went sailing on the Charles River. But the really new experience was flying. David was a pilot, and my presence in Boston triggered anew his passion. I took a few flying lessons. Several times we flew together from Hanscom Field in a rented Cessna. On those occasions, I would stay overnight at David’s house. Early in the morning, we listened to the weather forecasts and then drove to Hanscom Field where we would get a plane for the day from Patriot Aviation and share expenses. One of the most beautiful flights brought us to the Lakes Region in New Hampshire. The sky was as clear and deep blue as the water beneath us. We landed on a grass strip on a little island. It was very quiet. We walked to the water a few hundred yards away. There we sat for a few hours. We reviewed what we had done on stereopsis and decided to write a short paper for Science about it. David already had the opening sentence and the overall formulation was clear. We just had to sit down the next day and write. There was one white sail on the lake. We were encompassed by green, blue, and silence. David was happy and relaxed. So many more ideas and flights and forests and lakes awaited us! On our way back to Hanscom, the weather changed and rain started suddenly. On the final approach, David was very tense, his mind totally concentrated on the plane, the control tower, and the instruments. Many people were afraid of this concentration, which they mistook as a sign of unfriendliness or aloofness. I knew well the alertness of David’s mind when he was discussing science, lecturing, playing music, or flying, and I could physically feel the presence of his thoughts, his total concentration. There was an incredible intensity to his thinking. His reactions and his answers were incredibly quick and at the same time crystal clear, sure, and sharp. Our landing on the wet field at Hanscom was perfect. Five minutes later, the airport closed down.

On another flying expedition to Nantucket and Martha’s Vineyard, we got sunburned on the beach. Two days later, red like lobsters, we gave a lecture on stereovision at Harvard Medical School. We were making grand plans to fly across the United States for a month or so. Life was going to be a lot of fun! A few weeks before my return to Germany, we were right in the middle of the U.S. bicentennial. The tall ships were coming into Newport on their way to New York. On the weekend of July 2, the weather was beautiful, and David decided we should fly down to Newport. We came above the bay with our Cessna 170 to find that the blue sky was filled with flying objects: balloons, choppers, a Goodyear “blimp,” and many other planes. Tower instructions were to circle at a specified distance above the tall ships. The surface of the sea was covered by little white traces, glittering under the sun. Hundreds of boats of all sizes came to meet the tall ships. The scenery was superb. It was simply great, circling above the ships, together with so many other planes and boats. Hundreds of planes were scattered all over the field at Newport airport, many of them old-timers, happy and colorful. But in the afternoon, the weather deteriorated quite suddenly. There was a storm with ghastly winds. Back at the airport, we thought for a while about leaving the plane and going back to Boston some other way. David phoned several times to inquire about the weather at Hanscom. It was clear, so he decided to start out. Airborne again, drops of rain slashed across the windscreen until we came up from the low clouds out into the sun. It was the eternally beautiful weather to which poets have accustomed us. But the feeling in a small plane without instruments is quite different. David, however, was relaxed. There was nothing to do but fly straight and wait for the clouds to dissolve. Near Boston, the ground started to appear in short intervals through foggy holes in the white carpet below us. When we landed at Hanscom, the sun was setting against a clear sky.

It is not by chance that my deep friendship with David was associated with flying together. Flying and friendship, joy and beauty, freedom and living, are things that are made of the same substance. I did not fly anymore with a light plane after David became ill. I do not know whether I am ever going to do it again.

Tübingen—Biophysics of Computation

Sometime after I returned to Tübingen from MIT, I met Vincent Torre, who was a student of Borsellino in Genoa, as I had been. He was younger, so we never met during our studies. We met for the first time in the house of Antonio Borsellino in Genoa during one of my visits back home. Shortly afterward, we started working together in Tübingen on the biophysics of neurons and synapses. Later, while working with Christof Koch, I dubbed that direction of research “Biophysics of Computation” following the title “Physics of Computation,” a chapter in a well-known book by Carver Mead (C. Mead and L. Conway, Introduction to VLSI Systems, Addison-Wesley, Reading, Mass., 1980). Vincent, who went to work with Alan Hodgkin (whose theory of the action potential is a major achievement in biophysics) on photoreceptors in Cambridge, taught me about biophysics. I learned more about biophysics from a textbook that I used to teach cable theory at the University of Tübingen. I decided to teach because the topic was important but so boring that I would not have been able to finish the book by myself. At the end of the year, one student was left in my class!

Vincent and I started from a relatively well-known operation, the threshold operation of spike generation. We derived a mathematical formulation that could be used more easily to incorporate the key properties of single neurons in the quantitative description of a system consisting of many neurons and synapses. We ended up using a functional power series expansion called Volterra series (also called Volterra-Wiener series) that I had learned from a seminal paper of Bedrosian and Rice, and which is a natural extension of linear system theory. The fun part of the project came when we had to write the power series expansion of the inverse of a power series expansion. It turned out that Lagrange had solved the problem in his 1770 paper, and this was still the best place to find the result. In those years before the Internet, that meant visiting the rare book section of the Universitaet Bibliothek and consulting Lagrange’s article directly. The old French was not a problem, but the mathematical notation required quite a bit of decrypting. What I remember most is that there were quite a few mistakes in the derivation that somehow canceled each other out at the end!

Tübingen—Multi-Input System Theory

During this same period, I became very interested in extending linear, one-input system theory to nonlinear multi-inputs systems. The motivation was the visual system in the fly and in people. I had read papers about the behavior of Volterra series under white noise inputs. In the process, I started reading papers by Norbert Wiener and some of his MIT students such as Lee and Schetzen, and later, Amar Bose. I also interacted with classical mathematicians such as Bernard Coleman, who could not understand the mathematically crazy distributions such as delta functions that engineers were starting to use. In the attempt to make my mathematics more sound, I began a collaboration with Guenther Palm, who had just started to work with Valentin Braitenberg. Guenther was a mathematician with a fresh PhD in functional analysis. A lot of what I know today about function spaces, distributions, and different types of integrals I learned from Guenther. Guenther was a gentle bear, often appearing at our home for a beer around midnight.

Tübingen—More Stereo

David came to visit in Tübingen in the beginning of 1977. He stayed in the guest room at the institute and walked over to our home every morning for breakfast. We worked on the probabilistic analysis of stereopsis, discovering more difficulties every day. David wanted to think about a theory of human stereopsis. Eye movements were important. At that time, I had just heard from Jack Cowan of his work with Hugh Wilson on spatial frequency channels. David brought out Mayhew and Frisby’s Nature paper on rivalrous stereograms. Our starting point began with two ingredients, the apparent falsification by psychophysical experiments of our first algorithm and the need for eye movements. We read everything on stereovision from Barlow to Julesz. At some point, we were suffocating in my office under piles of bound volumes of the Journal of Physiology and Vision Research. We even did some informal experiments. At the end of the three weeks, we had written three-fourths of the analysis of the cooperative algorithm paper (I had to write the final quarter with Gunther Palm) and had some rough ideas about a new model of stereopsis.

David had brought his clarinet. I introduced him to Eric Buchner, a good cello player. With another friend, a very good pianist, they played together several times. We were all deeply impressed by David’s music. During his visit in Tübingen, the members of the Scientific Curatorium of the Institute—including its chairman, Sir Bernhard Katz—came one day to meet with the members of our institute. In the evening after dinner, David and other friends played Mozart’s “Clarinet Concerto in A Major.” I had never been so deeply struck by music as I was that evening listening to David and his clarinet. It was so beautiful and perfect, as full of emotion as to be almost unbearable. It was quite clear afterward that the audience had a similar experience.

At that time, David was quite alone in his work. He did not have anybody back at the MIT lab with which to work in the same way we had. I suggested he try to work with Shimon Ullman and share responsibilities of the group and the students. At that time, I knew Shimon only superficially but what David thought about him and his work left no doubt. David promised he would do it. That was an easier promise to fulfill than his promise to finally get out of his “craziness” and his “women problem.” He did not manage that until he met Lucia, one year later. Those three weeks in Tübingen were a lot of fun; life was full, warm, and happy.

In June 1977, David returned to Tübingen. He stayed a full month in “his” room in the institute. The first week of his visit was difficult because a month earlier I had started an anatomical project, the first and only wet experiment I had done all by myself. I was very interested in the circuitry of motion computation in the retina because of my work with Vincent Torre. I was going to explore the (small) possibility that cobalt injected in the ganglion cells could stain the presynaptic processes via retrograde transport and uptake by the presynaptic terminal synapsing onto the ganglion cells. The project failed and also managed to make David quite nervous about competing with a few frogs. After that, we worked hard together, developing our stereovision ideas and writing them down. The days were productive. The theory took form. Through all my work with David it was often impossible to say who came up with a specific idea; almost everything came from discussions and thinking together and reciprocal criticisms. But David had the power of veto: if I was unable to convince him, that was it. He also had the ability to keep us on course.

We finished our manuscript right on schedule with time left to take Polaroid pictures of the two authors sitting with the title in one hand and stereo glasses in the other. (In the original draft of the manuscript there were a few lines warning the secretary that at that particular point we had just had too much Courvoisier and, therefore, the following sentences were going to be particularly immortal.)

The whole month was continuously concentrated, happy, and playful. As so often with David, science was fun and freedom! I often ask myself why David’s presence had this incredible power. I still find it very difficult to give a full answer. But I know that part of it was the clarity and especially the force of his mind, of his thoughts. To think with David was for me an inebriating experience, a special feeling of playing and creating. Skiing downhill on a sunny day in the Alps gives me some smattering of this intellectual fun. In the spring of 1977, Werner organized a neurobiology meeting to celebrate the 500-year anniversary of Tübingen University. I helped organize the lectures. Many friends came: David Marr, Vincent Torre, David Hubel, Denis Baylor, Emilio Bizzi, Gunther Stent, Jack and Max Cowan, Bela Julesz, and others. David’s lecture was a beautiful jewel of intellectual brilliance and improvisation.

In the middle of October that same year, I flew to Toronto for the annual meeting of the Optical Society of America; I was invited by Whitman Richards, who organized a special session. The whole MIT vision group came. It was fun, although short and chaotic. A couple of days later, I flew to Boston to work with David for three weeks. It was a fight with LISP and probability (again!). Ellen Hildreth, a student of David’s and a good friend, wrote that “David was a very stimulating person; the energy level in the lab would suddenly double when David walked in (it would quadruple if Tommy [Poggio] was there too …) .”

I remember how part of the zero-crossing idea had originated. Coming out of the cafeteria in the AI building (which also housed the CIA, Polaroid, and IBM), I expressed my uneasiness about taking zero-crossing and peaks of the filtered images because filtering the images was roughly equivalent to making their second derivative zero-crossing correspond to extrema of the first derivative. This made sense. But peaks were something strange, at least at this level and from this point of view. For simplicity, and because of the relations between derivatives, difference of gaussians, and bandpass channels, I wanted to flush peaks and retain zero-crossing only. David thought a while and then decided that, for reasons I had not thought of, the idea was actually not too bad. It is still unclear whether he was right. At the end of my stay, we drove together in a rented car through the colorful fall foliage in New Jersey down to Bell Labs. I gave a lecture for Bela Julesz and his small group on a topic that was completely uninteresting to them, synapses. When we mentioned our probabilistic analysis of zero-crossings, Bela named some mathematicians at Bell Labs who had worked on somewhat similar topics. Among them was a name that we did not know, Ben Logan. We asked for the paper, and Bela sent his secretary to get reprints. Glancing through it I saw that his theorem was very suggestive of our notion of independent bandpass spatial frequency channels. In the hotel and later, in the car, I tried to convince David, who remained quite skeptical. The zero-crossing idea and its connection with Logan’s theorem is the kind I immediately like. Unfortunately, such ideas are often too nice to be biologically correct, and David was very probably correct in his skepticism.

La Jolla—Crick and Marr

I met Francis Crick at about the time when Francis and Odile moved from Cambridge, England, to the Salk Institute in La Jolla, California (1976). At Salk, he became a theoretical neuroscientist, following his second passion—after the mystery of life, the mystery of the mind.

I had visited Francis and Odile during the summer at their house on Portugal Place in Cambridge, England, with its golden helix above the front door. In La Jolla, I went with them and with the Orgels on trips to the desert. I saw him at the F. O. Schmitt’s Neuroscience Research Program meetings. And I saw him debating about consciousness with various guests at our home, and answering question from my son Martino, and from his Texas Instrument’s Speak and Math.

In 1979, Francis invited David and me to spend a month at the Salk Institute trying to understand the connection between the architecture of visual cortex and several intriguing aspects of visual perception. Francis always had the time, the interest, and an infectious enthusiasm for discussing scientific problems. He regarded us skeptically but seriously. A quite faithful account of those unforgettable conversations (mainly between Francis and David with me and sometimes with Leslie Orgel playing the role of the fan club) is in the third part of David’s posthumous book, Vision.

During this visit, I discovered the clarity of Francis’s mind and his incredibly intense focus. After hours and hours of discussion on a problem with the solution still escaping us, David and I were often tired, confused, and ready to give up for the day. Not Francis; he was relentless, forceful, critical, and enthusiastic. He was not a mathematician, but he knew how to use mathematics and how to visualize it. I still have his letters full of diagrams and equations dating back to the time when we worked on an extension of the sampling theorem, trying to understand aspects of motion perception.

During discussions with Francis, we began to worry about the function of the large number of neurons in layer 4c beta of V1 (prompted I think by a visit by David Hubel at Salk). We speculated about their possible role in image interpolation and hyperacuity. We had a phone conversation with Gerald Westheimer at Berkeley and ended up writing a paper with Francis. Once back in Tübingen, I was in charge of the appendix, which dealt with a little extension of Shannon’s sampling theorem to moving patterns. The writing of the appendix was a lot of fun because it involved a heavy exchange of handwritten letters full of equations and drawings with Francis. As a result of that side project, I began to work with Manfred Fahle in Tübingen. He was a bright new PhD–MD student, and this work led to interesting psychophysical work on spatiotemporal acuity.

Leaving the Max Planck Institute for MIT

Werner offered me the best position he could, just below directorship, with the promise that I might replace him once he retired. Being a director in the Max Planck Gesellschaft is unique: it includes tenure for the director and the entire lab and freedom from writing grants along with optional teaching. Werner was a great friend and my scientific father; we loved Tübingen and the Max Planck Institute—a kind of ivory tower of science. But it was too soon for paradise. My wife and I needed to experience the real world with competition and the fight for survival. So in 1980, I decided to move to the MIT Artificial Intelligence Laboratory and join the faculty in the same department (psychology) where David was.

We left Germany with plenty of insurance: both of us were given a two-year leave of absence and much encouragement to come back. I felt the need to buy a house in the United States to keep it from being too easy to go back! That was a tough act. In the summer that I was looking for a house, Paul Volker was fighting inflation and Barbara was on the beach in Levanto. Because of Paul, mortgage rates were rising every week by one percentage point, a rather unusual situation. I ended up with a 17 percent mortgage rate and a second mortgage generously contributed by MIT at the great rate of 18 percent! The person who was most instrumental in convincing us to move and who provided us with the most help, funding, and support was Whitman Richards. Whitman had created the computational vision group at the AI Lab, managing to pull together David Marr, Shimon Ullman, and me. Whitman had a long series of great students and was an inspiration for generations of MIT researchers.

When I arrived at the MIT, there were seven or eight faculty in the Artificial Intelligence Laboratory. Only Patrick Winston, who was the director, was born in the United States, the rest were foreign born. Patrick started his job as director of the lab when he was still a graduate student! I shared my LISP machine ($100,000 for a desk computer) with one of my most remarkable friends, Kobi Richter, then on leave from the Israeli Air Force. In return, Kobi helped me buy not one but two used cars by playing the tough guy and the expert.

My salary at MIT was considerably lower than in Tübingen, and my wife could not work because her neuropsychiatric specialization was not recognized in the United States. (She was the real breadwinner at home.) The mortgage was high. I figured out that most MIT faculty had consulting jobs one day a week to make ends meet. Fortunately, a consulting opportunity materialized soon in the form of Danny Hillis and “Thinking Machines.”

Thinking Machines Corporation was a supercomputer company started in 1982 by Danny Hillis and Sheryl Handler. It was an effort to turn Danny’s PhD thesis (with Marvin Minsky on massively parallel computing architectures) into a commercial product called the Connection Machine. When I arrived at MIT, Danny was finishing his thesis. As a graduate student in the AI lab, he had a rather large research group, composed mostly of undergraduates. The company’s ambitions were more scientific than commercial. Its motto says it all: “We’re building a machine that will be proud of us.” Thinking Machines was one of the first high-tech companies with its own kitchen and chef. It was more like a club of smart people than a company. Among the people I met there, in addition to Danny and Marvin, were Jack Schwartz and Steve Wolfram (before Mathematica) and most notably, Richard Feynman, with whom I had long conversation about vision in the fly and color vision in general.

The first years at MIT were confusing. I was dealing with the loss of David Marr, who died of leukemia in 1980, learning a new way of life, and learning a different way of doing research; I was much more alone. I also had to get grants and even teach, though not very much. Emilio Bizzi helped me during this period. I met many people, often without really understanding who they were. For instance, one day Sidney Brenner, whom I knew through Francis, dropped by my office at the AI Lab with David Baltimore, mentioning that David was about to start a new biological institute, which turned out to be the Whitehead Institute. Another day, Steve Jobs came to find out about AI and computer vision. He was shown our new stereo head system that mimicked eye and head motions by Keith Nishihara. Jobs was young and stiff and quite out of place, dressed in a jacket and tie.

In retrospect, normal life at the AI lab in those days meant that, on any given day, Steve Jobs might appear, as would Bill Gates. Once a small group of Italians arrived and asked Patrick Winston, the lab director, if they could take pictures of him and his AI colleagues. We ended up as models in a special issue of Vogue (Uomo Vogue) dedicated to fashion modeled by scientists. I discovered only recently that the photographer was Oliviero Toscano. Oliviero is very well known for his famous campaigns (e.g., Colors of Benetton). He is a great guy with a deep understanding of the human condition.

I was also trying to cope with two offices, one in the AI lab at 545 Technology Square, and one in the old psychology department, as well as with two research directions, biophysics and computer vision/psychophysics.

Biophysics

Christof Koch had been my first and only PhD student in Germany. Because I was not a professor at the University of Tübingen (where apparently Kant was denied tenure), Valentin Braitenberg had agreed to be Christof’s official advisor. Christof started working as a technical assistant on a C program to digitize trajectories of flying flies in 3-D. We then decided on a PhD thesis on the biophysics of computation by studying the computational properties of synapses and dendrites. Part of the thesis was based on anatomical data obtained from retinal ganglion cells from the nearby lab of Heinz Waessle. Christof finished his thesis a few months after I moved to the United States and then joined me after Werner Reichardt helped to get him a postdoctoral fellowship from the Franz Thyssen foundation.

With Christof and Vincent, we worked on the idea that shunting inhibition could mediate nontrivial information processing operations because the relationship between synaptic inputs, which are conductance changes and voltage effects, is nonlinear. In particular, shunting inhibition could be used to implement almost logical gates distributed over the dendritic tree, making a neuron more a very large scale integrated (VLSI) chip than a single transistor. This research direction had begun a few years earlier in 1977 in Tübingen with the proposal that a specific biophysical mechanism could explain directional selectivity in the vertebrate retina. It was Vincent who suggested it, based on work he had done in the Consiglio Nazionale delle Ricerche (CNR) lab in Pisa with Marchiafava.

Stereovision

I also continued to work on the problem of human stereopsis. At the time, we had reasonable success in terms of the computer performance of our stereo algorithms, but it was still unclear how the visual cortex solved the stereopsis problem. These days, artificial stereo systems are pretty good in absolute terms, and disparity maps obtained by them are used in a number of applications including a vision system for cars (by Mercedes). We still do not know in full how the human visual system computes stereo, but the mystery is not about performance anymore. There is an irony here, and perhaps some interesting work to be done. Algorithms like ours (Marr and Poggio, 1976; see also Parvati Dev and Michael Arbib) showed that Julesz’s random dot stereograms could be “solved” pretty well by simple excitatory and inhibitory interactions (our stereo algorithm was a Hopfield network before Hopfield networks were invented) that operate on low-level representations of the image. This demonstrated that Helmholtz was wrong, and recognition of objects and objects’ parts is not needed for matching the images from the two eyes. In fact, all modern stereo algorithms work on low-level descriptions of the images. The irony is that, in our everyday stereovision, the Helmholtz approach may be as important as low-level matching. Here is a conjecture (good for a PhD thesis): Low-level and high-level matching should be used by a stereo algorithm to obtain the best stereo results, and both are likely to be used in human vision.

One specific memory connects research on stereovision with some peculiar American realities. One day, I was visiting with Eric Grimson, another MIT professor, at a military lab in Washington. We were taken at some point to a room with some of the most recent photogrammetry tools, including one of the first Cray 1 supercomputers. Suddenly, while our host was describing some of the work on stereo, big red lights started flashing and loud alarm bells went off. The place exploded in a frenzy of activity. Eric and I were whisked out of the room by military police. Later, we were told that non-U.S. citizens were not supposed to be there, and they had just discovered that I was Italian and Eric, Canadian!

The work on stereovision also involved writing a review about computation and physiology with the other Poggio, Gian Poggio. Max Cowan was a great friend of the other Poggio and the editor of the Annual Review of Neuroscience, and he invited us to write it. We had the same last name; we were born in the same city, grew up a few blocks away in a similar circle of families, but were divided by 15 years or so. Ironically, we met for the first time in Belmont at a dinner in the home of our mutual friend Emilio Bizzi.

Zero-Crossings and Texture

Cambridge and MIT brought many visitors and new friendships. I met Edwin Land in a few visits with David Hubel. I met Don Glaser, the physicist who invented the bubble chamber, in 1981 in Klosters in one of Eigen’s skiing workshops. I met Don again later in Cambridge during his mini-sabbatical in 1982 in the Rowland Institute, a private lab, now part of Harvard, where Edwin Land, the founder of Polaroid, was studying human color perception. Don came to a vision conference I organized in 1984 in Erice. In 1992, we organized a Dahlem conference in Berlin entitled “Exploring Brain Functions: Models in Neuroscience.”

On the suggestion of Emilio Bizzi, then the chairman of the new Department of Brain and Cognitive Sciences, I started a Center for Biological Information Processing (CBIP) with Ellen Hildreth, which was one of the first hubs for computational neuroscience in the United States. In 1985, John Hopfield came to CBIP from Caltech for a yearlong sabbatical. I put him in an office with Christof Koch. A bit later, back at Caltech, John started the computation and neural system program; the first hire of the new program was Christof! A year later, in 1986, David Mumford, acclaimed for his work in algebraic geometry, came from Harvard to spend a year of sabbatical at the artificial intelligence laboratory next to my office.

Regularization in Vision: Edge Detection, Motion, Markov Random Fields

In the first three years or so at MIT, my research had been productive but somewhat directionless and opportunistic in terms of problem choices. In addition to biophysics, the overall theme was computational vision, but I was not following any new “big” idea. A new unifying theme emerged thanks to Vincent Torre during a trip to Genoa, where he introduced me to Mario Bertero and to inverse problems. It became clear to me that vision was an inverse and ill-posed problem and that regularization techniques “a la Tikhonov” would provide a general approach to such problems. Everything suddenly fit together: constraints advocated by David and used in our stereo paper were needed to regularize a problem and make the solution of the corresponding optimization problem unique and well-behaved. All problems in vision and more general perception were inverse problems, going back from the image to 3-D properties of objects and scenes. They were also, as typical for inverse problems, ill-posed. We used regularization techniques to “solve” specific vision problems such as edge detection and motion computation. In the process, we found that some of the existing algorithms for shape-from-shading, optical flow, and surface interpolation were a form of regularization. Our main contribution was to recognize ill-posedness as the main characteristic of vision problems and regularization as the set of techniques to be used for solving them. We wrote general papers on this (the Nature paper was first rejected at a neural network conference). We recruited Christof to explore an intuition I had—that analog electrical networks, and possibly simple properties of neurons and dendrites, could be used to implement regularization. As always, I was trying to connect different levels of analysis; in this case, I was trying to bridge the computation to the hardware.

Beyond Tikhonov Regularization: Markov Random Fields and Fusion of Information

It was quite obvious to me that Tikhonov regularization was a good beginning but not the full solution for regularizing ill-posed problems. Tikhonov regularization is a constraint on the norm of the solution. Usually, this norm constraint imposes smoothness of the solution, depending on the representation and its metric structure. In general, one would like to have a broader choice of regularization constraints than just smoothness. With Alessandro Verri, one of my great friends who came from Italy as a postdoctoral fellow, we tried to explore more general shape constraints in the framework of regularization—but the mathematics was hard.

At the time, I did not know about reproducing Kernel Hilbert spaces (RKHS) and focused on two possible directions, both probabilistic, for extending Tikhonov regularization. The first one was based on the observation that Tikhonov regularization could be interpreted in Bayesian terms. Minimization of the Tikhonov regularization functional is equivalent to a maximum apriori estimate (MAP) of the conditional probability distribution of the solution given the data under a particular Gaussian prior and the assumption of Gaussian additive noise in the data. The observation suggests that Tikhonov regularization may be a special case of a more general Bayesian approach. Estimates of conditional distributions may allow the expression of more complex and specific constraints than “smoothness.” I did not follow this approach at the time, mainly because of computational and conceptual difficulties. The Bayesian approach is so general (a very big hammer), and one pays so much for it, that I wanted to use it only as a last resort; it is almost equivalent to giving up understanding and resorting to greedy optimization with no guarantees. The second direction was more specific. It was the use of Markov random fields (MRFs) with line processes to deal with regularization with discontinuities as in surface interpolation. The research came from a very good student of Sanjoy Mitter and mine, José Marroquin, and matched well with the use of the Connection Machine, the first parallel supercomputer produced by Thinking Machines Corporation (TMC). As it turned out, Markov random fields were in our hands at the time a rather brittle technique, sensitive to parameter choices. The best computer vision use of them was to integrate information from different sources such as color, intensity, motion, and depth to find surface discontinuities in the scene. My daughter’s teddy bear demonstrated it on the cover of Science!

Color Constancy and Learning

The work on regularization had a number of specific applications in vision. We followed up on some of them, such as the computation of optical flow and color. I was, however, thinking of steering back toward my ultimate interest, the problem of learning. The opportunity came with a graduate student who was working on color perception. Anya Hurlbert was one of a small number of brilliant MD–PhD students in my career. It seemed to me that all of them were slightly masochistic; as if a PhD at MIT was not enough, they complemented it with an MD at Harvard. In any case, Anya, who was extraordinarily good in research, kept explaining to me the mysteries of color. Most natural objects are visible because they reflect light. The proportion reflected varies with wavelength, defining the surface reflectance function. The light reaching the eye is a product of the surface reflectance function and the spectral power distribution of the illuminant. If color is to provide a reliable cue to the surface, the visual system must compensate for changes in the illuminant. Object colors do tend to appear unchanged under different lighting, showing that color appearance is closely tied to surface reflectance. Many factors are thought to contribute to color constancy, which is a typical inverse problem. The illuminant changes during the time of the day and from outdoor to indoor, but our brain discounts the changes and computes a good approximation of the reflectance properties of objects, which is invariant to illuminant variability. Edwin Land had proposed an algorithm to achieve this goal. My question was whether one could do something similar by learning to associate to a variety of images with different illuminant the underlying “true” reflectances. We tried it out in a simple associative learning scheme in the spirit of the old work done in Tübingen, following up my interest in holographic memories. The subject could learn to extract the reflectance from the images reasonably well in toy problems. Moreover, the solution was a linear filter very similar to the algorithm proposed by Land!

Learning and Regularization

In 1988, I was still thinking about learning. The whole neural network fashion had started because of Hopfield networks (1982) and backpropagation (1986). I was skeptical. I claimed it was the usual recurrent epidemic of ideas about intelligence. Epidemics of the same flu virus tend to reoccur about every 20–25 years for obvious reasons. Scientific ideas have similar periods, about a generation long, as shown by William Goffman in a seminal Nature paper on the field of mathematical logic. I challenged Geoffrey Hinton in a meeting at Snowbird (that eventually became NIPS), asserting that there was nothing magical about neurons, that the term neural networks was just a sexy name for statistics, and that the field would in fact become part of statistics. In retrospect, I was mostly right. I missed completely, however, the importance of good metaphors for triggering good people to work in a field!

In 1988, I saw a paper about radial basis functions by Broomhead and Lowe on multivariate function approximation. The idea of looking at learning from the point of view of function approximation was appealing to me. It immediately connected the problem of learning with well-known mathematics. Furthermore, I saw a direct connection with regularization. I knew from work in computer vision, and in particular on edge detection, that Tikhonov-type regularization can be seen as a linear combination of a set of basis functions centered at the data point. I even knew how to get a Gaussian basis function from a particular regularizer. I had seen this in a paper by Alan Yuille and Norberto Grzywacz on a completely different problem—motion. Everything seemed to click: learning was an ill-posed problem as well, maybe the ultimate ill-posed problem of predicting from a subset of data, exactly what science tries to do. Fortunately, a great guy, Federico Girosi, had just joined my group, continuing a tradition that started with Vincent Torre (Alessandro Verri was a student of Vincent’s; Federico Girosi was a student of Alessandro’s). Federico was a better and more careful mathematician than I was; he was the ideal collaborator in that exciting time. Together, we wrote an AI memo entitled “A Theory of Networks for Approximation and Learning,” which generated a number of papers in Institute of Electrical and Electronics Engineers (IEEE) and Science and remains the most highly cited of all of my publications.

Learning, the Brain, and Object Recognition

In 1990, I took my first six-month sabbatical at a new institute in Trento, Italy, called Instituto di Ricerca Scientifica e Technologica (IRST). Luigi Stringa asked me to form and lead a vision group. I was helping with the vision of the institute. Bruno Kessler and Luigi Stringa made quite an impression on Barbara and me at a dinner at our home. I was happy to have the opportunity to spend more time with my mother in Genoa. She also came to spend time in my apartment in Trento. I went to Trento with some of my students and close collaborators such as Federico Girosi. After our theoretical formulation of the learning problem in terms of regularization and regularization networks, the playground was open to many applications.

I have always loved to collaborate across disciplines, and our development of a family of learning algorithms opened a big playground for me. I started working on applications of the new approach in a number of domains. Not surprisingly, the first problem I worked on was the problem of the brain in a manifesto entitled “A Theory of How the Brain Might Work,” which was a more modest version of the original “A Theory of How the Brain Works.” The paper claims that the ability to learn, generalize, and to predict is at the core of intelligence. Furthermore, regularization shows that learning is much more than memory—it can be regarded as an interpolating look-up table. The paper’s main message is that intelligence is memory-based computation. I believe this is a useful point of view and possibly a powerful insight, consistent with the evolution of intelligence.

At the same time, I thought about a computational model based on this point of view for explaining pose-invariance of object recognition in humans and primates. The model was equivalent to a network with neurons tuned to views of an object from different viewpoints. It was a toy model but made the point that 3-D models, then the standard wisdom, were not needed. Shimon Edelman, a new postdoctoral fellow, did the implementation. We used 3-D clips—that Shimon and Heinrich Buelthoff were starting to utilize for psychophysical experiments—as our test objects. We wrote a short paper for Nature. I went back to hyperacuity to find an explanation for visual perception in terms of the new learning framework. I had first started to work on this topic with Francis Crick at the Salk Institute and later with Manfred Fahle in Tübingen. This time I teamed up with Shimon Edelman and Manfred, who was spending his sabbatical in my group. We showed that hyperacuity is quite easy to learn from a relatively small set of examples without any additional circuitry.

Entrepreneurship

Life continued with fun science and fine friends coming to visit. Francis Crick used to come to visit from time to time. One of his visits started a tradition in my group that went on for ten years or so: a “Crick dinner” was a dinner for all of my students in which a well-known scientist was present, such as Francis on that first occasion. Don Glaser, Marvin Misky, Steve Smale, David Mumford, Thomas Kuhn, Graeme Mitchison, Anya Hurlbert, Christof Koch, Gian Poggio, and Shimon Ullman were all at one time or another the excuse for a Crick dinner. Some friends and colleagues were leaving for better positions (e.g., Heinrich Buelthoff became a professor at Brown, Nikos Logothetis took a job in Houston, and Manfred Fahle took a job in Tübingen and then Bremen). Unfortunately, some were leaving and not coming back—ever. Werner Reichardt died on September 18, 1992, a few days after a very nice workshop in Tübingen with all of his main collaborators celebrating his retirement. From 1968 to 1992, Werner Reichardt made important contributions to the understanding of visual perception, using the fly as a model organism. Werner was a member of many academies in Germany; a member of the prestigious order, Pour Le Merite; a foreign member of the National Academy of Sciences; a recipient (with his friend B. Julesz) of the Heineken prize of the Royal Dutch Academy; and also the recipient of many other honors of which he was rightly proud.

It had not escaped my attention that the learning framework had commercial applications. Furthermore, I had been consulting for TMC for almost a decade, but that important line of intellectual activity and extra income was in trouble. After receiving a great offer from IBM, which was declined by Sheryl Handler, Thinking Machines—the world leader in parallel supercomputing—went through a rough patch, eventually filing for Chapter 11 in 1994. In the meantime, I had ideas about applying the learning framework to graphics. If vision was an inverse problem, graphics was a direct problem, but one could look at it as the inverse of vision and use learning techniques to synthesize new images under the control of a few parameters from a training set in which pairs of images and control parameters were available. The idea turned out to be equivalent to multidimensional morphing. We had a plausibility demonstration with Roberto Brunelli at IRST. After Roberto declined to pursue the approach, I happened to team up with Steve Librande, a great student at the media lab at MIT. At the time, he was developing software tools to help animators draw characters. His group had funding from the creator of “Garfield.”

Steve combined his great artistic and software skills with radial basis functions and produced a video that is still captivating today on how to synthesize new drawings from a small set of original ones in the artists’

style. A number of visitors at the MIT media lab, which was just becoming glamorous, were interested. We were naturally led to a start-up while fighting with Nicholas Negroponte about intellectual property (the original patent was held by IRST and MIT; the media lab had to share it, and Nicholas did not want to). The technology licensing office suggested an investor with whom I met at the old AI lab, Charles Harris.

I remember that I offered to drive Charles to the airport because I liked this slightly odd businessman who seemed to be really interested in research and was wearing a perfect business suit with slightly unusual sneakers. Charles was a real gentleman. I came to appreciate enormously his and his wife Susan’s friendship, his intelligence, his wisdom, his curiosity, and his enthusiasm for life and for friends.

The MIT Technology Licensing Office (TLO) had proposed a possible chief executive officer (CEO) (Hoomin Toong); nFX started and soon moved to Silicon Valley in Mountain View, California. As it turned out, our technology was good but too early, ahead of the Web, and our CEO was the opposite of what the open atmosphere of the valley would have liked; nFX was not an easy ride for me and even less for people directly involved such as Steve Librande and Joel Voelz, the (very good) successor of Hoomin. Harris and Harris lost a couple of million despite the eventual sale of nFX to Adobe.

The other obvious application of learning techniques was to predict the stock market. In the late 1980s, I had been invited by Paul Glaser (via Patrick Winston), the technology chief at Citicorp under John Reed, to be part of an advisory group of faculty from some of the best computer science (CS) departments in the country, called the Strategic Technology Evaluation Program. We were about 14 hand-picked, world-class computer science experts chosen to advise Citicorp on innovative applications of technology. I remember Michael Stonebraker, Ron Rivest, Tomas Lozano-Perez, and Sal Stolfo. Through my work with Citi, I got in touch with Paul Ardern, head of a trading unit of Citicorp in London, who asked me to consult for them on their trading of Japan warrants. At the time I had a PhD student, Jim Hutchinson, who was getting ready to make a lot of money using machine learning in finance. I got him to help me consult with Citicorp. We set up a consulting partnership to which we quickly added a third partner, Xiru Zhang, who worked at Thinking Machines, and together with Jim had won an early competition by the Santa Fe Institute in predicting the future of a couple of time series. There was a potential conflict of interest because Jim was my student. I asked Patrick, the director of the AI lab, for advice. Patrick suggested that we get a thesis co-advisor, which we did. This is why I have a paper in a rather prestigious finance journal, the Journal of Finance. This is also how I started to collaborate with Andrew Lo, one of the smartest people I know at MIT, a collaboration that continues today. With our personal funds, PHZ started trading futures on the Nikkei from an office in Cambridge next to MIT. With some luck, we managed to have a good trading record for a few months. We then looked for outside investments. Harris and Harris and, a bit later, Commodity Corporation came in and became shareholders together with the three of us. A bit later, all four of us moved to Wayland to be closer to where Jim and Xiru lived. We grew to about nine people and to a capital of almost a billion dollars under management, which was then quite a bit of money. We did quite well until 2007, when the Lehman debacle surfaced. Unfortunately, Lehman was the broker for our European trading and quite a bit of our trading capital disappeared when Lehman went bankrupt. We recovered some of it years later, but, in the meantime, we had to close our doors.

Neuroscience of Object Recognition

Our model for viewpoint-independent object recognition was eventually supported by an elegant psychophysical experiment by Heinrich and Shimon, which showed, along with many other later papers, that Biederman’s object-based claims are not correct for immediate perception. I was thus able to convince Nikos Logothetis to do related physiology experiments to check the prediction of view-tuned units in a monkey trained to recognize the same objects from different viewpoints. I did very little work for the paper itself. My main contribution was the initial idea of the experiment, but much more importantly, to have pestered Nikos for so long and so effectively that the experiments were actually done.

Object Recognition and Computer Vision

Don Glaser and I continued to stay in close touch. When my son was in his last year of high school, I took him on a tour of the colleges on the West Coast. We started in March 1995 with Berkeley, where we stayed with Don and Lynn Glaser, who organized a fantastic party for us at their beautiful home at the top of the Berkeley hills. This was the time of Berkeley’s “golden parachute,” an offer to coax retirement-age faculty to indeed retire. The offer was so generous and flexible that everyone at the party had just retired including Don himself. It is there that I again met Steve Smale, who had also retired and accepted a new job in Hong Kong. The tour of the West Coast colleges ended with the University of California, San Diego, (UCSD) and a lunch with Francis Crick, who at the time was the president of the Salk Institute. Afterward, I took Martino to see the “gliderport” next to Salk on the cliff above Black’s Beach. On the impulse of the moment, while Martino was looking at postcards, I signed up for a flight and took off with an instructor, jumping on the Pacific and then “crabbing” alongside the cliffs.

Don was a hero to me. He was my first example of someone who was successful in science and in business. There are of course others, such as Shimon Ullman, but at the time, Don was the only one I knew. On that occasion and so many others in the years to come, I loved discussions with Don and the observations he made. Don was a charming mix of curiosity and innocence. His openness to possibility and discovery was the key to his path in life. Don was the least arrogant and most delightfully funny person you could hope to meet. His view of the world and the way he communicated his observations were simple, crisp, and deep. He carried his success in science and in high-tech industry in a graceful way. During his whole life, he retained the happy curiosity of a kid. The world for him was a garden of wonders. He was always able, in an apparently effortless way, to come up with new and refreshingly counterintuitive observations of things and of people.

Work in my group continued to focus on the applications of machine learning and in particular, regularization. The most interesting topics were in object recognition. Work with Roberto Brunelli at IRST used machine learning techniques for a few object recognition tasks, such as gender classification from face images. Face identification was a somewhat more difficult task. We did some preliminary work showing that approaches based on the geometry of faces, the dominant approach dating back to police identikits and Takeo Kanade’s PhD thesis, were far inferior to the correlation of filtered images (through a Laplacian of a Gaussian filter, similar to the tuning of ganglion cells). We also found that using a set of small templates rather than a single full-face template delivered better performance. These are simple but robust findings that resonated through later research on face recognition.

Kah-Kay Sung developed one of the first ever systems to learn to detect faces in images, which is now in every digital camera and phone. Kah-Kay started this project on his own and initiated a direction of research that continued for decades in my group. Kah-Kay was also the first of several great students in my lab that were from Singapore, a city-state whose people I admire. With Thomas Vetter, we looked at the role of symmetry in object recognition; symmetry can be regarded as guaranteeing additional virtual examples, thereby decreasing the sample complexity. We also studied shape-based categorization in terms of “nice” classes of objects. These are objects that can be represented in terms of a relatively small number of basic shapes. Faces are a good example. Empirically, almost every face can be represented as the linear combination of about 100 individual faces in 3-D. Several mathematical properties follow easily for “nice” classes. This approach was combined with regularization networks on real images by David Beymer to do image-based graphics and example-based recognition.

Amnon Shashua, who was a very independent student and postdoctoral fellow doing groundbreaking work in the geometry of computer vision, helped in some of this work. He is one of the smartest people I know and a very good friend. Perhaps because I found geometry difficult to understand, we interacted more on the business side, trying to help Takeo Miyazawa, a Japanese friend, with his start-up in Japan. Work on the geometry of vision, to which Amnon was a main contributor, was the last hurrah of computer vision as a field independent of machine learning. Thus Amnon was not directly involved in object detection, which was our first foray into machine learning for vision. Ironically, a company he started later in Israel, MobilEye, is at the moment the poster child for commercial success in machine learning. The chipset that the company makes provides vision for cars. One of its tasks? Pedestrian detection! I bet that the driver-less car of the future will not come from Google but from MobilEye. I am very proud of MobilEye and Amnon.

The lab took occasional diversions related to the main themes of learning and vision. Collaboration with a research center in Bari led to work with Nicola Ancona on optical flow, leading to efficient hardware implementation based on Green’s theorems. A recurrent topic in computational vision was whether certain tasks had to precede others, like edge detection before object recognition. Psychophysics shows that, in certain cases, this is so but in others the opposite is true. To provide a computational demonstration, we considered the problem of extracting the boundaries of an object, such as a face, from the image. It turns out that recognition helps, and we proved it by providing a working algorithm. This demonstration is directly related to the arguments in the magic theory of 2011 about modularity and class-specific modules.

Learning Theory and More Applications

Five years had passed since we published our papers with Federico Girosi on learning and regularization, and it was time for an up-to-date review that connected spines to learning, Gaussian kernels to sigmoids and integrals, and unsupervised density estimation with Parzen windows to regularization. Partha Niyogi was a great PhD student who had been working with me but mainly with Federico. Together with Federico, he brought together techniques from approximation theory and statistics to address the key question of generalization performance of learning algorithms. They showed that in order to understand the complexity of the problem, one needed results from both approximation and statistical learning theory. It is a paper that got many mathematicians involved in learning theory, presenting them with a clean description of a challenging problem.

Before Partha left for ATT in 1997, he and Federico and I wrote a paper on virtual examples, showing a kind of equivalence between information in new examples and information in the regularizer. Together with Kah-Kay Sung, who died prematurely, Partha and I teamed up to compare radial basis functions (RBFs) and support vector machines (SVMs) in a paper that was probably and wrongly biased in support of SVMs. Eventually, Partha went on to join the faculty in CS and statistics in Chicago and to get early tenure. After Partha left MIT, I had the good fortune to work with him and see him quite a bit more. He was one of us, a small number of researchers including Steve Smale, Felipe Cucker, Federico Girosi, and me, who made supervised learning theory an important part of mainstream mathematics. He carried on a similar mathematization program for manifold learning. Tragically, Partha died in 2010. His death stopped the final formulation of an ambitious framework to analyze high-dimensional data in terms of geometry, sparsity, and hierarchy. As a person and a scientist he was unique. He was curious about all things scientific, and he was never afraid of learning new tools, no matter how complex, if he thought they were needed.

During those same years, Federico discovered Vladimir Vapnik and his pioneering work in the theory of learning. We invited him to give a talk and hosted him and his linguist girlfriend for a week at MIT. Vladimir was writing his book and asked Federico for help. At lunch at Legal Seafood, Federico told Vladimir about reproducing kernel Hilbert spaces (RKHS) and clarified some important aspects of this work.

Minds of Friends

My love for science was born with a fascination for the scientists behind the great discoveries. There are many reasons for this. Above all is my interest in the problem of intelligence and what is behind the mind of a genius. I also realized very soon that science is fun and interesting not only because of the highs induced by scientific discoveries—these are equivalent to winning a sporting event. It is also fun because the process of research makes it easy to interact with smart people.

It was also clear to me early on that science is social—the papers and especially the books are just a history of events, recounting and inevitably deforming what really happened. The history of our ideas is like our memories. Unlike computer memory, retrieving one of our memories also means modifying it.

Over the years, I have interacted and collaborated with prominent people from diverse fields. I am presently collaborating with Steve Smale, a Field medalist mathematician. My lab has also spawned people destined to fame (my first graduate student was the well-known neuroscientist Christof Koch) who themselves are innovators in diverse fields: industry, engineering, finance, business, computer science, robotics, Web search engines, and more. For fun, I have listed all the Nobel Prize winners whom I have met during my career. I know some of them quite well. The list includes David Hubel, Thorston Wiesel, Eric Kandel, Bob Horvitz, Max Delbrück, Niels Jerne, Susumu Tonegawa, Phil Sharp, Richard Feynman, Bernard Katz, Hadlan Hartline, Alan Hodgkin, John Eccles, Francis Crick, Janni Nusslein, Don Glaser, Dan Kahnemann, Bob Merton, Paul Samuelson, Jim Watson, Gerry Edelman, Rita Levi-Montalcini, Dennis Gabor, Franco Modigliani, Bob Solow, Manfred Eigen, Sidney Brenner, Erwin Neher, Bert Sakmann, Frank Wilczek, and David Baltimore. Most of them are very smart; I know that at least two or three of them were extraordinarily smart: Francis Crick, Paul Samuelson, and Richard Feynman.

Apart from the list here, I have had the extraordinary luck to meet several extraordinary scientists and human beings, some of whom are no longer with us. Antonio Borsellino and David Marr are among them. Werner Reichardt is another great person. It is impossible for me to speak about Werner Reichardt only as a scientist. He was the most influential person in my life, both scientifically and personally. He was first and foremost my scientific mentor. Werner was a loyal friend whose word could always be fully trusted. He was a gentleman of science educated in the tradition of the great German schools. I always admired his intellectual honesty and his courage; he was someone you could trust in the small and great needs of life. I will never forget the long discussions with him in his office and at his home, mainly about scientific work and sometimes about his passion to make a difference in the politics of science and in the Max Planck Society—about which he cared deeply.

When Francis Crick died, there were many articles about him. They were mostly memories of the charismatic personality, the brilliant mind, and the great scientist, and the stories of his discoveries in molecular biology. After all, the names of Watson and Crick will be with us as long as Einstein’s and Planck’s. There were ample reasons for Francis to have been arrogant, but my memories of him are quite different. Arrogant? The reverse was true. I will remember forever what I would call intellectual generosity. He did not suffer fools who made claims based on flimsy evidence. Any scientific theory must be based on hard facts. He was, however, extremely patient with curious people. I remember him after a talk at MIT. He must have been quite tired, yet he patiently and gently answered what seemed an endless series of questions from students and random people who stayed on after the huge audience had left. He was a gentleman of science. I remember the many working conversations at breakfast in Odile and Francis’s kitchen overlooking the pool and more conversations next to it. It was a civilized, though deceptively relaxed, style of research. Most of all, I will remember forever his joy for life and for science—a wonderful gift from Francis and Odile to their friends. I am not sure he knew but visiting them, in the last few years in their house in La Jolla, was for me—two decades their junior—a unique way to refresh my mind, recharge my batteries, and to regain a sense of adventure and fun in research and in life. His courage was exemplary. He did not seem to worry about his disease and certainly he did not bother his friends. Of course, he knew well that he was given the great gift of a wonderful life. His enthusiasm for science and for conversation with friends continued unabated. A few weeks before he died, he talked to me over the phone—full of wonder and excitement about a new puzzle he was working on, a new paper he was just writing.

Don Glaser was another remarkable friend. Don passed away on February 28, 2013, at his home in the Berkeley Hills. Don won the Nobel Prize in Physics in 1960 for the discovery of the ingenious bubble chamber, made when he was 26. Later he co-founded Cetus, one of the very first biotech companies, acquired years later by Novartis. I always admired the grace with which Don carried his success in science and in the high-tech industry. Somehow, for his whole life, he managed to retain the happy curiosity of a child. For him, the world was a garden of wonders. He was always able, in an apparently effortless way, to come up with refreshingly counterintuitive observations of things and of people.

Partha’s life was much too short. He was a student of mine. He was generous, super smart, and a great and trusted friend. Partha was a pure intellectual with a strong family tradition in social and political commitments. He cared deeply about people and about science. He was a scholar with a broad and deep knowledge of mathematics and linguistics. He was my guide in many questions about science and math. Among all statisticians I know, he was the one I most admire and respect. In our field of machine learning, he knew more than anybody else and understood better than anybody else. His mind was as clear and crisp as a September day.

The New Century: 2000–10

Models of Visual Cortex

Just before the turn of the century (1997 or so), I was doing a six-month sabbatical at the Salk Institute, where I met very often with Francis Crick. Nothing specific came out of those meetings, but I began to dream about the visual cortex as a complex system adapting to the data. A bright new student had come on the scene, and I tried hard to convince him to choose MIT for his graduate studies. Max Riesenhuber was the son of a previous German minister of research and a fellow of the Studienstiftung des deutschen Volkes, just as Christof had been. Max’s task, after a somewhat failed project with Peter Dayan, was to simulate a two- or three-layer network consisting of filters and invariance operations. The conjecture was that such a system would work for object recognition by replicating the invariance properties for paperclips found by Nikos Logothetis in inferotemporal cortex (IT) neurons in the monkey. My main intuition came while running on the beach in La Jolla early in the morning outside of the condo that I was renting, right behind the La Jolla Shores Hotel. The intuition was inspired by the success of the strategy we had used for face detection, and more recently in pedestrian detection with Constantine Pageorgiou, which had so much impressed Jitendra Malik. In those systems, we used a scanning procedure to perform position invariant detection. The focus of processing was shifted in the x and y axes in lexicographic order, in this way scanning the whole image and performing classification at each step. Lexicographic scanning does not make much sense for the brain but is natural in computer vision, though apparently it became standard only later. My intuition was that the cortical equivalent of scanning might be a max operation performed in a hierarchical way over larger and larger neighborhoods. Max got the system to work. It was a toy system, but it managed to reproduce all of the basic properties found by Nikos. In addition, it worked much better than I had expected. I had begun working with object recognition in the early 1980s as a short project to disprove what I thought was a simplistic theory—the idea that a hierarchy of simple and complex visual cells in the visual cortex pass information up to hyper-complex cells. But in 1997, when we found that hierarchical processing worked better than expected, I got stuck on working on feedforward models of how the brain recognizes objects.

At the time, we did not know that Fukushima had implemented a similar system much earlier (even if it was not as faithful to the physiology as ours was). The work with Max, which led to a family of models dubbed HMAX by Mike Tarr, began a research thread in my group that is active today. The immediate aftereffect of the surprising success of the model was our attempt to get physiologists to do experiments to verify or falsify the model or to simply answer the questions it suggested. This is the type of interplay between theory and experimentation that I had learned from Werner Reichardt and in which I very much believe. This research was a main motivation for embarking in a big effort to get funding from NIH for a Conte Center in Neuroscience to fund collaborations on the topic of object recognition. This effort led to a breakup with Nikos Logothetis, who was angry to discover that Earl Miller was describing projects in which he was involved without asking his permission. It also led to my collaboration with Earl about processing stages beyond area IT for the categorization step described by HMAX. We also began collaborating with David Ferster and Ilan Lampl, convincing them to do an experiment with complex cells in cat visual cortex (V1) that seemed to provide support for a max-like operation assumed by our model.

It was natural to try to extend this model to dorsal stream visual processing in the parietal cortex. That meant working with image sequences. This was the project that Martin Giese, a postdoctoral fellow recommended by von Seelen, had been working on with a computer vision project. It became an interesting class of models combining motion and shape in the recognition of objects and motion sequences and relating them to cortical areas.

Some of the ideas generated by those models were reviewed in a paper with Emilio Bizzi, a scientist and friend whom I respect enormously but with whom I never before had the opportunity to collaborate. The paper expanded on the ideas presented earlier at Cold Spring Harbor regarding how the brain might work. A few ideas were, I think, particularly interesting. The first was that Gaussian-like tunings might play a key role in generalization. The second idea was that Gaussian tunings could be obtained via normalized dot products. To me, this meant that normalization operations, instead of being computationally trivial, might play a key role in learning and generalization. Furthermore, very similar circuits, for instance those based on silent or shunting inhibition, could implement both normalized dot products and max-like operations, as shown later in more mathematical detail by Minjoon Kouh in his thesis.

Videorealistic Speech Synthesis

The most successful project in videorealistic speech synthesis began with Steve Librande and was developed by Tony Ezzat, first in his master’s thesis and then in his PhD work with a system called Mary101. The system is still impressive today in its capacity to synthesize realistic video sequences of a specific person saying things that were never actually said. The system was tested in a version of the Turing test and it passed it: naïve observers could not decide whether the video sequence was real or synthetic. The paper was accepted at SigGraph, which was a major accomplishment because acceptance at SigGraph was then more difficult than Nature or Science. The Boston Globe learned about videorealistic speech synthesis from me when science writer Gareth Cook asked me about the new McGovern Institute. Gareth then wrote an article that appeared on the front page of the Globe emphasizing the ethical rather than the technological issues. I was a bit irritated initially, but it ended up being great PR. Other newspapers and magazines, hundreds of them across the globe, picked up the news. Television crews came. Tony and I found ourselves on the “Today Show” chatting (and flirting) with Katie Couric. I think that was the only occasion in which even non-scientist friends thought that I was doing something important!

Genomics and Machine Learning

When Sayan Mukherjee appeared at the Center for Biological and Computational Learning (CBCL) for a summer job, he came with negative recommendations from his previous boss and looked like a Tamil Tiger member. We had a thoughtful discussion with Federico on whether to take the calculated risk of accepting him. We did accept him, and I think it is one of the best risks I have ever taken. Life was not easy with Sayan. He consistently rejected anything that was organized. As a graduate student in the department of brain and cognitive sciences, he refused to have anything to do with neuroscience. I tried to get him to work in computer vision but had to give up. As a last desperate attempt to get him working, I took him with me to see my old friend Jill Mezirov, then working with Eric Lander at the Whitehead on the Human Genome project. Sayan fell in love with genomics and statistics, and the rest is history. One of the best compliments I ever received was at Duke a few years ago when some faculty members found out that I was Sayan’s advisor. They said, “You should send us many more guys like Sayan!” Together with Gadi, Sayan created a special CBCL atmosphere that benefited other great students such as Shasha Rakhlin and Gene Yeo. It was a combination of heavy-duty mathematics, even if not always correct, a deeply felt anti-Bayes attitude, and total disinterest in neuroscience.

Object Detection and Machine Learning

Until 2005 or so, I was involved in two informal subgroups, one focused on the brain and one focused on computer science and machine learning applications. In those years, the main application domain was object detection. Following Kah-Kay’s work on face detection, I decided to tackle people detection. It was a lucky choice because of the contacts I had as a consultant with Daimler Benz (of Mercedes Benz). In discussions with their technical management, I learned that cars and pedestrians were important objects for a camera-driven car. At the time, I was looking for object classes for research and had bought a few rubber toys including dinosaurs and other animals, but I was unable to come up with interesting uses for them. Pedestrian detection for cars seemed a quite good application for object detection. I asked Pawan Sinha for suggestions, and he came up with a set of templates that to me looked like Haar wavelets. Thus, we used a wavelet representation of images and templates obtained from examples of pedestrians and trained a classifier to detect people. In the hands of Constantine Papageorgiou, the system worked quite well. He spent a month in Germany implementing a faster and coarser version that ran on a PC in the trunk of an experimental Mercedes. Anuj Mohan, another great student who died tragically years later in Silicon Valley, improved on the system and made it more robust to occlusions by using an architecture comprising a hierarchy of SVM classifiers.

Learning Theory

Another five years had passed since the updated review of our progress on regularization for learning, and it was time for a third review. Federico had left for a second PhD and a second career, so I led the effort. I sweated blood for that paper in Advances in Computational Mathematics; neither Theos nor Massi helped much. It was a nice paper that ended with a number of interesting contributions. The most obvious one was to show that SVMs are a special case of regularization. This fact had been ignored by Vladimir Vapnik, who knew but perhaps did not want others to know, and by the rest who did not want to understand.

Somewhat later in 2000, I was invited to a workshop in Hong Kong celebrating the 70th birthday of Steve Smale. On the occasion of the symposium, his collected work was published in three volumes, more than 1,600 pages, and it was all math. The reason for publishing all of Steve’s work was that Steve is one of the greatest mathematicians of our time. I quote from the preface, “Many mathematicians have contributed powerful theorems in several fields. Smale is one of the very few whose work has opened up to research vast areas that were formerly inaccessible.”

The reason I was invited to the workshop is that a couple of years earlier Steve had started to work in the field of statistical learning. His first paper published in the AMS in 2001 was circulating at the time of the Hong Kong workshop as a preprint with the title “The Mathematical Foundations of Learning.” It had the stated goal of bringing learning theory into the mainstream of mathematics. I was quite proud that below the title there was a quotation from a review paper by Shelton and me that said, “The problem of learning is arguably at the very core of the problem of intelligence, both biological and artificial.” I had met Steve in Tübingen and again in Berkeley, but we did not really know one another. The workshop in Hong Kong and our common interest in learning theory brought us together in a friendship and in many reciprocal visits.

Francis Crick and Steve Smale are two of my scientific heroes. I admire both of them not only because of their scientific achievements but also because of their refreshingly young attitude toward life. Steve is not only a great mathematician but has given to his friends and collaborators the wonderful gift of a contagious joy for life and for science.

Stability in Learning

I have a long-standing interest in the epistemological resonances of learning theory, an area of thinking that had been raised earlier by Vapnik in the following way. The process of learning from example is a metaphor or perhaps a cartoon of science itself. Get experimental data (i.e., the examples), which can be thought of as input-output pairs, and then infer a theory or model that explains the data and that can predict the future. Without prediction, astrology and even economics would be scientific. What makes a field scientific is that a model inferred from data must hold for new data (i.e., the model must generalize and be predictive). Note that, from this point of view, models and theories are what make data useful—they help us to predict and to plan. Note the close relationship between prediction and compression: theories are a compressed version of the data because they allow prediction of much data without having to memorize them. What interests me most, because of my work on ill-posed problems, is the observation that scientific theories are “stable” for the same reason. Because they are supposed to predict future data, they should not change when new data come in. In this sense, the theory within a scientific domain (e.g., mechanics) should change only a little bit—mostly in response to new experiments. For example, Newton’s laws should change little, apart from low-probability events such as relativity.

On the surface, most of these statements appear to be tautologies. But in mathematics, tautologies that are proven formally become theorems, and the conditions under which they are valid are often important and far from obvious. In this spirit, around the year 2000, I realized that in my learning class we were motivating the use of regularization because learning is an ill-posed problem; that is, it is a problem for which the solution either does not exist or is not unique or is unstable. At the same time, I was also using regularization to obtain predictivity and generalization properties. Were well-posedness and generalization equivalent? At a certain level, they have to be. More precisely, when we formulate a learning problem, we require that the solution is a function that fits the data and generalizes; we also require that the solution is unique and is stable against perturbations in the data. These seem to be separate requirements, but are they? It is easy to see that ensuring uniqueness and existence is simple: the key condition is stability. So the question becomes: Do specific definitions of stability and of predictivity exist for which it is possible to prove that they are equivalent? It turned out that a few applied mathematicians had addressed stability properties in learning for somewhat different reasons. A paper by Bousquet and Elisseef, for which I was a (very positive) reviewer for NIPS, derived generalization bounds from a very strong definition of stability. There were also elegant papers by Partha Niyogi.

Together with Sayan, Rif, and Partha, I spent more than a year getting deep into technicalities and proving results that often turned out to be wrong. I did not sleep well and had nighmares about incorrect theorems. The usual routine was as follows. I formulated a new theorem and half-proved it. Sayan found a way to finish the proof, and Rif showed that it was wrong, usually by using a clever counterexample. Eventually, we got a few results right, at which point Partha distilled the whole into a few nice crystals. It was for us like a long sailing trip through storms and adversities that bound us for life. I am quite proud of the end product. Stability is necessary and sufficient for predictability! A paper was published in Nature; I think it is quite rare to have a paper in Nature on a theorem; however, it was pretty much ignored by the scientific community. I still think it is important and that eventually people may realize that. In fact, I am dreaming that in one of the future projects it may be possible to show that well-posedness, and in particular stability, are the connection between computer science and physical science, between bits and atoms, tying together notions such as models of computation, intelligence, scientific theories, generalization, compression, and the arrow of time.

Development of HMAX and the elusive theory

The model of the ventral stream developed initially with Max Riesenhuber was becoming more faithful to cortical data and more complex in the hands of Thomas Serre, a very effective PhD student. In terms of object recognition, it seemed to perform on par with the best computer vision algorithms. I became really interested when Lior Wolf, then a postdoctoral fellow in my computer science subgroup, told me quite seriously that HMAX was doing very well. In the following months, I realized that he was right. For the first time in my life, I saw a model that captured what we knew about a segment of neuroscience that performed better than engineered systems. Because of this, I no longer have separate computer science and neuroscience subgroups. We may be at that point in time when we know enough about the brain to actually inform engineering to guide some of this research.

For me this is a new paradigm, one maintaining that a computational model based on how the brain works is more powerful than one based on engineering principles; moreover, it can be used to test hypotheses about the brain itself. In fact, I was quoted as saying, “It’s a virtuous loop, because the model that is based on what neuroscientists know about how the brain works is also helping neuroscientists learn even more about the how the brain works. You need theories to drive experiments, and you need experiments to test the theories. I think we are now at the stage where we can use brain-based models to design and interpret neuroscience experiments for studying human behavior, and also mental disorders, and maybe someday improving human intelligence.” A study with Serre and Oliva involved flashing a variety of real-world photos and asking the model whether an animal was present. This was a difficult task because the animal could be a lizard, tiger, or bee, and it could be a lone profile or a detail in a crowded landscape. In both cases, the model performed just as well as human subjects, who were shown the same images. The model even made the same kinds of errors that the people made on ambiguous images. The model outperformed other computer programs designed by engineers.

Though Thomas was the key person in the new effort around HMAX, a number of other students and postdoctoral fellows contributed greatly, among them Gabriel Kreiman, Minjoon Kouh, Charles Cadieu, and Ulf Knoblich. The model could reproduce human performance in object recognition in conditions under which eye movements and detailed inspection were not allowed (i.e., rapid image presentations). The model was consistent with results from all the main cortical areas involved in vision, and it predicted several properties, including population invariant coding of object identity and category, in studies I had planned and for which I provided funding. (The experiments were eventually done by Chou Hung and Jim DiCarlo and analyzed by Gabriel Kreiman). A similar model for the dorsal stream matched human performance for classifying actions. This last feat required a daunting amount of computational power because it was processing not individual images but sequences of movements each with hundreds of image frames.

The model was working well. I think feedforward architectures such as HMAX are close to explaining feedforward processing in the visual cortex. Achieving human performance under general unrestricted conditions is close to achieving human intelligence, which requires computations over longer times, top-down connections, memory retrival, and nonvisual areas. I bet that two-thirds of the circuitry in the visual cortex is involved in the management and execution of non-feedforward processing. A small step in the direction of modeling recurrent connections is related to what is commonly called attention. We added more layers of complexity to the model, incorporating the influence of attention when scanning a scene cluttered by many objects. Other computer vision models become inefficient or fail at this challenging data-crunching task, but our model adopted the same strategy that human subjects use (as measured by tracking their eye movements)—homing in on areas of the image most likely to contain objects of interest and ignoring the rest. This move makes information processing more efficient and validates neuroscience research focused on how attention impacts perception.

On the theoretical side, the inability to understand why HMAX-type architectures work so well had become embarrassing. Finally, Steve Smale came up with a clean implicit neural equation and derived kernel formalizing hierarchical architectures in a way that should make it possible to study them mathematically. Sometimes models and simulations are not enough, and theories are needed. Unfortunately, this brave attempt led to a clean mathematical formulation but little more.

Phenotyping Behavior

The field of genomics has made staggering progress in recent years. Because of the genetically engineered mice used as models of mental diseases in our building at MIT and elsewhere, we understand the genome in a quantitaitve reproducible way. The behavioral phenotype on the other hand is understood only qualitatively most of the time. Ironically, phenotyping is the bottleneck in today’s genomics. If we could phenotype behavior as quantitatively and easily as we obtain the genotype, we would have a gold mine of data among which we could find important, subtle correlations. With this motivation in mind, we decided with Thomas Serre and Hueihan to adapt the model of the dorsal stream to categorize behavior of a mouse in a cage. The system recognizes and categorizes sets of behaviors by inventorying how often and when a laboratory mouse eats, grooms, explores, and so on. Again, the model was as accurate as human subjects. There is still much work to be done to make this system more robust to changes in illumination, and especially to extend it to groups of mice and their social interactions. It is quite feasible in a few years to be able to replace all the specific boxes and tasks used to measure specific behavioral traits with a general purpose vision system and video analysis.

The New Century: 2010 and Beyond

Intelligence in Brains, Minds, and Machines

The idea of an Intelligence Initiative was initiated by Josh Tenenbaum and by me in discussions with Rafael Reif, Mriganka Sur, and Marc Kastner at MIT. From the earliest stages, Mriganka and Marc strongly supported the idea and pushed Josh and me to make something happen. Trying to spread an I² infection at MIT, we discussed the idea with a number of MIT faculty, MIT friends, and agencies such as the National Science Foundation (NSF). A workshop at the American Academy of Arts and Sciences elicited a surprising amount of enthusiasm among MIT faculty. At the last moment, I sent in a proposal for a MIT150 workshop, which was accepted. The organization of the workshop was a lot of work, and it happened only because of my administrative assistant Kathleen and her incredible organization and energy. It was a big success. The idea of I² is simple: the problem of intelligence is the greatest problem in science and technology. The last serious attempt to do something about it was at the time of AI, 50 years ago. Much has changed since then in terms of computer power, neuroscience, and technologies. It is now time to try again! After a period of seed funding for projects across the institute, the initiative is now formalized in a Center of Brains, Minds, and Machines funded by the NSF.

I believe that the next few years will be a golden age for smart machines and smart applications such as Siri and future versions of Siri. This technology is the marketplace outcome of technologies developed in laboratories around the world, including ours, that have been focused on machine learning over the last two decades. However, we will not be able to build “really intelligent” machines unless we make substantial progress in a new cycle of basic research. I use the term “really intelligent” in the sense of human intelligence, that is, in the sense of being able to be like one of us and to pass a “full” Turing test. This is what we ultimately want to achieve in the Center for Brains, Minds, and Machines.

The Magic Theory

Two years ago, around March 2011, a number of ideas concerning a revision of the theory that we had tried to develop with Steve Smale began to converge in my head. The focus then had been on features; I decided to make a 180-degree turn and focus on invariances. The idea that the main computational goal of the ventral stream was to compute an invariant representation suddenly became very plausible. I asked Joel for a plausibility demonstration; how well can a simple classifier generalize to the concept of dog and of cat from a single example of a dog and a cat? Normally the answer would be “not at all.” Generalization performance is 50 percent (i.e., chance). Suppose however that an oracle rectifies the images so that they are always given from a standard viewpoint. Then suddenly generalization performance from a single example is quite good!

Many other related ideas began to click into place. Invariances could be easily learned during development, the tuning of V1 simple cells emerges from it (assuming Hebbian learning), the modularity of cortex can be predicted, and the obscure properties of face cells suddenly make sense. Around this time, I began to use the term “magic theory” because so many things suddenly made sense. Every day seemed to bring a new idea, a new twist, a new connection, and a new question. Of course, there were quite a few wrong turns in the process, such as the initial emphasis on factorization of invariances. It has been quite exhilarating for me. Unlike other projects, this one is quite big and involves a large number of ideas and mathematical tools. I managed to take one problem at the time and to solve it or decide that it was not important to making continuous and real progress. Initially, it was my personal project. I wrote a long technical report that appeared online in July 2011. Then I brought in several members of the group to help: Jim Mutch, Joel Leibo, Fabio Anselmi, Lorenzo Rosasco, and Andrea Tacchetti. I am a physicist. What I find most intriguing and potentially elegant about these theoretical results is that the computational goals, the hierarchical architectures, and that several of the tuning properties of cells in the ventral stream may follow from symmetry properties of the visual world.

References

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Hutchinson, James, PhD, February 1994; S.M., June 1986. PhD Thesis title: A Radial Basis Function Approach to Financial Time Series Analysis, Massachusetts Institute of Technology, Department of Electrical Engineering and Computer Science.

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Poggio, T. and F. Girosi. A Sparse Representation for Function Approximation, Neural Computation, 10(6), 1445–14454, 1998.

Poggio, T, and F. Girosi. A Theory of Networks for Approximation and Learning, AI Memo 1140/CBIP Paper 31, Massachusetts Institute of Technology, Cambridge, MA, July 1989.

Poggio, T. and C. Koch. Ill-Posed Problems in Early Vision: From Computational Theory to Analog Networks, Proceedings of the Royal Society London B, 226, 303–323, 1985.

Poggio, T. and C. Koch. Synapses that Compute Motion, Scientific American, 256, 46–52, 1987.

Poggio T., J. Mutch, F. Anselmi, L. Rosasco, J.Z. Leibo, and A. Tacchetti. The Computational Magic of the Ventral Stream: Sketch of a Theory (and Why Some Deep Architectures Work), MIT-CSAIL-TR-2012-035, Massachusetts Institute of Technology, Cambridge, MA, December 29, 2012.

Poggio, T. and W. Reichardt. Considerations on Models of Movement Detection, Kybernetik, 13, 4, 223–227, 1973.

Poggio, T. and W. Reichardt. On the Representation of Multi-input Systems: Computational Properties of Polynomial Algorithms, Biological Cybernetics, 37(3), 167–186, 1980.

Poggio, T. and W. Reichardt. A Theory of Pattern Induced Flight Orientation of the Fly, Musca Domestica, Kybernetik, 12, 185–203, 1972.

Poggio, T. and W. Reichardt. Visual Control of Orientation Behavior in the Fly. Part II: Toward the Underlying Neural Interactions, Quarterly Review of Biophysics, 9, 377–438, 1976.

Poggio, T. and W. Reichardt. Visual Fixation and Tracking by Flies: Mathematical Properties of Simple Control Systems, Biological Cybernetics, 40, 101–112, 1981.

Poggio, T., W. Reichardt, and W. Hausen. A Neuronal Circuitry for Relative Movement Discrimination by the Visual System of the Fly, Naturwissenschaften, 68(9), 443–466, 1981.

Poggio, T., R. Rifkin, S. Mukherjee, and P. Niyogi. General Conditions for Predictivity in Learning Theory, Nature, 428, 419–422, 2004.

Poggio, T. and T. Serre. Models of Visual Cortex, Scholarpedia, 8(4), 3516, 2013.

Poggio, T. and C. Shelton. Learning in Brains and Machines, Spatial Vision, 13(2–3), 287–296, 2000.

Poggio, T. and C. Shelton. Machine Learning, Machine Vision and the Brain, AI Magazine, 20(3), 37–55, 1999.

Poggio, T. and S. Smale. The Mathematics of Learning: Dealing with Data, Notices of the American Mathematical Society (AMS), 50(5), 537–544, 2003.

Poggio, T. and V. Torre. A Volterra Representation of Some Neuron Models, Biological Cybernetics, 27(2), 113–124, 1977.

Poggio, T., V. Torre, and C. Koch. Computational Vision and Regularization Theory, Nature, 317, 314–319, 1985.

Poggio, T. and A. Verri. Introduction: Learning and Vision at CBCL, International Journal of Computer Vision, 38, 1, 5–7, 2000.

Poggio, T., S. Voinea, and L. Rosasco. Online Learning, Stability, and Stochastic Gradient Descent, Cornell University Library, arXiv:1105.4701v2 [cs.LG], May 25, 2011.

Poggio, T., H. Voorhees, and A. Yuille. A Regularized Solution to Edge Detection, Journal of Complexity, 4, 106–123, 1988.

Pomeroy, S.L., P. Tamayo, M. Gaasenbeek, L.M. Sturia, M. Angelo, M.E. McLaughlin, J.Y.H. Kim, L.C. Goumnerova, P.M. Black, C. Lau, J.C. Allen, D. Zagzag, M.M. Olson, T. Curran, C. Wetmore, J.A. Biegel, T. Poggio, S. Mukherjee, R. Rifkin, A. Califano, G. Stolovitzky, D. N. Louis, J.P. Mesirov, E.S. Lander, and T.R. Golub. Prediction of Central Nervous System Embryonal Tumour Outcome Based on Gene Expression, Nature (Letters), 415, 436–442, 2002.

Rachlevsky-Reich, B., I. Ben-Shaul, N. Tung Chan, A. Lo, and T. Poggio. GEM: A Global Electronic Market System, Information Systems, 24(6), 495–518, 1999.

Rakhlin, A., S. Mukherjee, and T. Poggio. Stability Results in Learning Theory, Analysis and Applications, 3(4), 397–417, 2005.

Ramaswamy, S., P. Tamayo, R. Rifkin, S. Mukherjee, C.-H. Yeang, M. Angelo, C. Ladd, M. Reich, E. Latulippe, J.P. Mesirov, T. Poggio, W. Gerald, M. Loda, E.S. Lander, and T.R. Golub. Multiclass Cancer Diagnosis Using Tumor Gene Expression Signatures, PNAS, 98(26), 15149–15154, 2001.

Reichardt, W. and T. Poggio. Figure-Ground Discrimination by Relative Movement in the Visual System of the Fly, Biological Cybernetics, 35, 81–100, 1979.

Reichardt, W. and T. Poggio. A Theory of the Pattern Induced Flight Orientation of the Fly, Musca Domestica, II, Biological Cybernetics, 18, 69–80, 1975.

Reichardt, W. and T. Poggio. Visual Control of Orientation Behavior in the Fly. Part I: A Quantitative Analysis, Quarterly Review of Biophysics, 3, 311–375, 1976.

Reichardt, W., T. Poggio, and K. Hausen. Figure-Ground Discrimination by Relative Movement in the Visual System of the Fly. II: Toward the Neural Circuitry, Biological Cybernetics, 46, 1–30, 1983.

Riesenhuber, M. and T. Poggio. Are Cortical Models Really Bound by the “Binding Problem”?, Neuron 24, 87–93, 1999.

Riesenhuber, M. and T. Poggio. Hierarchical Models of Object Recognition in Cortex, Nature Neuroscience, 2, 1019–1025, 1999.

Riesenhuber, M., and T. Poggio. Models of Object Recognition, Nature Neuroscience, 3, 1199–1204, 1999.

Riesenhuber, M. and T. Poggio. Neural Mechanisms of Object Recognition, Current Opinion in Neurobiology, 12, 162–168, 2002.

Rifkin, R., S. Mukherjee, P. Tamayo, S. Ramaswamy, C.-H. Yeang, M. Angelo, M. Reich, T. Poggio, E.S. Lander, T.R. Golub, and J.P. Mesirov. An Analytical Method for Multi-Class Molecular Cancer Classification, SIAM Reviews, 45(4), 706–723, 2003.

Roy, J.E., Riesenhuber, M., T. Poggio, and E.K. Miller. Prefrontal Cortex Activity during Flexible Categorization. Journal of Neuroscience, 30, 8519–8528, 2010.

Schoelkopf, B., K.K. Sung, C. Burges, F. Girosi, P. Niyogi, T. Poggio, and V. Vapnik. Comparing Support Vector Machines with Gaussian Kernels to Radial Basis Function Classifiers, IEEE Transactions on Signal Processing, 45(11), 2758–2765, 1997.

Serre, T., G. Kreiman, M. Kouh, C. Cadieu, U. Knoblich, and T. Poggio. A Quantitative Theory of Immediate Visual Recognition, Progress in Brain Research, 104(15), 6424–6429, 2007.

Serre, T., A. Oliva, and T. Poggio. A Feedforward Architecture Accounts for Rapid Categorization, Proceedings of the National Academy of Sciences USA, 104(15), 6424–6429, 2007.

Serre, T., L. Wolf, S. Bileschi, M. Riesenhuber, and T. Poggio. Object Recognition with Cortex-Like Mechanisms, IEEE Transactions on Pattern Analysis and Machine Intelligence, 29, 3, 411–426, 2007.

Sinha, P. and T. Poggio. I think I Know that Face …, Nature (Correspondence), 384(6608), 404, 1996.

Sinha, P. and T. Poggio. Response to “Comment” article by Lamouret, Cornilleau-Peres, and Droulez, Cognitive Sciences, 1(2), 43–84, 1997.

Sinha, P. and T. Poggio. Role of Learning in Three-Dimensional Form Perception, Nature, 384(6608), 460–463, 1996.

Sinha, P. and T. Poggio. United We Stand: The Role of Head Structure in Face Recognition, Perception, 31(1), 133, 2002.

Smale, S., L. Rosasco, J. Bouvrie, A. Caponnetto, and T. Poggio, Mathematics of the Neural Response, Foundations of Computational Mathematics, 10, 67–91. 2010.

Sung, K.-K. and T. Poggio. Example-Based Learning for View-Based Human Face Detection. In: Proceedings from Image Understanding Workshop, (Morgan Kaufmann, San Mateo, CA), 843–850, November 13–16, 1994.

Sung, K.-K. and T. Poggio. Example-Based Learning for View-Based Human Face Detection, IEEE PAMI, 20(1), 39–51, 1998.

Sung, K.-K. and T. Poggio. Finding Human Faces with a Gaussian Mixture Distribution-Based Face Model, Recent Progress in Computer Vision, LNCS Series, New York: Springer-Verlag, 1995.

Tan, C. and T. Poggio. Faces as a Model Category for Visual Object Recognition, MIT-CSAIL-TR-2013-004, CBCL-311, Massachusetts Institute of Technology, Cambridge, MA, March 18, 2013.

Torre, V. and T. Poggio. On Edge Detection, IEEE Trans. PAMI, 8, 147–163, 1986.

Torre, V. and T. Poggio. A Synaptic Mechanism Possibly Underlying Directional Selectivity Motion, Proceedings of the Royal Society London B, 202, 409–416, 1978.

Verri, A. and T. Poggio. Motion Field and Optical Flow: Qualitative Properties, IEEE Trans. PAMI, 11, 490–498, 1989.

Verri, A. and T. Poggio. Regularization Theory and Shape Constraints, AI Memo 916, Massachusetts Institute of Technology, Cambridge, MA, September 1986.

Vetter, T., A. Hurlbert, and T. Poggio. View-Based Models of 3D Object Recognition: Invariance to Imaging Transformations, Cerebral Cortex, 5(3), 261–269, 1995.

Vetter, T. and T. Poggio. Linear Object Classes and Image Synthesis from a Single Example Image, IEEE Transactions on Pattern Analysis and Machine Intelligence (PAMI), 19(7), 733–742, 1997.

Vetter, T. and T. Poggio. Symmetric 3D Objects Are an Easy Case for 2D Object Recognition, Spatial Vision, 8(4), 443–453, 1994.

Villa, S., L. Rosasco, and T. Poggio, On Learnability, Complexity and Stability, arXiv 1303.5976 March 24, 2013.

Voorhees, H. and T. Poggio. Computing Texture Boundaries from Images, Nature, 333, 364–367, 1988.

Wehrhahn, C. and T. Poggio. Real-Time Delayed Tracking in Flies, Nature, 261, 43–44, 1976.

Wehrhahn, C., T. Poggio, and T. Bülthoff. Tracking and Chasing in Houseflies (Musca): An Analysis of 3D Flight Trajectories, Biological Cybernetics, 45, 123–130, 1982.

Wilems R.M. Re-appreciating the why of cognition: 35 years after Marr and Poggio, Frontiers in Psychology, 2, 1–5, 2011.

Yeo, G., E. Van Nostrand, D. Holste, T. Poggio, and C.B. Burge. Identification and Analysis of Alternative Splicing Events Conserved in Human and Mouse, Proceedings of the National Academy of Sciences (PNAS), 102(8), 2850–2855, 2005.

Yu, A.J., M.A. Giese, and T. Poggio. Biophysiologically Plausible Implementations of the Maximum Operation, Neural Computation, 14(12), 2857–2881, 2002.

Yuille, A. and T. Poggio. Fingerprints Theorems for Zero Crossing, J. Optical Society America A, 2, 683–692, 1985.

Yuille, A.L. and T. Poggio. Scaling Theorems for Zero Crossings, IEEE Trans. PAMI, 8, 15–25, 1986.

Zhang Y., E. Meyers, N. Bichot, T. Serre, T. Poggio, and R. Desimone. Object Decoding with Attention in Inferior Temporal Cortex, Proceedings of the National Academy of Sciences, 108(21), 8850–8855, 2011.

Zoccolan, D., M. Kouh, A. Pasupathy, C. Connor, M. Riesenhuber, and T. Poggio. Trade-Off between Object Selectivity and Tolerance in Monkey Inferotemporarl Cortex, Journal of Neuroscience, 27(45), 12292–12307, 2007.

Marcus E. Raichle, Sr.

BORN:

Hoquiam, Washington

March 15, 1937

EDUCATION:

University of Washington, BS (1960)

University of Washington, MD (1964)

APPOINTMENTS:

Intern and Resident, Medicine, Baltimore City Hospitals (1964–1966)

Resident, Neurology, Cornell University Medical Center (1966–1969)

Major, U.S. Air Force, (1969–1971)

Instructor, Neurology and Radiology, Washington University (1971–1972)

Assistant Professor, Neurology and Radiology, Washington University (1972–1975)

Associate Professor, Neurology and Radiology, Washington University (1975–1978)

Professor, Radiology and Neurology, Washington University (1978–present)

HONORS AND AWARDS (SELECTED):

Institute of Medicine (1992)

National Academy of Sciences (1996)

Fellow, American Association for the Advancement of Science (1996)

Charles A. Dana Award for Pioneering Achievements in Health (1996)

Fellow, American Academy of Arts and Sciences (1998)

Cori Award for Faculty Achievement (inaugural recipient), Washington University (1999)

Bristol-Myers Squibb Award for Distinguished Achievement in Neuroscience (1999)

Grawemeyer Award for Psychology (inaugural recipient) (2001)

Goldman-Rakic Award in Cognitive Neuroscience, Brain and Behavior Research Foundation (2004)

University of Washington School of Medicine Distinguished Alumni Award (2006)

Honorary Doctor of Science, University of Chicago (2006)

Ralph W. Gerard Prize in Neuroscience, Society for Neuroscience (2008)

George Miller Prize, Cognitive Neuroscience Society (2009)

MetLife Foundation Award for Medical Research (2011)

Second Century Award, Washington University (2012)

Marcus E. Raichle’s research began with studies of human brain circulation and metabolism under the tutelage of Fred Plum and Jerry Posner using the classical techniques developed by Seymour Kety and colleagues. He took that knowledge to Washington University in 1971 where he joined the laboratory of Michel Ter-Pogossian who had initiated the use of cyclotron-produced isotopes in biology and medicine. The announcement of the invention of X-ray computed tomography (CT) in 1973 shifted the focus to imaging and, in the course of the next several years, the first positron emission tomography (PET) scanners were produced in the Ter-Pogossian laboratory. Raichle focused on developing quantitative radiotracer techniques based on cyclotron-produced isotopes to provide the first, quantitative, 3-D images of brain circulation and metabolism in humans with PET. In the 1980s, attention was directed to measuring brain function with PET and, later, with functional magnetic resonance imaging (fMRI). With the help of Michael Posner, functional imaging techniques were combined with detailed analysis of human behaviors. More recently, the emphasis has been on the brain’s intrinsic activity as seen with imaging, both fMRI and PET. This work led to the discovery of the brain’s default mode network, which plays a central role in the functional organization of the brain in health and disease. Throughout his research, Raichle’s work has focused on the origin of imaging signals, neurophysiological as well as metabolic.

Marcus E. Raichle, Sr.

Prologue

I was born on March 15, 1937, in Hoquiam—one of three small towns (Aberdeen, Hoquiam, and Cosmopolis) nestled in the port of Grays Harbor on the coast of Washington State. My parents resided in the neighboring town of Aberdeen where my father, Marcus Simpson Raichle, was a practicing attorney (he later entered the savings and loan business where he worked until retirement). The only hospital in the area was the Hoquiam General Hospital; hence, that is my official birthplace.

My parents were the children of immigrants. My paternal grandfather, John George Raichle, was sent by his parents to the United States at age six with his sister Barbara, age 11, to live with relatives in the Midwest. They were from a family of 13 children residing in Dettingen, Germany, where the Raichle family and its descendants have resided since the 14th century.¹

The reception of the Raichle children, John and Barbara, was inhospitable, and they were eventually taken in by the Marcus Simpson family of Burlington, Iowa, who raised them; hence my father’s given name of Marcus Simpson. My grandfather Raichle married the daughter of another German immigrant family, Sarah Buhrmaster, and moved with his new wife to Yakima, Washington, where he built his own home, which stands to this day. He bought land, started a fruit orchard, and worked as an accountant for one of the large fruit companies in Yakima. The Raichle family of Yakima ultimately consisted of seven children, all of whom attended the University of Washington. My father then attended the University of Washington Law School, graduating at the peak of the Great Depression. He luckily found work upon graduation in a small law firm in Aberdeen, Washington.

My mother’s father, Lawrence Hopkinson, emigrated from Leeds, England, where he was a linotype operator.² He settled in Milwaukee, Wisconsin, and through his work as a linotype operator was able to raise enough money to bring his bride, Ada Hayward, his father and mother, brothers and sisters, and eventually some of his wife’s relatives to this country. Having accomplished this, he then decided to become a physician. He ultimately graduated from the Milwaukee Medical College and School of Dentistry in the class of 1897. He remained in Milwaukee, where he practiced medicine and continued to participate in the academic affairs of the Milwaukee Medical College. Eventually, he rose to the rank of professor of anatomy and lecturer on rectal diseases. My mother, Dorothy Margaret Hopkinson, was born in Milwaukee, the youngest of four children. She attended Milwaukee Downer College.

Although the Hopkinson family seemed to be thriving in Milwaukee, the climate was a problem for my grandfather (bitterly cold in the winter and hot and humid in the summer) and was in stark contrast to that of England. He ultimately decided to leave Milwaukee and settle in, of all places, Aberdeen, Washington, which at the time was a rough and tumble logging town. Little data exist on the reasons behind this decision other than climate. It is noteworthy, perhaps, that he was a member in good standing of the International Order of Foresters, an organization originating in England but active in North America promoting issues of importance to middle-class families and underserved populations. Likely, in the early 1900s, Aberdeen, Washington, represented an opportunity for someone with these interests.

My parents met and married in Aberdeen where they raised my sister, four years my junior, and me. In those days, Aberdeen, along with its sister communities of Hoquiam and Cosmopolis, was a vibrant place with thriving timber and fishing industries. The local school system, all public except for the local Catholic grade school, was excellent. College attendance rates were high.³ Extracurricular programs were varied and excellent. I was a mediocre athlete but competed in swimming through graduation.

Among the great strengths of the school system and the community in general were its music programs. Not only were the school programs above average, but this small community even had a respectable symphony orchestra in which I ultimately played. Both of my parents were musical. My mother had a lovely singing voice and, while growing up, regularly accompanied her father, a violinist, on the piano. My father was a gifted piano player who would relax in the evening by sitting down and playing popular music. All he needed was the tune, he could supply the chords! In this environment, I was required to take piano lessons, which I did from kindergarten through high school. In junior high school I fell in love with the oboe, a beautiful instrument when played well, which is something not easily done! I had a masterful teacher, Eugene Stensager, who was part of the high school music program. I had great success as an oboe player in high school⁴ and briefly considered a career in music. I have remained an active oboe (and English horn) player to this day as a member of a community symphony orchestra in St. Louis.

The Path to Science

As a reader of this essay, you might be wondering from where the seed of my scientific career came. Although my grandfather was a doctor, I did not enter kindergarten announcing that I wanted to be a physician. I did not own a chemistry set, and I did not collect bugs or other objects of scientific interest. In school, I took all of the science and math courses offered more because it was expected than for any other reason. I did well in these courses but was certainly not the class genius. My parents were told by my high school chemistry teacher, after the first quarter, that I was a daydreamer and needed to be more focused on the class work. (I was receiving a grade of C at the time but managed to pull it up to an A by the end of the year.) I did enjoy my geometry class, particularly working through the “proofs.” Solving problems and figuring out how things worked always fascinated me.⁵ But the classes in which I did equally well if not better were English, history, and current affairs. These were interests that I shared with my father. We often discussed the political issues of the day. He was a moderate Republican and was very distressed when John Dewey was defeated by that “failed haberdasher” from Missouri. My father would, I suspect, be surprised to know that Harry Truman has become one of my most admired public figures, although given the thoughtful way in which my father approached problems, he too might have become a convert.

My reading (a lifetime habit) during the transition from high school to college was rather wide ranging and foretold, in retrospect, a lifelong array of interests. A few examples may be of interest. The book Religions of Man by Houston Smith fueled an interest in the role of religion in society and in my own life, something that I continue to ponder. Winston Churchill’s Triumph and Tragedy, the final volume in his six-volume series on World War II was a marvelous read, stimulating an interest in history and political science that endures to this day. And, finally, the marvelous little book by George Gamow, One, Two, Three Infinity, was a spell-binding read fueling the latent scientist in me that I was only to discover much later.

Reinforcing my interest in the social sciences and in public affairs was my participation in an American Legion program known as Boys State (there was a separate Girls State in those days!). We spent several weeks on a college campus constructing a state government, which I enjoyed. Emerging from this was my election as a senator from the state of Washington and my subsequent participation in Boys Nation in Washington, D.C., where two from each state came together to operate as a United States Senate. This was a heady experience including sessions in the old Senate chambers of the U.S. Capitol and a meeting with President Eisenhower in the Rose Garden of the White House. After this, I was set to enter the University of Washington in Seattle in the fall of 1955 as a history and political science major with the ultimate goal of law.

I enjoyed college, both the academics and the extracurricular activities. I became a regular member of the University Symphony as an oboe player, president of my fraternity and also rowed with the University of Washington crew. (I was not a great oarsman but I had fun.) By the time I reached my junior year, I was made aware of the fact that I had to take some science courses in order to receive a bachelor’s degree from the college of arts and sciences. I had taken some math courses (through calculus) for reasons that escape me after these many years, but these did not qualify. My father suggested that I take zoology as he had when he was at the University of Washington. He even had some of his class notes and drawings, which I deeply regret were subsequently lost or discarded. So, I signed up for the beginning course in zoology, which was the turning point in my career.

In 1959, the introductory course in zoology was taught by a marine biologist named Dixie Lee Ray. She received her PhD from Stanford in marine biology, studying the peripheral nervous system of the fish Lampanyctus leucopsasus. The class was attended by several hundred undergraduates, so there was no direct contact with Professor Ray, only with her teaching assistants. Regardless, through her lectures, her effect on the class—and particularly me—was electric. It suddenly made me realize that there was a world of biology out there that had completely escaped my notice.⁶ To give you a sense of the impact of Professor Ray on a group of undergraduates, consider the fact that because of her interest in the peaceful use of nuclear energy she was appointed president of the U.S. Atomic Energy Commission by President Richard Nixon in 1973, the only woman ever to serve in this position. She returned to Washington State in 1976 and was elected governor, a post she held until 1981. On learning of her death in 1994, I was saddened by the fact that I had never had the chance to thank her for a career-changing experience, something that I suspect others had undergone as well.

Following my experience in Professor Ray’s class, I decided to plunge headfirst into a science curriculum with the aim of going to medical school. Although neither my mother nor my father had ever pressured me in my career decisions, I believe that my mother was quietly pleased when the possibility of my entering medicine emerged. The road ahead was far more challenging for me than I had expected. No class was ever as engaging as the one taught by Professor Ray. But it was not all biology; I essentially had to start over in my junior year taking freshman chemistry and physics. Then, of course, was the dreaded course of organic chemistry, the graveyard for many dreams of attending medical school. At the University of Washington, it was taught by a terrifying figure, Professor Shaw, who had introduced the course to decades of undergraduates by saying, “Look to your right, look to your left, they won’t be here by the end of the quarter.” I was still there at the end of the quarter but only barely so!

By the time I was approaching the midpoint of my senior year; I had most of the basic requirements for medical school but was still wondering whether I was ready. When I was home for Christmas break, my mother urged me to apply, “What have you got to lose?” (I still have a vivid memory of our conversation.) So, I hastily prepared the application for the University of Washington Medical School and mailed it. Several months passed before I received a letter from the school informing me that I had been rejected. I was disappointed but also eager to know why and what, if anything, it would take to improve my chances for the following year. So, I set up an appointment with the director of admissions.

At my meeting with the medical school director of admissions, I was informed that the reason for my rejection was that I had failed to show up for my interview! I was stunned and even more so when he showed me my application. In my haste to prepare my application I had made an error in my return mailing address (1616 East 47th Street instead of the correct 1617 East 47th street). One incorrect digit and I was faced with a decision: Do I do another year in pre-med or do I return to my original goal of law school? I finally decided that I was going to prove to myself that I could do this. I immediately applied for early admission and scheduled classes for the year that included advanced chemistry and biology. Early in the year, I received an invitation to interview at the University of Washington and shortly thereafter was offered early admission to the class of 1960.

Entering medical school was an exciting experience. A shirt and tie and white coats were required from day one in those more formal times. It was also, for me at least, a somewhat terrifying experience. I was surrounded by classmates most of whom had sought careers in medicine all of their life. Many had parents who were doctors. During our first quarter of classes some even complained that what we were studying was disappointingly similar to what they had already studied in college. To me everything was frighteningly new. Biochemistry was by far the worst. (I failed my first test!) I was clearly off to a rocky start; but fortunately, things changed in the second half of the first year when we headed into the neuroanatomy/neurophysiology course. This conjoint course was taught by a truly distinguished faculty. At the time, the standard textbook in the field of neurophysiology for medical and graduate students was that edited by Ruch and Patton. They were our professors along with a group of other excellent faculty who seemed to enjoy teaching as much as I enjoyed learning.

A weekly highlight of the neurophysiology/neuroanatomy course was an hour the freshman class spent with the head of neurology, Fred Plum, discussing clinical-pathological correlations. Dr. Plum was the youngest chair of neurology in the country and an articulate but intimidating presence. I will never forget my first exchange with him that occurred during one of these hours. He asked the class what sensory modality was related to itch. I raised my hand, something I rarely did as one of the shyest members of the class, and responded, when he called on me, with “pain.” It was the answer he wanted, and he was very complimentary. It was the ego boost of the year!

By the second year of medical school, the playing field had become much more level. The materials were new to all of us making the whole experience for me, in particular, much more enjoyable. It was in my third year of medical school, however, that my career trajectory moved even more in the direction of the neurosciences. Although I enjoyed and did well on my clinical rotations (I loved sewing up wounds, surgical and traumatic; delivering babies; ferreting out the diagnostic significance of heart sounds; as well as talking to patients), my rotation on the neurology service was particularly relevant to my emerging career goals. Once again, Fred Plum played a critical role.

The neurology service was at King County Hospital in downtown Seattle. Each week, Fred Plum would make rounds with the students and house staff on the service. This was a high stress event for all concerned. The two patients to be presented were carefully selected by the chief resident. A separate student was chosen to present each case, and the students were carefully rehearsed by the chief resident prior to rounds with Dr. Plum. The students could not use notes or refer to the patient’s chart, which had to be handed to Dr. Plum at the beginning of the presentation. The student stood on the patient’s left—across the bed from Dr. Plum. The setting and its preamble were seemingly designed to heighten anxiety in everyone, which they did quite effectively. To add to the drama, on this particular occasion, I was not rehearsed! The reason for this escapes me, but I have the vague recollection it had something to do with a disagreement I had with the chief resident!

The case I presented to Dr. Plum at King County that day in 1963 had symptoms most likely of hysterical origin. I presented the case succinctly and indicated as such. This, my second encounter with Fred Plum, went even better than the first! He seemed especially pleased with my summary of the case. I was clearly on my way to becoming a neurologist.

Later, in my junior year in medical school, Fred Plum was offered the job of chairman of neurology at the New York Hospital–Cornell Medical Center in New York City on the death of his mentor Harold Wolf. I asked him if I could spend my senior elective time with him on the neurology service at the New York Hospital. He agreed. It was a wonderful experience. In addition to my time on the neurology service, I needed to spend some elective time on a surgery rotation. Bronson Ray was then chief of neurosurgery at the New York Hospital. He had been the last resident of Harvey Cushing (the father of American neurosurgery) at the Peter Bent Brigham Hospital in Boston. Although Dr. Ray rarely took students on his service, he agreed to take me for an experience that I treasure to this day. He was a revered man of great dignity in and out of the operating room. There was never any shouting or instrument throwing. I had the distinct honor of holding the sucker on several occasions as he delicately operated on the pituitary gland through a large craniotomy. When I returned to Cornell as a neurology resident, I believe that he was disappointed I did not choose neurosurgery, but a research career was looming ever larger for me and I felt that neurology was a better venue for that (more on that later).

The Medical Scientist Training Program (MSTP) tract that exists in many, if not most, medical schools today, awarding to those lucky enough to be accepted to these programs a joint MD/PhD degree, did not exist when I was in medical school. But the University of Washington, being one of the most academically oriented state medical schools in the country, offered an extra year of training and a master’s degree to qualified medical students. I, of course, was not “qualified” as the lone social scientist in our class, and I have to admit that I was very envious of those selected.

During college, with the exception of one summer as a carpenter’s apprentice and during the first summers while a medical student, I was a lifeguard for the state of Washington at one of its parks on Puget Sound. It was not until the summer between my junior and senior year that I was able to get a laboratory rotation in the department of orthopedic surgery working with a team of surgeons studying spinal cord development. Although the work in which I was engaged was never published, I loved the experience, which was focused on the microscopic anatomy of the developing rat spinal cord.

A tremendous added plus to that summer’s laboratory experience was an early morning class on human neuroanatomy taught by the famous neuropathologist Ellsworth (Buster) Alvord. Each morning at 7 a.m., a small group of us gathered to listen to his lectures on neuroanatomy, and in parallel, we built models of the human using colored clays and wire. It was the first time that I achieved a clear three-dimensional (3-D) sense of the organization of the human brain. The model I built sits just outside my office to this day.

Graduating from medical school in the spring of 1994, I married my long-time sweetheart, Mary Elizabeth Rupert, also from Aberdeen, who received her undergraduate degree at the same time I received my MD. We had dated on and off for many years and also worked together as lifeguards for the state of Washington. I am writing this in our 50th year together with four grown children (a lawyer, an obstetrician, an economist, and a psychology professor—and 12 grandchildren).

Having spent nine years at the University of Washington, I thought it time to go elsewhere for training. Although I fully intended to become a neurologist and train with Fred Plum at Cornell, his program and many others required a minimum of two years of internal medicine, which I did in Baltimore at Johns Hopkins. In Baltimore, I divided my time between the Baltimore City hospitals and the Johns Hopkins hospital. In those days, a house officer’s schedule was 24/7 and all night every other day and every other weekend. It was stimulating and exhausting. But somehow the research bug had taken hold, and I found myself pursuing a number of things in the context of my clinical work.

An example of the type of research I did as a medical intern and resident was the analysis of spinal fluid in patients with intracranial bleeding. At the time, the breakdown of hemoglobin in spinal fluid, its chemistry and temporal dynamics, was reasonably well characterized but using it to estimate the onset of bleeding in individual patients had not been actively pursued. The instrumentation necessary to characterize the breakdown products of hemoglobin in cerebrospinal fluid existed in the laboratory of the National Institute of Aging situated on the campus of the Baltimore City hospitals. The laboratory was under the direction of Rubin Andrus. He was most agreeable to my coming to his laboratory at any hour of the day or night to analyze my specimens on his instruments. I had great fun doing this work through two years in the Hopkins system, and although I never published my results, which would have been difficult under the circumstances, I derived great satisfaction in collecting and analyzing data. I even organized a “research day” with other house officers where we presented our work to the attending medical staff that included Julius Krevans, who later became dean of medicine at the University of California, San Francisco, and Charley Carpenter, a world expert on cholera who subsequently became head of medicine at Case-Western Reserve School of Medicine.

In the summer of 1966, we moved to New York City to begin my neurology residency. Clinical duties dominated my time particularly in the first year of my residency. However, Plum made it clear that we were in a program that not only expected excellence in the clinic but also an acknowledgment of the importance of research. Emphasis was placed on how we thought about a problem, not whether we had the answer. At the time, Plum and his long-time collaborator Jerry Posner were pioneering a new, systematic approach to the problems of stupor and coma that placed special emphasis on the recognition and remediation of reversible causes, largely metabolic. As residents, we were learning a new approach to these problems with the galley proofs of the first edition of their classic monograph Stupor and Coma.

My first serious foray into research as a resident again began during my second year when I was the consult resident for the New York Hospital. This was a maturing experience where you operated largely on your own as a consultant to all of the services of the hospital. Of course, you had a backup, usually Plum, but you were expected to take charge. A year or two before I began this rotation, investigators at the Massachusetts General Hospital had introduced the use of massive doses of intravenous penicillin as a treatment for deadly, gram-negative bacterial infections. Although the therapy was effective in treating the infection, it had unexpected and unintended side effects. These manifest as the sudden onset of confusion and random jerking movements of the large muscle groups of the body (i.e., so-called multifocal myoclonus) that were aggravated by any attempt on the part of the patient to move. In some patients, the syndrome progressed to frank seizures and coma. All of this was typical of a metabolic encephalopathy. I realized that I was seeing increasing numbers of these patients. Although they presented with a variety of medical problems, the common denominator was the fact that they were all on high doses of penicillin.

From a neuroscience perspective, it had been known for some time that penicillin was epileptogenic when applied directly to the cortex of experimental animals. The idea that it could behave in a similar fashion when given systemically in large doses was less well appreciated and, prior to the use of massive does, was probably never encountered. When it was encountered, the clinical situation was often complicated with other conditions such as kidney failure, which could also cause a similar encephalopathy.

Clearly, there needed to be a carefully controlled study of the problem in the laboratory. To explore this association in more detail, I sought the assistance of Sidney Lewis, Henn Kutt, and Fletcher McDowell, members of the neurology faculty at Cornell with a research interest in epilepsy and with a laboratory fully equipped for small animal research of the type needed for this type of study. Working nights and weekends in the Lewis/Kutt/McDowell laboratory, I was able to sort this out with studies in 13 cats and 36 rats. Our most noteworthy finding was that intravenously administered penicillin produced an encephalopathy in animals that was similar in all respects to that observed in humans except that the effective dose was species specific—with cats most susceptible and humans least. Also, the toxic effect of penicillin on the brain was directly related to its antibacterial activity. This study led to my first published scientific paper, which appeared in the Archives of Neurology in 1971 (Raichle, Kutt, Louis, and McDowell, 1971). I had finally gone from bedside to bench, casting light on an important clinical problem and learning in the process how to do well-controlled experiments, analyze data, and write a publishable manuscript (probably the most challenging part of all). But doing this on nights and weekends was not ideal for preparing me in the ways of scientific research such that I could eventually operate on my own. Thus, I sought time off from my residency to work full time in the laboratory with Fred Plum and Jerry Posner.

As mentioned earlier, Fred and Jerry were deeply committed to an understanding of the metabolic causes of coma, and in the course of their research, quantitative measurements of brain blood flow and metabolism became increasingly important to their objectives. Fortunately, Seymour Kety and Carl Schmidt of the University of Pennsylvania had laid the groundwork for these measurements in the late 1940s (Kety and Schmidt, 1948). The majority of the work of Kety, Schmidt, and their colleagues focused on making measurements in humans. As a result, they were the first to provide us with quantitative measurements of human whole brain blood flow and oxygen consumption. To this day, their technique remains the “gold standard” of such measurements.

It is worth noting what was involved in the Kety/Schmidt technique as applied to humans. The technique was based on the Fick principle that, in essence, says that by measuring the blood concentration of what is presented to an organ minus what is leaving, combined with the rate of blood flowing to the organ, one can compute the rate at which, in their case, oxygen was used.⁷ The trick was how to measure, quantitatively, the blood flow. They devised an ingenious technique using the inert diffusible gas nitrous oxide and measuring the concentrations of the gas in arterial and in venous blood across the brain. This they did by placing a catheter in the femoral artery in the groin and a second catheter in the jugular bulb. From these data, it was possible to compute the blood flow to the brain. In the Plum and Posner implementation of the Kety-Schmidt technique, the radioactive inert gas Krypton 85 was substituted for nitrous oxide, making measurements of its concentration history in arterial and venous blood much easier.

The experimental question I inherited on entry into the Plum-Posner lab was determining whether the hydrogen ion was important in the matching of brain circulation to its metabolic needs. The logic behind the question emerged from two observations. First, the normal fuel for brain energy metabolism is glucose, and the metabolic extraction of its potential energy produces carbon dioxide and water. Thus, as glucose is consumed, carbon dioxide increases. Second, acute changes in arterial blood and, concomitantly, brain carbon dioxide tension have immediate and profound effects on brain blood flow (i.e., increases in carbon dioxide tension by inhaling low concentrations of carbon dioxide cause increases in blood flow, and hyperventilation causes a decrease). The answer seemed obvious—carbon dioxide was acting on brain blood vessels to change blood flow. Unfortunately, the situation was a bit more complicated. Changing the amount of dissolved carbon dioxide in the brain has a direct effect on brain pH because the brain is buffered by bicarbonate.⁸

The key to separating the roles of carbon dioxide and pH is the fact that the brain appears to normalize its pH during sustained periods of hyperventilation,⁹ suggesting to us that, if we hyperventilated anesthetized laboratory animals for several hours, we would see an initial drop in blood flow that returned to control levels despite significantly reduced arterial carbon dioxide tensions. However, despite carefully controlled ventilation and levels of anesthesia, we failed to observe the predicted change. In fact, blood flow not only dropped initially with the onset of hyperventilation but continued to fall during the five hours of the experiment. In a control experiment with arterial carbon dioxide tension maintained at a normal level, blood flow again fell across the five hours of observation. We could not explain this declining blood flow other than to surmise that it represented an unstable experimental preparation. The alternative we arrived at was to use ourselves as the experimental subjects. After all, the high altitude experiments leading to our work were done in humans, and the techniques we were using to measure brain blood flow and metabolism had been validated in humans by Kety, Schmidt, and their colleagues.

Not knowing for sure just how this was going to play out, I volunteered to go first. Gordon Potts, newly head of neuroradiology at the New York Hospital and later to become one of the leading neuroradiologists in the world, placed the catheters in my jugular bulb¹⁰ and femoral artery while I lay in a hospital bed in the same laboratory in which we had conducted our animal experiments.¹¹ I was fitted with a face mask for the inhalation of the radioactive gas to measure blood flow and also for the monitoring of my end-tidal CO₂. An end-tidal CO₂ meter was placed in front of me so that I could monitor my respirations. My brain blood flow and metabolism were measured at the beginning of the experiment while I relaxed, breathing at a normal rate.

Then the ordeal began—hyperventilating sufficiently vigorously to reduce my arterial carbon dioxide tension to half its normal value and holding it there by continuing to hyperventilate for five hours. Fred and Jerry took turns cheering me on while repeatedly measuring my brain blood flow and metabolism. Once in the routine, it was somewhat less difficult than I had imagined. At the end of five hours, I had to suddenly stop my hyperventilation, forcing my arterial carbon dioxide tension back to control. This proved to be rather difficult. Jerry Posner was next and somewhat more accustomed to the experience, having done the protocol once before without measurements of blood flow. Finally, it was Fred’s turn. He soldiered through without a problem until the very end when he suddenly had a shaking chill. Although never verified, we suspected sepsis—even though an autonomic reaction to the ordeal, in retrospect, was equally likely. For Jerry and me, the relief in getting through this was enormous (something like boot camp in the world of cerebral blood flow and metabolism). The relief was short-lived. The morning following Fred’s experiment he announced that we all needed to do it again to boost the “n”! Fortunately, the vote was two to one against, and Fred clearly had no alternative subjects waiting in the wings.

The data arising from this study proved to be exceptional (three measurements of blood flow, oxygen consumption, glucose utilization and lactate production before, during, and after sustained hyperventilation plus an additional subject, Jerry Posner, with arteriovenous difference measurements of all of the metabolites). The results definitely supported the hypothesis that the effect of carbon dioxide on blood flow was mediated by the hydrogen ion. In addition, the study’s comprehensive, quantitative data has proven invaluable to the present day.

Following my time in the laboratory with Fred and Jerry, I returned to my residency training, finishing in the spring of 1969 at the peak of the Vietnam War. Military service was a given for all MDs not heading to the National Institutes of Health (NIH). My service had been deferred until the completion of my residency at which time I was commissioned a major in the U.S. Air Force and assigned to the School of Aerospace Medicine. The experience there proved to be another important stepping-stone to my academic career.

The School of Aerospace Medicine had several missions. I was formally assigned to the medical evaluation unit staffed by a range of specialists, including four neurologists. Some of the physicians were career military officers, others like me were in for two years, and there were a few civilians. I was very impressed by the caliber of these individuals and by their dedication. Our job was to evaluate flying personnel in the Air Force (largely pilots and navigators) who had experienced a medical problem potentially impairing their ability to fly. We also did the medical screening of the Air Force Research Pilots (the people who would go out to Edwards Air Force Base and fly exotic new aircraft) and of the pilots who flew the U2 and SR71 planes.

In order to understand the conditions faced by the individuals we were expected to evaluate, we were strongly encouraged to attend the Air Force Flight Surgeons School as well as to attain qualifications in hyperbaric medicine (i.e., chamber certification in diving and altitude chambers). After all of this, we were placed on flying status and expected to fly on a regular basis. Given that the school did not have its own flying wing, we could pick and choose among the many aircraft at other bases. I did so liberally and enjoyed every minute of it.

Although my medical experience at the School of Aerospace Medicine was remarkable in many ways, putting the whole matter of brain function into an entirely new context, I was also exposed to a most remarkable research experience. In addition to its medical role, at that time, the School of Aerospace Medicine was very involved in understanding human adaptation to space flight. This was in part related to the intention of the air force to place a spy satellite in space and also related to the early work of NASA.¹² In pursuit of this, the military had assembled a remarkably talented group of civilian PhDs in the area of cardiovascular and pulmonary physiology and equipped them with absolutely remarkable research laboratories for the time. Although some human research was being conducted, the primary work was performed on rhesus monkeys. The school had a colony of 1,500 monkeys attended by a core of veterinarians.

Somehow the word got out that I had done research on brain circulation and metabolism with Fred Plum and Jerry Posner, and I was recruited to work with Lowell Stone, a young PhD in cardiovascular physiology who some years later became chair of physiology at the University of Oklahoma. His technique was to chronically implant Doppler flow probes on arteries of interest and monitor changes in blood flow continuously under a variety of experimental conditions. What they proposed was that they would teach me the techniques of implanting the probes and measuring flow if I would work with them on studies of brain circulation. The veterinarians were superb surgeons, and I quickly learned how to isolate the internal carotid artery and implant the probes. We even went so far as to implant a few probes on the middle cerebral artery. In addition, we developed in implantable device in the skull of the monkey over the superior sagittal sinus that allowed chronic sampling of cerebral venous blood. I was “handed the keys” to a Grass polygraph and told to learn how to use it. Our data were recorded on FM tape and analyzed on a massive analogue computer at the school that ran on vacuum tubes and was programmed uniquely for each study using a large “circuit” board and wires. It was an exciting time and yet relaxed when compared to the rather high intensity neurology residency I had experienced under Fred Plum.

To my surprise, one day at the school I received a letter from the organizing committee of a meeting on brain blood flow and metabolism to be held at the Royal College of Physicians in London. Unbeknownst to me, Fred Plum had submitted an abstract of our hyperventilation experiment and, as I later learned, he expected to be asked to present our data. The organizing committee, apparently seeing my name first, sent me the acceptance letter. I was delighted and immediately began figuring out how I was going to get to London—my first trip to Europe. My commanding officer kindly agreed to give me the time off to attend the meeting.

It is customary in the air force to look for planes going your way and to ask to tag along. The best jumping off place at the time was Dover Air Force Base in Delaware, so I got on an air force plane from San Antonio to Dover and went in to base operations to see what my options were. As it turned out, the only option available was to join an Iranian air crew that was flying a brand new C141 transport plane to Tehran via London. In my flight suit sporting my flight surgeon wings, I approached the crew, and they invited me along. The only problem was, initially, they did not understand the difference between a flight surgeon and a pilot (anyone in a flight suit sporting wings must be a pilot!). They kept insisting that I take the left seat and fly the plane. Fortunately, we managed to get to London safely.

Of course, I enjoyed my first presentation at an international meeting to a group of individuals who were already legends in the field of cerebral blood flow and metabolism. Many would become close friends over subsequent years. This meeting, however, was unexpectedly important in another way. Presenting one of the most interesting papers in London in 1970 was a PhD physicist from Washington University in St Louis by the name of Michel Ter-Pogossian.

Michel Ter-Pogossian was born in Berlin and grew up in Paris. His father was a member of the French diplomatic service prior to World War II. During the war, Michel allegedly worked for the French underground. Following the war, he came to the United States and Washington University to study physics. One of the motivating factors in his decision to choose Washington University was the fact that the chancellor was Arthur Holley Compton, a Nobel laureate in physics. The other factor was that Washington University had a cyclotron that, in its day, was a fairly substantial machine.

The cyclotron was purchased at the behest of the Mallinckrodt Institute of Radiology at Washington University (i.e., the department of radiology) to produce isotopes for nuclear medicine. Shortly after the cyclotron was commissioned, the United States entered World War II and the cyclotron became a major component of the Manhattan Project. When the war was over, cyclotron-produced isotopes were no longer of interest to nuclear medicine because of the more conveniently available generator-produced isotopes. Therefore, the cyclotron became a tool for research in chemistry and physics.

Into the setting of a now-available cyclotron on the Washington University campus and a team of chemists versed in its use from their experience in the Manhattan Project, came Michel Ter-Pogossian, an eager young graduate student. In the course of his graduate work, he became interested in the potential of cyclotron-produced isotopes for research in biology and medicine,¹³ a theme that he was to pursue throughout his entire academic career at Washington University. The isotope of particular interest to Ter-Pogossian at the time was ¹⁵O (half-life two minutes). To pursue his interest and convince others of its importance, he set up a small laboratory in a house trailer just outside of the cyclotron building. Into the building, he rigged a connection directly to the beam line of the cyclotron, permitting the administration of ¹⁵O-labeled air to rodents (they simply breathed the labeled air as it came into a small container in which they were placed). He then imaged the animals immediately after the brief exposure, using a simple nuclear medicine camera of the day. The resulting “images”¹⁴ were sufficiently impressive that the Mallinckrodt Institute of Radiology (MIR) agreed to put a small medical cyclotron in the basement of the institute.

Once the cyclotron was up and running in the MIR, the brain became a significant focus of attention. One of the compelling reasons for the emphasis on the brain was the fact that it was a large organ nicely isolated from other organs and, in contrast to the heart, it did not move. Also, friendships mattered. The then-head of the MIR was Juan Taveras, arguably the father of American neuroradiology and whose research interests centered around measurements of brain blood flow. Without his support, the cyclotron would never have been installed in the MIR. Also, Sam Guze, head of psychiatry and vice chancellor for medical affairs and a close friend of Ter-Pogossian’s, was very interested in the possibility of using measures of brain metabolism to study patients with psychiatric disease.

Two additional factors propelled brain studies with cyclotron-produced isotopes forward. First, Michael Welch, a young radiochemist who received his PhD at University College London and a postdoc at the Brookhaven National Laboratory, joined the Ter-Pogossian laboratory and immediately made the synthesis of ¹⁵O-labeled water, oxygen, and carbon monoxide routine.¹⁵O-labeled water was selected as the inert, diffusible tracer for the measurement of brain blood flow. ¹⁵O-carbon monoxide was the tracer for the measurement of brain blood volume because of its irreversible binding to hemoglobin. And, ¹⁵O-labeled oxygen was, in combination with the other two tracers, the key to measuring brain oxygen consumption. Second, a radiation detector system was constructed that was capable of assessing the concentration of these ¹⁵O-labeled radiopharmaceuticals in the human brain. The detectors, three on each side of the head, had to be shielded in substantial quantities of lead in order to capture the regional distribution of these high energy isotopes.¹⁵

With appropriate radiopharmaceuticals in hand and a detector system suitable for detecting them in the brain, research began to determine whether regional oxygen consumption could be measured in the human brain. It was the result of these very earliest experiments (Ter-Pogossian, Eichling, Davis, and Welch, 1970) that Michel Ter-Pogossian presented at the meeting in London in 1970 that I attended. At the meeting, he approached me and asked if I would be interested in joining his group in St. Louis to pursue studies of brain circulation and metabolism with cyclotron-produced radiopharmaceuticals. The prospect of being able to measure brain oxygen consumption regionally in humans for the first time was an opportunity too attractive to pass up.

I joined the faculty of Washington University School of Medicine in the summer of 1971 and have been a member of the faculty ever since. In retrospect, the appointment was unique in several ways. I was a clinically trained neurologist with a background in measurements of brain circulation and metabolism, recruited by a physicist (Michel Ter-Pogossian) to work in a radiology department laboratory populated by physicists, chemists, engineers, applied mathematicians, and computer scientists along with talented cyclotron operators, machinists, and technicians. At the time I was the only neuroscientist in the lab. Such an environment today would be considered typical of an interdisciplinary research operation, but, at the time, no one spoke of us in those terms.

The other important feature of the Ter-Pogossian lab was the fact that most of us resided in rather cramped quarters on the sixth floor of the MIR with the cyclotron in the basement, the neuroradiology suite with some of our research equipment on the third floor, and animal quarters, labs, and surgery on the floors above us. Interactions were inescapable and incredibly valuable.

Initially, I had a joint appointment in radiology and neurology, which has expanded over the years to include neurobiology, psychology, and biomedical engineering. My laboratory has always resided in the MIR. Initially, I was a member of the Ter-Pogossian laboratory but eventually acquired my own laboratory known as the Neuroimaging Laboratory, which presently consists of 23 faculty members from five departments in the university (radiology, neurology, psychiatry, psychology, and pediatrics) and 100 staff, students, and postdocs.

My introduction to the use of the ¹⁵O-labeled radiopharmaceuticals involved experiments in monkeys and humans. At the time, these radiopharmaceuticals were administered directly into the internal carotid artery by way of a catheter introduced into the femoral artery and threaded there under fluoroscopic control, a technique I mastered with the help of the MIR neuroradiologists. All human studies were performed on patients undergoing carotid angiography as part of the clinical evaluation. Data were collected on a classic Laboratory Instrument Computer (LINC) but analyzed by hand because of the limited computational capability of the LINC.¹⁶ Our initial objective was to validate the Ter-Pogossian method for the measurement of regional brain oxygen consumption, a technique he developed with his graduate student John Eichling. Having been schooled in the gold standard for such measurements in the Plum/Posner laboratory, it was a straightforward problem. The technique came through with flying colors (Raichle, Grubb, Eichling, and Ter-Pogossian, 1976).

In the early experiments in the Ter-Pogossian lab we discovered that ¹⁵O-labeled water was not, as advertised, a freely diffusible tracer. Although this was not an impediment in our use of the tracer for the measurement of blood flow, it opened up a line of investigation that remains incomplete to this day. The tantalizing insight that this discovery provided was the fact that the blood brain barrier was a flexible membrane that, with respect to water, mirrored many of the features and functions of the distal tubule of the kidney. We were having great fun pursuing this and other novel and unexpected findings when an event occurred that not only changed the practice of medicine but also opened up the prospect of safely obtaining true 3-D images of the anatomy and the function of the human brain. It was the invention of X-ray computed tomography by Godfrey Hounsfield, a self-taught engineering genius working for EMI Limited in England.

The Invention of Positron Emission Tomography

When first introduced, X-ray computed tomography (CT) only created images of the brain.¹⁷ The initial reaction to CT by the computer science and engineering folks in the lab was that they could design a better CT. It was certainly the case that the machine designed and built by Hounsfield achieved its success through a brute force engineering approach. Engineering niceties had been sacrificed in the interest of getting the job done. Work began almost immediately to create a new reconstruction algorithm, and collaboration was established between the MIR and a leading manufacturer of radiology equipment.

Meanwhile EMI began marketing their new scanners, and several major hospitals were acquiring them including the National Hospital for Neurological Diseases in Queens Square, London; the Massachusetts General Hospital; and the Mayo Clinic. This was too much for the then director of MIR, Ron Evens. He wanted MIR to be among the first to have this new device and waiting on algorithmic developments at Washington University and manufacturing elsewhere became unacceptable. He canceled the outside contract and immediately purchased an EMI scanner for the MIR. It was, as I recall, the fourth installed worldwide.

The cancellation of a project to build our own CT scanner was initially greeted with great disappointment, particularly by Jerry Cox and Don Snyder, the two engineers who had developed a CT algorithm that was ultimately to become one of the standards of the field. However, a casual afternoon conversation in the office next to mine on the sixth floor of MIR changed that. The conversation took place between Jerry Cox, whose orphaned algorithm was in need of a project, and Michel Phelps, a nuclear chemist who had joined the Ter-Pogossian laboratory at the same time I did. In the course of their conversation, Phelps asked Cox whether it might be possible to use his algorithm to reconstruct in 3-D the distribution of compounds labeled with positron-emitting radionuclides such as ¹⁵O, ¹¹C, ¹³N, and ¹⁸F.

An important element of the conversation between Cox and Phelps concerned the decay scheme of these radionuclides, which consisted of two high-energy photons going in opposite directions (i.e., precisely 180 degrees from each other) when a positron interacts with an electron in the tissue. In its simplest form, imagine placing two radiation detectors facing each other with the brain in between. When an event (i.e., a photon) is detected simultaneously by both detectors, the inference to be drawn is that an event has occurred on a line between the two detectors. Placing two detectors together in this manner is known as a coincidence circuit or detector. After going to the blackboard and doing the math the answer from Jerry was “yes.”

Phelps immediately seized upon the idea and brought it up with Ter-Pogossian who was not enthusiastic. Undaunted, Phelps and a young postdoc in the lab by the name of Ed Hoffman along with some electronics, a couple of detectors, and some lead blocks and, of course, Jerry and Don’s algorithm, worked nights and weekends to show that the idea was not only theoretically sound but feasible given the current state of electronics and computers. More proof was needed, however, to convince Ter-Pogossian. I was approached because I had the requisite number of detectors and electronics needed for the feasibility study. These were the components of a 26-probe detector system that had been built in the lab for me to conduct experiments on patients undergoing cerebral angiography for diagnostic purposes. It was situated in the third-floor angiogram suite of the MIR along with connections to our computers on the sixth floor and a pneumatic line to the cyclotron in the basement for the transmission of ¹⁵O-labeled water, oxygen, and carbon monoxide. Although I do not recall the conversations, I was obviously persuaded to relinquish the use of my detector system, which was never rebuilt, for the purpose of proving that the concept of positron emission tomography (PET) was viable. The resulting evidence obtained was sufficient to convince even Ter-Pogossian that the idea had merit. He brought the full resources of the lab to bear on the matter and, in short order, the first human PET scanner was conceived and built. It was called PETT III for positron emission transaxial tomograph and “III” because it followed the two initial tabletop versions. The first human study was performed in April 1974 and the full description of the scanner appeared in two papers published in 1975 (Phelps, Hoffman, Mullani, and Ter-Pogossian, 1975; Ter-Pogossian, Phelps, Hoffman, and Mullani, 1975).

Brain Mapping with Positron Emission Tomography

Obviously, I was a bystander in the actual building of the first PET scanner, but I had a ringside seat. It was clear that, if we were to exploit the ability of this instrument to make truly quantitative 3-D images of blood flow and metabolism in the human brain, there was still much work to be done. An initial element of the effort focused on our understanding of ¹⁵O-labeled water as a blood flow tracer. The idea was to use it as Seymour Kety and colleagues had used trifluoroiodomethane as a blood flow tracer for the measurement of blood flow autoradiographically in laboratory animals. In animals, the tracer was administered intravenously and a minute later the animal was sacrificed, the brain removed, frozen, carefully sliced, and laid on X-ray film. From the arterial time-activity curve of the tracer and the quantitative autoradiogram, they were able to calculate blood flow. Our idea was to substitute a quantitative PET image for the autoradiogram and make the same calculation. It actually worked splendidly until we decided to extend the duration of the PET scan beyond one minute and discovered that the longer the scan the lower the computed flow. After much theorizing and experimentation, we concluded that the simple one-compartment model used by Kety and associates only worked when all or most of the tracer remained within the brain during the experiment (one minute was the limit!) (Landau, Freygang, Roland, Sokoloff, and Kety, 1955; Kety, 1960). Some years later, I asked Seymour why they chose a minute, and he told me that when they went longer the values decreased, something not mentioned in any of their papers!

Implementing a means of measuring oxygen consumption proved more difficult. When a small amount of a patient’s or an animal’s blood labeled O¹⁵O was injected into the carotid artery, it was relatively easy to quantitatively estimate the fraction of available oxygen extracted by the brain. Knowing this plus the arterial oxygen content and the blood flow, the calculation of oxygen consumption was straightforward and accurate. In PET, the O¹⁵O was inhaled. Some of it was taken up by the brain and converted to water, which left the brain like a blood flow tracer. Some of the administered oxygen remained in blood as oxyhemoglobin behaving like a blood volume tracer. The difference with regard to the brain represented the fraction extracted, but this could not be estimated from the O¹⁵O data alone. Therefore, the inhalation of O¹⁵O was followed by an inhalation of C¹⁵O to measure blood volume (as required by the model) and an intravenous administration of H₂¹⁵O to measure blood flow. (We now refer to this cocktail of radiopharmaceuticals as a “triple pack.”) With Peter Herscovitch and Mark Mintun taking the lead, we developed and validated a model incorporating the data from these three tracer administrations to calculate regional oxygen consumption with PET (Mintun, Raichle, Martin, and Herscovitch, 1984). Knowing that we had a truly validated means of measuring brain oxygen consumption regionally proved to be invaluable as our work unfolded.

By 1980, an interest emerged in the lab in using PET to map functional activity in the brain. Work of this type had already begun using a PET adaptation of Lou Sokoloff’s ¹⁴C-deoxyglucose autoradiographic technique for the measurement of regional brain glucose utilization.¹⁸ The PET adaptation used ¹⁸F-deoxyglucose or FDG as it is most commonly known (Phelps et al., 1979; Reivich et al., 1979). As Sokoloff had shown in animals, the PET-FDG technique demonstrated a wide variety of task-specific changes in regional glucose metabolism in normal human subjects. From a brain mapping perspective, however, this technique had one critical limitation, the time necessary to make a single measurement, which was 40 minutes. The time was required to allow non-metabolized tracer to clear from the tissue. For steady state measurements of baseline metabolism, this was satisfactory, but for complex behavioral paradigms, this was a serious problem. The additional problem with FDG was its half-life of 110 minutes, which meant that considerable time (usually five half-lives) was needed between measurements for activity within the body to decay. For us the answer was blood flow.

Using measures of blood flow to map responses to changes in activity dates back to the late 1800s when Angelo Mosso first introduced the idea (Mosso, 1881). Kety, Sokoloff, and their colleagues introduced the technique in more quantitative terms with the autoradiographic technique (Kety, 1960). The idea was subsequently introduced in humans in the 1960s by David Ingvar, Jarl Risberg, Niels Lassen, and their Scandinavian colleagues (Lassen, Ingvar, and Skinhoj, 1978). They used ¹³³ Xenon. In their first experiments, the tracer was injected directly into the carotid artery. Later, Xenon was administered by inhalation. They monitored regional blood with radiation detectors arranged about the head in a helmet-like fashion. At the peak of their work, they were measuring activity in approximately 256 cortical regions. Although this was not a true 3-D representation of blood flow in the brain, it did give a good sense that regional changes did occur during task performance. Their measurement took approximately two minutes and could be repeated at least one time.

Blood flow measured with H₂¹⁵O as we had developed it for PET could be measured in less than a minute, repeated every 10 minutes due to the short half-life of ¹⁵O (two minutes), and repeated up to 12 times in a single experiment because of the low radiation dose, also a feature of the very short half-life. Because the use of ¹⁵O-labeled tracers had been a staple of the laboratory even before I arrived, producing and handling H₂¹⁵O with its short half-life (a two-minute half-life means all radioactivity has decayed in 10 minutes or five half-lives) had become a routine.

Because of our desire to take full advantage of the capabilities of ¹⁵O-labeled water as well as oxygen and carbon monoxide, we had designed and built in our laboratory a PET scanner optimized for this purpose. This was PET VI, an instrument meant specifically for brain research with full brain coverage and high count rate capability (Ter-Pogossian, Ficke, Hood, Yamamoto, and Mullani, 1982). It was, in my estimation, the best PET scanner ever built at Washington University. It served us superbly for 13 years (1980–1993) during which time all of the basic tools of brain mapping in cognitive neuroscience were developed and introduced.

Once equipped with a means of measuring blood flow repeatedly in a single experiment the next problem was to know the exact location of the changes we observed. Although various approaches had been proposed by others (for a more detailed review see Raichle, 2000), we were particularly attracted to the work of Professor Talairach (Talairach, Szikla, and Tournoux, 1967), a well-known French neuroradiologist. His beautifully developed stereotaxic means of localization in the human brain was designed for neurosurgeons and based on skull landmarks (i.e., the anterior-posterior commissural line). Working from his 1967 atlas, which was only available in France, we were able to implement his strategy by obtaining a lateral skull X-ray in all of our subjects while in the PET scanner. The orientation of the PET slices was imprinted on the X-ray using a small grid placed beside the subject’s head while obtaining the X-ray. With this information, we were able to relate the data from each subject to the HD6 brain in the Talairach atlas (Fox, Perlmutter, and Raichle, 1985). This was definitely a major step forward for us, but we had additional hurdles to overcome.

Data from individual subjects were often noisy. This raised the question of averaging across subjects to increase signal and reduce noise. This became a hotly debated subject in the lab. Proponents of averaging were certain that it would improve our data, but opponents argued that individual differences were simply too great even after careful stereotaxic registration to a common atlas space. The person most insistent that we try averaging was Eric Reiman, a young psychiatrist working in the lab. Mark Mintun, another young member of the lab and a physician trained in nuclear medicine and an MIT graduate with the mathematical and computer skills necessary to implement averaging, agreed to tackle the problem if Eric could raise the money to hire a programmer to assist. Approached by Eric, Sam Guze, head of psychiatry, agreed to provide the funds, and the work began. It took Mark close to a year to implement a strategy that was initially tried on a group of individuals undergoing a somatosensory stimulation paradigm. I do not believe that anyone present in the lab the day the first results of this effort were unveiled will ever forget the experience. The signal was enhanced and the noise suppressed in a most spectacular fashion (Fox, Mintun, Reiman, and Raichle, 1988). Also immediately suppressed were any doubts that averaging would work!

The next hurdle was deciding what was significant in our images. It was easy enough when the experiment was one of hypothesis testing. For example, does primary somatosensory cortex increase its activity when we stimulate the contralateral hand? We now had a means of anatomically localizing somatosensory cortex in a common anatomical space. Because we could make multiple measurements in each subject, we could measure the activity level before and after stimulation. With these paired measurements confined to a specific location in the brain, the statistics were straightforward. However, we were interested in much more complex stimuli and behaviors where results could not be predicted in advance. It was obvious even before we ventured there that we needed to develop a statistical strategy that allowed us to conduct hypothesis-generating experiments with reasonable efficiency.¹⁹ After all, we were venturing into unknown territory where it would have been presumptuous to assume that we knew in advance how the human brain was organized. We finally agreed on a statistical approach that, while incomplete, allowed us to move forward with our work (Fox, Mintun, Reiman, and Raichle, 1988). Much work on this problem has taken place since in laboratories worldwide resulting in strategies that are quite satisfactory.

The final piece of the puzzle was how to design the behavioral aspects of our studies that respected the constraints of the imaging environment but also dealt in a principled way with the complexities of human behavior. One of St. Louis’s most generous philanthropists, James S. McDonnell, came to the rescue. In addition to founding the McDonnell-Douglas aircraft company, he had a lifelong interest in the brain. Shortly before his death, he approached Washington University with a proposal to fund a brain research center focusing on the relationship between human behaviors and brain function. A proposal was drafted that, as Mr. McDonnell requested, included the hiring of a psychologist to direct the behavioral aspects of the research. Fortunately for everyone concerned, the person recruited was Michael Posner from the University of Oregon, one of the world’s leading cognitive psychologists.

Cognitive psychologists had pioneered behavioral strategies designed to dissect human behaviors into their component operations by combining tasks containing the operation of interest with sophisticated control conditions that contained all but the operation of interest (for example see Posner, 1986). A moment’s reflection should reveal just how perfectly this strategy meshed with the imaging strategies we had been developing. Mike fit into the imaging operation at Washington University like an eager young postdoc. We tackled many exciting things while he was with us (he returned to Oregon at the end of the 1980s) but probably the most enduring was our study of the cortical processing of single words.

Understanding the organization of language in the human brain had arisen over more than a century of careful study of patients with brain lesions, most commonly acute stroke. Noteworthy early contributions came from people such as Paul Broca and Carl Wernicke for whom specific cortical areas related to language derive their names. Our objective was to examine language organization in the normal adult human brain, something that had been difficult, if not impossible, to do prior to the advent of modern imaging techniques. We began by asking how common English nouns are processed. How does the brain react when they are seen or heard? What is added when the seen or heard nouns are spoken? And, finally, what parts of the brain are engaged when one is required to consider their meaning? These questions resulted in a hierarchical paradigm in which, first, words seen or heard were contrasted with simply viewing a blank screen with central fixation point. Next, subjects were asked to say aloud the word they heard or saw, and these images were compared to just viewing or hearing the words. Finally, subjects were asked to generate a verb appropriate to the nouns heard or seen (e.g., see hammer, say hit).

Our PET imaging study of single word processing (Petersen, Fox, Posner, Mintun, and Raichle, 1988) provided a clear delineation of the cortical and subcortical networks involved in the different levels of single word processing. It also represented the culmination of 17 years of work in assembling the necessary imaging equipment and strategies to perform the experiments. It was a team effort with gratifying results. Much related work followed including the demonstration of cerebellar involvement in novel, high-level cognition (Petersen, Fox, Posner, Mintun, and Raichle, 1989); more detailed analyses of words and word-like symbols (Petersen, Fox, Snyder, and Raichle, 1990; e.g., pseudowords, consonant letter strings, and false fonts); and the effect of novelty on the organization of brain networks (Raichle et al., 1994). Gratifyingly, most of the findings and concepts enunciated in these early works have been amply confirmed in a large number of studies by others (for a recent comprehensive review of language studies with PET and fMRI see Price, 2012).

A Return to Brain Metabolism

One of my earliest contributions to our understanding of the relationship between brain function and metabolism was a study I performed in St. Louis prior to the development of imaging. It had long been assumed that activity-induced increases in blood flow were required to provide the added oxygen needed for an increase in brain energy metabolism. This belief was supported by data collected prior to my arrival in St. Louis showing that, in the resting state, blood flow and oxygen consumption were regionally correlated. With the techniques available to me in the Ter-Pogossian lab and a new probe system in the neuroradiology suite, we were positioned to test the hypothesis that blood flow and oxygen consumption would increase together to supply the added energy requirements of increased neuronal activity. Unfortunately we were unable to perform an experiment in normal persons because of the risks associated with the insertion of a needle into the carotid artery. However, we did have a subject in for evaluation of mild cognitive impairment who agreed to rhythmically squeeze an inflated blood pressure cuff while we repeated his measurements of blood flow and oxygen consumption. Just as had been predicted, oxygen consumption increased with blood flow in the hemisphere contralateral to the active hand. Combining these data with the earlier studies in the resting state, we published our results in the Archives of Neurology in 1976 (Raichle, Grubb, Gado, Eichling, and Ter-Pogossian, 1976). For a number of years thereafter, this was my most cited publication. It troubled me, however, that our evidence that blood flow and oxygen consumption increased together during increases in brain activity was based on data from a single subject.

In the mid-1980s, Peter Fox and I decided to do the proper study with PET and validate our original observation that blood flow and oxygen consumption are correlated during changes in brain activity. We were certain that our results would confirm our earlier finding especially because that was accepted dogma. To our immense surprise, we could not replicate our original finding, try as we might with different stimuli (visual and somatosensory) and correcting for everything we could think of (e.g., venous contamination). Fortunately for what was to follow, we had done our homework with regard to our PET methods. They were, based on our earlier validation studies, giving us the correct answer.

We finally decided to present and publish our data. Oliver Lowry, the only member of the Washington University faculty who was a member of the National Academy of Sciences at the time, agreed to communicate our results to Proceedings of the National Academy of Sciences (PNAS). They were published in 1986 (Fox and Raichle, 1986), and the reaction was immediate, “The results couldn’t possibly be correct.” The criticisms, coming as they did from established figures in the field, seriously stifled discussion of the results at meetings. The reaction was particularly surprising given the fact that our finding was not novel.

In the early 1970s, a meeting was held at the Royal Danish Academy of Sciences under the auspices of the Alfred Benzon Foundation. The title of the symposium was “Brain Work: The Coupling of Function, Metabolism, and Blood Flow in the Brain.” In attendance were all of the major researchers in the field. Also present were several others including me. Most noteworthy was a researcher from the Bearden Epilepsy Hospital in England by the name of Ray Cooper. He was involved in the use of electrocorticography to locate epileptic foci in the cortex of patients with intractable seizures. Because he was using bare metal electrodes, he took it upon himself to measure cortical oxygen availability at the same time. Depending on the location of his electrodes, he asked his patients to perform various tasks from simple motor movements to more complex cognitive tasks. His results were unambiguous; increases in activity of the cortex were accompanied by significant increases in oxygen availability, directly analogous to our later findings with PET. Surprisingly, there was no reaction to his findings of the sort we experienced. Not even comments about how to explain them.

Undaunted, we pushed forward with a second study. The question was whether glucose metabolism also failed to follow blood flow during increases in brain activity. In our 1986 PNAS paper, we actually speculated that blood might be acting alone. Surprisingly, that was not the case. In our second paper, published in Science in 1988 (Fox, Raichle, Mintun, and Dence, 1988), we showed again that activity-induced increases in blood flow significantly exceeded increases in oxygen consumption but, contrary to our expectation, glucose consumption increased in parallel to blood flow. This brought up the role of glucose metabolism outside of oxidative phosphorylation, so-called aerobic glycolysis, a subject to which I will return later in this chapter.

The most immediate consequence of our observation that blood flow changes exceeded those of oxygen was to provide a physiological basis for the emergence of functional magnetic resonance imaging, or fMRI.

The Emergence of Functional Magnetic Resonance Imaging

Magnetic resonance imaging (MRI) emerged as an important imaging modality on the basis of Paul Lauterbur’s demonstration that, by combining classical nuclear magnetic resonance (NMR) with magnetic field gradients surrounding an object of interest, it was possible to create a 3-D image of the object. From this seminal observation emerged magnetic resonance imaging, or MRI.²⁰ The great strength of MRI was its superb ability to image soft tissues of the body, something that CT could not do. It was an immediate success in medicine. Also, it established itself as the technique for anatomical imaging of the brain, a role that it retains without rivals to this day. The idea that MRI could also image function was also present in the minds of many. The task was to find an MRI contrast agent that was sensitive to changes in blood flow.The first attempt at using an MRI contrast agent to look at changes in the brain was performed in the Martinos Laboratory of the Massachusetts General Hospital (Belliveau et al., 1991). They intravenously administered a paramagnetic contrast agent²¹ that was sensitive to changes in blood flow and were able to demonstrate that MRI could be used in this way to monitor changes in brain activity. The problem with an administered contrast agent such as the one used at the Martinos Laboratory was that rapidly repeated measurements of the type being performed with PET and H₂¹⁵O were not possible.

The answer for MRI came from the Bell Laboratories and the work of Seiji Ogawa and colleagues. Seiji received his PhD from Stanford in nuclear magnetic resonance (NMR), working on the structure of hemoglobin. He continued to pursue research on hemoglobin at the Bell Labs. He was aware of the 1936 work of Linus Pauling on the magnetic properties of hemoglobin (Pauling and Coryell, 1936). In that work, Pauling and Coryell demonstrated that deoxyhemoglobin was paramagnetic. Based on this old observation, Ogawa posited that if blood flow increased more than oxygen consumption during increases in brain activity then the MRI signal would increase locally due to the reduced amount of deoxyhemoglobin present. He tested the idea by varying the concentration of oxygen in the air breathed by rodents in his MRI machine. As the concentration of oxygen was increased, the dark lines representing veins in the rodent brains disappeared. From this, he coined the term blood oxygen level dependent (or BOLD) signal, which has subsequently become synonymous with fMRI (Ogawa, Lee, Kay, and Tank, 1990). Because of its versatility and availability, MRI has become the tool of choice for mapping the function and anatomy of the human brain as well as those of laboratory animals from monkeys to rodents. Four studies appearing almost simultaneously in 1991 introduced fMRI BOLD imaging in humans (Bandettini, Wong, Hinks, Tikofsky, and Hyde, 1992; Frahm, Bruhn, Merboldt, and Hanicke, 1992; Kwong et al., 1992; Ogawa et al., 1992) and all embraced our earlier work (Fox and Raichle, 1986; Fox et al., 1988) as the physiological basis of BOLD imaging.

Imaging has become an increasingly important part of research in neurosciences, as well as the social sciences, and it is also an important face for brain research in the lay community. Using the search term “fMRI” PubMed presently finds more than 21,000 papers in the world’s literature published since the introduction of fMRI in 2001. An additional 14,000-plus papers can be attributed to PET using the search terms “PET” and “brain.” The thirst for information about brain function is universal, and imaging, for better or worse, has become a medium for the discussion.

A Paradigm Shift

Functional brain imaging, first with PET and now with fMRI, has followed a long tradition in neuroscience: studying neuronal responses to stimuli and activity during task performance. In this work, the role of bottom-up versus top-down (or feedforward versus feedback) causality is frequently discussed, reflecting a debate that extends back at least a century on the relative importance of intrinsic and evoked activity in brain function.

“Intrinsic activity” is ongoing neural and metabolic activity that is not directly associated with subjects’ performance of a task. The distinction between intrinsic activity and task-evoked activity applies at many levels of neurophysiological examination, including events at the cellular level where ion channel proteins, receptors, and the components of signal transduction pathways turn over with half-lives of minutes, hours, days, and weeks (Marder and Goaillard, 2006). Brain imaging has recently entered this discussion with information that will likely be important in shaping future research. It suggests to me an impending paradigm shift (Kuhn, 1996) brought about by surprising discoveries in imaging research that have occurred against a background of complementary work in electrophysiology and cell biology. I briefly review evidence that persuades me of this view.

Since the beginning of the 20th century and possibly earlier, two views of brain function have existed (for a comprehensive review, see Raichle, 2010). One view, pioneered by the early work of Sherrington (1906), posits that the brain is primarily reflexive, driven by the momentary demands of the environment. The other view is that the brain’s operations are mainly intrinsic, involving the acquisition and maintenance of information for interpreting, responding to, and even predicting environmental demands, a view introduced by a disciple of Sherrington’s, T. Graham Brown (1915). (For a review of his work in a modern context, see Yuste, MacLean, Smith, and Lansner, 2005.) The former has motivated most neuroscience research including that with functional neuroimaging. This is not surprising because experiments designed to measure brain responses to various stimuli and carefully structured tasks can be rigorously controlled, whereas evaluating the behavioral relevance of intrinsic activity can be an elusive enterprise. How do we adjudicate the relative importance of these two views in terms of their impact on brain function?

One means of evaluating the relative importance of evoked and intrinsic activity is to examine their cost in terms of brain energy consumption. In the average adult human, the brain represents about 2 percent of the total body weight but accounts for 20 percent of all the energy consumed (Clarke and Sokoloff, 1999). This high energy consumption occurs in the resting state—a behavioral state characterized by quiet repose either with eyes closed or open with or without visual fixation. During the resting state, subjects experience an ongoing state of conscious awareness largely filled with stimulus-independent thoughts (i.e., mind wandering or daydreaming). It is noteworthy that in rats and monkeys, the brain accounts for 2.4 and 5 percent of the energy consumed by the body, significantly less than in humans. Furthermore, relative to the very high rate of ongoing or “basal” energy consumption in humans, the additional energy consumption associated with evoked changes in brain activity is remarkably small, often less than 5 percent (Raichle and Mintun, 2006). This low figure likely applies to stimulus-independent thoughts as well. From these data, it is clear that the brain’s enormous energy consumption is little affected by task performance, an observation first made more than 50 years ago (Sokoloff, Mangold, Wechsler, Kenney, and Kety, 1955; for prescient insights, see also Creutzfeldt, 1975).

What is the nature of this ongoing intrinsic activity that commands such a large amount of the brain’s energy resources? Measurements of brain energy metabolism using magnetic resonance spectroscopy (Sibson et al., 1997, 1998; Shulman, Hyder, and Rothman, 2001; Shulman, Rothman, Behar, and Hyder, 2004) in a variety of experimental settings have indicated that 60–80 percent of overall brain energy consumption is devoted to glutamate cycling and, hence, neuronal signaling. Complementary analyses using extant anatomic, physiologic, and metabolic data (Wong-Riley, 1989; Ames, 2000; Attwell and Laughlin, 2001; Lennie, 2003) to assess the cost of different components of excitatory signaling in the gray matter have arrived at similar conclusions. Such estimates leave for future consideration the demands placed on the brain’s energy budget by the functional activity of inhibitory interneurons and glia (Magistretti and Chatton, 2005; Buzsaki, Kaila, and Raichle, 2007). That evidence notwithstanding, it is likely to remain the case that the majority of brain energy consumption is devoted to functionally significant intrinsic activity. The challenge, of course, is how to study these intrinsic brain processes. Functional brain imaging has provided some intriguing new insights.

Unmasking the Brain’s Intrinsic Activity

Prior to our first published work on the subject, the idea that there might be an undiscovered network emblematic of the intrinsic organization of the brain simply did not exist. This network, now routinely dubbed the brain’s default mode network (DMN) emerged from an entirely unexpected observation made during our early work using PET to map human brain function. In this work, we routinely included an eyes-closed or a simple visual fixa-tion condition as one of the control conditions in our experiments. To some extent, this violated one of the canons of cognitive psychology in not controlling all of the variables in a control condition except the one of interest in the task itself. Whereas the control condition was simply resting quietly with eyes closed, it was clear that subjects were likely experiencing random thoughts unrelated to the experiment (i.e., mind wandering, daydreaming, or, more technically, stimulus-independent thoughts). Although we were very much aware of this “rule,” many of our earliest experiments were based, for example, on the presentation of visual stimuli, comparing their properties or position in the visual field to the absence of the stimulus. It was not clear what the control for such an experiment might be other than the absence of the stimulus. Over time, of course, our experiments became ever more complex, as I have indicated earlier, including increasingly sophisticated tasks as well as control conditions. Being creatures of habit, however, we continued to include a simple eyes-closed rest or visual fixation condition in many of our experiments. In hindsight. I can think of no other rationale.

Because the purpose of early brain mapping experiments was to look for regional increases in brain activity, so-called “activations,” the idea that areas of the brain other than those activated might reduce their activity was simply not considered and certainly not looked for. I do not recall when I first happened to look at the full spectrum of activity changes (i.e., decreases as well as increases) in subtraction images but when I did I was struck by the fact that, when using visual fixation or eyes-closed rest as the control condition, the most prominent decrease was in the posterior cingulate and adjacent medial precuneus. Attracted by the striking nature of these task-induced localized decreases in activity, I began collecting examples among our many ongoing experiments, and I placed them in a file entitled MMPA for “medial mystery parietal area.” A literature on this part of the cerebral cortex does exist, but it did not seem helpful in understanding our observations.

Several years after I began tracking the medial mystery parietal area, Gordon Shulman initiated a meta-analysis in our group of nine PET brain-mapping studies. His objective was to identify the network of areas comprising the brain’s attention network. This study appeared in three publications, one of which (Shulman et al., 1997) featured a network of brain areas that decreased its activity in all nine of the studies making up the meta-analysis. The most prominent component of this network was the MMPA (i.e., the posterior cingulate cortex and adjacent precuneus), but it also included all that we have come to know as the brain’s default mode network, or DMN (i.e., lateral parietal cortex bilaterally; dorsal and ventral medial prefrontal cortex; and medial temporal cortices).

The immediate response to the discovery of the DMN was a reminder from the scientific community that we had inadequately controlled for the ongoing mental state of our subjects and, therefore, could not interpret the results (for a review, see Raichle and Snyder, 2007). Our rejoinder (Raichle et al., 2001), published four years later and titled “A Default Mode of Brain Function,” showed that the areas in questions (i.e., the DMN) were not activated during the resting state (i.e., the DMN did not exhibit the dissociation between blood flow and oxygen consumption typical of activated regions).

Creating a physiological distinction between activation and ongoing or intrinsic activity in a brain area or network of brain areas, based on quantitative measures of regional brain circulation and metabolism (Raichle et al., 2001), opened up a discussion of the importance of the brain’s intrinsic activity that had been dormant for many years. Leading this discussion has been the brain’s DMN, but the characteristic features of its intrinsic activity are shared by all other brain systems and their subcortical connections. This expanded view came to light through the rediscovery of an observation made many years ago that spontaneous fluctuations in cortical oxygen availability (so-called oxygen waves) exhibit patterns of spatial coherence (for a review of this early work, see Raichle and Mintun, 2006). At the time that these patterns were observed in experimental animals, the focus of the research was on the mechanics of capillary physiology (i.e., did capillaries of the brain exhibit spontaneous opening and closing that characterized capillaries in other vascular beds such as the lung?). Evidence against this hypothesis was, in part, that homologous areas of the cerebral hemispheres exhibited correlated fluctuations. The focus of this research was definitely not on how this correlated activity might reflect a basic feature of brain functional organization. Once the argument was settled, these remarkable observations were largely forgotten.

As a graduate student at the Medical College of Wisconsin, Bharat Biswal was assigned by his thesis advisor, James Hyde, to investigate the origin of spontaneous “noise” in the fMRI BOLD signal. Prior to his work, this “noise” was removed from mapping studies by image averaging. During the course of his investigation, he and his colleagues asked if this spontaneous activity in one area of the cerebral cortex was correlated with activity in any other part of the brain. Choosing somatomotor cortex in one hemisphere, they immediately discovered that the spontaneous fluctuations in that area were strongly correlated with activity in the contralateral somatomotor cortex (Biswal, Yetkin, Haughton, and Hyde, 1995).

Much controversy surrounded Biswal’s observation with concern that what he observed might be related to respiratory-induced fluctuations in CO₂ or fluctuations in cardiovascular dynamics (e.g., slow variations in cardiac output). We were aware of Biswal’s observation but did not pursue its implications until Michael Greicius and colleagues at Stanford examined the pattern of spatial coherence arising from spontaneous fluctuations in the fMRI BOLD signal in the posterior cingulate and adjacent precuneus (i.e., a primary node of the brain’s DMN) (Greicius, Krasnow, Reiss, and Menon, 2003). What they observed was the complete anatomy of the DMN. We were astonished! Almost overnight this observation galvanized our interest and that of others.

Studies of the brain’s intrinsic activity using resting state fMRI BOLD imaging have become a dominant theme in human brain mapping (for review, see Fox and Raichle, 2007). By latest count, there are almost 3,000 papers on the subject on topics ranging from development to aging in health and disease. It is playing an increasingly important role in issues related to mental health where disorders of the intrinsic functional organization of the brain likely will be critical to their understanding and treatment. It is also becoming an important tool for presurgical planning and even intraoperative guidance (MRI scanners are appearing in increasing numbers in neurosurgical operating rooms). The DMN has remained central to this story, assuming a preeminent role in the brain’s functional organization.

Metabolism, Development, and Disease

Brain metabolism has been a constant theme in my work, beginning with my indoctrination in the laboratory of Fred Plum and Jerry Posner through my studies of the origin of the fMRI BOLD signal and the identification of the DMN. Remarkably, for me at least, the theme continues with a focus on the role of glucose metabolism outside of oxidative phosphorylation (i.e., referred to as glycolysis or aerobic glycolysis depending on whether you are an endocrinologist or an oncologist, respectively). In my 1970 paper with Fred Plum and Jerry Posner (Raichle, Posner, and Plum, 1970), our data revealed that aerobic glycolysis accounted for 10–12 percent of glucose metabolism. At the time, we took little note of this.

In my 1988 paper with Peter Fox, Mark Mintun, and Carmen Dense (Fox, Raichle, Mintun, and Dence, 1988), we observed that glucose metabolism increased with blood flow but oxygen consumption did not. Many discounted this as unimportant because of the small amount of energy produced by glycolysis alone. However others, particularly Pierre Magistretti and Luc Pellerin, pursued this lead and were able to show that glycolysis plays a critical role in the removal of glutamate from the synapse (Magistretti, 2011). Specifically, glycolysis fuels the Na⁺/K⁺-ATPase in astrocytes where glutamate is taken up along with sodium. Their work and that of others have shown that lactate may not only function as an alternate fuel source for neurons (now referred to as the “reverse Warburg effect” [Pavlides et al., 2010]) but also as a signaling molecule (for example, see Suzuki et al., 2011).

In 1994, Peter Lund Madsen and colleagues in Copenhagen reported that not only did glycolysis increase more than oxygen consumption during brain activation but that following the completion of the task glycolysis persisted for well over an hour despite the fact that blood flow and lactate production returned to control levels (Madsen et al., 1995). They suggested that one of the possible explanations was that glycolysis was participating in biosynthesis related to learning and memory, a hypothesis consistent with the well-known role of glucose in proliferating cell systems (e.g., in cancer where it is known as the Warburg effect after its discoverer). Consistent with this view was our much earlier work (Altman, Perlman, Volpe, and Powers, 1993; Powers, Rosenbaum, Dence, Markham, and Videen, 1998) and that of others (Kennedy and Sokoloff, 1957; Settergren, Lindblad, and Persson, 1976; Chugani, Phelps, and Mazziotta, 1987) on human infant metabolism, which showed that the newborn was remarkably glycolytic (approximately 30 percent of the metabolized glucose); that by age of two, the glucose metabolism of the developing human infant was already at adult levels and, by the end of the first decade, it was twice the adult level at a time of rapid synaptic proliferation in the developing brain.

All this prompted us to ask whether, in the adult brain, aerobic glycolysis was distributed uniformly or not. Nobody had ever bothered to ask that question. The results of the query were quite astonishing (Vaishnavi et al., 2010). Aerobic glycolysis was very nonuniformly distributed in the normal human adult brain. It was highest in the DMN and lowest in the cerebellum and the medial temporal lobes. And, although the DMN has a relatively high metabolic rate, it is second to the primary visual system where aerobic glycolysis is much lower than in the DMN. Thus, aerobic glycolysis is not a simple function of the overall metabolic rate of a brain region.

Following the discovery of the nonuniformity of aerobic glycolysis in the human brain, we have been trying to determine what functions it is performing. The strategy we have chosen is to examine regional gene expression in the human brain in collaboration with the Allen Institute in Seattle and to determine on an anatomical basis what genes vary in their expression with the level of aerobic glycolysis. Our studies (Goyal et al., 2014) so far indicate that aerobic glycolysis correlates with gene expression typical of infancy and is related to synapse formation and neurite growth (i.e., transcriptional neotony). In contrast, regions with high rates of glucose oxidation (e.g., primary visual cortex) express genes that are related to mitochondria and synaptic transmission. Our findings are consistent with the view that “each neuron is constantly rebuilding itself from its constituent proteins using all of the molecular and biochemical machinery of the cell” (Marder and Goaillard, 2006), a view consistent with our recently published work on gene expression-based modeling of synaptic density in the human brain (Goyal and Raichle, 2013).

Finally, our work on the functional organization of the brain’s intrinsic activity and its unique metabolic features has focused our attention on Alzheimer’s disease. One of the pathological hallmarks of Alzheimer’s disease is the accumulation of amyloid plaques in the brain. Several years ago, investigators at the University of Pittsburgh developed a PET-based radiopharmaceutical (Pittsburgh Compound B, or 11C-PiB) that binds to amyloid plaques (Klunk et al., 2004). One of the first revelations was that plaques accumulate preferentially in the DMN even before the onset of clinical signs and symptoms of the disease. One of the striking features of this association is the relationship between amyloid plaque distribution and the level of aerobic glycolysis (Vlassenko et al., 2010). This association between a unique brain network, its unusual metabolism, and the occurrence of Alzheimer’s disease has opened up new ways of thinking about the pathophysiology of this dreaded disease.

Summary

It has now been 55 years since I entered the classroom of Dr. Dixie Lee Ray at the University of Washington. I was a junior majoring in history and political science envisioning a career in law like my father. I suddenly realized that there was a fascinating world of biology to be explored that I had never considered. The abrupt change in my career trajectory was a challenge, at times a bit frightening, but one that I have never regretted. The opportunities afforded me over the years have been extraordinary. The thrill of discovery remains undiminished.

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¹For many, the name Raichle is often associated with the famous ski and hiking boots by that name. The business was started by brothers of my grandfather. The Raichle family in Dettingen ran a blacksmith shop behind their home. How boot-making became an interest and a trade is unclear.

²My grandfather Lawrence Hopkinson was a descendent of Thomas Hopkinson (1709–51), who immigrated to Philadelphia from England in 1731. He was the first president of the American Philosophical Society and a founder of the University of Pennsylvania. His son, Francis Hopkinson, was a signer of the Declaration of Independence.

³Seven in my high school graduating class of 276 went to Stanford. I was also accepted but opted for the University of Washington, a choice I have never regretted.

⁴My penultimate performance was the Mozart quartet for oboe, violin, viola, and cello that I performed with my high school classmates Jim Enden and the Cole sisters, winning top honors in the state high music competition. The last time I performed the piece was at our high school graduation.

⁵This dismayed my parents when I was young. They would often find things dismantled, such as the toaster, due to my tinkering and inability to properly reassemble the device. Sometimes it bordered on the serious, I am told, when it involved lamps and light sockets at a time when safety devices to keep the hands of inquisitive children out of danger were not available. The desire to understand how things work has possessed me all of my life and has ranged from the carburetors of my 1960 Mercedes Benz roadster to the brain.

⁶The one science course I had not taken in high school was biology!

⁷This, of course, can be applied to other metabolites, most noteworthy being glucose as well as lactate, an important product of glucose metabolism.

⁸The basic relationship of carbon dioxide to bicarbonate was first described by Lawrence Henderson in 1908 and later expressed by Karl Hasselbalch in logarithmic form. Crediting the work of both, it is classically referred to as the Henderson-Hasselbalch equation. Carbon dioxide concentration is the numerator and bicarbonate is the denominator of this simple equation. Decreasing carbon dioxide concentration decreases hydrogen ion concentration (i.e., increases pH, which is the negative logarithm of the hydrogen ion concentration).

⁹This was observed in high altitude experiments performed by John Severinghaus, Tom Hornbein, and their colleagues.

¹⁰I will never forget the squeaking sound in my right ear as the catheter was advanced percutaneously into my jugular bulb.

¹¹No consent form was signed and no consultation with an institutional human studies review board even discussed!

¹²All of the original Mercury astronauts were medically evaluated at the School of Aerospace Medicine.

¹³This was in part stimulated by the work ongoing at the Hammersmith Hospital in London where the first cyclotron for biomedical research had been installed in a hospital setting several years earlier.

¹⁴These experiments were occurring more than two decades before the introduction of imaging as we know it today.

¹⁵Positron-emitting radionuclides decay by the emission of a positron that travels a few millimeters in tissue before interacting with an electron. This interaction produces a pair of 511 keV photons traveling at 180⁰ from each other. Prior to the invention of positron emission tomography (PET), the only way to know where this radiation was coming from was to surround detectors with lead to focus or collimate what they received.

¹⁶Data consisted of residue curves following a pulse injection of the radiopharmaceutical into the internal carotid artery. The data were printed out on semilog paper for analysis. Several analysis strategies were employed as described in our early papers.

¹⁷It is of historical interest that the original CT scanner, known at the time as the EMI scanner for the company in which it was developed, was specifically designed to image the brain. The reason for this had largely to do with the sources of funding available to Hounsfield and his colleagues (for historical reviews see Raichle, 2000).

¹⁸Deoxyglucose is an analogue of glucose and is readily taken up by brain cells and phosphorylated to deoxyglucose-6-phosphate. In contrast to glucose, deoxyglucose cannot be metabolized further and cannot be dephosphorylated. As a result, it is trapped in the cell in an amount that reflects the rate of the initial step in glucose metabolism.

¹⁹It is obvious that one could do a hypothesis-generating experiment first followed by a hypothesis-testing experiment but then the question arises, “How many areas of interest do you include in your analysis” As the number of areas increases, so does the required level of statistical significance. We used to refer to it as being “Bonferroni’d to death” after the Italian mathematician Carlo Emilio Bonferroni who proposed a method used to counteract the problem of multiple comparisons. His is considered the simplest and most conservative method but, unfortunately, deals a crippling blow to most complex imaging paradigms.

²⁰The term nuclear was dropped to avoid any association with ionizing radiation.

²¹The presence of a paramagnetic contrast agent reduces the strength of the MRI signal that can be detected in the MRI image. Because deoxygenated hemoglobin is paramagnetic, veins appear dark on an MRI image of the brain.

Photo by Luis Delfin, Quo, Mexico

Pablo Rudomin

BORN:

Mexico City, Mexico

June 15, 1934

EDUCATION:

National School of Biological Sciences, National Politechnic Institute, Mexico, BS (1954)

Center of Research and Advanced Studies, National Polytechnic Institute, Mexico, PhD (1961)

APPOINTMENTS:

Professor, Center for Research and Advanced Studies

National Politechnic Institute, Mexico (1961–1995)

Executive Chairman, National Program of Basic Sciences, Mexico (1985–1992)

Emeritus Professor, Center for Research and Advanced Studies, National Politechnic Institute, Mexico (1996)

Member of El Colegio Nacional (1993–present)

HONORS AND AWARDS (SELECTED):

Prize “Alfonso Caso,” Mexican Academy of Sciences (1972)

National Prize of Sciences, Mexico (1979)

Fogarty Scholar in Residence, National Institutes of Health, Bethesda, MD (1984–1987)

Prize “Príncipe de Asturias” for Scientific Investigation, Spain (1987)

Prize “Luis Elizondo” in Medical and Biological Sciences (1989)

Endowed Chair, Council of Science and Technology, Mexico (1995–2013)

Chairman of the Scientific Advisory Council to the President of Mexico (1995–2003)

Medal and Prize “Lázaro Cárdenas,” National Polytechnic Institute, Mexico (1996)

Emeritus Investigator, National System of Investigators, Mexico (1996)

PhD, Honoris Causa, Puebla Autonomous University, Mexico (2003)

Special Recognition, Independence Bicentennial, State of Mexico, Mexico (2010)

PhD, Honoris Causa, Nuevo León Autonomous University, Mexico (2011)

PhD, National Autonomous University, Mexico (2011)

Award “State of Mexico,” Mexico (2012)

Medal for Outstanding Research, University of Veracruz, Mexico (2013)

Pablo Rudomin has carried out fundamental neurophysiological work on the functional organization of the spinal cord. His major contributions have centered on the mechanisms and pathways involved in the presynaptic control of the synaptic efficacy of sensory fibers. These studies have demonstrated that the intraspinal terminals of the sensory fibers are not hard-wired routes that send divergent excitation to spinal neurons but are instead dynamic pathways that can be centrally controlled to address information to selected neuronal targets.

Pablo Rudomin

Introduction

When I was invited by Larry Squire to write my scientific autobiography, I hesitated because it was not just a matter of presenting a perspective of the research I have done throughout the years. Although science is universal, we scientists live in specific countries and are products of the circumstances that surround us. It is not the same to be a scientist in the United States or in Europe as to be a scientist in a country where science is not yet a tradition. For those who live in countries such as Mexico, the challenge has been, and still is, to create the material and social conditions required to have an active and productive system of science and technology. In Mexico, this process started not long ago and was headed by a small group of scientists and physicians who founded the institutions where many of my generation could work.

Although many of us benefited from their efforts, there is no such thing as a free lunch. We inherited the responsibility of doing the best science we could. This was not a matter of just having good working conditions. It was also the responsibility of training students, contributing to the formation of new investigators, and of developing the strategies to convince society and government that science and technology should be considered as a national priority. It was also the continuous and everlasting struggle against local indolence and bureaucracy.

Writing this text has been a journey to the past and an occasion to examine my scientific and personal endeavors under the perspective that one acquires with experience. What is clear to me is that all my contributions have been “me and my circumstances” as Ortega y Gasset used to say. It has been me and my origins, me and my family, me and my friends, me and my colleagues, and, of course, me and Mexico.

Seen in retrospective, for me to do science in Mexico has been a wonderful experience, despite all the drawbacks. It has been very rewarding to know that besides some scientific achievements, I could modestly contribute to the development of science. To quote Newton: “I was like a boy playing on the sea-shore, and diverting myself now and then finding a smoother pebble or a prettier shell than ordinary, whilst the great ocean of truth lay all undiscovered before me.” That is the way I feel. Science has been to me an enjoyable game that even now I like to play.

These are fascinating times to be in science—new findings and new discoveries every day. Yet, as time passes, I am more and more concerned about our social inability to use the available knowledge to construct a free and peaceful world without racism and poverty.

My Origins

I came from a Jewish family of immigrants. My father, Isaac, was born in 1896 in Smorgon, a small town, at that time part of Russia, and of Poland between World Wars I and II. He was from a rather poor family who migrated to the United States in the early 1920s, after the Soviet revolution. It was never clear to me how his parents, brothers, and sisters could enter the United States and why he, being the youngest in the family, went to Mexico where he stayed for a couple of years. He moved to New York around 1926–1927 where he remained until 1929, the height of the Great Depression. Back in Mexico, he worked as a peddler traveling around the country, selling the merchandise he could carry in a small suitcase. Later on, he settled in Mexico City and started a small business buying and selling metal junk.

The family of my mother, Sonia, arrived in Mexico in the mid-1920s. She was born in 1915 in Proskurov, Ukraine. Her mother, Rivka Barzaj came from a wealthy family that lost everything during the Soviet revolution. She was married to my grandfather Moses Zevnovaty, who soon after the wedding was drafted into the tsar’s army and went to the front during World War I. He was caught and imprisoned somewhere in the Austrian-Hungarian camps where he remained until the end of the war. At that time, my mother was four years old.

Somehow, the family learned that Grandfather Moses was still alive, and my Grandmother Rivka traveled alone through devastated camps and cities until she found him. Apparently, it was necessary to pay for his release. He was a handsome man. Family stories relate that, while a prisoner, he was sent to take care of the gardens of a Hungarian duchess. She would not let him go when the war was over so, when my grandmother came, both escaped in the middle of the night, being chased by the servants. Back in Ukraine, they survived the pogroms and the revolution and somehow were able to leave for Mexico around the early 1920s.

To them, life in Mexico City was rather difficult. To complement the family’s low budget, Grandmother Rivka walked through the streets selling live fish that she carried in buckets filled with fresh water. Later on, my grandfather got a job on one of the first tomato farms in Tamazula, Sinaloa. They stayed there some time until they moved to Guadalajara, where they opened a shoe store. By then, my mother was 17 years old. My grandparents had some friends in Mexico City, and they invited my mother to visit them. This is when she met my father. They soon married and settled in Mexico City. It must have been around 1933. I was born in June 1934.

My First Years

I have vague memories of my first years at primary school. I have an image of myself as a shy boy, not very good at sports. When I turned 13 years old, I entered secondary school. One my teachers, Gilberto Hernández Corzo, introduced me to Oparin and his theories on the origin of life. The other, Luis O. Batres, was the first to talk of evolution and natural selection. He gave me some books to read. One was Microbe Hunters by Paul de Kruif, where he tells the stories of Leeuwenhoek, Spallanzani, Pasteur, Koch, Metchnikoff, and Ehrlich, among others. The other book was Heroes of Civilization. I believe it was written by José Rebolledo. This book described the life of Gutenberg, Columbus, Galileo, Franklin, and others that I do not remember now. What I do remember is that these readings had a great impact on me. I wanted to be a scientist even though I was not fully aware of what this meant in real life.

At that time, I discovered Verne and Dumas and was fascinated by their novels. I read most of them. It was also then that I learned about Galileo and Giordano Bruno and their problems with the Inquisition. What impressed me most was the reluctance (and even opposition) of the Church to accept the new concepts emerging from science. It was the search for knowledge that motivated me. I wanted to know. I wanted to learn. I had too many questions to ask and few answers. Because I came from a non-religious family, faith dogmas were unable to provide me the answers I was looking for.

In 1949, I left the secondary school and went to study at the Escuela Nacional Preparatoria of the National University. This was a new and exciting world. I made good friends and was exposed to a new and exciting environment. There was one, René Villanueva, whom I still remember with great affection. At home, my exposure to music was very limited—at most, Tchaikovsky and Chopin. René introduced me to Bach, Beethoven, Schubert, and Mozart. He later became the director of a well-known group of folk musicians. It was also a time of intense reading: Tolstoy, Dostoyevsky, Chekov, Gogol, Andreyev, Balzac, Victor Hugo, Dumas, Rolland, Istrati, Hess, and Gorki, and also the beginning of my awareness of social problems. I read Marx and Engels as well as Hegel and Kant.

My First Steps in Science

When I entered the National Preparatory, I wanted to be a chemist. At home, my father allowed me to have a small laboratory, where I tried, together with Marcos Rosenbaum, a good friend of mine, to repeat some of the experiments that we learned about at school. It was mostly a game, but it was fun and quite motivating.

I had wonderful teachers such as Esteban Minor in mathematics, Antonio Ramírez-Laguna in biology, and Salvador Mosqueira in physics, all of whom I remember with gratitude and affection. It was at that time when G. Hernández Corzo, with whom I kept in contact since I left secondary school, invited me to visit the research laboratories at the National School of Biological Sciences of the National Polytechnic Institute.

He was teaching there, and his brother Rodolfo was the director of the whole institute. I was captivated because I saw, for the first time, active laboratories and scientists who took their time to explain to me, a young inexperienced student, what they were doing. I learned that a fair number of the teachers were Spanish scientists who were able to escape from the civil war and settle in Mexico. It did not take me long to decide that this was a good place to study. And so it was.

I still remember some of my teachers with pleasure and gratitude. There were only a few students in the group, so we could really interact with all of them. I believe that this interaction, and knowing firsthand the research that some of them were doing, greatly contributed to my decision to become a scientist.

In 1952, I attended the physiology course given by Ramón Alvarez-Buylla. At the end of the course, he invited me to join his laboratory. He was around 33 years old at that time. He had come to Mexico from the Soviet Union where he had gone at the beginning of the Spanish civil war. He was a student of Pyotr Kuzmich Anokhin, himself a student of Ivan Petrovich Pavlov. During his stay with Anokhin, and later on in Mexico, he had made substantial contributions to understanding the information conveyed by single vagal chemo- and baroreceptor afferents.

When I joined his laboratory, he suggested that we should use the conditioned reflex as a tool to disclose which of the effects of a hormone were due to its direct action on the effectors and which resulted from activation of reflex pathways. We expected that effects mediated through a reflex action would be conditioned, while effects due to a direct action on effectors would not.

I started with adrenaline, Mauricio Russek with cyanide, and Juan Carrasco Zanini with insulin. The experiment I was to perform was relatively simple: to place a dog in a sound-isolated chamber and inject a small dose of intravenous adrenaline through a catheter while ringing a bell. After many of these trials, we would ring the bell without injecting adrenaline. As expected, we were unable to condition the increase in heart rate and blood pressure or the increase in blood sugar that was produced by the systemic injection of adrenaline. This was consistent with the well-known direct actions of this amine on the effectors. Quite surprisingly, we were also unable to condition the reflex bradycardia produced by the increased activation of the vagal baroreceptors that followed the rise in blood pressure, but we were able to condition the increase of glucose in the urine (glucosuria), even though there were no changes in glucose concentration in the blood. Later on, we found that conditioned glucosuria could not be produced in animals with chronically denervated kidneys and concluded that this effect was mediated by reflex pathways that controlled tubular reabsorption of glucose. One pending issue was to disclose the afferent and efferent pathways involved in this reflex.

These studies led to my first paper, which was published in Acta Physiologica Latinoamericana (Rudomin, 1957). Since then, I have not followed the literature on nervous control of renal functions. The role of renal nerves on the regulation of glucose handling and other organic and inorganic solutes was questioned after observations that transplanted kidneys regulated glucose, sodium, and potassium adequately before renal reinnervation was achieved. However, direct assessment of the effect of splanchnicotomy on renal handling of glucose in dogs showed a decrement of tubular reabsorption with a consequent increased glucosuria (Szalay et al., 1977). Also, bilateral renal denervation in diabetic rats increased urinary glucose and reduced the content of the glucose transporter GLUT-1, indicating a role of renal nerves on the regulation of tubular glucose transport (D’Agord et al., 2003). It thus seems that, after all, the nervous control of the tubular reabsorption of glucose plays a role in the homeostasis of blood sugar level.

My First Job

I earned my degree in biology by August 1956 and felt I should contribute to the house income. At home, they were not really eager for me to become a scientist. Jobs were scarce, and salaries were really low. Despite being a good student, I could not get a position as a research assistant in Alvarez-Buylla’s laboratory or a teaching position at the school. The dream of my father was that I should study mechanical engineering and help him in his business. But I wanted to keep with science.

Finally we reached an agreement. Within the next year, I would look for a job in science. If I could not find it, I would then study mechanical engineering as my father wished and also help him in his business. A good friend of mine told me that Juan García Ramos, then working at the Institute of Neumology, was looking for somebody to help him with the experiments. García Ramos was a former disciple and collaborator of Arturo Rosenblueth. I went to see him, and I was hired as his assistant. The salary was more symbolic than real but was my first paid job.

With García Ramos, I studied the dynamics of pulmonary circulation. We used oxymetry to measure the effects of vagal stimulation and systemic adrenaline and acetylcholine on the oxygen concentration in the blood circulating though the carotid artery. In cats under constant ventilation, we found that that the nervous system was able to regulate the number of alveolar capillaries involved in gaseous exchange. We also provided evidence for a direct vasodilator action of anoxia on the pulmonary capillaries, in opposition to the usual view of a vasoconstrictor action. The work I did with García Ramos was published in 1957 and 1958 in Acta Physiologica Latinoamericana (García-Ramos and Rudomin, 1957, 1958).

At the National Institute of Cardiology

After one year or so, García Ramos was leaving the Institute of Neumology to work at the department of physiology in the medical school of the National University. Because he had no way to find a position for me, he asked me if I would be interested in working in the department of physiology of the National Institute of Cardiology, headed by Arturo Rosenblueth.

I could not believe it. Rosenblueth was the most famous Mexican physiologist, and he had spent many years at Harvard working with Walter B Cannon and was a good friend of Norbert Wiener, with whom he had published a series of seminal papers. As a student of Alvarez-Buylla and as an assistant of García Ramos, I had attended Rosenblueth’s lectures at El Colegio Nacional, the Mexican equivalent of the College of France. His lectures were really interesting, and I was impressed by his clarity of exposition.

So I went to see him. I still remember how nervous I was. I feared that he would soon discover the many things I did not know that I was supposed to know. And I told him about these concerns. He just smiled and assured me that I should not worry because I would not be alone but would work together with a more experienced investigator. We agreed that I would start to work on January 16, 1957.

We lived relatively close to the Institute of Cardiology, so on the morning of January 16, I walked to the institute. I was so happy! By noon, I went back home for lunch. Quite unusually, my father was there. He did not feel well, so I called the cardiologist. He came, took an electrocardiogram (EKG), and told me not to worry. He prescribed some medicines that I bought and gave him and went back to the laboratory. One hour later a neighbor called and told me I should came home immediately because something terrible happened. I hurried but it was too late. My father had passed away. He was alone with Malka, my 13-year-old sister. At that time, he was 62 years old.

While I am writing this, I still remember the sense of guilt I had for not having been there and perhaps having a chance to save him. My mother was in my father’s shop and soon came. There was a sense of despair and impotency.

Soon after, the question was raised as to who should take care of my father’s business. My mother, then 42 years old, used to help him, but this was not a place for a young woman. I learned that we lived day by day. My father had no life insurance and left no savings but also no debts. There was a family reunion, and they expected that I should help my mother at the shop. But to keep up with science was my dream, and I was not ready to give it up, precisely when I was just starting to work under Rosenblueth’s guidance!

I reasoned that the salary that I was about to earn would allow us to survive. We could pay the rent and buy food, and this would give us time to find an alternative solution. In the meantime, my grandfather, then 67 years old, agreed to help my mother. A few weeks later, Ilana, my oldest sister and her husband Zvi, came from Israel, where they were living. My brother-in-law agreed to work at the shop, so I could stay with science. Nevertheless, I felt guilty. I believe that this feeling contributed to my commitment to science throughout all these years, perhaps to convince myself that this was the right decision.

I worked in Rosenblueth’s department for two and a half years. These were the days when open-heart surgery was beginning. Ernesto Deutsch and I were asked to examine the effects of successive periods of hypoxia on the excitability of the heart muscle and on the blood pressure–controlling mechanisms. We expected that this information could be of some use to the heart surgeons. In the normal animal, hypoxia increases blood pressure. We found that this response was reduced with successive episodes of hypoxia and eventually resulted in a blood pressure fall, even though the animal had recovered its control blood pressure. At the same time, the cardiac cycle was lengthened because of increased vagal activity. The auricular and auricular-ventricular conduction velocity was reduced, and the threshold of the cardiac muscle to direct activation was increased. Perhaps the most interesting feature of this work was the demonstration of cumulative changes in vasomotor control that gradually impaired the dynamic response to hypoxia. It was clear that the initial state of the system was a factor that determined the subsequent response of the system to situations that endangered its integrity (Rudomin and Deutsch, 1958).

With David Erlij and Peter Eberstadt, I examined the effects of hypoxia and of hypoventilation on the cardio inhibitory reflexes (Rudomin et al., 1959). We found that these procedures increased the reflex slowing of the heart (bradycardia) that was produced by electrical stimulation of the depressor nerve. We concluded that this effect was mostly due to the activation of circulatory chemoreceptors, which facilitated impulse transmission along the cardio-inhibitory reflex pathway. Soon after, Rafael Rubio and I showed that the increase in reflex bradycardia produced by hypoxia resulted from a preferential activation of lung vagal chemoreceptors (Rudomin and Rubio, 1959).

These findings led to a series of studies on the influence of asphyxia and of some drugs known to activate lung, aortic, and carotid chemoreceptors on the bradycardia produced by stimulation of the depressor nerve and of the bulbar reticular formation (Rudomin, 1959a,b). I found that reflex bradycardia was more facilitated after injecting small amounts of cyanide and veratridine into the right auricle than into the left auricle, a finding suggesting a possible contribution of lung chemoreceptors. In contrast, lobeline and phenyl-guanidine, assumed preferentially activate carotid and aortic chemoreceptors, were unable to facilitate the cardio-inhibitory reflex. These observations indicated that lung chemoreceptors and aortic and carotid chemoreceptors played different roles in the homeostatic control of blood pressure and heart rate.

Seen in retrospective, I still believe that these were original and interesting findings that contributed to understanding the role played by circulatory chemo- and baroreceptors in vasomotor control. Unfortunately, all these findings were barely referred to by researchers in the field, most likely because they were published in Spanish in a Latin American journal of rather limited circulation. At that time, my English was rather poor (even now), and I was not encouraged by my mentors to publish in internationally reputed journals, mostly because they were convinced that we, as Mexicans, should publish our best contributions in Latin American journals.

Starting a Family

In November 1957, I married Flora Goldberg, and we are still together after 56 years! This was the best decision in my life.

Flora’s parents were born in Poland at the beginning of the last century. Because of their political activism, they were jailed and later forced to leave Poland. They went to Belgium and afterward to Paris, where Flora was born in 1935. When the Germans invaded France, being non-citizens of Jewish origin, had no other alternative but to leave Paris and escape to Nice, still part of “free” France. This was not an easy journey. The family was divided. Flora traveled with her mother (Ruth) and her small brother (Juan). Flora’s father (David), who had joined the French resistance, traveled alone, while Flora’s sister (Juliana) traveled to Nice with some family friends to meet her father. Flora and her brother and mother went through different towns, sometimes taking trains and other times walking through the woods, always hiding from the Germans and their dogs. They all arrived safely at Nice.

At the beginning of 1942, Flora’s family was able to get a visa to Cuba. They traveled to Marseille and from there to Casablanca, where they took a cargo ship heading to Havana. The ship was also carrying many Spanish Republicans as well as some Jewish refugees from Austria who were granted a visa as political refugees by Gilberto Bosques Saldívar. He was a Mexican career diplomat. As a consul in Marseille, Vichy France, Bosques took the initiative to rescue tens of thousands of Jews and Spanish Republican exiles from being deported to Nazi Germany or Spain. So it happened that the boat went first to Jamaica and then to Veracruz. Flora’s parents were tired and were sick of the trip and tried to stay in Mexico. It turned out that the minister of internal affairs, Miguel Alemán, later on president of Mexico, came to greet the refugees, and Flora’s father could talk to him. He managed to get permission so that the whole family could remain in Mexico. This was very fortunate because they learned later on that many refugees heading to Cuba were forced to return to Europe, even though they had visas to enter the country. To return to Europe in those days meant to be sent to the concentration camps.

Once in Mexico, Flora’s family settled in Tulancingo, a small textile town. After a couple of years, they moved to Mexico City, where I met Flora. She was studying chemistry at the National University, but one day Diego Rivera, who was a good friend of her parents, visited them at home and saw her drawings. He told her that she had talent for art. After some thought, she decided to leave chemistry and went to work in Diego Rivera’s studio and later on to study art in La Esmeralda. She kept with art and has become a well-known, outstanding artist.

We have two sons. Isaac was born in 1959. He got his PhD in computer sciences at the University of Pennsylvania in Philadelphia, returned to Mexico where he spent almost 20 years, and he now lives in Barcelona, working at the Supercomputing Center. Adrian was born in 1963 and studied at the University of Southern California (USC) to become a movie director. He has made several films and now lives in Los Angeles. He has two sons and one daughter: Diego now 21, Sofia, 12, and Sebastian, 9.

While writing this section, I could not resist including some lines about the family of Flora’s mother. She was born in Warsaw in 1909 and was brought up in a very religious Hassidic family, and had six sisters and two brothers. When the Germans invaded Poland, Stephanie, her oldest sister, was able to escape to Russia. She returned with the Russian army, leading them to Warsaw through the woods and small paths she knew well. Sometime after the end of the war, she was appointed as the Polish ambassador to Indonesia. I met her in the 1980s during one of my visits to Warsaw. She lived in a rather small apartment with her husband and had one daughter, Irena, who was married, had two children and lived close by. I was impressed by Stephanie’s disenchantment with the political situation. She told me that that this was not what she had fought for, and that she had sympathies for the solidarity movement of Walesa. She died not long ago, and she was buried in Warsaw with military honors.

There was another sister, Anna. She was a young, gifted violinist who remained in Warsaw during the war. She assisted Janusz Korczak in the ghetto. Years later, when Flora’s mother visited Warsaw, she learned that some friends had offered her a way to get out of the ghetto, but she had refused and said that she would never leave the children. She stayed and was arrested by the Schutzstaffel (SS) together with Janusz and the 200 orphans. They were all taken to Treblinka where they were murdered in August 1942.

Two other sisters, Leah and Itte, and their families were able escape to Russia and ended up in Siberia. When the war was over, they all returned to Poland. Sometime later, Leah and her family went to Israel. Flora’s parents helped them come to Mexico where they arrived in the early 1950s. Itte’s family stayed in Poland until the mid-1950s, when one of their two sons, Ludwig Margules, got involved in the student uprising against Russian control and was to be arrested. Somehow, Flora’s parents were also able to bring them all to Mexico. Over the years, Ludwig became a well-known theater director and received the National Prize of Arts in 2003. He died in 2006.

My Stay at the Rockefeller Institute: Studies on Cortical Neurons

During the fall of 1956, just before I started to work at the Cardiological Institute, I had the opportunity to travel to New York to visit my father’s family. I thought this could be a good occasion to visit some research centers. I was advised by García Ramos to visit the Rockefeller Institute, where he had spent some time working with Rafael Lorente de Nó. At that time, I was already aware of the work of David Lloyd on spinal reflexes, and I went to see him. I also visited Vernon Brooks who had just returned from Canberra where he was working with J. C. Eccles. He was very open and spent a fair amount of time explaining the research he was doing.

While in Rosenblueth’s department, I did all my work recording blood pressure and heart rate changes, first with a kymograph and later with a Grass polygraph. I felt it was important for me to learn how to record the activity of single neurons in the mammalian brain so I could use those techniques for the analysis of the functional organization of the cardio-inhibitory reflexes.

I told Rosenblueth that I wanted to learn these techniques and that the best way to do it would be to spend some time in a laboratory where they were already using them. He agreed, and I wrote Brooks who suggested I should apply to the John Simon Guggenheim Foundation for a fellowship. To my surprise, my application was approved, even though I was just starting and I had published only eight papers. It was clear to me that Rosenblueth’s support was crucial.

We were about to leave for New York when we found out that the U.S. Embassy in Mexico would not grant a visa to Flora. This was rather unexpected because in 1956 she had spent several months in a farm close to New York, being trained to work in a kibbutz in Israel, where she intended to live. She had returned to Mexico because her 16-year-old brother was killed in a motorcycle accident.

We went to the U.S. Embassy to inquire about the reasons for such a decision. Somehow Flora appeared in their lists as member of a leftist group, and there was no way to convince them that they had the wrong information. It probably did not help that her parents were involved in political activism and that she was a student of Diego Rivera.

My first reaction was to write to the Guggenheim Foundation to inquire if I could transfer my fellowship to some place in Europe. They said that this was not possible! Giving up the fellowship after all the plans we had made was really very disheartening. It happened that I knew the husband of my mother’s cousin, Jack Kranis, who was a city councilman in New York and a good friend of the former mayor of New York City, William O’Dwyer. Quite naïvely, I believed that once I was there, he could help us get a visa for Flora.

So I went to New York and contacted him. Rather soon it became clear to me that there was nothing he could do (or wanted to do), particularly in those post-McCarthy days when people were still afraid of being involved in those matters. In addition, I was advised by my father’s family in New York not to comment on the reasons why my wife and my six-month-old son, Isaac, were not joining me. They were afraid of losing their jobs. So I decided it would be unfair on my side to generate problems because of their association with us. Nevertheless, I contacted people at the Mexican Consulate to see if I could get some help from them. I gave myself a one-month period to see if something could be done. Otherwise I would return to Mexico.

In the meantime, I started to work with Vernon Brooks. I got involved in recording the activity of single pyramidal neurons in the motor cortex of the cat. These neurons were identified by their antidromic responses to stimulation of the pyramidal tract (Brooks et al., 1961a,b). Our studies indicated that the majority of the pyramidal neurons had a specific sensory modality. Their responses to tactile stimuli were fast adapting. In contrast, neurons responding to pressure and leg position had slow adapting responses. One of the most interesting observations was that the responses produced by tactile stimulation of the skin decreased with repetition and increased again after a brief interruption of the cutaneous stimulus or after a different type of afferent stimulation, just as happens during habituation and dis-habituation of behavioral responses.

Another interesting and related finding was that some cortical neurons had fixed, and others had labile, sensory fields. The neurons with labile fields had relatively small sensory fields that expanded with repetitive stimulation and shrunk after interrupting the sensory stimulus. The sensory fields of non-pyramidal neurons located in the posterior sigmoid gyrus were rather fixed, although those located in more rostral areas were clearly labile. These studies suggested the existence of two sensory-motor projections, probably with two different roles in movement control. The complexity of the involved pathways did not allow us a more detailed analysis of the mechanisms involved in this phenomenon but were, I believe, a starting point for studies in the cerebral cortex of behaving animals.

Siena, Italy: Sensory Activation of Hypothalamic Neurons

Almost at the end of the month I got an invitation from the Mexican Consulate to attend a reception at the Waldorf Astoria in honor of the president of Mexico, Adolfo López Mateos, who was visiting the United States. I thought, naïvely again, that this was a good opportunity to ask him for some help to get my wife’s visa. I wrote him a long letter explaining the entire situation. I also mentioned that I was working in one of the most famous scientific institutions in the United States and that I was learning new methodologies to record neuronal activity that I intended to use upon my return to Mexico. So I went to the reception. When the president entered the room, there was a long line to greet him. I was shy, but some friends at the consulate, who knew the whole situation, pushed me to get in line and insisted I should give him the letter. I shook hands with him and shortly explained to him why I needed his support. He smiled and told me he would do what he could and handed the letter to a military aide that was at his side. By looking at his face, I could anticipate that nothing would happen and at that moment I decided to return to Mexico.

Next day, I met Vernon and explained to him why Flora had stayed in Mexico. It was not because of some problems with the leg of my son Isaac (he had a small congenital problem in one foot that required wearing special shoes) as I told him before, but rather because the U.S. Embassy denied her the visa, in view of her suspected “political activism.” He was astounded and suggested we should talk with Detlev Bronk, then president of the Rockefeller University and, if I recall well, ex-officio member of the Science Advisory Council to President Eisenhower.

I knew who Detlev Bronk was because of his beautiful work on sensory receptors. So, Vernon and I went to see him. He was quite receptive, told me he would do his best, and asked me to write a letter explaining the whole situation. A couple of months later, Flora was contacted by the U.S. Embassy asking her if it was true that our son Isaac needed medical treatment that was available only in the United States. She told them that that we had good physicians in Mexico and that they should instead verify their information sources because they got it all wrong!

So the whole process was again delayed. I kept waiting and working in the lab and visiting Mexico almost every two months. Staying in New York under those conditions was difficult for me, but I was fortunate enough to make good friends. One was Victor Wilson, who was next door. I used to visit him quite often and watch his experiments. We developed a close friendship that continues to this day. The others were Alexander Mauro, Keffer Hartline, and Harry Grundfest, who was a good friend of Rosenblueth and was at that time at Columbia University. They all expressed deep concern about what was going on and made my stay in New York bearable. I remember that I used to visit Keffer Hartline’s lab to see his experiments with Floyd Ratliff on the Limulus eye. He told me once that I should know that many Americans opposed the witch-hunting started by McCarthy and encouraged me not to despair. A few years later, Alex Mauro visited us in Mexico and gave a magnificent series of lectures on membrane physiology. While at Rockefeller, I also became a good friend of Hiroshi Kuriyama, who was studying the excitation-contraction coupling in smooth muscle cells.

In the meantime, I learned that there were some fellowships to spend the summer at Woods Hole to work in the laboratory of Stephen Kuffler. This was an attractive possibility, and I applied for support, which was granted. There I met Rodolfo Llinás, Richard Orkand, David Potter, and Ed Furshpan.

During one of his visits to New York, Raúl Hernández Peón, a well-known Mexican neuroscientist, told me that there were plans to create a neurological institute that would include a brain research unit that he would direct, and he invited me to join once I returned to Mexico. I still wanted to stay abroad and, in view of Flora’s difficulties with the U.S. visa, I thought that it would be best to spend some time in Europe. He suggested Siena, Italy, where I could work with Zanchetti and learn the then “fashionable” stereotaxic techniques and single-unit recording that could be very useful for my future work. I liked the idea, particularly because I thought that Flora, being a plastic artist, would enjoy this visit.

On one of my visits to Mexico, I talked all this over with Rosenblueth. He was very supportive. Although he expected me to return to work at his department, he told me that there would be no problem if, at the end of my stay in Italy, I decided to work with Hernández Peón. Because I could not extend the Guggenheim Fellowship to Europe, he suggested that I apply to the Rockefeller Foundation.

In due course, the Rockefeller Foundation accepted my application for a fellowship and asked me to send them a formal assurance that, once back, I would have a position and facilities to work in at the neurological institute. I talked with Hernández Peón, and we both went to see his boss, Dr. Manuel Velasco Suárez, at that time vice-minister of health, who agreed to send the necessary assurances.

Just before leaving for Woods Hole at the end of the summer, I got a phone call from the U.S. State Department telling me that all was cleared up and that Flora would soon get her visa. However, by that time, we had already made all the arrangements to travel to Siena. Once there, I started the recording of unitary and population neuronal responses evoked in the diencephalon by sensory nerve stimulation with Alberto Zanchetti, Alberto Malliani, and Giancarlo Carli.

These were pioneering studies (Malliani et al., 1965; Rudomin et al., 1965a,b). Besides mapping the sensory projections in different diencephalic structures, including the hypothalamus, we addressed the issue of the possible local or remote origin of the recorded activity. We could show that in many instances monopolar recordings from the rostral part of the hypothalamus were not reversed when passing small currents through the recording electrodes, suggesting that they were produced by activity generated in remote regions. This was in contrast with other recordings that reversed their polarity from negative to positive, as expected if the sources become sinks and suggesting a local origin, in agreement with the recording of unitary activity in those regions. At the time when these studies were done, information concerning the sensory projections to the hypothalamus was rather scarce and fragmented. These studies are still cited and gave rise to more detailed investigations.

While in Siena, Malliani, who became a close friend, and I traveled every two weeks to Pisa to attend the seminars at Moruzzi’s institute. There I met Moruzzi and Pompeiano and made two good friends: Emilio Bizzi, a former student of Zanchetti who had just moved to Pisa, and W. Alden Spencer, who was there for the summer. I developed a special relationship with him that continued until his unfortunate death in 1977. I still remember the long discussions we had afterward on the possible mechanisms involved in the plasticity of flexor spinal reflexes, an issue that captured my attention after I attended J. C. Eccles’ talk on presynaptic inhibition, which was delivered at the symposium that Moruzzi organized in Pisa during the summer of 1961, just before I returned to Mexico.

My interest in the presynaptic control of transmitter release started one year earlier, during the summer at Woods Hole. This was the time when Stephen Kuffler and Joseph Dudel were writing their famous paper on presynaptic inhibition at the crayfish neuromuscular junction. In some species (I do not remember which), in addition to the excitatory axon, the muscles receive two inhibitory axons instead of one. So, the question rose whether both inhibitory axons were able to produce presynaptic inhibition. Although I was unable to complete these studies during the short time I was in Woods Hole, I remained interested in presynaptic inhibition.

My encounter with Eccles at the Pisa symposium was a rewarding experience. I had the opportunity to have a long talk with him. When he learned that I was in Rosenblueth’s department in Mexico, he recalled the old disagreements they had pertaining to the electrical versus chemical origin of synaptic transmission in the central nervous system, even though they never had met personally. It was at this time that Ricardo Miledi returned to Mexico from Australia. He was back at Rosenblueth’s place but had some disagreements pertaining to how much time he could devote to his own projects, and he was considering the possibility of moving to London to work with Bernard Katz. Eccles told me that if I ever had problems with Rosenblueth, I should consider the possibility of spending some time working with him in Canberra.

When I saw Anokhin at the Pisa symposium, I approached him and identified myself as a student of Alvarez-Buylla. He was quite receptive; he embraced me and started to tell everyone that I was his scientific grandchild! I learned through Alvarez-Buylla many of his views on functional systems that I believe have influenced my work. I still remember the faces of Eccles, Buser, and Bremer wondering what it was all about.

The Center of Advanced Studies

While I was still in Italy, Rosenblueth was invited by the Mexican government to be the founding director of a new research institute. At the beginning, he was quite reluctant to accept this invitation and presented an ambitious plan with the hope that it would not be accepted. His idea was to create a multidisciplinary research and graduate center. He asked for a fair number of full-time positions with good salaries, well-equipped laboratories, and academic and administrative independence.

To his surprise, all this was granted, and he had no choice but to accept. He was appointed as director in 1961 while I was in Italy. He started the whole project by inviting a small group of leading scientists in different areas as heads of departments, who were in turn asked to invite other scientists. He took care of the department of physiology and first invited García Ramos and Alvarez-Buylla. I was not invited at that time because I was already committed to join Hernández Peón’s brain research unit upon my return from Siena.

In the early 1950s, Hagbarth and Kerr (1954) and Hernández-Peón and Hagbarth (1955) suggested that transmission of sensory information at the first synapse in the dorsal horn column nuclei was subjected to central control. Yet, the mechanisms involved in this control were unknown. I thought that if I was going to join the group headed by Hernández Peón, I could start searching for possible presynaptic control of the sensory information transmitted at the dorsal column nuclei as well as in other brain stem nuclei, and he was definitely interested.

But things do not always go as planned. Once in Mexico, it turned out that the whole project of Hernández Peón was breaking down, mostly because of discrepancies he had with Velasco Suárez. It was clear that this was not a place for me. So I went to see Rosenblueth for advice. He invited me to join the department of physiology at his new institution. Because one of the requirements was that only investigators with a PhD degree could be part of the staff, I had a four-year appointment during which I was committed to work toward my doctorate. This meant taking a series of courses (physics, mathematics, and statistics), doing experiments, and writing a thesis.

While they were constructing the new premises, we had provisional space, first at the medical school at the National Polytechnic Institute and later on at the school of physics and mathematics of the same institute. In the meantime, I took several courses in physics and mathematics. Soon after we moved to the new building, Leon MacPherson joined the group. He was a skilled British electronic engineer who had spent several years in Venezuela working with Gunnar Swaetichin on the visual system. He could not stand British weather and decided to stay in Latin America. Once I had the basic equipment (a Grass polygraph and a stimulator), I convinced him we should work together on the dynamics of the mechanisms involved in the maintenance of a steady blood pressure.

To this end, in anesthetized rabbits we lowered blood pressure by electrical stimulation of the depressor nerve. When the pressure dropped to a predetermined level, the pen-writer of the Grass polygraph activated a microswitch that stopped the electrical stimulus to the depressor nerve and reapplied it when blood pressure recovered its original control values. This generated a series of blood pressure oscillations.

The relationship between the stimulation and non-stimulation periods allowed us to detect features of the system that we would not have been able to just by examining the system under stationary conditions. We found that when the blood pressure was driven away from its state of equilibrium, excitatory as well as inhibitory mechanisms were activated to restore the system to its original conditions. In intact preparations, the mechanisms that inhibited the vasoconstrictor activity induced by electrical stimulation of the depressor nerve were found to be coupled with those controlling recovery after the inhibition. They became decoupled by interrupting the information conveyed through the aortic and carotid vagal baroreceptors, as well as during deep anesthesia. That is, the effectiveness of the recovery after disturbing the system depended on the integrity of other baroreceptor afferents (see Rudomin and McPherson, 1963a,b).

I soon became aware that, to advance understanding of the central control of the cardio-inhibitory reflexes, instead of recording changes in heart rate and blood pressure as I did before, I should try to stimulate the depressor nerve and to record the reflex responses in the efferent vagal fibers that mediate heart slowing. In an initial series of experiments, I found that in the cat anesthetized with chloralose, stimulation of the depressor nerve as well as stimulation of trigeminal afferents and of the motor cortex or the pyramidal tract produced polysynaptic reflex discharges in both vagal nerves (Rudomin, 1965a,b).

I soon realized that these responses were not due to activation of the slow conducting vagal fibers inducing heart slowing but to activation of fast-conducting motor axons innervating the laryngeal muscles. Cortical stimulation produced early facilitation and a prolonged inhibition of the laryngeal reflex responses generated by vagal or trigeminal stimulation.

Having established that the reflex responses recorded in the vagus nerve were due to the activation of motor axons innervating the laryngeal muscles, I thought it would be important to examine the functional organization of these reflexes. As a first step, I selected the cricothyroid muscle for analysis, mainly because it was possible to record its activity without disturbing the larynx or its innervation, and also because this muscle received its sensory and motor innervation through separate nerve branches. This feature allowed me to examine changes in muscle activity during active shortening and passive stretch before and after proprioceptive denervation (Rudomin, 1966b,c).

At that time, the general view was that the cricothyroid muscle was activated during inspiration only. However, I found that in the lightly anesthetized cat, the cricothyroid muscle had its highest activity during the expiratory phase of the respiratory cycle. By deepening the anesthesia, or by increasing the respiratory dead space, expiratory activity was reduced and motor units were recruited whose activation was instead maximal during inspiration. I assumed that the level of central excitability at that moment would determine whether the motor units were activated during inspiration or expiration.

Later on, I showed that stretching the cricothyroid muscle had little influence on its own activity, and when there was some effect, it was inhibitory. The passive shortening of this muscle produced by the contraction of the cricothyroid muscle on the opposite side also had little effect, in contrast with the intense activation produced by mechanical stimulation of the laryngeal mucosa or by trigeminal stimulation. These observations suggested that the changes in length and tension imposed on the cricothyroid muscle, in contrast with other skeletal muscles, do not initiate compensatory activity that opposes the induced changes in muscle tension and length.

Another interesting finding, related to the absence of proprioceptive control of the cricothyroid activity, was the lack of effects of deafferentation on the synchronized activity of the cricothyroid muscles on both sides. Afferent signals should play only a modulatory role, but the synchrony appeared to be centrally determined. This concept was developed later on by other investigators in the field, and it is now accepted as a basic principle of the organization of locomotion, which is assumed to result from highly correlated activity in the spinal neuronal sets responsible for the flexor-extensor alternation, still subjected to a central control.

It was never clear to me why, when I wrote these papers that were published in 1966, I did not relate the finding of the prolonged depression of laryngeal reflexes produced by stimulation of the trigeminal nerves or by cortical stimulation to presynaptic inhibition, even though at that time I was already aware of Eccles’s work. Curiously enough, the journal reviewers also missed this point.

I remember that, in one of the department seminars, I suggested that such a prolonged inhibition could be of presynaptic origin. Rosenblueth, who attended the seminar, was very reluctant to accept that the synaptic efficacy of the sensory fibers could be subjected to a central control. In fact, he argued that all these findings could be properly explained using the model on spinal monosynaptic reflexes he developed with Norbert Wiener (Rosenblueth et al., 1949).

Nevertheless, it seemed to me that I should test more directly if the depression of the laryngeal reflexes produced by stimulation of the trigeminal nerve and of the motor cortex had a presynaptic component. To this end, I examined the effects of different experimental procedures on the excitability of laryngeal afferents ending within the solitary tract nucleus. I found that these afferents were depolarized by conditioning stimulation of other laryngeal afferents, as well as by stimulation of vagal and trigeminal afferents, and that their synaptic actions were depressed with a similar time course. I also suggested that this inhibition had a presynaptic component (Rudomin, 1966a, 1967a,b). Quite interestingly, lung inflation, which produces respiratory inhibition via pulmonary stretch receptors, also depolarized the terminals of the laryngeal afferents.

An important and unexpected finding was that even though the vagal visceral afferents were able to depolarize the laryngeal fibers ending within the brain stem, they, as well as the aortic baroreceptors, showed no primary afferent depolarization by conditioning stimuli that very effectively depolarized the laryngeal afferent terminals (Rudomin, 1967b, 1968). This makes sense if we consider that the aortic baroreceptors are part of the homeostatic mechanisms that regulate blood pressure level, where it is essential to preserve information on the state of the variable to be controlled, in this case blood pressure via the information sent by the arterial baroreceptors. Presynaptic inhibitory mechanisms would clearly modify this information, and this could lead to a faulty regulation. In fact, I now believe that presynaptic inhibition should not be envisaged only as an inhibitory mechanism but rather as a means to change the information generated in the periphery in a “context depending” manner.

My First Studies in the Spinal Cord

I met Guillermo Pilar in 1958, when he arrived from Argentina to work at the Cardiological Institute with Arturo Rosenblueth and Jesús Alanís. From Mexico, he went to Salt Lake City to work with Robert Martin on synaptic transmission in the ciliary ganglion of the chicken. Around 1983, I visited him, and I had the opportunity to meet several really outstanding investigators who were working in the department headed by C. C. Hunt. I met Carlos Eyzaguirre, with whom I developed a long-lasting friendship, as well as Edward Perl and Motoy Kuno. If I remember correctly, Dick Burgess was there. I met him while a student at the Rockefeller Institute, and we remained good friends for many years. What really impressed me was the analysis that Motoy Kuno made of the quantal nature of synaptic transmission of muscle spindle afferents on spinal motoneurons, and I invited him to visit us in Mexico. To my surprise, a few months later, I got a letter from him saying that because he entered the United States with an exchange visitor visa, he was required to leave for some time before being able to re-enter the country. He was not very eager to return to Japan and felt attracted to the idea of spending a year or so in Mexico. I went to see Rosenblueth, and he agreed to appoint Motoy as visiting investigator. He arrived in Mexico with his family in the summer of 1965 and stayed for one whole year.

It was known at that time that antidromic stimulation of the ventral roots or the motor nerves could inhibit spinal monosynaptic reflexes via the Renshaw cells that were activated by the motoneuron axon collaterals. Although pharmacological studies already supported a possible cholinergic activation of the Renshaw neurons, we felt that it would be important to show that acetylcholine was indeed released in the spinal cord by stimulation of the motoneuron axon collaterals, and that this release was correlated with the activation of the Renshaw cells.

So, inspired by the demonstration of acetylcholine release by stimulation of the vagus nerve in the perfused frog’s heart by Otto Loewi many years before, we devised a method to perfuse the deafferented spinal cord in situ to stimulate muscle nerves and measure the acetylcholine collected in the perfusate. The acetylcholine content would be examined using some of the biological assays available at that time (blood pressure fall in the eviscerated cat or inhibition of muscle tone in leeches).

After several disappointing attempts, we were finally able to show that stimulation of the motor nerves increased the acetylcholine release by 1.9–9 times (Kuno and Rudomin, 1966). The amounts of acetylcholine released by stimulating the motor nerves with different frequencies showed a high correlation with the changes in the activity of the Renshaw neurons in response to these same stimulation frequencies. The injection of dihydro-beta-erythroidine, which blocks Renshaw cell activation, had no effect on acetylcholine release. It thus seemed fair to conclude that the intraspinal collaterals of the motoneurons release acetylcholine (Ach), as in their peripheral branches, and that this Ach activates Renshaw cells in the spinal cord.

While writing this text, I thought how nice it would have been if we would have had the analytical methods that are now available. But at least I learned how to handle the leeches with chopsticks and also to use chopsticks to eat Chinese and Japanese food!

Motoy wanted to stay in Mexico for a longer time, but he returned to the United States because he felt indebted to C. C. Hunt, at that time at Yale. The collaboration with Motoy Kuno shifted my research on presynaptic inhibition from the brain stem to the spinal cord. I learned from Motoy that if one has a dream he should pursue it until it becomes real. I have had several dreams through my professional life and in moments of doubt, or when I was ready to give up, Motoy’s example was always inspiring.

Variability of Monosynaptic Reflexes: A Fresh Look at an Old Problem

In 1965, Harold Dutton joined the department of electric engineering in the institute where I was working. He was born in Yucatan, the son of Thomas Dutton who settled in Mérida in 1906 and was the British consul for many years. If I recall correctly, Harold had one PhD from MIT in systems control and another in mathematics from Columbia University.

I met Harold at the institute’s cafeteria. He was interested in feedback control of muscle reflex activity and used to ask questions for which I had no answer. While attempting to explain to him the differences between pre- and postsynaptic inhibition, he asked me: “Regardless of the involved mechanisms, how does the system ‘know’ that the inhibition produced by afferent conditioning volleys is pre- or postsynaptic?” In other words, were there any differences in the features of the responses of the motoneuron population to a given Ia input when they were inhibited to the same extent pre- or postsynaptically?

While discussing this with Harold, I recalled the paper of Barron and Matthews (1935), where they described the intermittent conduction of impulses in sensory fibers and regarded this as a mechanism of inhibition. Their findings suggested to us that, in addition to the mean of the monosynaptic reflexes, we should also measure their fluctuations. Online measurements were essential for doing the experiments. At that time, we had no digital computers to measure the reflexes and to calculate their fluctuations. Based on his experience with analog computation, Harold used operational amplifiers, condensers, and resistances to construct a device that allowed real-time continuous estimates of the mean and variance and correlation of the monosynaptic reflexes (Dutton and Rudomin, 1968).

With this system in operation, we found that monosynaptic reflexes inhibited by conditioning stimuli that produced a strong primary afferent depolarization (PAD) had a smaller variability than reflexes inhibited by stimuli assumed to produce only postsynaptic inhibition (Rudomin and Dutton, 1967, 1969a). We explained these effects by assuming that the spontaneous activity of some neuronal networks produced a background-correlated depolarization of a substantial number of muscle spindle intraspinal terminals, and that conditioning volleys to cutaneous nerves would temporarily reduce such a correlated PAD as well as the fluctuations of the monosynaptic reflexes (Rudomin and Dutton, 1968, 1969b). This interpretation was further supported when we showed that the correlation between the monosynaptic reflexes generated simultaneously in two different populations of motoneurons was reduced by conditioning stimuli that produced PAD (Rudomin et al., 1969).

In short, these studies indicated that the variability of monosynaptic reflexes was not just “noise” in the system but was the result of the activity of specific sets of neurons involved in the control of the information transmitted by the afferent fibers.

In 1967, Dutton and I sent a note to Brain Research describing the effects of conditioning stimuli producing pre- and postsynaptic inhibition on the mean area and variance of monosynaptic reflexes. A few weeks later, we got back the manuscript with a rejection note from the editor, K. Akert. This letter included no comments about why the note was rejected. I was surprised and wrote back to Akert asking him for the reviewer’s remarks. I think I mentioned to him that I believed that, besides publishing research articles, one of the roles of scientific journals should be to provide proper scientific feedback, particularly to young investigators in “developing” countries.

Soon after, Akert sent me a copy of the reviewer’s remarks. If I remember well, the reviewer said: “This is very interesting but neither me, Lundberg, nor Lloyd found something like this.” He also pointed out that because I was not showing the original records, but just the area of the reflexes, it was not clear if the electronic gate we used to measure the area comprised only the monosynaptic component or if it also included oligosynaptic components. This was a reasonable concern. I then wrote back a detailed response to Akert asking him to forward it to the reviewer. I suspected that the reviewer was J. C. Eccles, but I said nothing.

In the meantime, Dutton and I revised the note and included all the remarks made by the reviewer. We also added one figure with original records of the monosynaptic reflexes and their areas and submitted the note to Nature. A couple of weeks later, I met Rodolfo Llinás at a meeting in Mexico City. At that time, he was already working with Eccles in Chicago. I told him the whole story about the paper we sent to Brain Research and that I was sure Eccles reviewed it. He said that he was present when Eccles was reading the paper and that he commented he would not recommend its publication.

I was disappointed because I thought that Eccles’s concerns were quite mild and did not justify the rejection. So I told Rodolfo that I would travel to Chicago to present him my data. He became somewhat anxious and asked me not to mention our conversation. I told him not to worry.

I wrote Eccles that I was visiting Chicago and that I would like to discuss recent findings with him. He agreed. Yet, I felt it would be good to have the opinion of somebody else before seeing Eccles. I thought of William Willis who was in Dallas and was co-author with Eccles and Robert Schmidt of many papers on presynaptic inhibition. Even though we had never met before, I wrote him, and he invited me to give a seminar on my way to Chicago.

Meeting Bill was really nice, and it was the beginning of a friendship that has lasted many years. Years later, he came to work with us in Mexico, and I worked with him when he moved to Galveston. So I visited his lab in Dallas and gave a seminar. He found our findings sound and interesting. At the end of the talk, he invited me to have dinner in a fancy restaurant. When we arrived, I stepped out of the car and took my old briefcase with me. Halfway to the restaurant, Willis said: “You don’t need to carry your briefcase to the restaurant. Why don’t you leave it in the car?” I replied. “If I were in Mexico, I wouldn’t do it.” Well, he said, “You are not in Mexico!” Because I had just met him I did not want to start an argument, so I went back to the car and left the briefcase. But halfway to the restaurant I told him, “Let me be a little distrustful and pick up my passport, airplane ticket, and money.” He just looked at me and smiled.

After the dinner, we returned to the car and found that somebody had broken in and taken away my briefcase! Bill was really sorry, and he apologized. I was really relieved because I had taken the money and documents with me. Suddenly, I realized that the briefcase had all the material I intended to show to Eccles. But, fortunately, in my hurry to leave for the restaurant, I had forgotten to pick up my slides from the lecture room.

I left the next morning for Chicago. Rodolfo Llinás came to pick me up at the airport. I was really worried about not having all the material with me that I was to show to Eccles. Rodolfo suggested that early in the morning we should go to the lab’s darkroom and use the slides as negatives to make paper copies. We did that. The copies were still wet when I showed them to Eccles. Suddenly he said: “Now I understand.” I asked him, “Now?” He hesitated and said, “Well, you were not very clear at the beginning.” After a thorough and fruitful discussion of our data, I left without telling him that I knew he had reviewed my paper.

A few days later, I returned to Mexico and found three letters on my desk. One was from Eccles, which I still have, saying that he had reviewed my paper and that he was apologizing for not having understood the relevance of our observations. He added that he wrote to the editor of Brain Research that he should accept the note for publication. The second letter was from Akert saying that Eccles wrote him about our meeting, and that he would be very happy to publish the note. The third letter was from Nature saying that our paper was accepted for publication (Rudomin and Dutton, 1967). So I sent a copy of this letter to Akert with a paragraph that said that next time he should be more receptive to papers sent by young scientists working in developing countries such as Mexico.

A couple of weeks later, I got a letter from the Dallas police. They had found a briefcase with some letters addressed to me and assumed it was mine. I wrote them back explaining all that had happened, and I asked them to send the briefcase to Willis so that he could send me just the contents. One day I came to the lab, and I saw a big box. I opened it, and there was my old briefcase, all destroyed. I was glad to recover all the material, particularly my old pipe. Bill must have paid a fortune to ship it by air.

Several years later, during the International Congress of Physiology in Paris, I was invited to have dinner at Denise Albe Fessard’s house. Akert was sitting close to me. I was wearing a badge with my name, and he just looked at me and said, “I am really sorry about what happened with your paper several years ago, but what else could I do if the Nobel Prize told me not to accept it?” I just said: “You should have listened to me and sent him back my reply and asked for a second opinion.”

My Sabbatical at the National Institutes of Health

If I recall well, it was December 1962 when Rodolfo Llinás, with whom I developed a close friendship while I was in Woods Hole, visited Mexico on his way from Canberra to Colombia. He was waiting for his fiancée, Gill, to join him in a couple of days. They had decided to be married in Mexico before going to Colombia, and he asked me to be his wedding witness.

She came one day before Christmas. I think it was the morning of the 24th. All the government offices were to close by noon. I used my best skills to convince the judge to marry them and so he did. A couple of days later, both of them left for Bogota to meet Rodolfo’s family.

I agreed to send them the marriage certificate as soon as possible so that Gill could enter the United States. When I went to pick up the certificate, I found that the marriage was not valid. Both required permission from their embassies because they were not Mexican citizens. It was a rather complicated business to have it all straightened out, and I asked for help from our institute’s legal adviser. Even so, it took him several weeks to arrange things with the embassies and with the judge.

In the meantime, Rodolfo flew to Minnesota and left Gill in Bogota. Rodolfo’s father was calling me every day to see if we were finally able to get those documents. After a couple of weeks, everything was arranged, and Gill could join Rodolfo.

I had long talks with Rodolfo about his experience in Canberra, and it seemed to me that it would be a rewarding experience to spend some time working with Eccles. Soon after, I wrote him a letter reminding him of our conversation in Pisa. I had no response until a few months later after he received the Nobel Prize. He told me that he had a long list of visitors and that my visit was not feasible at that time. A couple of years later, I got an invitation from him telling me that if I still wanted to come he had one open position for a visiting scientist to start, if I recall well, around the fall of 1967.

We had already made all the necessary arrangements for the Australian sojourn when I got a phone call from Eccles telling me that he was moving to Chicago because he was going to be 65 years old and could not continue with his appointment in Canberra, so there was no point for me to go if he was not going to be there! This was very frustrating. David Curtis told me years later that I could have gone anyway and worked with him or with somebody else because I was already appointed as visiting scientist.

It was around that time when I came across the superb series of papers published in 1967 by Frank, Rall, Burke, Nelson, and Smith. I still recall the emotion I felt when I read those papers, and I decided that this was the place to go. I wrote Michael Fuortes, whom I had met while in Woods Hole in 1960, and he arranged a six-month visit starting in the fall of 1968. Six months was a very short time for a sabbatical. I thought it would be nice if I could also spend some time working with Vernon Mountcastle so, in the future, I could examine the role of presynaptic inhibition in behaving monkeys during the execution of specific motor tasks. To this end, I applied—again with Rosenblueth’s support—to the Guggenheim Foundation for a second fellowship.

The summer of 1968 was a difficult year in Mexico. It was just before the Olympics, and there was a growing demand, mostly by young students, to have a more open society. This feeling was also shared by many faculty members. The government’s disastrous response was repression. I left Mexico in September 1968 and stayed in Phil Nelson’s house while I searched for a place where Flora and our two children could stay comfortably. I found a small apartment in Bethesda, just walking distance from the laboratory.

The family was scheduled to arrive in Washington by October third. But just one day before, the news covered with detail the events in Mexico City. Many persons, mostly students, were killed while they were gathered in a demonstration. I was alarmed and worried and I called home. Fortunately, everything was all right with the family, and they were ready to travel.

The next day, I went to the airport to greet them, but they did not show up. I was worried because I thought that perhaps the borders were closed in view of the events of the previous day. It took me several hours to contact them. They were fine but had missed the flight because they were not aware of the change in the winter time schedule. They arrived the next day after a long detour. They came to Washington via Chicago, where they were delayed for several hours by immigration even though by then Flora had a valid visa.

I started to work in the neural control section. The lab chief was Karl Frank, who was also responsible for one of the NIH extramural programs. Robert Burke was a member of the section and had recently returned from Lundberg’s department in Goteborg. Ladislav Vyklicky came from Prague and was to stay for six months, and Felix Zajak had just joined as a postdoctoral fellow.

I still remember that just several weeks before I started to work at NIH, there was an international meeting in Washington where Manfred Zimmermann presented observations that were not supporting the gate theory of pain proposed by Melzack and Wall. According to this theory, activation of C fibers was expected to inhibit the background PAD in large cutaneous afferents and lead to a concurrent presynaptic facilitation of their synaptic effectiveness and activate nociceptive pathways. Yet, Zimmermann’s observations showed that C fiber stimulation during selective electrical block of the A fibers in a cutaneous nerve produced instead negative dorsal root potentials that were taken as a sign of primary afferent depolarization and presynaptic inhibition of the cutaneous afferents (see Janig and Zimmermann, 1971).

One problem with Zimmermann’s experiments was that the C fibers were activated synchronously, and it was not clear if these fibers transmitted nociceptive information, as required to test Melzack and Wall’s proposal. Ladislav suggested we should instead use radiant heat, which was known to activate C fiber nociceptive afferents in a more selective manner.

Our studies showed that pulses of intense radiant heat applied to the plantar pad in unanaesthetized spinal cats evoked post-synaptic excitation of flexor and post synaptic inhibition of extensor motoneurons as well as negative dorsal root potentials (DRPs) and hyperexcitability of cutaneous intraspinal terminals due to primary afferent depolarization (PAD; see Vyklicky et al., 1969; Burke et al., 1971).

To the extent that PAD causes presynaptic inhibition, these observations indicated that pulses of intense heat applied to the skin, instead of producing presynaptic facilitation as proposed by Melzack and Wall, presynaptically inhibited transmission from the affected primary afferent fibers to second order neurons, thus confirming and expanding the observations of Zimmermann.

At the end of the six months at NIH, I was supposed to move to Mountcastle’s laboratory in Baltimore. The adaptation of the children to life in Bethesda was rather difficult because of the change in language and environment. Yet, six months later, they were already adjusted to school and had made new friends. Moreover, living within walking distance from the laboratory allowed me to spend more time with my wife and children, even during those long-lasting experiments when we used to take turns during the evening so I could walk home and have dinner with the family. It was not at all surprising that I was somewhat reluctant to move to Baltimore and start all over.

I drove to Baltimore to meet Mountcastle. I arrived early and Gian Poggio, whom I knew from Italy, was there. We had a long chat, and he warned me about the disadvantages of living close to the lab. It was a dangerous neighborhood, particularly at night, and it was clear that I would need to live far away and commute every day. This further discouraged me from leaving Bethesda. While waiting for Mountcastle to arrive, with Gian’s approval, I lit up a cigar. The first thing Mountcastle said when he entered the room was: “Pablo, if you are going to work with me, better give up your cigar!” I thought at that moment that this was not a polite way to ask me to give up smoking, which I would certainly do if he would have been more courteous. It seemed to me that he was an authoritarian person, and I wondered whether I could really enjoy working with him. So I told him: “My dear Vernon … if you force me to choose between you and my cigar, the decision is made: I keep my cigar.”

I then returned to Bethesda, talked with K. Frank, and he invited me to stay for six more months. Seen in retrospective, my response to Mountcastle was clearly arrogant and foolish, but, curiously enough, over the years we became good friends. In fact, when he was president of the Society for Neuroscience, he invited me to become part of the board of publication trustees of the journal that was launched in 1981.

I spent part of the remaining months in Bethesda finishing the analysis of the data on PAD and radiant heat. In addition, because Robert Burke was primarily interested in the mechanical properties of single motor units, we started a new series of experiments where we examined the changes in muscle tension produced by intracellular stimulation of single motoneurons with different stimulation paradigms (Burke et al., 1970, 1976).

We found that the tension output of slow-twitch motor units was quite sensitive to the patterns of stimulus intervals in the train. The presence of only one stimulus interval that was much shorter than the others in the train could cause a marked, long-lasting tension enhancement. We suggested that this “catch” property could extend the range of output tensions that can be produced by a given motor unit without a large change in mean firing frequency of the motoneuron. This effect could be of functional significance because double discharges at short intervals are not uncommon, particularly during stepping (when motor units fire in short bursts). This was long before the discovery of the plateau potentials in motoneurons (Hounsgaard et al., 1984, 1988).

While at NIH, I developed a special friendship with Robert Burke that has lasted throughout all these years and also with Ladislav Vyklicky until the end of his life. My relationship with Karl Frank was also very special. He encouraged me to write my first NIH grant application and advised me on how to do it. This grant was funded in 1971 and was renewed throughout the following 38 years. It allowed me to stay and work in Mexico.

Back in Mexico

While in Bethesda, I considered the possibility of not returning to Mexico because of the government’s authoritarian repression of October 2, 1968. I commented on this to Vernon Brooks who had already moved to Canada, and soon after, I got a letter from Szerb, the chairman of the physiology department in the medical school in Halifax. He invited me to visit the department and to consider the possibility of working there. I still remember that I flew from Washington to Boston and from there to Halifax. When I arrived, the immigration officer told me that I could not enter Canada because I had no visa! Fortunately, it was a small airport and Szerb, who came to pick me up, arranged my admission.

The visit to Halifax was really nice. I stayed a couple of days, visited several laboratories, and gave a lecture. I left with the idea of moving there once I finished my commitment with NIH. It was Saturday afternoon when I flew back to Boston. To my surprise, I could not re-enter the United States because I had an exchange visitor visa that was valid for one entrance only. It did not matter that I told the immigration officer that I just went out to give a lecture in Halifax, that I was working at NIH, and that my family was in Bethesda. He was ready to send me back to Halifax, which meant I would need to stay there for the weekend and then go the next Monday to the U.S. consulate for a visa!

I really did not know what to do, so I asked the officer to call his chief, with the hope that he would understand the whole situation and allow me to enter the United States. He came, but all was hopeless. As a last resort, I told him that I was expected at NIH that evening to perform a series of important experiments that required my presence and could not be postponed. I asked him to call some of my colleagues at NIH to confirm my story and took out my pen to write the phone number where he should call. He looked at the pen—it was one of those black ballpoint pens that everybody used at the lab, labeled as “Property of the U.S. Government.” To my surprise, he said: “Now I believe you. You can enter the U.S.!”

A couple of months later, when I was about to decide between returning to Mexico or accepting Szerb’s invitation and moving to Halifax, I got a letter from García Ramos, who recently became the chairman of the physiology department at CINVESTAV. He invited me to return to the department at the end of my sabbatical leave.

García Ramos studied medicine at the Escuela Médico Militar and became a close collaborator of Rosenblueth at the cardiological institute beginning in 1945. When Rosenblueth became director of the new institute in 1961, Ramos joined the department of physiology as full professor. I had worked with him in 1956 and, at that time, we got along pretty well. However, as acting chairman, he was quite authoritarian and our relationship became somewhat crisp, particularly during the 1968 events, when many of us were demanding more participation in the government decisions that affected our lives and professional activities. Nevertheless, his invitation was conciliatory; he assured me that things would be different and that I would have more participation in the definition of department policies.

It was about time to make a decision, when Bob Burke and I went to visit Ladislav. He had spent six months at NIH and then moved to Philadelphia to spend another six months at the school of dentistry. It was just a couple of weeks before he and his family were returning to Prague. Yet, it was not clear to both of us why Ladia wanted to go back, particularly at that time when the Prague Spring was over, the Soviet tanks were in the streets, and many persons that were against the invasion were put in jail.

According to Bob, because Ladislav was already in the United States with his wife and kids, it should not be a problem to arrange things so they could stay for a longer period of time. Ladia said that, if everybody left Prague, who would stay there to keep things moving? He felt very committed to the institute and to his colleagues and decided that the best he could do was to return, even with the risk of being imprisoned.

I was impressed with his decision, and I am sure that his example, together with Flora’s and my strong commitment and gratitude to Mexico for having so generously accepted our families, contributed to our decision to return to Mexico.

The work that I did together with Harold Dutton between 1967 and 1968 (Rudomin and Dutton, 1969a,b; Rudomin et al., 1969) showed that correlated fluctuations of the monosynaptic reflexes were reduced by conditioning stimuli that produced PAD and presynaptic inhibition. At that time we suggested that this effect resulted from the reduction and/or desynchronization of the activity of the PAD mediating interneurons.

Once back in Mexico, José Madrid and I decided to examine the effects of sensory stimuli on the correlation between the monosynaptic responses of pairs of individual motoneurons (Rudomin and Madrid, 1972). As expected, conditioning stimulation of cutaneous nerves was found to reduce the correlation between the monosynaptic responses of the pairs of motoneurons. We also found that the changes in the joint firing probabilities of the motoneuron pair allowed a fair prediction of the changes in population variance. Using the Shannon-Wiener definition of information, we also found that the reduced joint firing increased the information transmitted by the two-neuron ensemble. Yet, it was not clear if this effect was of presynaptic origin.

To this end, together with Robert Burke, we examined the effects of conditioning volleys to muscle and cutaneous nerves on the monosynaptic potentials elicited in pairs of motoneurons by stimulation of muscle spindle (Ia) afferents (Rudomin et al., 1975a). As expected, this correlation was positive and was reduced by conditioning volleys to cutaneous nerves. Quite often, these changes occurred without affecting the mean EPSP amplitude and time course, suggesting a presynaptic origin.

Further evidence supporting a presynaptic origin of the fluctuations was obtained later when we showed that the mean and variance of the Ia-motoneuron monosynaptic EPSPs could be reduced by conditioning volleys to sensory nerves without affecting the monosynaptic EPSPs elicited in the same motoneurons by stimulation of the ipsilateral vestibulo-spinal tract (Rudomin et al., 1975b).

In the late 1980s, Lorne Mendell visited our laboratory. One of the questions pending from our previous study on the fluctuations of Ia-EPSPs was the extent to which the reduced correlation between pairs of Ia monosynaptic EPSPs induced by conditioning stimulation of cutaneous nerves could be ascribed to changes in the background synaptic activity generated by neurons acting on the Ia afferents and/or motoneurons. To this end, we recorded the monosynaptic EPSPs produced in single motoneurons by stimulation of a single muscle spindle afferent (Solodkin et al., 1991).

We found that the differences in mean EPSP amplitude for a given connection under conditions of low background synaptic noise (no muscle stretch) and high background synaptic noise (induced by stretching the homonymous muscle) were minimal. Yet, in some cases, the increased variance observed during the EPSPs evoked under low noise conditions was reduced during high noise conditions.

Using de-convolution techniques, we also found that the variance of the “noise free” EPSPs was smaller than the directly measured EPSP variance. These differences were explained by assuming a negative correlation between the Ia-EPSPs and the baseline synaptic noise. Simulation studies revealed that the variance increase during the EPSP was highly dependent on the correlation between signal and noise, suggesting that non-linear interactions between background activity and evoked EPSPs could also affect the interactions among neurons within the network. In other words, the reduction of the correlated fluctuations of the monosynaptic reflexes induced by conditioning stimulation of sensory nerves could be due, at least in part, to reduced activity of the interneurons acting on the Ia-motoneuron pathway.

Comparative Studies on Presynaptic Inhibition

Frogs

In 1972, when David Carpenter, whom I had met while I stayed at NIH, came to our laboratory for a three-month visit, we thought it would be interesting to study the functional organization of PAD in other vertebrates besides mammals, and we focused on the frog. To this end, we developed an in vitro preparation of the neuroaxis together with the left hind limb nerves that were dissected and left in continuity up to their entrance to the muscles (Carpenter and Rudomin, 1973).

In this preparation, we could show that stimulation of the motor axons produced dorsal root potentials (DRPs) that were larger than the DRPs produced by stimulation of sensory nerves. The DRPs produced by stimulation of nerves innervating the extensor muscles were larger than those produced by stimulation of nerves to flexor muscles. We thought that this made some sense because when the frog jumps there is a descending activation of extensor muscles, and in this case, the motor-nerve-induced PAD could prevent interfering influences of sensory inputs during the jump. This being the case, we assumed that the effectiveness of the descending fibers would not be subjected to presynaptic control.

With Silvio Glusman (Glusman and Rudomin, 1974), we recorded the field potentials produced by antidromic stimulation of motor axons and of the lateral column, in the intact as well as in the chronically deafferented spinal cord of the frog. We found, as in the cat, that the synaptic effectiveness of the fibers descending through the lateral column (probably vestibulo-spinal) was not subjected to a presynaptic (GABAergic) modulation. In addition, we could show that in the chronically deafferented spinal cord the antidromic stimulation of motor nerves no longer produced the intraspinal current flows associated with PAD. Ultrastructural studies made in frogs with chronic dorsal root lesions or with chronic spinal hemisections further indicated that the degenerated terminals of the damaged descending fibers, unlike the afferent fibers, showed no close appositions from neighboring interneurons suggesting axo-axonic synapses (Glusman et al., 1976).

In the early 1970s, the DRPs produced by antidromic stimulation of the ventral roots and/or motor nerves were assumed to be generated by the activation of cholinergic axon collaterals that would in turn activate the GABAergic interneurons that produce PAD. Yet, very little was known about the intraspinal mechanisms involved in the generation of these potentials. In 1978, José Galindo and I examined the effects of gallamine on the intraspinal field potentials and DRPs produced by antidromic stimulation of motor fibers (Galindo and Rudomin, 1978).

We found that gallamine increased the duration of the negative field potentials produced by antidromic activation of motoneurons, often without changing their amplitude. This resulted in an increased passive spread of the antidromic action potential toward the dorsal dendritic regions, where afferent fibers terminate. In addition, antidromic stimulation of motor axons produced a late negative dorsal root potential (VR-DRP) that was depressed after gallamine administration. Quite unexpectedly, we found that abolition of the VR-DRP was frequently associated with the appearance of short latency, conducted responses in the dorsal roots that we interpreted as being generated by electrical interaction between motoneurons and afferent fibers. These findings suggested that the motoneuron-afferent fiber interaction initially described by Decima (1969) and Decima and Goldberg (1969) in the cat could be a consequence of such coupling. Seen in retrospective, it is possible that our inability to confirm Decima’s findings (Gutnick et al., 1975) was due to a limited passive spread of the antidromic action potential toward the distal dendrites in the motoneuron.

With Ana Cardona (Cardona and Rudomin, 1983), we focused our attention on the possible effects of the activation of serotonergic pathways on the homosynaptic depression of the monosynaptic responses produced in the frog spinal motoneurons by repetitive stimulation of the lateral columns. We knew from previous work that their synaptic effectiveness was not subjected to a GABAergic control of the type seen in afferent fibers.

We developed a preparation that included the isolated spinal cord and brain stem nuclei. Serotonin added to the bath, or stimulation of the brain stem midline raphe nuclei, but not of the lateral reticular formation, reduced the magnitude of the low frequency depression of the motoneuron responses produced by stimulation of the lateral column. These actions were abolished by methysergide, a specific antagonist of serotonin. It thus seemed that the magnitude of the homosynaptic depression of monosynaptic responses of motoneurons could be controlled by descending serotonergic mechanisms, and we suggested that these effects could be an important component of the arousal behavior mediated by the brain stem raphe nuclei.

Studies on the action of descending fibers on PAD elicited by stimulation of afferent fibers and/or stimulation of the motor axons were continued in the 1990s with Hortensia González and Ismael Jiménez (González et al., 1992, 1993). These studies showed that, as in the cat, stimulation of the bulbar reticular formation produced PAD in cutaneous afferents and inhibited the PAD elicited in muscle spindle afferents.

Stingrays

In the mid-1970s, I spent several summers at the Marine Biological Institute in Galveston working with William Willis and Robert Leonard on the functional organization of the spinal cord of the stingray (Leonard et al., 1978; Rudomin et al., 1978). Quite unexpectedly, we found that the dorsal (afferent) and ventral (motor) roots do not merge in the peripheral nerves but run in different fascicles that can be separated by dissection. We found that the sensory branches of the peripheral nerves have mostly Aα and Aδ fibers and relatively few C fibers. Electrical stimulation of one nerve increased the intraspinal excitability of Aα and Aδ fibers in nearby nerves. However, in contrast with what is observed in the frog spinal cord, antidromic stimulation of motor axons produced no PAD. It was not clear, however, if the axon collaterals of the motor fibers activated some inhibitory interneurons like the Renshaw cells in the cat.

We also analyzed the locomotion patterns in the stingray (Leonard et al., 1979). These animals swim with an active elevation-depression sequence of the pectoral fin resembling an extension-flexion sequence. During forward locomotion, this sequence passes caudally along the pectoral fin. Immediately following high decerebration, stingrays are capable of locomotion, and the pattern of muscle activity closely resembles that of intact animals. Spontaneous and midbrain evoked rhythmic motoneuron discharges could be recorded in paralyzed, decerebrated animals. In contrast to dogfish sharks, stingrays with high spinal transections do not locomote.

Unfortunately, it was not possible for me to continue with this work because other commitments prevented me from visiting Galveston during the summer, but Robert Leonard took over and spent a fair amount of time on the characterization of some of the descending fiber systems involved in the control of motor behavior.

The Search for the Primary Afferent Depolarization–Mediating Interneurons

In the mid-1970s, I spent my sabbatical in Goteborg working with Elzbieta Jankowska. Our goal at that time was to identify the last order interneurons that mediate the PAD of muscle and cutaneous afferents. The question was where to look in the spinal cord. Available evidence was not clear about this, although there were a couple of papers by Eccles and collaborators where they assumed that these interneurons were somewhere in the dorsal horn and intermediate zone.

The idea was rather simple but technically difficult. It required impalement of a single afferent within the dorsal horn or intermediate zone to record the PAD produced by stimulation of muscle and/or cutaneous afferents as well as by intraspinal stimuli applied at different depths in the spinal cord. We found that the shortest latencies of the sensory evoked PADs were compatible with activation of a pathway involving two interneurons (Jankowska et al., 1981). The lowest threshold PADs produced by intraspinal stimulation appearing with the shortest latencies (about 0.8 ms) were attributed to direct activation of the last-order interneurons in contact with the afferent fiber and were found when stimulating fairly restricted areas within laminae V–VI for group I muscle afferents and within laminae III–IV for cutaneous afferents. Both areas corresponded to the regions where the largest monosynaptic field potentials were evoked by fibers receiving presynaptic depolarization. It thus seemed that the first and last order interneurons mediating the PAD were located within these areas.

To work with Elzbieta was one of the most rewarding scientific and personal experiences in my life. It was also the beginning of an enduring friendship. Once back in Mexico, we aimed to record the spontaneous activity from interneurons in laminae V–VI and use the interneuronal spikes to trigger the averaging of the DRPs from the central end of a small dorsal rootlet. In addition, we used the sucrose gap technique to disclose, by means of spike triggered averaging, the motoneuron synaptic potentials (VRPs) associated with interneuronal activity (Rudomin et al., 1987).

With this approach, we were able to identify one group of interneurons located in the intermediate zone that appeared associated with short lasting inhibitory VRPs but not with DRPs (Class I interneurons) and a second group that was time locked to slower inhibitory VRPs and also to short latency DRPs (Class II interneurons). Subsequent studies with Jiménez, Quevedo, and Solodkin (Rudomin et al., 1990), showed that the postsynaptic inhibition produced in motoneurons by Class I interneurons was glycinergic and that the inhibition associated with Class II interneurons was most likely GABAergic.

The finding that the activity of Class II last-order interneurons was associated with postsynaptic inhibition in motoneurons as well as with a monosynaptic DRP in afferent fibers, suggested that pre- and postsynaptic inhibition could coexist. This was an unexpected finding considering that the general view was that pre- and postsynaptic inhibition were mediated by separate spinal pathways. However, later on, Maxwell and collaborators provided ultra-structural evidence showing that the same synaptic bouton could make synapses with the motoneurons and also with the afferent fibers contacting these motoneurons (Maxwell et al., 1990).

The functional implications of the coexistence of pre- and postsynaptic inhibition have been discussed in several publications (for review, see Rudomin and Schmidt, 1999). Activation of Class II interneurons by supraspinal inputs, for example, during the execution of a voluntary movement, would transiently inhibit the motoneuron and at the same time depolarize the Ia afferents synapsing with that motoneuron, thus ensuring that the activity conveyed by these afferents does not interfere with the programmed descending inhibition.

Primary Afferent Depolarization and the Potassium Accumulation Hypothesis

In the earlier 1970s, Somjen and Lothman (1974) and Kriz et al. (1974) used ion exchange resins to measure the concentration of potassium ions in the spinal cord. They found that stimulation of the dorsal roots and/or of the tibial nerve with strong, high-frequency trains increased extracellular concentration of potassium ions from three to about ten micromoles in the dorsal horn and intermediate zone. This led to a proposal by Vyklicky and collaborators (Kriz et al, 1974) that the increase in the extracellular potassium was the main cause of PAD. This contributed to the view that the PAD elicited under these conditions was rather unspecific because potassium accumulation would depolarize neighboring neurons and afferent fibers (for review, see Rudomin and Schmidt, 1999).

These findings were somewhat puzzling because there already were several observations that could not be easily explained with the potassium accumulation hypothesis. For example, Eide et al. (1968) and Rudomin et al. (1975b) showed that conditioning stimulation of sensory nerves inhibited the Ia monosynaptic EPSPs recorded in spinal motoneurons without changing their time course and also without inhibiting the monosynaptic EPSPs produced in the same motoneuron by stimulation of descending fibers. Yet, it seemed possible that the descending fibers reached the motor pool without giving collaterals to the dorsal horn and to the intermediate zone where potassium accumulated following stimulation of sensory nerves.

But it was not until the late 1970s, when Elzbieta Jankowska and Ingemar Engberg visited Mexico, that we tried to approach this question more directly by measuring the effects produced by conditioning stimulation of sensory nerves on the intraspinal threshold of single Ia and descending fibers, both ending closely to each other in the intermediate zone (Rudomin et al., 1980). Group I afferent terminal arborizations, both in the intermediate and motor nuclei, appeared to be the target of specific presynaptic depolarizing (presumably GABAergic) pathways. Rubrospinal, but not vestibulo-spinal, fiber terminals were weakly depolarized by stimulation of sensory nerves but such a presynaptic depolarization did not appear to result from the activation of GABAergic pathways.

Extracellular accumulation of potassium due to massive activation of neuronal elements seemed to account for the depolarization of the rubrospinal terminals. However, judging from the relatively small changes in the firing threshold of the rubrospinal terminals, the depolarization produced by non-GABAergic pathways appeared to be rather small and possibly of no consequence for synaptic transmission, in contrast with the transmitter-mediated depolarization that depressed synaptic transmission.

Yet, the challenge was to measure the local changes in potassium concentration at the site where conditioning stimuli increased the excitability of single group I muscle and cutaneous afferents. For several years, I invited Ladislav Vyklicky to visit Mexico to do these experiments together, but I was never successful because his government would not allow him to leave Prague. I learned later that my mistake was to invite Ladia by name instead of asking for collaboration with somebody “expert in presynaptic inhibition that had developed electrodes to measure changes of potassium in the spinal cord”!

In 1983, I was invited by the director of the Mexican Council of Science and Technology (CONACyT), Edmundo Flores, to join him on an official visit to Poland, Hungary, and Czechoslovakia. While in Prague, I told him about all those failed attempts to have Ladislav visit our laboratory in Mexico. At the meeting, Edmundo Flores stated that he saw no point in pursuing a collaboration program with Czechoslovakia, because Mexican scientists were not allowed to invite persons with whom they wanted to collaborate. He gave as an example my failed attempts to invite Ladislav. They first suggested I should instead come to Prague, but Edmundo Flores insisted that I was the vice president of our Academy of Sciences and that my duties prevented me from leaving the country for an extended period of time, as required to perform the research we had in mind, and that they should instead allow Ladislav to work with us in Mexico. The Czechoslovakian authorities left the room and a couple of minutes later they returned and told us that they would allow Ladislav to spend three months in Mexico.

Ladislav brought the ion exchange resin he was using in Prague, so we could soon start experiments. The idea was to measure changes in the extracellular concentration of potassium at the same site where we tested changes in the intraspinal threshold of single muscle afferents.

To my delight, we found quite soon that stimulation of afferents from flexor muscles could strongly reduce the intraspinal threshold of single Ia and Ib afferents (from muscle spindles and tendon organs, respectively) ending within the intermediate zone without significantly changing the concentration of potassium measured at that same intraspinal site. In contrast, stimulation of cutaneous afferents, particularly with high-frequency trains, produced a smaller PAD of the tested afferents despite the notorious increase in extracellular potassium (Jiménez et al., 1983, 1984).

It was clear that there was no correlation between the magnitude of the PAD of muscle afferents and the changes in the local concentration of potassium ions. At the beginning, Ladia was somewhat skeptical about these findings, but since they were consistent and were obtained using the same resin that he used in Prague, and since he could not blame the air pollution that often interfered with the filling of the micropipettes, nor the Mexican cats, he ended up accepting the evidence.

This settled a discussion of many years. By excluding extracellular accumulation of potassium ions as the main cause of PAD, the GABAergic hypothesis for the origin of PAD became more feasible. The selectivity of PAD would then depend on the location of the GABAergic axo-axonic synapses in the intraspinal arborizations of the afferent fibers.

Functional Organization of the Pathways Mediating Primary Afferent Depolarization

Until the late 1970s, changes in PAD were mostly inferred from changes in the DRPs, which are electrotonic recordings of the depolarization generated remotely in the intraspinal terminals of the afferent fibers. This prevented proper identification of the afferent fibers subjected to PAD. Later on, PAD was inferred by measuring the changes in the amplitude or area of the antidromic compound action potentials recorded in sensory nerves after intraspinal stimulation (Rudomin and Dutton, 1968).

In 1979, after I returned from Goteborg, we developed a computer-controlled procedure that allowed a continuous estimate of the intraspinal threshold of single afferent fibers (Madrid et al., 1979). In contrast with intrafiber recordings of PAD that lasted only a few minutes, this method allowed us to measure for hours the changes in the intraspinal threshold of single afferents produced under different experimental procedures and infer the changes in PAD. A similar system was developed by Curtis almost at the same time (Curtis, 1979).

With this method, we examined the effects of a variety of segmental and descending stimuli on the intraspinal threshold of single Ia and Ib afferents (Rudomin et al., 1983). We found that Ia fibers were depolarized by conditioning stimulation of group I afferents from flexor muscles but not by stimulation of cutaneous afferents, nor by stimulation of the reticulo-spinal, rubro-spinal, and cortico-spinal fibers (Type A PAD pattern). In contrast, Ib afferents were depolarized by all of these conditioning stimuli (Type B PAD pattern). This led to the proposal that the PAD of Ia and Ib afferents was mediated by separate sets of last-order PAD mediating interneurons. This assumption differed from the suggestion initially made by Eccles et al., (1952) that the same last order interneurons mediated the PAD of both Ia and of the Ib fibers.

In a more detailed study made in 1986 (Rudomin et al., 1986) we found, in addition to the two PAD patterns described earlier, that many Ib fibers were also depolarized by reticulo-spinal and rubro-spinal stimuli but not by cutaneous stimuli that instead inhibited the PAD elicited by stimulation of gr I flexors (type C PAD pattern).

These observations were still compatible with the proposal that the synaptic efficacy of Ia and Ib fibers is presynaptically controlled by at least two different sets of interneurons. This possibility was particularly attractive in view of their extensive convergence onto the same spinal cord interneurons because this could, at least in principle, allow independent adjustment of length feedback and force feedback to the needs of specific motor tasks.

In these studies, group I fibers were classified as Ia and Ib on the basis of their peripheral thresholds and conduction velocities. It thus seemed necessary to have a more reliable identification of the afferent fibers whose PAD patterns were being investigated. This was achieved by intrafiber recordings of the PAD from afferents whose peripheral axons were left in continuity, so we could also record the orthodromic action potentials produced by muscle stretch and contraction and use them to classify the afferents as either from muscle spindles or from tendon organs.

These studies confirmed the general conclusions derived from studies where Ia or Ib fibers were classified on the basis of their peripheral thresholds, conduction velocity, and projection to the motor pool (Jiménez et al., 1988). As in the previous study (Rudomin et al., 1986), we showed that most tendon organs had a type C rather than a type B PAD pattern.

One question that remained open was whether there was any correlation between the PAD produced by conditioning volleys to muscle nerves and the functional characteristics of the target muscle spindle afferents, for example, their responses to muscle stretch. We investigated this with Manuel Enríquez (Enríquez et al., 1996a). By using a variety of tests for receptor identification, we found that the largest proportion of muscle spindle afferents had a type A PAD pattern. However, there also was a significant number of spindle afferents with a type B and with a type C PAD pattern. In confirmation of previous studies, most tendon organs had a type C PAD pattern, a fair number of them a type B PAD pattern, and some a type A PAD pattern.

Quite interestingly, we found that the profile of PAD patterns of the population of functionally identified group Ia and Ib fibers changed after chronic nerve crush (Enríquez et al., 1996b). Two to three weeks after the nerve crush, there was a significant increase in the number of Ia afferents with a type C PAD pattern, while most tendon organs showed a type B and few a type C PAD pattern. These changes were partly reverted by six months after the nerve crush and probably reflect changes in central connectivity and/or synaptic effectiveness of the pathways that mediate the PAD of these two sets of afferent fibers. We suggested that the changes in the PAD patterns of the reconnected Ia afferents were due to an increased ability of supraspinal structures to produce PAD that could be part of a compensatory mechanism that allows central control of inadequate information arising from the damaged fibers.

Selectivity of Primary Afferent Depolarization

In 1987, Hans Hultborn and collaborators (Hultborn et al., 1987) devised a clever non-invasive method to examine in humans changes in the synaptic effectiveness of muscle spindle afferents synapsing with motoneurons. They found that just prior to a voluntary muscle contraction there was a differential modulation of the tonic presynaptic inhibition of Ia muscle spindle afferents; it was reduced in Ia afferents innervating the muscles that were to be contracted and increased in Ia afferents innervating the non-contracting muscles. Encouraged by these findings, we started a series of studies aimed to examine with more detail the effects of conditioning stimulation of sensory nerves, motor cortex, and bulbar reticular formation on the intraspinal threshold of pairs of collaterals of the same or different single afferent fibers that ended in close vicinity or in different spinal segments (Eguibar et al., 1994, 1997; Quevedo et al., 1997; Lomelí et al., 1998).

We found that stimulation of some regions in the motor cortex could have differential effects on the PAD of pairs of collaterals of the same fiber. That is, cortical stimuli could reduce the intraspinal threshold of one collateral without affecting the threshold of another collateral of the same fiber or else inhibit the PAD in one but not in the other collateral. We also found that the PAD produced by group I flexors in pairs of collaterals of the same muscle spindle afferent could be differentially inhibited by conditioning stimulation of cutaneous and articular afferents, and that such a differential inhibition was under supraspinal control.

I really don’t remember when I met Robert Schmidt, but it was surely during one of the Society of Neuroscience meetings. With time we developed a friendly relationship that changed to an active scientific collaboration. During one of his visits to Mexico in the early nineties, we examined the changes in the PAD of muscle afferents elicited by stimulation of joint afferents (Quevedo et al., 1993) that led to a series of studies on the selectivity of the pathways mediating PAD in joint afferents and on the changes in their synaptic effectiveness during the inflammation produced by the intradermic injection of capsaicin (Rudomin and Lomelí, 2007; Rudomin et al., 2007; Rudomin and Hernández, 2008).

Altogether, these observations indicated very clearly that the intraspinal collaterals of the afferent fibers are not fixed routes for information transmission, as was assumed for many years, but rather dynamic substrates in which the information flow can be centrally directed to particular neuronal targets as needed for the execution of specific motor tasks. These studies provide a clear demonstration of local character and selectivity of PAD in muscle and in articular afferents.

Where Are We Now?

Our interest in the neuronal circuits and synaptic mechanisms that regulate the relationship between individual and population monosynaptic responses started in the early 1970s (Rudomin and Madrid, 1972), but it was not until 1987 that we tried to identify the spinal interneurons that mediate PAD of group I afferents (Rudomin et al., 1987).

As discussed earlier, we found neurons that had the features expected for last-order interneurons mediating PAD and presynaptic inhibition of group I afferents. It was then when we became aware that the spontaneous action potentials of these neurons were not only time locked to DRPs and VRPs but were also preceded by a slow negative cord dorsum potential lasting 50–150 ms that started 10–20 ms before the interneuronal spikes. This fortuitous observation raised the possibility that the neurons that we assumed mediated PAD were driven by neurons located in more dorsal regions of the spinal cord.

But it was not until the end of the 1990s that we started a series of systematic observations with Manjarrez aimed to disclose the origin of the spontaneous cord dorsum potentials (CDPs) that preceded the spontaneous activation of the PAD-mediating interneurons (Manjarrez et al., 2000). As expected, we found spontaneous CDPs similar to those disclosed using interneuronal spike-triggered averaging. A detailed analysis of the intraspinal field potentials associated with these CDPs indicated that they were generated by the activity of neurons located in the dorsal horn, which responded to electrical stimulation of low-threshold cutaneous nerves, often with monosynaptic latencies.

Recording the spontaneous CDPs simultaneously from different sites in the lumbosacral spinal cord further indicated that a fair number of them appeared synchronously along several spinal segments (Manjarrez et al., 2003). Later on, we found that the coupling between the CDPs recorded from nearby segments on the left side (L5 and L6) was partly reduced after an interposed lesion of the ipsilateral dorsolateral fasciculus (DLF) and completely abolished after a contralateral DLF lesion at the same level (García et al., 2004). These findings were consistent with our previous suggestion that the CDPs were generated by a longitudinally distributed set of interconnected neurons on both sides of the spinal cord.

Already, in 1987, we had noted that most of the CDPs associated with the activity of Class I interneurons were negative (nCDPs), while those associated with Class II interneurons were negative–positive (npCDPs). This led to the proposal that separate sets of dorsal horn neurons generated the nCDPs and the npCDPs (Rudomin et al., 1987). However, more recent experiments (Chávez et al., 2012) have provided evidence suggesting instead that both the nCDPs and npCDPs are generated by the same ensemble of interconnected neurons that are distributed along several segments, in agreement with our previous proposal (Manjarrez et al., 2000).

The generation of nCDPs or npCDPs appeared to depend on the synchronization between the spontaneous firing of the neurons in the network. Under conditions of weak synchronization, nCDPs were preferentially generated. Increased synchronization, as seen after the acute section of a cutaneous nerve, would increase the temporal summation of the synaptic actions in some sets of interneurons and recruit the segmental pathways mediating PAD (Chávez et al., 2012).

Fractal analysis of the spontaneous CDPs simultaneously recorded from several segments has further indicated that the fluctuations of the CDPs are not random but have an underlying structure, even after the acute section of a cutaneous nerve or after partial spinal lesions (Rodríguez et al., 2011). This raised the question of the meaning of “fractal structure” in terms of functional neuronal interconnectivity.

To approach this question, we assumed, as a working hypothesis, that the magnitude of the correlation between the spontaneous CDPs recorded from a given pair of segments represents the strength of the synaptic connectivity among the neuronal ensembles generating these CDPs. It then follows that the correlation between pairs of CDPs recorded from different segments in the lumbosacral cord represents the spatio-temporal configuration of the connections among the different segmental sets of neurons involved in the generation of the CDPs. That is, the “state” of neuronal functional interconnectivity.

We have found quite recently that intradermic injection of capsaicin produces a long-lasting increase in the spontaneous and evoked activity of dorsal horn neurons responding to noxious and non-noxious stimuli. But the most impressive finding is the change that capsaicin produces in the patterns of correlation among the spontaneous activities recorded from different spinal segments. They acquire a different, albeit structured, configuration that may persist for a couple of hours. Quite interestingly, the systemic injection of very small amounts of lidocaine transiently resets the patterns of intersegmental correlation to the configuration observed before capsaicin. The resetting produced by systemic lidocaine could underlie its analgesic action observed in humans during inflammatory and neuropathic pain.

We are now facing the question of how to explain these changes in terms of neuronal connectivity. One possibility could be that the network has a limited repertoire of small groups of highly coherent neuronal aggregates (modules?) with relatively stable interconnections and that capsaicin and lidocaine switch from one configuration to another, selected from the available repertoire.

An alternative possibility would be that all these changes are the expression of a self-organizing system that has compensatory mechanisms that prevent its disintegration when subjected to perturbations that exceed a certain limit. Once this limit is exceeded, the system is destabilized and leads to a rupture of internal structure. If the perturbation persists, the different neuronal ensembles are reorganized and lead to a new structure capable of dealing with the perturbation.

Although we still lack many of the concepts and tools necessary to deal with these kinds of questions, the evidence so far collected provides a better understanding of the dynamics of neuronal networks and how they may adjust themselves to the ever-changing needs of the organism. These adjustments are not random but appear to be highly structured and can be viewed as part of homeostatic processes that tend to preserve the integrity of the organism.

Seen in retrospective, it would appear that our studies on presynaptic inhibition were variations of the same theme. What is interesting, however, is that as time went by, our way of perceiving these questions shifted from a static and relative reductionist view to a more dynamic, multidimensional approach. As Anders Lundberg once told me when I was somewhat discouraged by going back to the same old questions: “More than moving in closed circles, it seems that you have been moving in ascending spirals. That is, you have been viewing the same problems, but with a different perspective.”

To study the way in which the different neuronal networks interact is now one of the most important challenges faced by the neurosciences. This knowledge is required to understand, a little more, the generation of voluntary movements and of some basic cognitive processes including those mechanisms that contribute to pain perception—also how we learn, how we forget, and how these functions are changed during aging and different pathologies.

My Incursions in Science Policy

I wondered for a while whether or not to include this section in my “scientific autobiography.” I am still not very sure because to some of the readers the names and situations may have no meaning. But I decided to do it because, as I stated in the introduction, the conduct of science depends on the particular conditions in each country. It may be perhaps a little anecdotal, but these were my circumstances and no others.

The Academy Prize in Science and the National Program of Basic Sciences

Since 1961, the Mexican Academy of Sciences delivers the yearly Prize in Science in recognition of the scientific contributions of young investigators (less than 40 years old). In 1971, the academy awarded two prizes, one to Manuel Peimbert, a well-known astrophysicist, and another to me.

Before 1971, the academy’s awards were presented at the National University, but that year the awards were delivered by the president of Mexico, Luis Echeverría, at the National Palace. This ceremony had a special meaning because the relations between the scientific community and the government were at their lowest since the 1968 events.

During the February 1972 ceremony, President Echeverría, who took office in 1970, invited Peimbert and me to join him in a visit that he was about to make to Japan in a couple of weeks. It was precisely then when R. Burke and I were starting to have successful simultaneous intracellular recordings from pairs of motoneurons, and the idea of going to Japan was not really appealing to me.

So I thanked the president for his invitation and told him that I had a distinguished scientist visiting my lab for a few weeks and that we were doing rather difficult but important experiments that were just coming out and that it would be a pity to interrupt them at that moment. He replied very politely that I should not worry, that this was a standing invitation, and that I should visit Japan whenever I could do it.

The ceremony continued and Eugenio Méndez Docurro, who was the first director of the recently founded Council of Science and Technology (CONACyT), stood up and announced that the president extended his invitation to the wives of the awardees to travel with him to Japan. I could just see the smiling face of Flora and knew in that moment I was to go to Japan!

As I expected, at the end of the ceremony, Flora asked me if I was going to Japan, and I said: “Well I am not sure because I have a lot of work to do at the lab,” and she replied, “You may not go, but I am going since the president invited me.”

Several hours later, I returned to the lab and had a phone call from the director of our institute, Guillermo Massieu. “Pablo,” he told me, “How could you say no to the president? Your refusal could be interpreted as a rejection because of the 1968 events when he was minister of interior. Think about how important it could be for science and for our institute to have a renewal of relations between the scientific community and the government.” A few minutes later, I got a phone call from the president of the academy, Raúl Ondarza, who expressed similar concerns and asked me to accept the president’s invitation.

A couple of days later, I was still considering whether or not to join the president on his trip to Japan when I got an invitation to attend the presentation by Méndez Docurro of the first-year activities of the Council of Science and Technology. The meeting was to be held at the official residence of the president in “Los Pinos” in front of distinguished members of the scientific community and the directors of academic and research institutions—not more than 30 persons. It was clear that I could not ignore this invitation. So there I was.

When President Echeverría entered the room, everybody went to greet him. I was shy and stayed in the back of the room. The president looked at me and said: “Now Rudomin, tell me, are you coming with me to Japan?” So I had no option but to say, “Yes, Mr. President. It will be an honor for me to join you on that trip.”

The trip to Japan was very interesting. In addition to meeting some of the most distinguished Japanese scientists (if I recall correctly, I met Yasuji Katsuki, Masao Ito, Kazunori Furukawa, and Toshinori Hongo), I also visited some of the science-based industries. But above all, it meant the possibility of having contact with persons involved in the design and conduct of the Mexican government’s scientific policy. Soon after returning from the trip to Japan, I got an invitation from the new director of CONACyT, Gerardo Bueno, to become part of an advisory group. I soon found that few of the activities of the council contemplated support of basic research. After long and sometimes tough discussions, I was able to convince G. Bueno to start a program specifically addressed to support research in basic sciences.

He asked me to chair this program, but I was concerned that this would distract me from my research. I remember I discussed this with a good friend, Jerzy Plebansky, who was at that time chairman of the department of physics at CINVESTAV. He was born in 1928, in Warsaw, where he stayed during the war, and he was a specialist in the field of general relativity and mathematical physics. He told me: “Pablo, it does not matter what you decide, you will always be sorry. The question is if you are sorry for having done it, or for not having done it.” Good advice for somebody expert in general relativity! I ended up accepting Bueno’s invitation because I thought it would be unwise on my part not to do it, particularly after my comments at the academy’s award ceremony that the government was not supporting science as it should.

I chaired the National Program for Basic Sciences for eight years, three with Gerardo Bueno and five with Edmundo Flores as directors of CONACyT. Support to basic sciences has continued since and is now part of the regular activities of the council. Yet, the struggle to substantially increase the support to those activities and to science in general is still going on.

The Mexican Academy of Science and the National System of Investigators

In 1979, I was awarded the National Prize of Sciences, the highest distinction given by the government. Soon after, I was invited by the president of the Mexican Academy of Sciences to run as a candidate in the election of the next president of the academy.

As elected vice president of the academy, it soon became clear to me that the academy activities were mostly centered on local issues, and that very little was done to expand our relationship and collaboration with other academies. I was particularly interested in developing a good and standing relationship with the National Academy of Sciences in the United States, at that time presided over by Philip Handler. He was quite receptive when I wrote him, and we organized a meeting between the directive boards of the two academies to discuss possible collaboration that was scheduled for May 1981. As a result of this interaction, we were able to start several collaborative projects, some of which still are in operation.

I took over as president of the academy in November 1981. My first commitment was, of course, to convince the government of the need to increase the support for science. This became an urgent matter when, on September 1, 1982, President López Portillo nationalized the banks and limited the acquisition of foreign currency. Even research institutions could not get the currency to acquire and import the necessary substances that scientists needed to keep up with their research. CONACyT was also unable to get all the necessary funds, and scientists turned to the academy. Unfortunately, there was little we could do because this happened a few weeks before the end of President López Portillo’s term in office.

The federal administration changed on December 1, 1982, and Miguel de La Madrid became president of Mexico. It was also the end of my appointment as chairman of the National Program of Basic Sciences in CONACyT, but I still had one year left as president of the academy. A couple of days later, I received a phone call from the office of the new minister of education, Jesús Reyes Heroles, that he needed to contact me urgently. I called and arranged a meeting for the next day.

I knew Reyes Heroles from a trip we took together to Argentina, on which we had been invited by President Echeverría. I asked myself: “Why such urgency, just two days after his appointment?” I thought that the hurry was because he would invite me to join his team, and I could not sleep all night. Next morning, I said to myself: “If I couldn’t sleep all night for this, it means that to be involved full time in public administration is not for me.”

So I went to see Reyes Heroles. When I entered his office, he was smoking a cigar and offered one to me. After recalling our trip to Argentina he told me: “Pablo, I liked very much the speech you gave a couple of weeks ago during the ceremony of the academy awards, and I want you to help me to improve science in this country.” I answered: “It will be an honor.” He then asked me “What would be the first thing you would do?” I answered: “To set up a program where good scientists could get the support and salary they need to do their research, without looking for extra jobs or becoming administrators or politicians!” He then asked me: “Does this apply to all? What about you?” I answered “Beginning with me.” “OK,” he added, “Let’s start with this.”

And it was then when I presented to him the proposal of creating a program based on the recommendations made in a panel organized by the academy several weeks before, which took as a starting point the proposal originally presented by Carlos Gual when he was the academy’s president. This program considered salary compensation for the scientists as well as the funds they required to perform their research.

Reyes Heroles asked for names of people whom he could invite to work with him. I gave him a list of several scientists whom I knew well and believed would be interested. Among them was Jorge Flores, a renowned physicist and former president of the Mexican Academy of Sciences (1976–77). He was soon contacted by Reyes Heroles and appointed as vice minister of education.

As vice minister, Jorge Flores started to work on this project, which was to be announced by the president of Mexico during the award ceremony that I chaired as president of the academy. José Sarukhan, who succeeded me as president (1984–85) and Jorge Flores, together with Salvador Malo, worked on the elaboration of the bylaws for a program named “National System of Investigators” that was formally initiated July 26, 1984.

This is not the place to discuss in detail the achievements and the limitations of this program that started around 30 years ago and is still functioning. The number of investigators incorporated into the program has increased with the years. It started with 1,396 investigators. By 2011, 27 years later, there were 17,637 members.

Besides the increased number of scientists incorporated into the system, I feel that this program changed the way that society perceives scientific activity. Although it was initially conceived as a selective mechanism to provide salary compensation to the investigators in times of crisis, with time, it became a symbol of “status” in the sense that being a scientist was socially relevant.

El Colegio Nacional and the Science Advisory Council for the President

Throughout all these years, I have received several public recognitions for my contributions to science, among them the award given by the Mexican Academy of Sciences in 1972, the National Prize of Sciences in 1979, and Spain’s “Principe de Asturias” prize for scientific investigation in 1987. I must say that the Principe de Asturias was particularly gratifying because it signaled an international recognition for the work I performed in Mexico during so many years and gave me the opportunity to have a stronger interaction with Spanish scientists and to develop a collaboration that is still vigorous.

In 1993, I was appointed a member of El Colegio Nacional. El Colegio Nacional was founded on April 8, 1943, for the purpose of promoting Mexican culture and scholarship in a number of different fields. It is a lifelong appointment and is meant to include the most distinguished personalities in science and in the humanities. As an elected member of El Colegio Nacional, I have delivered a series of public lectures, usually 10 per year, in different academic and scientific institutions throughout the country. These lectures have been mostly addressed to students in different areas such as medicine, biology, chemistry, and engineering. The attendance has been really impressive, usually between 150 and 200 per lecture. After the lecture, I spend some time with a small group of students answering their questions and discussing relevant issues in education and science with them. Some of these students have appeared to be really motivated by science, and a couple of them ended up working for some time in my laboratory.

In addition, as member of El Colegio Nacional, I have had the opportunity to interact with several of the most distinguished personalities in Mexico (outside of science) whom I would not otherwise have met in my daily routine. The discussions with them, at our monthly meetings, have enriched my vision of different aspects of life in Mexico and led to the organization of a series of symposia and publications where many of us have presented our views and studies on different issues of general interest, such as “The Frontiers of Complexity: The Mysteries of the Brain,” “An Integrative Vision: Universe, Life, Man, and Society,” “The Concept of Reality: Truth and Myths in Science, Philosophy, Art, and History,” and “Free Will versus Determinism.”

In 1988, some of the members of El Colegio Nacional talked with President Salinas about the possibility that the executive branch of the Mexican government should create a science advisory group of whom the president could ask opinions on specific issues of national relevance. In 1989, in response to these suggestions, President Salinas created the Consejo Consultivo de Ciencias (Science Advisory Council). This council was formed, in an honorary and voluntary manner, by those scientists who had been awarded the National Prize of Sciences. It was to be coordinated by one of them, elected from among the council members.

The first general coordinator was Dr. Gillermo Soberón, member of El Colegio Nacional, former rector of the National University, and former minister of health. The council could not have been in better hands. During his appointment as general coordinator, he promoted a series of studies on issues of national relevance that were then sent to the president. He also organized several meetings with President Salinas where the members of the advisory council could present him with studies and opinions on significant issues in science and technology.

He promoted the creation of the Prize “Mexico” that was awarded to scientists from Ibero-America (with the exception of Mexico because they already had access to the National Prize of Science) for their contributions to science and technology. This award is now given annually and is handled by the Science Advisory Council and CONACyT.

In addition, Dr. Soberón was instrumental, together with California congressman George Brown, in the creation of the United States–Mexico Foundation for Science. As general coordinator of the advisory council, Dr. Soberón was a member of the governing board of the foundation.

In May 1995, I was elected as Dr. Soberón’s successor, but it was not until 1996 that I could have a formal meeting with President Ernesto Zedillo. My first task was to learn his plans pertaining to the destiny and activities of the Science Advisory Council. When we met, he expressed his interest in its continuation. Among the plans he had for the council was a study of the structural changes required for a better and steadier support of research in science and technology in order to make them more responsive to national needs.

Together with specialized lawyers, we analyzed the third article of the Mexican constitution that explicitly indicated the commitment of the Mexican State to support scientific and technological research. This was the basis for the revision of the bylaws necessary to comply with the constitutional mandate.

Revision of the bylaws required a close collaboration between the Scientific Advisory Council, the Mexican Academy of Sciences, CONACyT, and the ministry of education. In the process, I learned how difficult it is to make a law and how careful one should be with each word, to avoid erroneous interpretations and, at the same time, not to transform the law into a straightjacket.

After we had the first draft, we met with the commissions of science and technology of the Congress. It took some time to have a text that was satisfactory to all. Once available, it was submitted to the presidential legal advisers. This meant additional discussions and changes until finally, President Zedillo sent the proposal to the Congress on December 15, 1998. It was approved unanimously by April 30, 1999, and published by the executive branch on May 21, 1999.

Proper application of the law required decisions at the highest level in the government. In August 1999, I presented a study to President Zedillo suggesting the creation of a cabinet of science and technology headed by the president himself and integrated with the ministers of education, health, environment, agriculture, economy, and treasury, and with the director of CONACyT and the general coordinator of the Scientific Advisory Council as invited guests. The idea was that they should meet several times per year to advise the president and make decisions on important issues pertaining to science and technology, including the application of the law.

President Zedillo approved the proposal. The bill creating the cabinet was published on December 2, 1999. The cabinet met only once, on May 9, 2000, but even so, it was able to decide about several important issues, among them the creation of special funds for research in priority areas that would be supported by CONACyT and by other government agencies (health, education, etc.). These programs are still active. The Cabinet on Science and Technology has been recently revived, after 12 years of hibernation during the past two administrations.

My first term as general coordinator of the advisory council was for three years, and I was re-elected for another term. The last year was under the presidency of Vicente Fox. He appointed José Sarukhan as commissioner. He had, among other things, the responsibility of dealing with science and technology. We had a good interaction and started to analyze possible strategies aimed to further strengthen and increase the funding of scientific research. Unfortunately, he resigned two years later, and the proposed changes were not implemented.

Epilogue

Seen in retrospective, to be involved in scientific policy was very time-consuming. I worked hard not to be away from the laboratory, and I could do it to some extent because I had the enthusiastic collaboration of my colleagues and students, who were not afraid of remaining for long hours with experiments, as well as family’s understanding and support. I am now back full time in the laboratory and with my commitments to El Colegio Nacional. This, together with the time I now spend with my family, fills up all my days. Unfortunately, traffic in Mexico City is so hectic and unpredictable that it often prevents me from meeting with friends I have made through the years. This is the price we pay for living in an overcrowded but still attractive place such as Mexico City.

We have still a long way to go. We need to teach our students and our young investigators to be more self-confident and more competitive and to seek quality instead of quantity in their scientific contributions. We also need to convince our authorities to reduce administrative and bureaucratic obstacles that, instead of helping, prevent and delay scientific research.

Yet, being in a country like Mexico has its advantages. I am now almost 80, and I can be active thanks to the institutional support that provides me space, technical and secretarial help, and a small amount for current expenses. I compare my privileged condition with that of some of my peers in the United States or in Europe. Some retired because they became tired of dealing with grant applications and merciless competition. Others were forced to retire to make space for the new generations. I wondered whether I could have done my research if I had moved to one of these countries. I doubt it because here in Mexico I had time to think, and I was not enslaved by the inevitable need to justify my existence. Unfortunately, this is not the case for most of our young investigators who, unable to find the proper research positions in our academic institutions or in the industry, must leave the country. I just hope that working conditions soon will be sufficiently attractive so that these young people stay in Mexico.

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Anne Treisman

BORN:

Wakefield, Yorkshire

February 27, 1935

EDUCATION:

Cambridge University, Modern and Medieval Languages, BA (1956)

Cambridge, University, Natural Sciences, Psychology, BA (1957)

Oxford University, Psychology, PhD (1962)

APPOINTMENTS:

Medical Research Unit in Psycholinguistics, Oxford (1963)

Visiting Research Scientist, Behavioral Sciences Department, Bell Labs, Murray Hill, NJ (1996)

Fellow of St. Anne’s College, Oxford (1967)

University Lecturer in Psychology, Oxford University (1968)

Fellow at the Center for Advanced Study in the Behavioral Sciences, Stanford, CA (1977–1978)

Professor of Psychology, University of British Columbia (1978)

Fellow of the Canadian Institute for Advanced Research (1984)

Professor of Psychology, University of California, Berkeley (1986)

Visiting Scholar, Russell Sage Foundation, New York (1991–1992)

James S. McDonnell Distinguished University Professor of Psychology, Princeton University (1993–2010)

HONORS AND AWARDS (SELECTED):

Society of Experimental Psychologists (1979)

Killam Senior Fellowship (1982)

James McKeen Cattell Sabbatical Award (1982)

Fellow of the Royal Society, London (1989)

Howard Crosby Warren Medal of the Society of Experimental Psychologists (1990)

Distinguished Scientific Contribution Award of the American Psychological Association (1990)

William James Fellow of the American Psychological Society (1992)

National Academy of Sciences, Foreign Associate (1994); Member (1999)

D.Sc., Honoris Causa, University of British Columbia (2004)

Elected to American Philosophical Society (2005)

D.Sc., Honoris Causa, University College, London (2006)

George Miller Prize from Cognitive Neuroscience Society (2008)

Grawemeyer Award in Psychology (2009)

Elected to British Academy (2009)

Governing Council of National Academy of Sciences (2011)

National Medal of Science, USA (2013)

Wiley Prize for Psychology, British Academy (2013)

Anne Treisman explored the mechanisms of attention, first in audition and later in visual perception. She proposed the “filter attenuation” theory of selective attention to speech. Later, she put forward the “feature-integration” theory, suggesting that selective attention to locations binds features to form integrated representations of visual objects. The theory led to the discovery of conjunction errors in the binding process and explained diverse phenomena in search, in visual organization, and in the peculiar symptoms of patients suffering from Balint’s syndrome. Finally, Treisman investigated the capabilities of distributed attention in extracting information in scene perception.

Anne Treisman

Looking back, I feel that I have been extraordinarily lucky in my career. I have seemed in some ways to lead a charmed life, perhaps because I chose goals that came easily to me. I began with essentially no real training in science or psychology, and yet I got pretty much all the grants I applied for (this was in the good old days before the present tightening of scientific funding). I ended up with far more recognition than I expected and probably than I deserved, and I retired in 2010, before working in my field became really tough. I managed to have four children, who graciously allowed me to work without exhibiting too many signs of neglect. I had students who were fun to work with and full of ideas; and my career spanned a period of real development and little competition, an era in which my amateurish approach could still yield interesting results.

Family and Early Years

My mother, Suzanne Touren, was French, and I spoke French before English, which I learned when I was four or five. I remained bilingual, although English became my dominant language. My mother’s father, her brother, and her nephew were all physics teachers in Paris. They were descended from Protestants, although they were no longer religious. My grandfather (as well as my uncle, cousin, and mother) wrote a memoir, following the example of his own great-grandfather who, according to the memoir, was a soldier in Napoleon’s army and had many adventures, including being shipwrecked in Africa on an expedition to put down Toussaint L’Ouverture’s rebellion in Haiti and being saved by an African woman who took a fancy to him.

My French grandmother came from Pithiviers, a village in north-central France, where her father owned the pharmacy. My grandmother and her sister were known in the village as the demoiselles Kuss. My grandmother and her family were also Protestants, which is why my grandfather met my grandmother—with a view to an arranged marriage—because, apparently, Protestant girls were few and far between in his circle in Paris. I do not think my grandparents were actually religious. I never knew of them going to church, but it would have been a Protestant one if they had. My grandmother was a wonderful woman. She had left school at 16 but was always reading books—history, current affairs, and so on. She had a great sense of humor and would infect my mother and me with le fou rire—a fit of giggling—which amazed and irritated my grandfather. He loved opera and the theater, but I think he did not understand his wife very well.

On my father’s side, I know much less. My paternal grandfather died young, in his early fifties, as did my father, Percy Taylor, and his brother. My English grandmother, Bessie, was quite enterprising. She was one of seven sisters from Lidgate, a village in East Anglia, but she decided to explore the world and went to Italy to earn her living as a nanny to an aristocratic family. The head of the family, an Italian count and novelist, Alberto Denti di Piraino, dedicated one of his novels to her. When she came back to London, she married and had three children, of whom my father was the youngest. After her husband died, to make ends meet, she opened a boardinghouse for young women from abroad, which was how my mother met my father. My mother came to England to improve her English and to get over a previous unhappy love affair. Achieving both goals, she married my father.

This binational background made me feel somewhat different from the other children I knew. I was happy but did not always feel that I belonged. I have had a similar experience as an adult in the United States. I have always felt at ease but have never fully absorbed the culture around me. To this day, I do not know the rules of baseball or American football.

Because of the Great Depression, jobs were hard to get in England in the early 1930s, and my father, after being turned down for many school teaching jobs (perhaps because his letter of recommendation said that he was “no great athlete”), was lucky to be offered a position in education administration in the Yorkshire mining town of Wakefield. That is where my parents started their married life and where I was born, in 1935. Wakefield was something of a shock to my mother, who had to adapt to the smoke and the black coal dust that settled on their clothes, in a place that had neither bookstores nor theaters. It was quite a contrast to the cosmopolitan culture she had been used to in Paris. My father’s next job was in Lancashire, in another mining town, where my sister, Janet, was born. When I was five, my father got a job as chief education officer for the Medway towns—Rochester, Chatham, and Gillingham—in Kent.

Soon after we had moved to Kent, World War II broke out. We had been going to Paris every year to see my French relatives, but the war ended those visits, and we were cut off from them until 1945. The separation was hard on my mother, but my parents protected me and my sister from the terrors of the war. My sister and I would be carried down to shelter in the cellar whenever the air raid sirens went off. We took our cat with us, and his gentle purring masked the sound of planes flying overhead. Our house was right in the path of the V-1 flying bombs heading for London—doodlebugs, as they were called. My sister and I would always include a doodlebug in the sky in the pictures we drew.

At the beginning of the war, my mother, my sister, and I were evacuated to Scotland, leaving my father in Kent, where his work was deemed essential. In Scotland, we stayed in a large country house near Oban, owned by a friend of my father’s, together with several other mothers and their children, one of whom (I was told) was my first (unrequited) love. Meanwhile, the Battle of Britain was fought in the skies over Kent, where my father was. Later, we were evacuated to another village where the house we were staying in was later bombed, while ours in Kent survived unscathed.

My parents got tired of being separated. After a year in Scotland, where we went for walks over the hills and through the frequent, if not continuous, “nice drop of rain,” my mother decided to go back to Kent, and we spent the rest of the war there. Our everyday life was filled with reminders of the war—blackouts, air raids, taking refuge in the cellar or under the Morrison shelter, gas masks at school, barrage balloons in the sky just beyond our garden floated there in an attempt to bring down the doodlebugs before they reached London, ration books and limited food, dried eggs, “bananas” made from parsnips and banana essence, and whale meat for protein. We picked rose hips and blackberries for vitamin C and mushrooms and ripening wheat in the local fields. I remember studying the flags with which my father marked the advances or retreats of the Germans on a large map. I went to the village school, which was run by a somewhat sadistic headmaster with seven canes of different thicknesses, with which he kept order in the school. I managed not to be a recipient of the caning. The class teachers were kind, and I was timid enough that the worst punishment I received was to write out a hundred times “I will not be late.”

After the Germans overran France, we had no word from my French family, except toward the end of the war, through Red Cross letters that were capped at 26 words. One contained a coded message about the escape of a Jewish friend, who had been helped by my uncle, who was in the French Resistance. It said “La poupée et St. Paterne sont les meilleurs amis du monde”—“The doll and St. Paterne are the best friends in the world.” The Jewish friend had a niece called Poupée, and St. Paterne was the name of my uncle’s manor house.

I was 10 when the war ended. I remember the excitement of traveling to France by boat, of course, and being greeted at the train station in Paris by 20 or so relatives, all of whom hugged me while announcing their names and none of whom I remembered, apart from my grandparents.

After the war, we went to France twice every year, once at Easter, to stay with my grandparents in their house near Paris, and once to a holiday place, either in the mountains—the Alps—or by the sea in Brittany. When I was 12, I spent a whole term with my grandparents, going to a French school—le Lycee Marie Curie in Bourg la Reine. My grandparents often came to stay with us until they got too old to travel. In his eighties, my grandfather succumbed to Alzheimer’s disease, but he was always so cheerful and charming that it did not seem tragic. One conversation he had with my grandmother and my mother went as follows (in French): “Tell me, Zette”—my mother’s pet name—“What exactly are you to me?” My mother replied, “But I’m your daughter, of course.” He looked pleased and said, “Ah! I’m delighted to hear it.” Then, after a short silence, “And do you know who your mother is?” My mother replied, “Yes, of course I do. She is sitting right beside you in the arm chair.” “Ah,” he said, turning toward her. “Did you know that, Jeanne?”

My father’s last promotion was to run the state education system in Reading, Berkshire, and we moved there when I was 11. He was very good at the job and was much loved in the town. When he died of a heart attack at age 53, my mother received hundreds of letters expressing that affection. When he took the job, in 1945, he had set himself the task of reorganizing education in Reading, which had been sadly neglected for years by an inefficient chief officer. My father transformed secondary education first, developing a sort of comprehensive school system before the term had been coined. The introduction of continuing technical education and the building of the College of Technology were other innovations. The motto he chose for the technical college was borrowed from Michelangelo in his old age: Ancora Imparo—“I am still learning.” He took a special interest in deaf children and started classes for the partially deaf, with the novel idea of integrating them into the life of a normal school, an idea that was copied later by many authorities but that I believe was unique at the time. He knew he had succeeded when he heard that normal children were coming home with bits of plastic stuck in their ears “to be like the others.” People sometimes wondered why there were so many deaf children in Reading. The answer was simple: Their parents had chosen to live there. A new form of youth club was one of his last accomplishments.

Education

I went to the girls’ grammar school in Reading—Kendrick School—-wearing the school uniform of black tunic, white blouse, black blazer edged in red, a black-and-red tie, and a hat or beret in black and red. We had to wear the uniform all day, including the hat when we were out of doors, and we were not supposed to eat in the streets, but I remember feasting on fish and chips. The school day started with prayers and a hymn, with all the students assembled in the school hall. The Jewish pupils were allowed to sit quietly in a classroom and filed in at the end of the religious service for any general school announcements. Each class had a class teacher, but we were taught certain subjects by other teachers, some much better than others. I enjoyed biology and physics the most but did not get very involved. I do not think any of the teachers were really inspiring. I had to wait until I got to a university for intellectual thrills. I do remember being given a microscope one Christmas and being amazed to see, and to draw, all the normally invisible creatures that swam in a tiny drop of pond water.

Education in England was very specialized. We had to narrow down to three subjects from the age of 15. Initially I chose the sciences, but after a few weeks my father panicked, thinking I would grow up without any culture, and persuaded me to switch to French, Latin, and history, which I did for my last three years at high school, dropping math and science completely, which was a sad loss for me—although giving up the arts would have been equally bad. It seems like a terrible thing to force such an early choice on children. The idea was that undergraduates would then become experts, studying their chosen subject in depth in their three years at a university. To my mind, the cost greatly outweighs that benefit.

My school had not sent any students to Oxford or Cambridge for many years; the teachers feared that the Oxbridge standards were higher than they could reach. But my father wanted me to try for those universities because he had been a student at Oxford and had happy memories of his time there. So the school agreed to let me try the entrance exam and two of my friends did the same. As it happened, we were all offered places, and I think that from then on the school did encourage students to try.

I chose Cambridge, perhaps to be different from my father, and I became an undergraduate at Newnham College, where I read modern languages. That was something of a revelation to me. My tutors were eccentric and interesting. As must be common, I suppose, I remember irrelevant details better than anything I was taught. My English supervisor had a strange verbal tic; she said “wuther” at least once in every sentence. Eventually we learned to tune that out, but at first it was the only thing we heard. Newnham’s French tutor, Claude-Edmonde Magny, is best known for her Lettre sur le pouvoir d’écrire—“Letter on the Power of Writing”—which she wrote, in 1943, to a young man who read it only after being released from Buchenwald. It is quite a moving discussion of what it means and what one needs to write literature. In 1954, when I had supervisions (the Cambridge term for tutorials) with her, she appeared more interested in shocking her students than in teaching. I got more from the university lectures that I went to than from my sessions with her. Reading French literature was a very different enterprise from the boring translations in which I had engaged at high school. I did well in the modern languages tripos, getting a starred first, although I sometimes felt a little as though I were bluffing, rather than deeply understanding the poets and novelists that I read. I am very grateful for the glimpse of another intellectual world that I had during those years.

Newnham then was a college for women only. If we went out after dark, we had to wear our gowns, and one of our amusements was to run away when we saw a proctor coming toward us, enticing him to chase us. The gowns were also worn at dinner in Hall, where, as a scholar, I had to say grace before the meal. I was at Cambridge in the early 1950s, and we still had ration cards for food and for coal. I remember some very cold evenings. Friends used to share their coal and spend evenings together, talking or gossiping in one another’s rooms. I made some good friends during those three years, and I joined a number of clubs, including the Folk Song Society, the Newnham Orchestra (where I played the violin), a choir (the highlight was singing in the Verdi “Requiem”), an acting society, and many others. That was certainly the time in which I sampled the widest variety of experiences.

Thinking that I would need to earn my living, I applied for a job teaching French at Oxford High School. Luckily, I was turned down, perhaps because I did not know what the letters GPDST stood for (Girls Public Day School Trust—a select association of girls’ high schools). If I had known that acronym I might have had a very different life.

In the meantime, Cambridge offered me a research fellowship to work toward a doctoral degree in French literature. Although I had very much enjoyed my undergraduate degree, I panicked at the thought of focusing on a single 16th-century poet for the next three years. So I asked if I could use the fellowship money to do a second undergraduate degree, in psychology, instead. My French supervisors were horrified. I remember one of them saying, “But that’s all about rats in mazes!” I said I thought that rats could be interesting, and my request was granted.

Psychology, Bachelor’s of Arts, and Doctor of Philosophy

I switched to psychology in 1956, at a time of rapid change in the discipline: behaviorism and learning theory’s hold on psychology was fading, and the “cognitive revolution” had started. Many psychologists were attracted to a new view of the mind as an information-processing, symbolic system, and the computer was beginning to replace the telephone switchboard as the dominant metaphor for the brain. I was very lucky to be assigned Richard Gregory as my supervisor. He told me not to bother too much with learning theory and to read instead about information theory and vision. Most importantly, he showed me the experiments that he was doing.

In one experiment, he had subjects look at a face mask from the inside. If the subject was stationary, the concave mask was usually seen as if it were a normal convex face. Richard’s explanation was that the strong visual bias favoring seeing a normal convex face rather than a hollow mask reflects the effect of top-down knowledge on perception. As soon as one moves one’s own head and eyes, however, the mask becomes concave again and seems to follow one around. We tried out several of the other illusions and perceptual effects that are described in Richard’s first book, Eye and Brain (1956). I remember that he had built a little railway in his lab, which allowed him to study how perception is affected by motion. It was an exciting year. Richard was a wonderful teacher but not a conscientious one. The tutorials I had with him were not serious discussions of standard topics. If I produced an essay that did not involve perception, Richard would soon say, “That sounds fine. Would you like to try out an experiment I’ve just thought up?” This was an inspiring way to get a student to want to discover more, and it was also always great fun. For Richard, so far as I could tell, psychology was always about having fun.

There were just 12 undergraduates reading psychology at Cambridge that year (including John Morton, who proposed the logogen theory of reading, and Pat Rabbitt, who did great work on skills—and was also very funny). There were only about six journals to read, so it seemed a little less absurd than it would be now to get a degree in one year with no science background whatsoever. Some of the lectures, those by Alan Watson for example, were still about behaviorism and rats, and I did find them interesting, although less inspiring than those by Richard or by Oliver Zangwill, one of the early founders of neuropsychology. There was also an exciting series, by Alan Welford, on what were the beginnings of cognitive psychology. C. G. Grindley, who was, by then I believe, an advanced alcoholic, lectured on perception. He demonstrated the after-effects of motion by making us watch a rotating spiral and then look at his nose, which was already quite red and, in the after-effect of rotation, seemed to be expanding alarmingly. Another lecturer was W. E. Hick, of Hick’s Law (which says that reaction time increases logarithmically with the number of alternatives being discriminated). He did not like lecturing and got out of it easily by beginning his courses with the sentence, “This is rather like casting pearls before swine.” He also avoided teaching a class in clinical psychology by telling us, in his first lecture, about a patient who had a fetish about prams, which he sprayed compulsively with cans of oil. When we laughed at the story, Hick professed himself so shocked that he refused to teach us anything more.

Once I had my bachelor of arts degree, I thought I might become a clinical psychologist, but Richard Gregory persuaded me to stay in research. His argument, as I remember it, was that I could not help people unless I understood the mind, and the mind depended on the brain, and the eye was a really convenient bit of the brain to study because it has been pushed out to the periphery. So my best strategy would be to study vision. I was again offered a scholarship to do research, this time at Oxford, so I moved there, though not initially to work on vision.

The requirements for a doctor of philosophy degree at Oxford were minimal at that time. There were no lectures for graduate students, no exams, and no duties, except to produce a thesis at the end of three or four years. We did go to department seminars, and I listened to Tony Deutsch and Stuart Sutherland, two brilliant psychologists, argue vehemently about their models of rat learning and octopus perception and about what psychology ought to be. These discussions had a big influence on me, by illustrating the power of simple theoretical models to explain perception and behavior in animals. Tony and Stuart debated with no holds barred and plenty of wit. Stuart was an impressive character, quite ruthless in conversation, never suffering fools gladly, but funny and very likable. I remember the day that he came in to coffee having absent mindedly put on two ties. When everyone started laughing, he said, “That just shows the difference between manners in the psychology department and in Magdalen College. When I was there for lunch today, nobody said anything, much less laughed at me.”

New graduate students, on arrival in Oxford, were left to pick a topic for their research. I wondered what to choose. Still thinking of doing something clinical, with the idea of helping patients, I asked my advisor, Carolus Oldfield, for suggestions; he proposed that I look at aphasic patients, perhaps using a framework put forward by Colin Cherry, in his book, On Human Communication (1957). After that, I was pretty much on my own. Oldfield was quite shy, and so was I. For several years, we would pass each other in the corridors, and he would ask how things were going, and I would say, “Fine, thank you.” He did find my thesis quite interesting when I handed it in.

I decided to use a paradigm that Cherry had developed, in which simultaneous passages of prose are presented on different channels (in my case, the right and left ears through headphones). Participants are asked to attend to and repeat back one of the two messages, staying a couple of words behind the stimulus. This task, which Cherry called “shadowing,” is a very effective way to keep attention on the selected message. It also allows the experimenter to monitor how well the participant is doing because any lapse of attention results in missed words in the shadowing. Cherry had shown that participants in the shadowing task know very little about the message that is presented on the rejected channel. For example, they even fail to notice if the unattended message is in another language. However, they immediately notice a switch to a new voice, or other physical changes, such as tones inserted into the speech.

I started going on hospital rounds to learn about aphasic patients and even tested a few on their ability to attend to a selected speech message when there was interference from another. Because I knew almost nothing about brain-damaged patients, it was not surprising that my project quickly failed. I was very reluctant to press the patients to try a task that they were obviously incapable of doing, so I decided to start with some normal controls—and did not go back to investigating clinical patients (not aphasics) for at least 30 years.

At about the same time that Cherry’s book came out, Donald Broadbent was working in Cambridge on applied problems of attention in air traffic control operators and developing his general filter theory of attention, which he published in 1958, in his seminal book, Perception and Communication. Neville Moray and I were both beginning graduate students at the time. We read his book and more or less learned some chapters by heart. We both decided to do our theses on selective listening, testing Broadbent’s theory. This was a functional model of attention, a flow chart of events in the brain when participants focus attention on one of two simultaneous messages. Broadbent’s idea was that we take in different sensory stimuli simultaneously on separate “channels”—for example, the two ears, when each is receiving a different speech passage. The stimuli reach a central bottleneck when the amount of information exceeds our capacity to understand both. To protect us from interference between the two, attention selects one and “filters” out the other, blocking it completely from further processing. Hence, in the case of two simultaneous speech messages, we are aware that there are, for example, two speakers, one on each ear, but we know nothing about what the unattended one is saying.

This kind of model was a new departure in psychology. B. F. Skinner’s approach, which dominated American behaviorism at the time, rejected any speculation about what might intervene in our brains between the arrival of sensory stimuli and the selection of behavioral responses to them. Broadbent, however, was trying to understand those processes in functional terms.

Moray and I were each given a two-channel tape recorder, headphones, and tapes, and left to get on with whatever experiments we wanted. Apart from the papers by Cherry and by Broadbent, so far as we knew, nobody had done or was doing any research in the field of selective listening, so we had it more or less to ourselves. This would be hard to imagine for graduate students in this day and age. We were competing to have the best ideas for experiments and to carry them out, and then to find the most convincing interpretations, within the framework that Broadbent had set out in his book. We both challenged the claim of an all-or-nothing filter by showing that some information did appear to get through. We used Cherry’s paradigm in which participants repeat back (or “shadow”) the passage of prose coming in on one ear and ignore the prose on the other unattended ear. Normally, they identify none of the words on the unattended ear. However, Moray showed that if the participant’s own name was included in the unattended message, participants would hear it about 30 percent of the time (Moray, 1958). I showed that if the attended and the unattended messages switched places, participants occasionally repeated one word from the previously attended message, now on the unattended ear. I also showed that bilingual participants, presented on the unattended ear with a translation of the attended message, lagging by two or three seconds, occasionally realized this.

Moray and I each proposed a modification to Broadbent’s filter theory. Moray proposed that a very important word, such as one’s own name, might have a special “analyzer” dedicated to detecting it at some pre-filter stage. This could account for his result but not for my subsequent findings because any word could be made highly probable in the context of the attended message.

My suggestion was that two forms of selection might be combined to achieve a more flexible system involving two separate mechanisms. I suggested that the general filter that Broadbent had proposed might attenuate, rather than block, the unattended messages (See Figure 1). In addition, a top-down lowering of thresholds might ensure that important stimuli, such as one’s own name or currently relevant stimuli in the context of the attended message, would get through to awareness even in their “attenuated” state. This would allow attention to focus on the most relevant set of stimuli, while also monitoring for any highly relevant stimuli that might appear on unattended channels. This was an early hypothesis about priming, which is now a very central topic in cognitive and social research.

This modification of Broadbent’s theory became known as the filter attenuation theory. Its main rival at the time was a late selection theory proposed by Deutsch and Deutsch (1963), claiming that the attention bottleneck arose beyond the level of perceptual processing, at the stage of memory and response selection. The two hypotheses were very difficult to distinguish empirically using behavioral data. Riley and I (1969) ran an experiment that I thought might be decisive, in which we eliminated response competition and memory load by asking participants to stop shadowing immediately and press a button if they heard a digit in either the attended or the unattended message. We compared cases in which the digit was in the same voice as the shadowed message or in a different voice and found that participants detected almost all the digits in the different voice (which would be analyzed before the filter) and very few of those in the same voice, which would require the post-filter speech analyzers. Response and memory load were the same in the two cases, and only the complexity of the perceptual processing differed.

However, the early selection camp did not retain its preferred status for very long. A finding by Corteen (1972) challenged the basic assumption that we had been making. He showed that a conditioned fear response, induced by associating mild electric shocks with city names, was quite often elicited even when a city name was presented on the unattended channel, and even though the participant was unaware that she had heard a city name. In the 1960s, we had assumed that anything that was perceptually detected would also reach awareness. If perceptual processing could result in “unconscious perception,” the story became more complicated. In the 1980s and 1990s, further examples of unconscious processing (e.g., Marcel, 1983), as well as challenges from skeptics, began to appear. By now, it is clear and generally accepted that some stimuli can be registered without reaching awareness, even when they require quite complex analysis.

The early versus late selection controversy was essentially resolved by Nilli Lavie (1995) in her load theory of attention. Her suggestion was that the perceptual load presented by the tasks that were competing for attention would determine the level of selection. If we assume that the perceptual system uses all the capacity available at any given time, we can predict early selection when the current load exceeds the capacity and late selection when it does not. I had anticipated this in 1969, when I wrote, “It may be that the nervous system is forced to use whatever discriminative systems it has available, unless these are already fully occupied with other tests or inputs, so that we tend to use our perceptual capacity to the full on whatever sense data reach the receptors” (Treisman, 1969). But Lavie developed the idea into a convincing theory and published an extensive body of research supporting this claim and extending it further.

Fig. 1.    The model I proposed for selective listening, combining attenuation of unattended messages with top-down prediction of incoming words (Treisman, 1960): The selective filter reduces all the sensory information coming from the rejected ear, making it less likely to activate the corresponding words in the mental “dictionary.” Words are shown as nodes in the dictionary network, which are heard when they reach a high enough threshold of activation. Within the dictionary, the thresholds are permanently lower for identifying important signals such as your own name and are also temporarily lowered for stimuli (e.g., words B and C) that are likely in the context of the preceding stimuli (such as word A) that was heard on the attended channel. The combination of the attenuated signal from the rejected ear (word C) and its lowered threshold in the context of the previously attended word (A) increases the chance that word C will reach its activation threshold and that you will therefore hear the unattended word, C. So, for example, if you have just heard the attended words “sitting at the mahogany,” the word “table” is a likely continuation of the sentence and may be heard even though it arrives in an attenuated form from the rejected ear.

In parallel with this behavioral story, developments in cognitive neuroscience led to similar conclusions. Back in 1973, Steven Hillyard and his colleagues had shown very early effects of attention on evoked potentials to auditory stimuli, beginning around 80 to 110 ms from onset, confirming that at least some selection can occur early. However, Stanislas Dehaene and colleagues (1988) used another electroencephalogram (EEG) component (the lateralized readiness potential), as well as functional magnetic resonance imaging (fMRI), to show that high-level semantic priming of words could affect response-selection processes without any awareness by the observer. Many other examples, of early selection-reducing (though not eliminating) responses to unattended stimuli and of high-level discrimination without awareness, have been shown using fMRI and other indices of neural processing. It seems that both sides were partially right in the early/late selection debate; meanwhile, our understanding of the more complex and interesting story has become much more refined.

During these early years in the Oxford department, I also came across a simple handheld stereoscope, which allowed one to present different stimuli superimposed to the two eyes. Nobody was using it, so I appropriated it and decided to look for any analogues to dichotic listening using binocular vision. When I presented two different prose texts in different colors, one to each eye, I found that participants were able to attend to and read either one, although they sometimes had difficulty because the combined binocular image, unlike the binaural combination, superimposed the two images spatially and gave rise to rivalry in which the two alternated in conscious experience.

I became interested in the more standard use of the stereoscope, which was designed to evoke the sensation of depth from slight disparities in the locations of stimuli in the two eyes, corresponding to the two different views received by the two eyes because of their horizontal separation. When two such two-dimensional images are seen by the two eyes with the appropriate positional disparities, the brain combines them into a single image experienced in three-dimensional depth. I was still a graduate student at the time and did not find all the previous work that had been done in this area when I searched, so I just enjoyed myself trying to discover how the brain dealt with binocular stimuli. This research typifies my research style, so I will describe it in some detail.

One question I explored was the relation between two findings—stereoscopic depth and binocular rivalry. When two different incompatible images are presented to the two eyes, we experience either one of the two (with the images often alternating) or a patchwork combining parts of both. This alternation or dominance of one of the two images is known as binocular rivalry. I wondered whether it would be possible to combine stereopsis and rivalry and get the sensation of depth from a combined image at the same time as rivalry between the images in the two eyes. I found that this was indeed the result when I combined two stereoscopic images, one in red and one in green. I used the same simple stimulus in all these experiments: two circles were presented to each eye with the inner one displaced toward the nasal retinae in each eye. When fused, this stimulus is seen in depth, with a concentric inner circle closer to the observer than the outer circle. In order to induce rivalry, I made the circles green in one eye and red in the other. I found that participants experienced the depth difference, despite suppression of the color in one eye. One property of a stimulus (its color in one eye) could be suppressed while information about others (its relative location and shape) was preserved to give rise to depth. This was an early precursor of my interest in the idea that separate systems or analyzers independently process different aspects of the same stimuli. The dissociation cast some doubt on the idea that rivalry is always between the eyes and occurs at a relatively low level. My results argued that it can also be at a higher level, involving selection of particular aspects of the stimuli.

In the next experiment, I explored what has to differ between the eyes in order to give rise to rivalry. I presented circles in the same gray but with positional disparities to the two eyes, using a white background in one eye and a black background in the other. Instead of fusing, the identical gray-colored shapes went into strong rivalry between a perceived light-gray shape in one eye and a dark-gray shape in the other, and no depth was perceived. The backgrounds of the stimuli, meanwhile, would fuse to give a gray or silvery background, against which the contours of the shapes went into clear rivalry, competing or alternating. On the other hand, if the monocular contrast was in the same direction in the two eyes, a large difference between the brightness of the monocular circles posed no problem for fusion. A dark-gray figure on a black background in one eye and a white figure on a light-gray background in the other fused well and gave good stereoscopic depth, despite the large difference in brightness of the figures. Problems arose only when the contrast between figure and ground was in opposite directions in each eye. Rivalry depended on the direction of contrast in the monocular stimuli; when it was the same, depth could be seen, but when it differed, it was extremely difficult to achieve a fused image of the circles and to see them in depth. The backgrounds, however, were relatively easy to fuse, and the monocular contrasts were seen relative to the binocular fused background. I related these results to the recently published findings by Hubel and Wiesel (1959) on the “on” and “off” receptors in the cat cortex. A paper reporting my findings was published in 1962 (Treisman, 1962).

After completing these studies of binocular vision, I returned to the research for my thesis, which was mainly on selective listening but also included some studies of the role of expectancy in speech perception. I looked at the effects of predictability in language processing, using a way of controlling the transition probabilities between words. To generate passages differing in predictability, I asked each person to guess the next word in a prose passage when shown a varying number of preceding words. A “second order approximation” to English would result from showing each person only one preceding word and an eighth order approximation would result from showing the preceding seven words, and so on. Various tasks, such as shadowing, translating, and remembering were strongly influenced by this manipulation, suggesting that people in listening to speech are predicting what the likely next words will be and are influenced by the context extending some way back.

I ran about 14 experiments on the effects of selective attention and top-down expectancies on speech processing and produced a 240-page thesis reporting them all, thus earning my D.Phil. in 1962.

Early Career; Oxford

In 1960, I married Michel Treisman who was also a graduate student, in psychophysics, and then a junior lecturer at Oxford. With my D.Phil completed, I was offered a research position in the Medical Research Council (MRC) psycholinguistics research unit at Oxford. I had the first of my four children (Jessica) in 1963 and 16 months later the second (Daniel). I had thought I would take time off work but found that I missed it too much. So I started taking Jessica to work with me. I had a soundproof cubicle in my office because of my work on auditory attention, and it was occasionally of help with a fractious baby (although I would never leave her there for long!). I continued with research on selective listening, extending and writing up the experiments from my thesis, although my own attention was somewhat divided between work and the babies. St. Anne’s College (then a women’s college), where I had a teaching position, was enlightened enough to open a nursery when several of its Fellows had babies. I could take mine there each day and see them whenever I wanted to. I was and am very grateful for how easy the college made it for me to continue working—a real contrast with what is happening now to many academic women in the United States.

Perhaps the fact that I had no brothers, was educated with girls only until the age of 17, and then went to a women’s college at Cambridge made me less aware of any obstacles due to gender than I might otherwise have been. It was not a very salient dimension for me. I did not pay much attention to occasional sexist comments—just took them for granted as a regrettable part of social life. I assumed that I could do whatever I was capable of and wanted to do, and that assumption in my case proved to be true. But, of course, I was lucky. Other women had a more difficult time. I was never disadvantaged, although I was the only woman on the psychology faculty at Oxford for my first few years in the job.

From 1966 to 1967, Michel and I spent a wonderful year as visiting scientists at Bell Labs, in New Jersey. When we asked what research they would like us to do, we were told that they might question the relevance to Bell Labs of research on the sex life of the octopus, but otherwise we were free to work on any topic that we wanted. The psychology department was excellent, with several brilliant members, including Saul Sternberg, George Sperling, Bela Julesz, and Charlie Harris, among others. I did some work with Saul Sternberg and learned a lot. He was developing his ideas about using additive effects in reaction time to infer independent processes (Sternberg, 1969). He was a perfectionist in all the experiments he ran, which was a salutary counterweight to my more slapdash style.

We lived in a beautiful rented house in Morristown. My mother came with us to help look after our two children. (My father had died a few years earlier.) She was a little shocked when she went for a walk close to our house to be told by a policeman that she could not do that (i.e., walk alone on the local roads). Everyone drove everywhere. We were invited to our first Thanksgiving dinner and were impressed by the custom of inviting strangers to share the celebration with the family. We also had the shock of driving through the racial riots in Newark in 1967. We were invited to give talks at a number of universities in the East (MIT.and Harvard) and in California, where we visited the campuses of the University of California at Berkeley, San Diego, and Irvine (the latter still a brand new campus, which reminded me vaguely of the pyramids, with its large new buildings seemingly isolated in the desert). I was still giving talks about my thesis research; work on selective attention seemed to generate a great deal of interest at the time.

The cognitive revolution was definitely underway in the United States by then. Jerome Bruner’s A Study of Thinking (1956), George Miller’s Magical Number Seven Plus or Minus Two (1956), and Miller, Eugene Galanter, and Karl Pribram’s Plans and the Structure of Behavior (1960), had all come out in the previous decade. Ulric Neisser’s book Cognitive Psychology was about to be published, in 1967, definitively marking the end of behaviorism and its taboo on concepts such as imagery, mental representations, and cognitive models. Contrary to the behaviorist idea that stimuli activate responses to produce behavior, the cognitive revolution saw stimuli as conveying information—reducing the uncertainty about possible states of the world by modifying mental representations—a major conceptual change. Attention was central to cognitive psychology from the beginning, in part because it involved a purely mental event that changed what people perceived.

When we came back to Oxford in 1967, I returned to my position at the Oxford MRC psycholinguistics research unit and assumed that I would go on doing research. But then I was put on a search committee to replace an animal psychologist who was leaving the Oxford faculty. While I was on this committee, another faculty member (Marcel Kinsbourne) resigned his lectureship to move elsewhere. The search committee discussed the possibility of choosing someone from the current list of candidates to fill his position, rather than going through the advertising process again. At that point, I realized that this might be my last chance of finding a position in roughly my area of psychology for quite a while. So I told the others on the committee that I would like to apply for it. As I remember it, although this seems a bit farfetched to me now, they asked me to leave the room, and then after a short time they came out and said, “You can have it.”

Taking for granted the idea that I could combine being a mother with an academic career, I had two more babies, Stephen, in 1968, and Deborah, in 1970. Stephen turned out to be a Down syndrome child. Initially, of course, this was a huge shock. But, as it happened, my doctor at the time also had a Down’s son and he told me that, although it might seem impossible to me with the news fresh in my mind, it would turn out that this baby would be a joy. And so, in fact, it did. I believe this often happens with Down’s children. They are generally happy, affectionate, lovable, funny, and very likable human beings. Stephen became a focus in the family for our other three children, who were and are still as attached to him as we are.

The research I was doing for my remaining years at Oxford was mainly on selective listening, writing up and extending the results of my D.Phil. thesis. But my work with Saul Sternberg at Bell Labs had made me wonder about visual attention and the perception of objects. There was in the air at the time a notion that perception involves the analysis of a number of different features, including shape, color, orientation, and motion, which could be separately attended to. I had been exposed to this notion of analyzers by Sutherland in my early years at Oxford, and I had used it to interpret my results on binocular rivalry and stereoscopic depth perception. In 1969, I tried to write an overview of attention that could encompass more of the findings that were available at that time. I distinguished different forms that attentional selection might take: selection of inputs to analyze (defined by their sources or locations), selection of analyzers (which properties to attend to), selection of items (or objects, defined by the sets of features that characterize them), and selection of which responses to make. In Cherry’s and Broadbent’s selective-listening task, participants attend to one of two or more competing inputs (in this case auditory messages). In the Stroop task (1935), in which participants named the colors in which other color names are printed, they attended to the analyzer for color and suppressed the outputs of the word analyzer. This is a difficult task because of the interference from the word, but quite possible. I showed that these different selective processes function differently in various tasks. I pointed out that it is much easier to select between competing inputs than between competing analyzers perhaps because the analyzers are independent systems that can be used concurrently, whereas two similar inputs compete for the same brain mechanisms (cf. my earlier discussion of Lavie’s load theory of attention).

The idea of separate analyzers raised a further problem, which I also mentioned in the same paper and which would occupy me for the following two or three decades. This is the question of how we recombine the outputs of the separate analyzers correctly when we identify objects. In the 1969 paper, I raised the possibility that mismatches might sometimes occur in selective attention, so that, for example, “a particular word may be heard or remembered in the wrong voice or position.” I came back to this question in the 1970s, taking another example: If the color system registers a green object and a red object and the shape system independently registers an X and an O, how would we know that the X is red and the O is green and not the reverse? This was later termed the “binding problem.” One solution might be to use their shared spatial locations. I had the idea of a spotlight of attention traveling over the visual field, joining together the features that it finds in each location as it passes through it. Perhaps we could identify the correct conjunctions simply by focusing on each location in turn. If attention was directed to one location at a time, any features that were present in that location should normally belong to the same object.

I remember trying a paper-and-pencil experiment on my children, sitting on our lawn in Oxford one day. I asked them to find the red X on a page of red Ts and green Xs. The result was quite surprising. It took them much longer to find the red X than to find either a blue letter or an O in the same background of red Ts and green Xs. Note that two features define the search targets in each task: red and X versus blue or O, but they seemed to pose a very different level of difficulty in search. It seemed that binding features together (the red color and the X shape) to locate the red X target was much harder than finding either of two unique features without having to bind them. So I ran the experiment with proper reaction-time measures on proper participants (Oxford undergraduates). The results matched the predictions quite closely: search times increased linearly with the number of items in the display when the target was defined only by how its features were combined, but when the target was defined by a disjunction of features—either blue or O—search times were almost independent of the number of nontargets. When binding was required to identify the target, the ratio of the slopes on target absent to target present trials was close to two to one, suggesting that search was not only serial but self-terminating, ending when participants found the target (which would be on average halfway through the display) or continuing to the end of the display when it was not present. The finding was consistent with the idea that the brain might analyze separate features in specialized areas and then integrate each pair in turn to form the correct conjunctions. I suggested that this might be done by focusing attention on different locations one at a time and integrating whatever features were currently in the window of attention (Treisman and Gelade, 1980).

Move to Canada: Feature Integration Theory

Meanwhile, my first marriage had broken up and Daniel Kahneman and I were invited to spend the year 1976–77 at the Center for Advanced Study in the Behavioral Sciences in Stanford, California. We had an exciting year there, during which I began to write up my ideas and the data I had collected so far on the role of visual attention in binding features together to form perceived objects. We also applied for possible university jobs to which we could move together when the year at the center was over. We were lucky enough to get offers from Michigan, Illinois, and the University of British Columbia (UBC) in Vancouver. We fell in love with the beauty of Vancouver when we visited there, and, the following year, we moved to UBC. We spent the next eight years very happily in Vancouver. The department was a good one, with Peter Suedfeld as chair, Richard Tees and Tony Philips in neuroscience, Michael Chandler and Janet Werker in developmental psychology, and many others. We felt at home with various aspects of Canadian politics and culture, which were more akin to the welfare states we were used to in Britain and Israel. In fact, we came very close to applying for Canadian citizenship.

My children went to schools in Vancouver, all except Stephen, who was barred from immigrating either to Canada or to the United States. We had a difficult time with the immigration officials, who wanted also to bar me as the mother of a Down syndrome child. It was never very clear why, but perhaps the fear was that we would later apply to bring him in as well and that he would become a drain on the government finances. We were fortunate enough to find a wonderful village for mentally handicapped Jewish people in England (Ravenswood Village, in Berkshire). He has lived there ever since, visiting us each year for two or three weeks. It is a happy place, and Stephen has thrived there, delivering the mail, acting as disc jockey for the village dance parties, and joining in many other community activities. He has been on fundraising bicycle rides all over the world (on tandems with a non-handicapped partner).

Eventually the Canadian immigration official who had given us a hard time, keeping us in doubt for most of the year, moved to Hong Kong and was replaced by a much more reasonable one, who acknowledged that there was no problem with my application and gave us our visas without further ado.

In Vancouver, I continued to test my feature integration theory in a number of different tasks, hoping to get converging evidence for the ideas. I ran about nine experiments testing various types of feature conjunctions. I wondered whether difficulties in combining features would also appear with other kinds of features (e.g., parts of letters). For example, an “R” can be made by combining a P with the diagonal from a Q. A “T” can be made by combining the top of a Z with an I. Sure enough, search for a target R in a background of Ps and Qs gave search times that increased linearly with the number of items in the display, as did search for a T among Is and Zs. The pattern was different with the control conditions I used: search for an R among Ps and Bs and search for a T among Is and Ys. The similarity between the nontargets and the targets was, if anything, greater in those control conditions, but the slopes were less steep and nonlinear. The pattern was consistent with serial search when the target required binding of letter parts but was not when there was no binding problem.

The theory also makes predictions about perceptual grouping. In order to organize all the items into homogeneous areas separated by clear boundaries, we need to be simultaneously aware of multiple items within and across the groups. This should not be possible for objects defined only by conjunctions if these require focused attention to each item in turn. Observers who were asked to decide whether the boundary between two groups was vertical or horizontal were much slower when the two sides of the display shared the same features and differed only in how they were combined than when they differed in one feature and matched in the other. For example, blue Os and red Ts on one side of the boundary and red Os and blue Ts on the other did not produce a clear impression of a boundary between the two areas. I did these experiments in a variety of versions, varying the stimuli and other parameters, which I wrote up in a paper called “A Feature Integration Theory of Attention” (Treisman and Gelade, 1980).

The theory made another prediction—that if attention is overloaded or diverted elsewhere, the observer might get the binding wrong and see illusory conjunctions. With some trepidation, I tested the prediction. My research assistant, Hilary Schmidt, prepared some tachistoscope cards with three colored letters and flashed them briefly, while I tried to report any combinations of color and shape that I saw. After a few trials I said, “This isn’t working. I can see them quite clearly. We need another theory.” Hilary laughed and said, “You actually made a number of switching errors, mismatching colors and letters.” We quickly ran the experiment properly with participants who did not know what to expect. In order to load attention and prevent them from focusing attention on any single letter, we gave them a primary task of reporting two black digits (which we presented one at each end of a central row of three colored letters) and then identifying any colored letters that they were able to see. Just as I had, on about a third of the trials, they made an illusory conjunction error in which they reported a letter that was presented in the color of another presented letter. We subtracted a baseline of feature identification errors in which they reported a shape or color that was not presented. On a quarter of the trials they were binding features from two different objects and seeing a wrongly integrated combination. What convinced me that these were genuine illusions was the fact that about half the observers at some point reported that they saw colored digits, despite the fact that they had been told, correctly, that the digits would always be black (Treisman and Schmidt, 1982).

Around this time, neuroscientists, including Zeki (1978, 1993) and Van Essen et al. (1992), independently discovered evidence suggesting that different features are analyzed separately in different areas of the brain. Visual perception seemed to register different features in a whole array of specialized maps. It seemed that our data from psychological experiments might be converging with data from the brain. So the theory aroused a fair amount of interest and got me invited to conferences in neuroscience and computer science as well as in psychology. One morning, I even received a phone call from a man who identified himself as Francis Crick. Not knowing at the time about Crick’s interest in neuroscience, I wondered who was playing a joke on me, but he soon made it clear that he was telling the truth, and he invited me to visit him in La Jolla to talk about my findings on vision. With some excitement, I went there and presented my theory and findings to a group of vision researchers and discussed them with Francis. I believe I went several times as Francis struggled to make sense of some of the disputes with others in the field and reached the somewhat disappointing conclusion (for me) that perhaps psychology was not a clear and simple route to the truth. I was enormously impressed by his sharp and incisive analyses of my claims, as well as by his friendly approach.

My theory had indeed run into some problematic results. One finding (Nakayama et al., 1986, and then Wolfe et al., 1989) was that search for conjunctions of features could sometimes look parallel rather than serial (in other words, the latency of detecting the conjunction target could be unaffected by the number of nontargets in the display), casting doubt on the idea that binding was always a serial process requiring focused attention to each item in turn. Ken Nakayama’s and Jeremy Wolfe’s computer displays used highly discriminable features, relative to my tachistoscope cards, which were made with colored ink pens. Wolfe and I each suggested a modification to the theory. I went back to an earlier result we had found, suggesting that adjacent items that are identical can be grouped and treated as a single item because illusory conjunctions could not occur within the groups (Treisman, 1982; Treisman and Sato, 1990). If highly discriminable features can also be grouped and rejected before attention is directed to them, the display would be essentially segregated into two separate feature search tasks. Wolfe proposed a similar account based on selective activation of items with the attended features. Both could be correct if attention could both activate items with one target feature and suppress items with one or both nontarget features. On the tachistoscope cards that I used in those pre-computer days, the features were less discriminable than they are with bright computer displays, and we had never observed the parallel processing pattern of latencies.

In the information flow model that I proposed to account for the findings (Figure 2), stimuli are registered in a map of filled locations and also at the same time in different specialized feature maps. Attention can be focused on particular locations in the master map and, through those, can retrieve the features that they contain. The locations selected can include groups of identical objects. The features in the attended location are collected together to form a temporary representation of the currently attended object or group in what we later called an “object file” (see following). These can be bound together because they all coincide in the attended location. Attention can then move on to another location where the process is repeated. Simple features are available in parallel before the binding, but to get the correct conjunctions, the binding process must be applied to each object in turn.

Fig. 2.    The model I proposed for feature integration theory (Treisman, 1988): At the earliest stage, visual stimuli are represented in a map of locations specifying where they are and also in separate stacks of feature maps representing which colors, directions of motion, orientations, and so on are present. In order to bind together the features that are in the same location, attention moves around the map of locations selecting one location at a time thus specifying which features it contains. The selected features in a particular location are combined in what we called an “object file” that specifies which features belong to that object and the relationships between them. So in the figure, attention is temporarily focused on the object in the lower right corner and retrieves its features— in this case, red and horizontal. Of course, there would be many more feature maps for other properties such as direction of motion, and simple elements of shape, size, and so on. The representation of the currently attended object is compared to a store of known objects to be identified or, if it is unfamiliar, recognition fails but the object is still perceived as a particular conjunction of properties at a particular time and place. Unattended objects remain unbound as “free-floating” features, but we also have access to the general layout of filled locations. In this case, we would know that there are two objects, in the lower left and upper left locations, but their features may combine wrongly so that, for example, an illusory blue vertical conjunction may be seen.

This theory attracted a fair amount of attention. Why? I think because it proposed an underlying mechanism for how our conscious perception could result from testable brain functions of which we remain unaware. Its claims were surprising and counterintuitive. We have no sense that stimuli are in any way decomposed and recomposed. The implication of the theory was that in some ways we create our experience rather than its being determined directly by a camera-like process. Perception is more like a controlled hallucination than like an automatic registration of stimuli. The theory made some testable predictions about, for instance, the occurrence of illusory conjunctions in normal people and the failures of perception in brain injuries (see following). In addition, it integrated a range of different findings with a single general account. Finally, it was relatively easy to test. I had stuck my neck out in an inviting way. As often happens in controversies like this, the theory was condensed into a simple summary—search is parallel when the target is a simple feature and serial when the targets are conjunctions. People tend to ignore the other findings that prompted the theory, as well as later modifications of the theory, and dismiss it if it fails any of the original predictions.

The main alternative theory put forward more recently is the biased competition model of Desimone and Duncan (1995). The claim here is that the neural representations of objects compete in the brain and that attention can bias the competition in favor of one alternative. The goals of the two theories and the data they were designed to explain were rather different. Biased competition theory offered no clear explanation for the occurrence of illusory conjunctions or for the contrast between serial search for conjunctions and parallel search for simple features. This is not the place to review the theory in detail, but it is an interesting hypothesis. Future research will help to determine which theory accounts best for all the data or whether the two can be integrated into a more comprehensive account.

Moving Objects

In the 1980s, while we were still in Vancouver, I began to do some collaborative research with my husband, Daniel Kahneman, and his student, Brian Gibbs. We were interested in how representations of objects are formed and updated over time as the objects move or change.

In one of our many experiments, we used a succession of two displays each consisting of two letters. In the examples shown in Figure 3, the initial display consists of the letters B and M and two pluses. The second display also consists of two letters, which are displaced horizontally and vertically from the original letters. In all the cases shown in the figure, the displacement is up and to the right but on randomly mixed trials, it was up and to the left, or down and to the right, or down and to the left, so that the observer could not predict from the first display in which direction they would move. The second display was shown immediately after the first was removed, creating a compelling impression of a single pair of letters moving coherently from the initial to the final locations, along the trajectory shown by the arrows in the figure. The observer’s task was to name the letter that was closest to the plus, B, K, and T, respectively, in the three conditions. We found that the letter was named about 30 milliseconds faster in the first condition than in the other two, which differed by only a few milliseconds.

Fig. 3.    Examples of stimuli used in our experiments with moving objects (Kahneman et al. 1992): Each figure represents two successive intervals of time, chosen to give an impression of apparent motion between the two displays (shown by the arrows). (a) Same object means that the cued object to be named is seen to remain the same as it moves; (b) different object means that the cued object matches the other object from the first display rather than the one that seemed to move to the cued location; and (c) no match means that neither of the objects in the second display was shown in the first. Priming (speeded response) is shown only in the same object condition, although the information in the first display is neutral with respect to which will be the relevant letter. Both are equidistant from the cued location. The location of the irrelevant (uncued) letter in the second display is what determines the direction of the apparent motion of both letters. If the S in the same object example had appeared to the left of the cued location, the motion would have been seen as between the M and the cued B, which would have made it an example of the different object condition.

What makes this finding interesting is that it is not a conventional priming effect. We normally think of priming as the lingering effect of an earlier stimulus on the perception of a subsequent one. In the three panels of Figure 3, however, the original displays are identical. The differences between conditions can be caused only by a “reviewing process” that occurs after the presentation of the second display. When a new display is presented, the visual system establishes a correspondence between perceived objects, by “looking for” the previous state of the same object and integrating the two in a single “object file.” The selection of the previous state of the same object is determined by its apparent spatiotemporal continuity. We ran five other experiments testing this general hypothesis, using real motion as well as apparent motion or stationary objects with continuity determined by a shared spatial position, and all gave similar results—a previewing benefit of around 30 ms. We called this object-specific benefit the “reviewing effect.”

It seems that perception of a later state of the same perceptual object is faster than perception of a new or different object. The effect could not be due to priming from a previously seen letter because when it was seen as a different object, the naming latency was if anything slightly slower than when the initial letters were replaced by asterisks. Nothing in the initial display indicated which of the two previewed letters would be seen to move into the target location and thus to “become” the target letter. The target letter was equidistant from the two initial letters. Lingering activation in particular spatial locations could generate only nonspecific benefits.

We proposed that seeing an object is a separate process from identifying it. Identification depends on matching a current perceptual representation to a stored description of features and their relationships. Before this is done, we must collect and bind the features that belong together in a particular “object file,” and this is done on the basis of shared location at a particular time or of continuity of perceived motion over time. An object file is defined as a temporary “episodic” representation that mediates conscious awareness of a present object in its current location, from the particular viewpoint and in the particular illumination in which it is seen. If the object moves or changes, the object file is updated to maintain the continuity and identity of the representation. (One analogy is to the file that the police might open to record a particular incident. It would be labeled by the time at which it occurred and the location, and any further details would be entered as they accrued.) We distinguished these temporary representations from the permanent mental dictionary of object identities used to identify instances as members of a category (Kahneman et al., 1992). These ideas have proved useful in explaining the perception of dynamic events and also in the development of object perception in infants.

This experience of collaboration also taught us a lesson about research. We initially had different ideas about one aspect of the underlying model. Danny thought that perceptual objects were present preattentively and I thought that they were created through an act of attention. We had planned to present our findings in two successive papers at a meeting of the Psychonomic Society. The fact that we had this theoretical disagreement was of some concern, but we thought that by the time we gave the talks, we would have gathered enough evidence to settle the argument one way or the other. We then embarked on a series of experiments that we each expected to decisively convince the other, only to find that that task was harder than it seemed. If an experiment appeared to prove Danny correct, I would quickly see why it was not in fact a good test, and he did the same to my results. In the end, we had to leave the contested point open. We finally managed to write a paper that we were both reasonably happy with. Recent research on our paradigm has continued to explore the ideas, some aspects of which remain controversial, but the distinction between “seeing” and “identifying” and the question of how object representations are established and maintained across time and space are recognized as significant issues.

University of California, Berkeley

Although we were happy in Vancouver, we became restless, and in 1985, we considered moving to the United States. We were offered positions by a number of universities and ultimately decided to move to the University of California, Berkeley. Berkeley is a special place—a great state university with a history of intellectual debate and left-wing politics. The beauty and wonderful climate of the Bay Area were additional assets that made our time there precious. There were many exceptional people working in the psychology department, some of whom became our close friends. They included Al Riley who was the chair, Ervin Hafter in psychoacoustics and auditory attention, Steve Palmer in perception, Russ and Karen DeValois in vision, Alison Gopnik in developmental psychology, and Dan Slobin in psycholinguistics. Cognitive science was also strong at Berkeley with John Searle and Bert Dreyfus, among others, on the faculty. We stayed an extra year in Vancouver in order for my youngest daughter, Deborah, to finish high school there and then settled for six years in Berkeley where Danny and I both had faculty positions in psychology and Deborah was accepted as an undergraduate. Jessica and Daniel had both done undergraduate degrees at Oxford, where their father was on the faculty.

In Berkeley, Danny and I continued to share a lab as we had done in Vancouver. We attracted considerably more graduate students and, at one point, we had 12 or more working with us, mostly women as it happened. Men in our field were more likely at that time to apply to Stanford. For some years, my research continued to deal with feature binding and object perception, but I also became interested in extensions of the theory to memory for novel objects and to practice effects and automaticity. To outline these different lines of research, I will start with the ones that followed most directly from feature integration theory.

Balint’s Patient: The Role of the Parietal Lobes in Feature Binding

While we were in Berkeley, I was lucky enough to get results from a very different situation that confirmed a possible link between my feature integration theory and the brain. Lynn Robertson, a neuropsychologist, came across a patient with Balint’s syndrome and asked if I would like to study him with her and her student Stacia Friedman-Hill. Balint’s patients have bilateral lesions in the parietal lobes, which result in several striking symptoms. First, they exhibit a severe loss in the ability to localize objects; our patient could not tell if a spot was at the top or the bottom, or the left or the right of the screen. Second, they suffer from simultanagnosia; our patient could see only one object at a time even when many were present in the field. So his visual world was reduced to a single object with little sense of where that object was. I wondered if the Balint’s symptoms were due to the loss of a representation of space and a consequent loss of the ability to focus attention within space and therefore to bind features. If a patient with damaged parietal lobes could not make divisions in space, then he should not be able to bind different features into separate individuated objects. (PET and fMRI testing has shown that the parietal lobes are active when normal people do search tasks involving conjunctions of features.)

We tested our patient with just two colored letters in a display, leaving them present for several seconds at a time. Sure enough, he had huge difficulty in telling us which letter was in which color, and he reported illusory conjunctions on a large proportion of trials—far more than my normal subjects had when we flashed displays much more briefly. The size of the letters did not seem to matter and neither did the distance between the letters. The search difficulty in Balint’s syndrome seems to be specific to binding. Our patient could report a single target color in a display of items in another color—a red O, for example in a display of green Os and Xs, no matter how many there were—because he did not need to scan them serially. However, he could typically only see that one red item. But he was quite incapable of finding a red O among green Os and red Xs.

These deficits specific to binding in search are consistent with the predictions of feature integration theory and they illustrate the dramatic effect that a loss of the ability to bind features can have on perception. As we wrote in the paper reporting our findings (Robertson et al., 1997):

One morning RM mentioned that he had found a good way to improve his vision. With the help of his granddaughter, he had made a tube through which he looked at whatever he wanted to see more clearly. This is a striking observation. One of the defining characteristics of Balint’s patients is that they can see only one object at a time, so it seems initially surprising that RM should need external aids to restrict his vision to one object at a time. But it follows nicely from the feature integration theory (FIT) account. If the damage to his ability to represent space prevents the normal binding of features to locations without preventing their detection at early levels of visual processing, the features of different objects should tend to coalesce into a single object, producing illusory conjunctions or confusing mixtures of features in the one object that is seen. RM did complain of such illusions. For example, the following are comments he made at various times in our binding experiments: ‘‘When I first look at it, it looks green and it changes real quick to red. I see both colors coming together…. I get a double identity. It kind of coincides.” His descriptions sound very much as though he has no perceptual space in which to separate and individuate the letters and bind the colors to the shapes. The tube he invented may have helped by restricting the early detection of features to those of a single object. Essentially, he constructed an external window of attention to supplement his defective internal window.

Search for Absence

Feature integration theory suggests that focused attention is needed to bind the features of objects in the correct combinations. A related prediction for normal people is that without focused attention we should not be able to search for the absence of a feature that was present in all the other items in the display. That would require binding the critical feature to the items in which it was present in order to locate the one item that did not have it. We used search for an O among Qs. It turned out that search again appeared serial here (linear increases in search time with added nontarget items in the display), whereas the converse—search for a Q among Os—was easy and independent of the display size. To detect a single Q among Os, you need only to detect the presence of a slash anywhere in the display, whereas in a search for the absence of the slash, you have to bind each slash to each O to make sure that they are all Qs.

We could now use this striking search asymmetry as a diagnostic for what counts as a feature for the visual system. Some people had suggested that line ends might be automatically detected. So we tried search for a C among Os, which does turn out to be easy—whereas locating an O among Cs seems to require serial search. The line ends (or terminators) created by the gaps in the Cs are detected automatically in parallel whereas the closed circle is not. Using the logic drawn from the Os and Qs experiment, we could argue that the gap (or the pair of line ends) functions like the slash, whereas there is no unique feature detectable in the closed circles. Closure could have been detected by this diagnostic but seemed not to have been. We tested multiple potential features using search asymmetry as a diagnostic and confirmed that, by this criterion, “tilted” (as opposed to vertical) and curved as opposed to straight are features. Each of these extra features pops automatically out of a display, just like the slash on the Q in a field of Os. On the other hand, when we search for straight or vertical lines, we have to use focused attention to check that each straight or vertical line is not combined with the tilts or curvatures that are present everywhere else in the display. This research was begun with my student Janet Souther in Vancouver (Treisman and Souther, 1985) and developed with my research assistant Stephen Gormican in Berkeley (Treisman and Gormican, 1988).

These experiments were also useful for shoring up a potential weakness in my feature integration theory. Critics had suggested that the theory was circular. If search looked parallel (i.e., no increase in latency as the number of items in the display increased), it had to be mediated by a simple feature; if it looked serial (a linear increase in search time as the number of items increased), it depended on binding features. Clearly we needed an independent way of determining what counted as a feature for the visual system.

The alphabet of basic features for the visual system was not known in advance nor did it necessarily correspond to the set of properties that we traditionally identify as different physical dimensions. So, for example, properties such as looming, closure, and terminators or line ends could potentially all be features. Whether or not they were was an empirical question. My theory suggested several independent tests of “featurehood” beyond the parallel search that I had used in the early work. One was that features could recombine to give rise to illusory conjunctions; another was that they could mediate rapid and easy texture segregation; another was that they could create an impression of apparent motion when their location changed in a background of stimuli with other properties; finally, detection of a feature was not helped much by an advance cue to its spatial location, unlike the detection of a conjunction which benefited greatly. Ideally, evidence from neuroscience would also help us determine what properties were coded independently of others. Search asymmetries provided a new criterion. If a curved line popped out of a display of straight lines, but not vice-versa, then “curved” was a feature and “straight” was coded as the absence of that feature.

Memory for Novel Objects

Comparing Explicit and Implicit Memory A natural question, once we have set up new object representations, is how and for how long they survive in memory. I decided to investigate this question in collaboration with my student, Gail Musen (Musen and Treisman, 1990). We used novel shapes created by joining a subset of five or six dots in a three by three matrix (see examples in Figure 4). We found long-lived priming on a perceptual test after a single exposure, measured by the difference in accuracy in drawing a briefly flashed picture that had been previously seen and drawing a novel shape. The priming lasted at least eight days with little or no loss. The priming results contrasted with the results in recognition memory (“Have you ever seen this object?”), which was subject to substantial loss over time.

Fig. 4.    On the left, I show examples of novel shapes used to compare explicit and implicit memory (Musen and Treisman, 1990). On the right, I show examples of novel shapes used to test implicit memory in negative priming (DeSchepper and Treisman, 1996).

A different form of recognition memory can also be tested for specific exposures to a previously experienced item. We do not ask, “Have you ever seen this item before?” but “When did you see this item before—was it on the previous trial or on some earlier trial?” Tulving’s concept of episodic memory requires a record of a specific experience or event rather than a distinction between familiar and unfamiliar (Tulving, 1983). We found evidence that the traces formed of novel items can mediate all three types of memory retrieval—perceptual priming or facilitation by pre-exposure, conscious recognition (this shape is familiar or not), and specific event memory (I saw this at a particular time and place)—but that the three depend on different, at least partially independent, representations. There was no correlation between these different tests of accuracy, and the memory survival times were clearly different. Thus novel objects can lay down separate traces for each occasion on which they are experienced as well as a general representation shared by all experiences of the object. The type-token distinction that we need to explain our results with moving objects also applies here.

Negative Priming with Novel Objects I ran another experiment on memory for novel objects with my student, Brett DeSchepper (DeSchepper and Treisman, 1986). We adapted an interesting paradigm known as negative priming, introduced by Stephen Tipper (1985). When observers are asked to attend to one of two overlapping outline pictures of objects and to name (for example) the red one, ignoring the green one, they do this very well. However, if a previously ignored picture is presented again on the next trial as the attended picture, the naming response is slightly slower than the response to a control picture that was not previously ignored. It is as if ignoring a picture makes its representation harder to attend to on the next trial. We wondered if this negative priming would work only for previously familiar objects that had preexisting representations that could be inhibited by attention, so we used as stimuli some novel nonsense shapes that had never been seen before. We made a collection of about 250 outline nonsense shapes (hand-drawn, see examples in Figure 4) and repeated the Tipper experiment using these. We argued that if negative priming is also shown with novel shapes never seen before, they must have created and left memory traces that remained available on the next trial and slowed the response when they were reactivated. We found that negative priming was just as strong with these novel objects as with familiar pictures. A single presentation of a novel nonsense shape evidently leaves a memory trace even when it is ignored and not consciously perceived.

The next question was—how long would the memory trace survive? We looked for negative priming not on the immediately succeeding trial but on the following one, then on one 10 trials later and even 100 trials later, and to our surprise, negative priming was in effect across all these delays. We also used a recognition task in which we asked people to pick out the shapes that had been presented among an equal number of unseen shapes, to confirm that there was no conscious memory of the shapes. It seems that a single presentation of a novel nonsense shape can leave an implicit memory that survives across many intervening presentations and even across a delay of up to four weeks. I believe that this persistence depends on the shape being presented once only. New exposure to the shape during the interval would presumably clear the inhibition that was attached to it when it was suppressed on the initial presentation. The findings imply a surprising degree of plasticity in the visual system, although the memory traces are not explicitly available to conscious memory (Treisman and DeSchepper, 1996)

Memory for Novel Objects in Skill Automatization Finally, yet another kind of memory effect is involved when we acquire a skill through extended practice. What changes in the brain when we carry out a task repeatedly—for example, searching for the same target shape in different displays over hundreds of trials? Does it eventually become an integrated object in our perceptual system and begin to pop out of the displays as though it were a simple feature? More specifically, can we form unitized representations of feature conjunctions, bypassing the binding process, and if so how? With another graduate student, Alfred Vieira, and my research assistant Amy Hayes (Treisman et al., 1992), I designed several studies to find out. In one experiment, we used the nonsense shapes also tested by Musen and Treisman (1990). Would these line patterns become unitized over successive sessions of search? If so, would they behave as features in other tasks such as mental rotation, boundary detection, and apparent motion in more complex displays? We found that although practice in search had a large effect in reducing search latencies for the practiced conjunctions, there was little transfer benefit to other tasks in which simpler features naturally speed processing. Even changing the layout of the search display or the contrast of the figures (black on white versus green on black) substantially reduced the benefit of practice. The main benefit we observed was only on tests for liking: the participants did come to like their practiced line patterns much more than the unpracticed ones!

In another test of whether the learned patterns behaved as features rather than conjunctions, we found little transfer across locations in search for such patterns. Repeated exposure to a multi-feature pattern yielded a search advantage that was mostly restricted to presentations in the same place. This result suggests that attention was still required to bind the features and that search was speeded by learning which locations to search first. We concluded that automatization through practice does not necessarily result in the creation of integrated conjunction detectors. Although search speeds up with practice for the learned conjunctions, we believe that participants develop other strategies to achieve this. In the case where search even becomes parallel, we suggest that what happens is that participants may discover one or more new “emergent” features and develop a grouping strategy that allows them to inhibit all items with this feature, even in intermixed displays. Consistent with this account is the fact that it has so far proved impossible to acquire parallel processing of displays in which the nontargets consist of different arrangements of the same features (e.g., T’s among L’s in any orientation, or a red-and-green circle differing only in which half of the circle is colored red and which half is green). These are just a sample of the research studies that my U.C. Berkeley lab did between 1986 and 1991.

In 1991–92, Danny and I spent a sabbatical year at the Russell Sage Foundation in New York. I was not a typical visitor there. Most of the fellows there are involved in social science with the goals of “diagnosing social problems and improving social policies.” But Danny fell into that category, and they stretched the definition to include my research so that we could both spend the year there. It was a very interesting year for me, interacting with the other 12 visitors and attending talks outside my usual preoccupations, as well as writing up the data that I had accumulated in the previous few years.

While we were there, in October 1991, there was a huge fire in Oakland. Our Berkeley house burned down, together with 3,354 other homes and a large number of apartments. Twenty-five people were killed. On the day of the fire, my students gave me constant updates on the situation, telling me, “It looks bad.” At the peak of the fire, houses were disappearing at the rate of one every 11 seconds. My daughter, Jessica, was living in our house while we were away, so we had some moments of panic, but we managed to get her on the phone and discovered that she and my other daughter, Deborah, had been spending the day on the beach. She was not able to go back into the fire area so, with just her shorts and T-shirt, she took refuge at Deborah’s apartment in San Francisco while all her possessions were consumed, along with ours. The house burned to the ground, and when we later visited the site, we found that only the mailbox had survived along with a metal urn that was encrusted with ashes, some bed springs and the remains of a bicycle.

Despite this traumatic event, we enjoyed the experience of living in New York, and Danny became very interested in the idea of moving there, partly a result of losing our Berkeley house. He made some tentative enquiries with local universities, and we took the next year back in Berkeley to decide what we would do. Eventually, we chose to move to Princeton. I was reluctant to do this because I loved Berkeley, but New York also had strong attractions, including the fact that Deborah was working there. Her career was meteoric. She worked first at Harper’s, then at the New York Review of Books, and was then the managing editor of a literary quarterly, called Grand Street, before taking the position of deputy fiction editor at the New Yorker. In 2002, aged 32, she became the fiction editor—her dream job, which she has held ever since. Jessica also moved back to New York, where she had done her doctorate in molecular biology at Rockefeller University before doing a postdoc at Berkeley. In 1996, she was made an assistant professor at the Skirball Institute of New York University and was later promoted to full professor there. My son, Daniel, in the meantime, had become a professor of political science at the University of California, Los Angeles (UCLA), after completing his PhD at Harvard.

Princeton: Research on Scene Perception and on Distributed Attention

We spent the next 17 years in Princeton. Here again, I found excellent colleagues and friends, including Sam Glucksberg, Charlie Gross, Phil Johnson-Laird, Marcia Johnson, and later Jon Cohen, Sabine Kastner, and Ken Norman. While we were there, the department persuaded the university to develop a program in cognitive neuroscience and to buy an fMRI machine. At the end of the 20th century, psychology was becoming more and more influenced by and integrated with neuroscience. The development of imaging techniques with which brain processes could be explored during the performance of various cognitive and social tasks made it possible to link psychological processes with brain activity and to develop models of how brain and mind interact. The department hired Jon Cohen to develop this approach, and he was able to attract several excellent people to join the thriving Neuroscience Institute.

My research on the binding problem was still a central thread in my activity, and I encouraged my graduate students to learn the techniques of imaging and of electroencephalography and to try to explore the brain mechanisms involved in binding. But I also began to explore a new psychological question that had troubled me for some time.

I had always been aware of the implausibility of the idea that we can perceive the world only by serially scanning each object in turn. When we open our eyes on an unknown picture or scene we do not experience objects appearing one at a time as their features are bound by serial allocation of local attention. Clearly, we know a great deal about the scene as soon as it appears. This raises a question: What information do we get in the first glance with attention spread over the scene as a whole? We already knew that focused attention is not needed to detect the presence of a unique color, shape, or motion. An item will pop out of the field and attract focused attention if it is distinguished from other items by a single feature. We also knew that in the state of diffuse/spread attention people cannot accurately bind the features of objects. What then do observers see when their attention is spread over the whole display? I tried two ways of answering this question.

Semantic Categorization of Scenes

With my student, Karla Evans, I tried to reconcile results by Li et al. (2002), showing apparently attention-free high-level categorization of natural scenes, with our claim that binding features requires attention. Li et al. found that participants could detect the presence of animals in natural scenes concurrently with another attention-demanding task. We wondered whether their performance reflected the detection of disjunctive feature sets rather than high-level binding. We presented very rapid strings of pictures of natural scenes, with occasional animals (or vehicles) included, and explored what information was available when participants reported one of these targets. We found that they frequently failed to identify or to localize the targets that they had correctly detected, suggesting that detection was based on only partial processing. If we have evolved the ability to detect such natural features as fur, legs, wings, wheels, or windows, it may be possible to effect this high-level semantic processing through the detection of disjunctive feature sets without the necessity to bind these features together. Our participants showed severe attention limits when they were asked to identify two concurrent targets, although when they were asked only to detect their presence they performed quite well. Detection can be based on one or more target features, whereas identification usually requires binding (Evans and Treisman, 2005).

This interpretation requires us to expand our set of potential features to include more than elementary visual properties. There is in fact neural evidence for the existence of single neural units that respond to hands or faces (Gross et al., 1972). Considerable plasticity in neural coding has also been demonstrated through the existence of neural units in monkeys that respond to learned combinations of object features relevant to a particular task (e.g., Sigala and Logothetis, 2002; Riesenhuber et al., 2002). We have not proved this alternative interpretation of performance in the processing of natural scenes under extreme time pressure, but we believe it is an alternative to the claim that binding poses no limits in the real world perception of natural scenes.

Distributed Attention

Another contribution to solving the problem of perception in the real world despite the attention limits shown in our laboratory experiments comes from distributed as opposed to focused attention. It is possible that the information available differs when we spread our attention over a scene as a whole rather than focusing it narrowly on one object.

My research on this topic was prompted by a 2001 paper by Ariely, which suggested that people may form an accurate statistical representation of the characteristics of an array of objects without forming representations of individual objects. Ariely (2001) used two different tasks. In both, he showed a display of multiple circles followed by a single probe circle. One task was to say whether that probe circle had been in the previous display. Another was to say whether the circle was larger or smaller than the mean size of the circles in the whole display. The results were surprising: People were very bad at saying whether the probe circle had been in the display but very good at judging whether it was larger or smaller than the mean size. Also, the accuracy of the size judgments was unaffected by the number of items. With my graduate student, Sang Chul Chong, I showed that these judgments can be made very fast, within 50 msec, which rules out any possibility of serial scanning (Chong and Treisman, 2003). We also found that statistical processing did not require attention; accuracy was little impaired by a demanding concurrent task (Chong and Treisman, 2004).

The ability to evaluate averages at a glance is not restricted to the dimension of size. Tatiana Emmanouil and I found similar results for orientation and for speed of movement (Emmanouil and Treisman, 2008). I subsequently found averaging even for more complex stimuli, such as shapes. In Figure 5, the average of the four shapes on the left, shown on the right, is produced by taking the average location of each of the six vertices of each shape. When we gave observers a brief exposure of four shapes, then asked whether they recognized a new shape as one that had been included in the display, we found that they were more likely to “recognize” the average shape than to recognize any of the shapes that had, in fact, been presented.

Fig. 5.    Shapes used to test statistical averaging with distributed attention: The four shapes on the left are a typical display, and the one to the right is the average of the four in the display.

The extraction of averages does not seem to require any effort. We showed that they can be estimated concurrently for two separate interspersed groups of items. We also found that the accuracy of the evaluation of the average was not reduced by dividing attention with another concurrent task. We used displays in which four shapes were interspersed with digits. Observers were required to attend to the digits interspersed in the display and report if a letter was present. They were almost as accurate in evaluating the average shape as they were without the extra letter-digit task, as shown by their tendency to report the average shape rather than one of the shapes that was actually presented in a recognition test. In a series of elegant studies by Jason Haberman and David Whitney (2007), observers could evaluate the average happiness of 16 faces from an exposure lasting less than 500 msec. Clearly, we are good at extracting a prototype from complex displays. Distributed attention supports a separate mode of global processing, which is distinct from the focused mode that binds and individuates separate objects.

The statistical capabilities of distributed attention suggest a solution to the puzzle that had troubled me. When first exposed to an unfamiliar scene, we can immediately segregate it into separate areas based on feature information. Top-down information (e.g., a wide area of green is likely to be a grassy field) provides hypotheses about the scene. Within each area, distributed attention provides statistical information about the objects it contains, allowing us to recognize a herd of sheep in the background. Meanwhile, more detailed representations are generated by focal attention binding local features at a rate of perhaps 20 to 40 a second, allowing us, for example, to recognize a friend’s face in the crowd (Treisman, 2006).

During my years at Princeton, Shaul Hochstein from the Hebrew University of Jerusalem and I developed several joint grant proposals. We met two or three times a year, either in Princeton or in Israel, and had a large effect on each other’s thinking—although (alas!) we did not get around to producing any joint publications. I was very impressed and influenced by his “reverse hierarchy” account of perception (Hochstein and Ahissar, 2002), and we had many discussions on how this related to my feature integration theory. One of the last experiments I did, together with my postdoc, Seth Bouvier, explored the possibility that feature binding is accomplished through a process of reentry, in which a first rapid pass through the visual system registers the features that are present and segregates the different areas of the scene (Bouvier and Treisman, 2010). Then, if required, processing returns to earlier visual stages to retrieve the locations of potential objects and to bind their features. We showed that masking the stimuli in ways that are known to specifically impair the perception of objects also impaired perception of conjunctions, leaving the features intact. This finding illustrates the benefit of combining our binding hypothesis with Shaul’s reverse hierarchy theory.

My work has been recognized by a number of honors, including my election in 1989 to a fellowship of the Royal Society, London; in 1994, to the U.S. National Academy of Sciences; and in 1995, to the American Academy of Arts and Sciences. I won the Distinguished Scientific Contribution award of the American Psychological Association in 1990, the Grawemeyer prize in 2009, and (much to my surprise) the National Medal of Science in 2013. In 2002, Danny was awarded the Nobel Prize in Economics, and we had a dream week in Stockholm, together with the 16 guests we were allowed to share it with. In 2011, Danny published a book, Thinking Fast and Slow, outlining most of his past work and ideas, which to his surprise (but not mine) became and still is a best seller (Kahneman, 2011). I am very happy that his work is now collected and embodied in a single (large) volume, which will remain available for many future years.

Conclusions

The ideas I presented in this chapter have been quite controversial, and they are obviously provisional, reflecting the conclusions I reached at each stage in my research and all before I retired in 2010. The claims I made in the earlier papers have been expanded and/or modified in later papers, by me and by others. New findings have been made and alternative accounts proposed. In some cases, modifications to the original ideas were proposed (many by me), and in some cases, refutations were claimed (mostly by others). But that is the way that science progresses. A very useful sampling of developments, theoretical and empirical, can be found in a book edited by Jeremy Wolfe and Lynn Robertson (2012), which included a selection of my papers accompanied by commentaries of current experts. I was grateful to these colleagues and friends for their diligent work and grateful as well for the title of the collection, From Perception to Consciousness: Searching with Anne Treisman.

What are some general changes that seem to characterize this overview of my life in cognitive psychology? Psychology has changed enormously in the half century of my career, moving from a rather narrow behaviorism through the cognitive revolution to the interactions of linguistics, philosophy, and computer science under the cognitive science umbrella, and now with cognitive neuroscience, linking mind to brain.

Most obviously, the field has increased enormously in its number of findings and in their complexity. I checked the Web site of Science for the number of articles on selective attention published in each decade since 1950. It grew from 2 to 11,218—and that does not include such closely related topics as priming, distributed attention, or the underlying brain mechanisms. Inevitably, the papers have become far more specialized and detailed, but psychology is perhaps more interesting now than it ever was.

Probably the most important changes in my lifetime have been in the degree of interaction between behavioral findings in cognitive tasks and in our understanding of the neuroscience of the brain. The two fields met in the early years mainly in research on the effects of brain lesions on psychological tasks. Now, with the advent of brain imaging, they have essentially fused into one field, cognitive neuroscience. Partly as a result of this fusion, the behavioral models have moved from a pipeline of successive stages or operations to a much more interactive system with as many feedback as feedforward pathways. In perception, the notion of reentry allows stored sensory data to be compared with tentative hypotheses based on more central processing to either confirm or discard them.

One topic that I have not discussed much is the control of attention—how we select which stimuli to attend to and how we set the size of the focus. From the beginning, I assumed that the focus could be adjusted depending on the task, analogous to the zoom lens model of Charles Eriksen and James St. James (1986). My recent research on how distributed attention differs from focused attention suggests the differences that may result as we adjust the size of the focus. But the mechanisms that control the setting are now an important topic of research, with the frontal lobes implicated in the allocation of attention.

I have worked with many graduate students and have learned a lot from them, but I have not often collaborated with colleagues in my research. Danny and I worked together on the moving-object project as well as on a theoretical paper on attention. Lynn Robertson and I had a fascinating time working together to explore feature binding in a Balint’s patient and also in some patients with neglect. Finally I learned a great deal in my interactions with Shaul Hochstein and our two theories benefited from the discussions that modified each of them in turn. But otherwise, I mostly worked alone, perhaps because I am too fond of having my own way!

I was fortunate in being able to combine a large family with an academic career, and I am now blessed with three successful children and four adorable granddaughters. Stephen, my Down syndrome child, is perhaps the happiest of them all. My impression is that combining career and family is getting harder as the pace and pressure of academic work increase. Many young academic women are trying to decide whether they should have one baby or none. I find this sad, and I am not sure that so much is gained by accelerating the pace of papers published, tenure demands, and grant getting. If less emphasis were placed on quantity and more on quality, science would be unlikely to suffer and our personal and social lives would be enriched and more civilized.

The part of my career that I enjoyed perhaps the most was the interactions with my graduate and postdoctoral students. In Berkeley and at Princeton they formed a community, enjoying one another’s company and supporting one another, as well as getting excited about our findings. In Berkeley, where Danny and I shared a large space, and in the early years in Princeton (before the building was rebuilt and we were relegated to small labs shared by the whole area), I spent most of my working day in the open area of the lab talking to students, trying things out, arguing about the results. The weekly meetings in which students presented their findings and ideas were an enjoyable social event, as were the birthdays when a talented baker would bring a cake.

I have mentioned some of my graduate students in connection with the joint papers that we wrote. In addition, I have fond memories of Gillian Cohen, Nigel Harvey, Maryanne Martin, Gail Walker-Smith, Robin Russell, and Geoff Cummings at Oxford; Mirjam Eglin, Randy Paterson, and Debbie Butler at the University of British Columbia; Marcia Grabowecky, Beena Khurana, Kathy O’Craven, Meg Wilson, and Todd Horowitz at the University of California, Berkeley; and Tracey Leacock, Paul Downing, John Zhang, Shlomo Sher, Mary Wheeler, and Ming Meng at Princeton. My postdoctoral students also often had an important influence on my work: they include Bill Prinzmetal in Vancouver; Nancy Kanwisher, and Nilli Lavie in Berkeley; and Ofer Fein, Miriam Berkowitz, Robert Ward, Adriane Seiffert, Liqiang Huang, Hagit Magen, Seth Bouvier, and Liat Goldfarb in Princeton. Working with them was a privilege and a pleasure.

As I said at the beginning of this chapter, I have been very lucky in the timing of my career. It has been an exciting ride and impressive progress has been made. I have thoroughly enjoyed being part of the evolution of ideas and communicating them to students in my undergraduate teaching. What I tried to pass on to my graduate students and postdocs is the thrill of collecting and making sense of data, testing ideas within the larger framework of current research, and generating their own new insights into the human mind. Although this chapter appears in a volume dedicated to neuroscience, it contains mostly behavioral experiments. I have always tried to interpret the results in terms of the underlying neural mechanisms when these were known. I hope that, together with many others, I have illustrated how behavioral questions and data are central to our understanding of the brain. To understand the brain’s function one must look at the problems it is trying to solve and the errors and latencies with which it performs the tasks that face it. I do not think any account can be complete without this functional level of description.

Selected Bibliography

Ariely, D.Seeing sets: Representation by statistical properties. Psych Sci 2001;12:157–162.

Bouvier, S., Treisman, A. Visual feature binding requires reentry. Psych Science 2010;21:200–204.

Broadbent, D.E. Perception and Communication. London: Pergamon Press, 1958.

Bruner, J.S., Goodnow, J.J., Austin, G.A. A Study of Thinking. London: Chapman & Hall, Ltd. 1956.

Cherry, C. On Human Communication. New York: Wiley, 1957.

Chong, S.-C., Treisman, A. Representation of statistical properties. Vis Res 2003;43:393–404.

Chong, S.-C.,Treisman, A. Attentional spread in the statistical processing of visual displays. Perc and Psychphys 2004;66:1282–1294.

Corteen, R. S., Wood, B. Autonomic responses to shock-associated words in an unattended channel. J Exp Psych 1972;94:308–313.

Dehaene, S., Naccache, L., Le Clec, H.G., Koechlin, E., Mueller, M., Dehaene-Lambert, G., Van de Moortele, P-F., Le Bihan, D. Imaging unconscious semantic priming. Nature 1988;395:597–600.

DeSchepper, B., Treisman, A, Visual memory for novel shapes: implicit coding without attention. J Exp Psy: Learning, Memory and Cognition 1996;22:27–47.

Desimone, R., Duncan, J. Neural mechanisms of selective visual attention Ann Rev Neurosci 1995;18:193–222.

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Anne Buckingham Young

BORN:

Evanston, Illinois

December 30, 1947

EDUCATION:

Vassar College, Summa Cum Laude, AB (1969)

Johns Hopkins University Medical School, MD (1973)

Johns Hopkins University Medical School, PhD (1974)

APPOINTMENTS:

Assistant, Full Professor of Neurology, University of Michigan (1978–1991)

Julieanne Dorn Professor of Neurology, Harvard Medical School (1991–2012)

Chief, Neurology Service, Massachusetts General Hospital (1991–2012)

Distinguished Julieanne Dorn Professor of Neurology, Harvard Medical School (2012–present)

HONORS AND AWARDS (SELECTED):

Member, Institute of Medicine (1994)

Fellow, American Academy of Arts and Sciences (1995)

Dean’s Award for Support and Advancement of Women Faculty, Harvard Medical School (1999)

Marion Spence Faye Award for Women in Medicine (2001)

President, American Neurological Association (2001–2003)

President, Society for Neuroscience (2003–2004)

Fellow, Royal College of Physicians, England (2005)

Milton Wexler Award, Hereditary Disease Foundation (2006)

Johns Hopkins Medical School Distinguished Alumni Award (2007)

Vassar College Distinguished Alumni Award (2010)

As a graduate student, Young provided the first biochemical evidence of glutamate as a neurotransmitter of the cerebellar granule cells. She developed biochemical techniques to measure inhibitory amino acid neurotransmitter receptors in the mammalian brain and spinal cord. As a faculty member at the University of Michigan, Young and her late husband (John B. Penney, Jr.) established the first biochemical data that glutamate was the neurotransmitter of the corticostriatal, corticobulbar, and corticospinal pathways. They developed film-based techniques for quantitative receptor autoradiography. They also provided evidence for their most widely cited model of basal ganglia function. Their model has suggested novel interventions in Huntington’s and Parkinson’s diseases such as deep brain stimulation. Dr. Young has worked more recently on gene expression changes in Huntington’s and Parkinson’s diseases and on therapeutic approaches to neurodegenerative diseases.

Anne Buckingham Young

Early Life

I was born in Evanston Hospital, Evanston, Illinois, on December 30, 1947. I grew up in a privileged environment in Winnetka, Illinois. My ancestors were pioneers who eventually made and lost fortunes during the settling of Chicago. My father was a businessman, and my mother a housewife. Both parents were interested in science, however. My father had majored in chemistry at Harvard, and my mother in physics at Vassar. In her later years, my mother edited and wrote books on science for nonscientists. Science and Scientific American were on our coffee table. Even as a young child, we were always talking about scientific issues at the dinner table. Gravity was discussed at breakfast. I have an older brother who liked math and physics. He eventually became a professor of economics and business at Johns Hopkins and at the University of Oxford. I was more interested in biology. I have a younger sister who loved animals and who eventually became a physical therapist.

In school, I was a very poor reader, never coming close to finishing the story on the standardized reading tests. Every year I was one to two grades behind in reading, but because I did well on everything else, I was passed each year. I was never given any special instruction but my slow reading has influenced the rest of my life. It was not so much reversing letters and so on but rather the words would mean nothing to me unless I said them in my head first. I had to read aloud to myself at a slow pace. I was incapable of skimming. Therefore, the fastest I can go in a fiction book is about 30 pages an hour. It has always been awkward when somebody hands me something and says, “Read this.” I have to ask them to tell me what it says or be prepared to wait a while. My writing is not affected, and in fact, I am a good proofreader because I have to look at every word. I am a poor proofreader when I have to identify missing parts of sentences.

My family would spend the summers on my mother’s family farm in southern Ohio. I was a tomboy and hung out doing projects with my father. He called me “Tiger Annie.” My father taught me how to fight with my fists and later in life how to fight with a knife or a broken bottle. Most of the time when we were there on the farm, however, we had to entertain ourselves. We trapped snapping turtles, hunted arrowheads, built huge kites, and helped with haying and milking the cows and with feeding the pigs. Experiences on the farm gave me a fascination with biology.

I went to a small private day school in Winnetka for middle and high school. There I enjoyed science and math and avoided history courses where reading was too demanding. I also participated in all sports and was on the varsity field hockey, basketball, and softball teams. In high school, I became fascinated with DNA and memory and learning. I began to read Scientific American and Science.

When I applied to colleges, I was turned down at my first choice, Radcliffe, and instead I got into Vassar and Mount Holyoke. I decided to go to Vassar. At Vassar, I decided to major in chemistry and minor in art history and philosophy: chemistry because I wanted to be a biochemist with a solid fundamental understanding of chemistry; art history and philosophy because neither required much reading (everyone reads philosophy slowly). I did not take the freshman English course that required reading a book a week.

I went to all my classes and studied intently. I never went on any of the social “weekend” trips to male colleges—not because of studying, though. Instead, I went out with locals and played on the local sporting goods store basketball team. There were only nine chemistry majors in my class, and I was the only student interested in biochemistry. We all had keys to the chemistry building, which had a nice cozy library. I spent free time in the chemistry library reading things such as Faraday’s diary. Even though I was a slow reader, I was fascinated by how he thought and planned experiments. In my junior and senior year, I had use of the entire biochemistry lab except for the one afternoon a week when it was occupied by the students taking biochemistry. For the first time, I was able to conceive of, execute, and interpret my own experiments. It was exhilarating.

I loved framing a hypothesis and seeing if I could prove or disprove it. My biochemistry professor, Anne Gounaris, was incredibly supportive and encouraging. She helped with teaching me techniques, but she also gave me a lot of freedom in the lab. We worked on pyruvate decarboxylase biochemistry. I wanted to purify and characterize the enzyme. I worked out my own colorimetric assay so I could do many samples much more quickly than the previous Warburg assay. Some of the work was published in the Journal of Biological Chemistry.

I decided I wanted to be a scientist—studying human disease and, hopefully, ultimately making a difference for people. I wanted to get a PhD in biochemistry from Rockefeller University. My hometown pediatrician suggested I pursue a combined MD/PhD, however. In a way it made sense because then I would be able to do research on human disease more easily. So, I also applied to Rockefeller, Johns Hopkins, and the University of Wisconsin (the latter two had good MD/PhD programs by reputation). I did not get into Rockefeller but I got into the other two programs and decided to go to Johns Hopkins University.

Medical School

Medical school in Baltimore was very different from Vassar. The school was in one of the most impoverished areas of the city, and our dorms were in a partially protected compound. There were nine women in a class of 110. The men could belong to the all-male eating club. The first night I was at Hopkins, I was at a party at the eating club, and during the party, there were shots outside—a man had been shot. All the eager med students rushed outside to help. The man was carried to the emergency room around the corner. Later, I would find that you could tell how active the emergency room was by looking at the dripping blood leading up to the emergency entrance. Then the rain would wash it away, and the process would start over again. There were bullet holes in the windows of the laboratory where I worked.

In my first year, I went to a party at a biochemistry professor’s house and he told me that he was on the admissions committee when I applied, and that they found two Anne Youngs had applied. At a special meeting of the admissions committee, they divided the Anne Young documents into two piles—one the Anne Young they liked (which was me) and the other the Anne Young they did not. However, in the middle of the table was a letter saying that Anne Young was crazy and should never be a doctor. A Vassar alum who was a doctor at Hopkins came up in the fall (before the final admissions decision) to see if it was true and decided I was okay after a brief interview. In fact, I knew this letter was about me because not only had I gotten very depressed at Vassar, but I became hypomanic and was locked up for five days in the hospital. This letter was from the psychiatrist, and it was sent in because I had naively released all my medical records for the admissions process.

Hopkins had a southern flavor and its politics were conservative. What a change from college! I gravitated to a small group of anti-war, pro–civil rights students who sat in the back of the classroom. Classes were all large lecture courses taught by men with famous names. We had our own names for all of them—such as the pulmonary professor, deadspace Sheppard. We also had some incredible lectures such as those from Richard Johnson about efforts to discover the cause of transmissible spongioform encephalopathies such as kuru, scrapie, and Creutzfeld Jakob disease. He showed us all the exotic places such as Papua New Guinea, where he had gone to study the illnesses.

With only nine women in the class, the lecturers definitely catered toward the men. In almost every lecture, nude pinups or cartoons of nude women would be shown just for entertainment. This was somewhat irritating. In my second-year radiology class, I noticed that the lecturer always put his slides into the projector before lunch for our afternoon lecture. I got hold of a full-frontal picture of a nude man, all buffed and greased on a cliff, and one day during lunch, I slipped it into the lecturer’s carousel. As he lectured, first came up the usual pictures of nude women, and then suddenly there was this nude man. The lecturer turned pale and flipped it to the next slide. All the men in the class started laughing and made him back up and show the slide for the women. It was very funny, and the lecturer never showed another nude during the course.

One of the members of the little group of liberals in the back of the lecture room was Jack Penney (John B. Penney, Jr.). He had been to college at Dartmouth and was a member of Students for a Democratic Society (SDS). We liked each other and started going out. He was from New England and most recently had lived in Newton, Mass. His father managed the parks for the town of Newton, and his mother was a dental hygienist. Jack was very vocal about civil rights but, in general, he was a quiet New Englander with a dry sense of humor. He was encyclopedic in his knowledge, had a photographic memory, and was a very fast reader. We liked the same things such as hiking, skiing, and swimming and our relationship grew. We moved in together in the second year of medical school.

To pursue a combined MD/PhD degree, I arranged to meet with the dean of students to discuss my options. Much to my surprise, he said there really was no formal MD/PhD program; rather, each individual was encouraged to construct his/her own curriculum. I asked if I could use the year and a half of elective clinical time pursuing my PhD work and still have it count toward medical school. He said yes. I asked if I could get it in writing, and he agreed.

During the first year of medical school, I looked into laboratory opportunities. I was thinking about biochemistry when a biochemistry graduate student suggested I talk to a young assistant professor of pharmacology, Solomon H. Snyder, MD, who was working on the biochemistry of the brain and the role of drugs in brain function.

I made an appointment to see him and brought with me (at the suggestion of the graduate student) a written proposal for a summer project. We talked, and he said he would be pleased to have me join the lab in the summer. A couple of weeks later, we met again and discussed my project and somehow, without even a bump in the conversation, I left the office thinking I had written a great project but that I would actually pursue an even better project instead. Talking to him was really energizing. He thinks very broadly and outside the box. That summer, in Sol’s lab, I learned a whole slew of new techniques including dealing with gradients, radioactivity, and with subcellular fractionation. The people in the lab were diverse and interesting, and the problems of neurotransmitter function in the brain fascinated me. After that summer, I wanted to do my PhD in Sol’s laboratory. He agreed to have me join the laboratory when I was done with my medical school requirements.

I met with the head of the department of pharmacology and asked if I could be a graduate student with Dr. Snyder and if I could count my med school physiology, pharmacology, and biochemistry courses toward my PhD in pharmacology. He said yes. I asked to get it in writing. He said fine.

Over the next year and a half I finished up my medical school courses—nine months of basic science and nine months of required clerkships. The clerkships were medicine, surgery, pediatrics, ob-gyn, and psychiatry. I did not intend to take any elective rotations. During my medicine clerkship in the summer of 1971, Jack and I got married. We were both fascinated by the nervous system and wanted to be neurologists. Neither of us had neurologic disease in our families. We found the diseases of the brain particularly interesting and challenging. We also thought it provided a large understudied universe to explore.

PhD Program

I started full time in the lab in January 1972. I studied homocarnosine and homoanserine in the rat brain, to determine whether they could be functioning as neurotransmitters. First, I had to devise a quick and accurate assay to measure the dipeptides. Sol was a wonderful mentor. He figured out what made each person in the lab tick. Some he punished to work harder and others he would pat on the back. He loved to look at the primary data coming out of the scintillation counter. He would ask probing questions and come up with intriguing ideas based on reading a very diverse set of topics and literature within and beyond neuroscience. He would listen carefully to my ideas as well, and conversations were always lively.

All was going well until Saturday, February 19, 1972. That day Jack and I and four friends went winter camping in western Maryland on the Appalachian Trail. The snow was up to mid-thigh and we trudged three miles only to find that the lean-to we wanted to stay in had collapsed under the snow. Back in Baltimore after a long and exhausting hike, I went out to pick up a pizza and was hit by a car as I crossed the street. I fractured my femur and cut my head. One day later, I mentioned to Jack that I was seeing things fly by my vision. I was not too concerned because I was on painkillers and I thought it was just a side effect. The second night, my roommate called the nurses twice to tell them I was having trouble breathing—nothing was done. I was supposed to go to surgery in the morning and Jack came in to see me. He found that the nurses had me in four-point restraints because I bit a nurse and pulled out all my tubes and catheters. I was gasping for air. They got a blood gas and my p02 was 40; a chest X-ray showed a whiteout and I had petechiae in my nail beds and sclerae. I went straight to the intensive care unit (ICU). It eventually became clear that I had fat emboli to the brain and lungs. (Emboli composed of blood fat occur very rarely after the fracture of a long bone.) I almost died. Jack was told I had a 50-50 chance of survival. Fortunately I lived, and after three months on crutches and a cane I could walk independently. I got back to the lab within three weeks of being home from the hospital. I was never quite the same afterward and developed a streak of paranoia that never went away.

While I worked on homocarnosine and homoanserine, I became intrigued by the idea of using neurotoxins (the way alpha-bungarotoxin was being used to study nicotinic acetylcholine receptors at the neuromuscular junction) to measure the receptors for putative inhibitory neurotransmitters, such as the amino acids glycine and gamma-aminobutyric acid (GABA). Sol was completely supportive of my interest and encouraged me to pursue the project.

I worked across the bench from Candace Pert who was trying to measure opiate receptors using high specific activity opiate agonists and antagonists. Actually, Candace began looking at receptors because Pedro Cuatrecacas was on the same floor and he was doing work on the insulin receptor using iodinated insulin. That gave Candace the idea that she could measure the opiate receptor using a similar approach. She had done a rotation in Pedro’s lab and was convinced this could be used more broadly. In Sol’s lab, Shalesh Banerjee iodinated nerve growth factor to look for that receptor.

I figured that certain centrally active neurotoxins would be very potent and bind tightly to neurotransmitter receptors. At the time, researchers were just starting to accept GABA as a neurotransmitter, and glycine’s role was still hypothetical. I thought that if glycine were the neurotransmitter of the Renshaw interneurons and the 1a afferent–linked interneurons in the spinal cord, then strychnine, which seemed to block these responses, might bind tightly to the glycine receptor and allow its characterization. Similarly, bicuculline appeared to block GABA receptors.

I had strychnine and bicuculline labeled with tritium by New England Nuclear. They returned a vial of 5 millicuries of brown and green material for each. After I purified the strychnine sample by thin layer chromatography, I obtained tritiated strychnine with very high specific activity. With that, I was able to show that strychnine binding was distributed in the rodent brain and spinal cord exactly as would be expected for an agent binding at glycine receptors for inhibitory interneurons in the spinal cord, brainstem, and thalamus. The purification of the bicuculline was more difficult, and the specific activity was poor. I sent off for a new batch. In the meantime, I was able to characterize strychnine binding in detail. I showed that it bound to a site on the receptor that was distinct from the glycine binding site and that it affected glycine binding allosterically. This was the second neurotransmitter receptor characterized using tritiated antagonists as labels for the receptor.

The tritiated bicuculline turned out to be unstable. Instead, we found that measuring the GABA receptor with [3H]GABA turned out not to be difficult once we had a good batch of tritiated material with high specific activity. In the last few months in the lab, I studied [3H]GABA binding the same way that I had the strychnine binding site. A medical student, Steve Zukin, worked with me on the project. Later, as I was leaving the lab, Sam Enna came to the lab as a postdoc, and he continued the GABA project.

Jack was working in his elective time in the laboratory of Robert Herndon, Leslie Weiner, and Dick Johnson studying the virus responsible for progressive multifocal leukoencephalopathy (PML). He was able to show the virus in the spinal fluid of PML patients and identify it as a polyomavirus (the JC virus).

While he was in the lab, he told me of a graduate student, Mary-Lou Oster-Granite, who was working on a virus that killed all the granule cells of the cerebellum without damaging other cerebellar neurons. I knew Mary-Lou from anatomy because she was one of my anatomy partners when we disseced our cadavers. I thought perfect! I could collaborate with her, and we could find the neurotransmitter of the granule cells of the cerebellum. It was a project that took three weekends.

The first weekend, I did high affinity uptake of all the neurotransmitter candidates on a litter of animals without granule cells. Aspartate and glutamate uptake were the only things affected. The next weekend, I studied the kinetics of glutamate and aspartate uptake, and only the number (not the affinity) of uptake sites was affected. The third weekend, I put samples over the amino acid analyzer and found that only glutamate levels were decreased. This study was the first to associate glutamate with a particular neuron type and solidified its putative role as a neurotransmitter.

Collaborating with the neurovirologists introduced me to many of the neurologists. I also developed several other projects with others in the neurology department including with Don Price and Jack Griffin. Reading for my thesis defense also led me into many neurology journals, and I began attending neurology grand rounds and brain cutting.

Jack applied for residency in neurology and got into his first choice, the University of California, San Francisco (UCSF). He stayed with me in Baltimore for his internship. I applied for internship and residency a year later. When I came to defend my thesis, 30 months after I started in the lab, I had ten publications and I passed my oral defense without problem. Nevertheless, the pharmacology department told me that I had to stay another year in the program. I asked why, and they said otherwise it would look as if Hopkins gave out cheap quickie PhDs (I was going to get my MD in 1973 and PhD in 1974). I told them I had the letter that the department chief had signed two and a half years ago, agreeing to my proposed program. They changed their minds and gave me the degree.

Internship and Residency

I matched to internship at Mt. Zion Hospital in San Francisco—a community hospital with a fairly good resident-run teaching service. I applied to UCSF for residency. They were dubious because I had never even taken a clerkship in neurology. I urged the faculty I knew at Hopkins to lobby for me, and I got in.

San Francisco was a great place to do an internship and residency. The institution had outstanding neurology faculty and residents, the weather was nice, and California seemed cool—relaxed, casual, and liberal. Jack and I loved it. We bought a house up high on the hill south of the Sunset district. We rented a 20-foot sailboat with some fellow residents. We worked very hard as house staff, but we knew that our days off could be spent in some beautiful outdoor setting such as Mount Tamalpais and Stinson Beach or Point Reyes.

I started out with six residents in my class. Ed Chaplin was a pediatric neurology resident—so, in the second year, he focused on peds. One of our residents dropped out. Then Rick Rosenbaum finished early after the second year because he had had a year of time in neuromuscular already when he started. Then Seth Finkelstein left early to go to Mass General to do stroke with C. Miller Fisher. So that left two of us, Justin Zivin and me, to be the only third-year residents. I was chosen chief resident and had to organize schedules to cover all the services. It was a challenging third year made more complicated by outside events.

During my second year of residency, I became pregnant and I had a daughter, Jessica, that February. My chairman, Dr. Robert Fishman, was not thrilled. Jack and I persuaded him that we would be able to cover our duties. Jack was a year ahead of me so he was finishing his residency a few months after the baby was due. We hired a young 19-year-old high school dropout, Joan, to live with us and take care of the baby while we worked our long work weeks.

It was clear at the end of residency that the only jobs available at UCSF were low-level ones without much of a start-up package. We started looking at places with new chairs who would have good recruitment packages for two people. The University of Michigan offered us very good packages with big labs, excellent equipment, and funds for start-up and technicians. Jack was going to do one more year of fellowship with Sarah Winans Newman in the anatomy department working on immunocytochemistry before starting his lab. I was going to go as an assistant professor. We decided to take the jobs. We asked Joan, the babysitter, to help us during the move. She came, and stayed, and ended up living with us all through our 13 years in Michigan. Her presence made a huge difference to us. She became part of the family. We felt comfortable leaving the girls (we later had another daughter, Ellen, in Michigan) alone with her if we had to go to meetings together.

University of Michigan

Sid Gilman was the chair of neurology at the University of Michigan (U of M). He was a fantastic mentor. He taught us how to write a grant, how to talk to program people, and how to arrange a site visit. He critiqued our grants and papers. He introduced us to people in neurology and at the National Institute of Neurological Disease and Stroke (NINDS) and suggested us for talks at major meetings. He involved us in program project grants, and we not only did basic science work but we started working on positron emission tomography studies of Huntington’s disease (HD).

I wrote my first grant when I was still a resident. I had been struck during my residency by the fact that neurologists and neuroscientists had not even identified the neurotransmitter of the corticospinal tract and knew little about the neurotransmitters of the local circuits in the spinal cord in conditions such as spasticity. Having worked on the glycine and GABA receptors as a graduate student, I decided to examine what happened in the spinal cord in spasticity. In those days, one could submit both a K award and an R01 at the same time. I got the K award but my score on the R01 was miserable and, I thought, not fundable. Sid told me to call up my program person who looked after the grant administratively at NINDS. Nancy Wexler was the program person! I had heard of her and her work with Huntington’s disease. I was afraid to call but I mustered up the courage to do so. She was very nice. She told me that, even though the priority score was poor, my grant would be funded because spasticity was of interest to injured veterans. I was elated. Nancy was later to play a very important role in my life. Having gotten a grant, Jack and I decided to have another child. We had another daughter, Ellen.

Then came the experiments. They turned out to be hell for the rats and pretty close to hell for us. Rats with severed spinal cords are paralyzed, try to eat their lower limbs, and are in spinal shock for some time. We had to crede their bladders every eight hours and paint their legs to keep them from gnawing on them. On top of that, it was not easy to show any changes in glycine or GABA levels, receptors, or in turnover. I began looking for side projects.

Jack and I started working together with one of Sid Gilman’s colleagues, Mark Bromberg, who was studying cats with primary motor cortex lesions. We wanted to examine his cats biochemically to identify the neurotransmitter of the corticospinal tract. Jack did the anatomy, the Fink-Heimer stains, and the punch biopsies of postmortem tissue. I did the high affinity uptake and levels of putative neurotransmitters by high performance liquid chromatography (HPLC). Glutamate was the only transmitter that fit the bill. We did the experiments in primates with Sid and glutamate again turned up as the associated putative neurotransmitter.

Sid Gilman and George Dauth were using [14C]-2-deoxy-D-glucose to measure tissue metabolism in spastic monkeys with quantitative autoradiography. We wondered if we could measure neurotransmitter receptors with film autoradiography. We needed film that could measure tritium decay, and Amersham had just come out with such. We made standards of tritium in brain paste and then plastic and worked out the methodology. We found we could easily measure receptors in 20 micron brain secions with excellent signal to noise, excellent kinetics, and pharmacology, and with outstanding anatomical delineation. We published the methodology in 1981. The technique was the first to make it possible to measure receptor levels, affinity, and pharmacology in tiny areas in individual animal brains. It was a true advance over the prior bind-and-grind techniques.

At this time, I was hiring for a laboratory manager and lab technician and I interviewed a man named Zane Hollingsworth for the job. His ambition was to be an outstanding laboratory manager. He seemed excellent, and I hired him on the spot. Zane lived up to every expectation. He soon learned everything about the equipment in the lab but also about all the experiments as well. He made sure everything was written down in notebooks and that all the protocols were clear. He managed the students coming through the lab in terms of their use of equipment and documentation. He managed all the lab supplies and expenditures. He was also a great resource for anything in Ann Arbor. Once, I wanted marionettes for my daughters, and he knew just where to get them. He was also a regular all-around good guy, and we got to know him and his wife well over the years. He moved with us when we later relocated to Boston, and he worked for me until 2013 when he retired.

Jack and I partnered in all of our research. We essentially joined laboratories. Our graduate students knew that Jack knew the anatomy, the stereotactic surgery, all the computer programs, and the statistics, and I knew the pharmacology and physiology. Partly because of my dyslexia, and partly because of Jack’s photographic memory, he was the reader. He would read all the literature and then tell me about it. I was the writer. I could express my ideas more fully than Jack, who would distill a very complex idea into an obscure pithy comment only to find it hard to elaborate. I would draft the papers and grants, and he would reference them. He did all the anatomical figures, and I did the graphs and diagrams.

We partnered clinically as well. Although we had no formal training in movement disorders, we co-directed the U of M’s Movement Disorders Clinic. Sid let us hang up our shingle and say we were experts. There was no competition in Ann Arbor. We should not underestimate learning by doing. We made mistakes, but I still do today. What we learned from our patients, our basic research, and Jack’s reading soon made us actual experts. Our lack of formal training meant we had fewer preconceptions about the field, so our imaginations were able to run freely.

Although we both saw a bit of everything, Jack became the expert in hypokinetic movement disorders such as Parkinson’s disease, and I focused on hyperkinetic movement disorders such as Huntington’s disease and Tourette’s syndrome. Jack joined the local Parkinson’s support group and I joined the local Huntington’s disease chapter. We ran a resident and fellow Movement Disorder Clinic, and we each had a private practice clinic.

James Neel had been head of human genetics at Michigan and had canvassed the state in the 1950s to identify Huntington’s disease and its prevalence. He wrote many of the classic papers on the genetics and epidemiology of Huntington’s disease. As a consequence of his work, the neurology department was responsible for caring for a large number of HD patients and their families. I had the opportunity to take over the HD clinic when the neurologist caring for them left Michigan to go to the Mayo Clinic. I found it very rewarding to care for and interact with the HD families and affected individuals.

We noted that other researchers were looking at postmortem human brain neurochemistry, but they could not look at the neural circuits easily because they had to homogenize the brains to look at the neurochemicals. We decided to do autoradiography of receptors in secions of postmortem human brain. Many receptors were known or suspected to up- and downregulate in response to under- and overactive input, respectively. Therefore, we could get some idea about how certain circuits were working by looking at receptor numbers. Jack became adept at taking 50-micron frozen secions of an entire hemisphere of human brain, and our laboratory used these to measure GABA, glutamate, dopamine, and other receptors. It was in these brains that we first saw alterations in GABA and glutamate receptors in the basal ganglia in Huntington’s disease and also cortical glutamate receptors in Alzheimer’s disease. When we saw something in human brain, we could take it to the animal and vice versa.

We were fortunate to have my first MD/PhD student work in the laboratory, John Timothy Greenamyre. Jack and I had been instrumental in defining glutamate as the transmitter of the corticospinal tract, and Tim was the first to measure [3H]glutamate binding autoradiographically in a rat brain. He then measured [3H]glutamate binding in HD and Alzheimer’s brains. He developed autoradiographic techniques to measure all the subtypes of glutamate receptors defined physiologically. Glutamate was achieving great general interest. What had been a limited field absolutely exploded, and we were able to ride the wave at the forefront of the field. Other wonderful people to earn their PhDs in our laboratory were Helen Pan, Jang-Ho Cha, Sharin Sakurai, Claudia Testa, James Olson, Eric Richfield, William Maragos, Anthony Kincaid, John McDonald, and Brian Ciliax.

Jack and I spent our free time talking about how the basal ganglia might work. How did the message get to the spinal cord? Why did chorea initially look so fluid and then, as one lost fine motor coordination, elements of dystonia emerged? How could you be choreic and slow at the same time? Why did Parkinson’s patients walk faster and faster and find it hard to stop? Could it be that in Parkinson’s disease, there is not so much as too much inhibition but rather too much excitation? We wrote our theory in a review in the Annual Review of Neuroscience.

We decided to see what happened to GABA receptors in various parts of the basal ganglia circuit when we made lesions to different nodes of the circuit. We predicted that if a node became underactive, postsynaptic receptors in its projection zone would upregulate; whereas if a node became overactive, postsynaptic receptors would downregulate. We did the experiments in rodents. Helen Pan, a graduate student in the laboratory, spearheaded the work. We started with the striatum. Lesions caused upregulation of GABA receptors in globus pallidus, entopeduncular nucleus, and substantia nigra pars reticulata. Receptors were downregulated in VL thalamus through trans-synaptic changes in activity. When we lesioned the cerebral cortex, GABA receptors upregulated in globus pallidus but were unchanged in entopeducular nucleus and SNr, which did not fit the simple circuit model we initially envisioned. Then, we lesioned the SNc dopamine cells, and receptors dramatically downregulated in globus pallidus and upregulated in entopeduncular nucleus and SNr. The simple circuit we hypothesized was clearly wrong.

The best explanation came from concluding that dopamine inhibited striatal GABAergic cells projecting to the globus pallidus and excited striatal GABAergic cells projecting to the entopeduncular nucleus and SNr. That only made sense if there were two circuits involved and the subthalamic nucleus was part of the second circuit. For the model to explain most of our findings, the subthalamic nucleus had to be excitatory. The current thought by others was that it was inhibitory. What was its neurotransmitter? Experiments by others had excluded all the monoamines, the peptide neurotransmitters, and acetylcholine. The most likely neurotransmitter was an amino acid.

Roger Albin, MD, was a postdoctoral fellow in the lab who took on the problem of the circuits with a vengeance. First, he looked at the subthalamic nucleus. We were able to obtain antibodies to glutamate, glycine, and GABA. We showed that only the anti-glutamate antibody stained the neurons in cat subthalamic nucleus. Other researchers followed shortly, and their data showed the same thing.

Our data on dopamine’s differential effects on GABAergic output to the striatal projection zones also made sense with data from other labs showing that dopamine inhibited encephalin striatal turnover and enhanced substance P striatal turnover. Furthermore, others had found that substance P was present in about half of striatal neurons and encephalin in the other half. Finally, electrophysiologists had long provided evidence that application of dopamine onto medium spiny neurons of the striatum could be either excitatory or inhibitory. We hypothesized that, taken together, the data suggested that dopamine was excitatory on striatal cells projecting to the entopeduncular nucleus (medial globus pallidus in the human) and substantia nigra pars reticulata and inhibitory on striatal cells projecting to the globus pallidus (lateral globus pallidus in the human). The pathway through the cortex to striatum to entopeducular nucleus and substantia nigra pars reticulata could reinforce movements. The pathway from cortex to striatum to globus pallidus to subthalamic nucleus to entopeduncular nucleus could inhibit unwanted movements. We published our theory in 1986 in Movement Disorders. The model predicted that in Huntington’s disease, the striatal encephalin neurons projecting to the lateral globus pallidus would drop out first before the substance P striatal neurons projecting to medial globus pallidus and to substantia nigra pars reticulata. Second, the model predicted that the subthalamic nucleus and medial globus pallidus would be overactive in Parkinson’s disease.

Roger wanted to delve deeper into the problem. He set up a collaboration with Anton Reiner, PhD, from the anatomy department, who was a good immunochemist and who wanted to get more experience in human brain. Anton’s prior work as a comparative anatomist was with birds and turtles. Soon, however, we had data on substance P and encephalin immunoreactivity in Huntington’s disease brains and in postmortem controls. As we had hypothesized, the encephalin neurons dropped out early and the substance P later.

Our theory that two circuits controlled basal ganglia output was new, and now we had to see if it also explained other researchers’ discoveries. Mahlon DeLong and colleagues, and Michel Filion and colleagues, both were studying basal ganglia output in normal and parkinsonian monkeys. They noted the differential increase in internal and external pallidal output but were not sure how this could be understood in underlying pathways. We met and talked to them at a meeting in Manchester, England, in 1986. When Filion was presenting his work, I leaned over to DeLong and asked him if he knew how the circuits explained the findings, and he said no. I told him how our theory would explain his and Filion’s work. We elaborated our thoughts in a chapter we wrote for the meeting in 1988.

Most people worked on Parkinson’s disease to examine the basal ganglia, but Jack and I studied Huntington’s brains as well. Our considering Parkinson’s and Huntington’s diseases together told us a great deal about the circuits that were affected the earliest in both diseases. In early Huntington’s, the striatal encephalin neurons were affected earliest. We were able to show this in postmortem human brain from symptomatic persons and also in the brain of a presymptomatic individual whom we had seen. This latter person had committed suicide with intravenous potassium because of fear of HD. We obtained two other brains from people with early Huntington’s disease who had committed suicide. One of them was a patient of mine whom I had hospitalized because of depression and whom a judge let out prematurely. The patient and her sister committed suicide together a day later.

My patients’ double suicide threw me into a depression that lasted for months and disrupted my family life. Even the most beautiful days were bleak, and I was despondent and irritable. I knew how it had affected my whole family when my daughter’s preschool teacher called me up and told me that my daughter had done show-and-tell on Huntington’s disease and suicide. Nancy Wexler came to my family’s and my rescue psychologically, but it was a very tragic experience for me. (Nancy had become a very good friend on our trips to Venezuela—see later in this chapter.)

Devastating as those suicides were for so many people, the fact that we obtained the brains of all three victims was incredibly valuable for research. The first patient was mine and had moderate HD, her sister had very early HD, and the third person was part of a longitudinal study of at-risk sibships who had been examined two years previously with positron emission tomography (PET) scanning, psychological testing, and neurological examination. All of the at-risk person’s studies had been normal, but the brain, like the two symptomatic patients, showed upregulation of GABA receptors in external globus pallidus, loss of encephalin neurons, and little loss of substance P neurons.

Roger, Jack, and I sat down to describe a new way of thinking about how the basal ganglia regulated movement in health and disease. We made a new set of box and line drawings of the circuits underlying Parkinson’s and Huntington’s disease. In 1989, we published it in Trends in Neuroscience. It turned out to be the most cited paper I have ever written. Despite huge amounts of subsequent work on the basal ganglia, our basic model has stood the test of time, and people still refer to it.

Venezuela

A most notable part of my life and Jack’s began in 1981 when Nancy Wexler invited me to participate in the Venezuela Huntington’s disease project. We barely knew each other. I had met her several times casually—once at the Society for Neuroscience meetings, once when she was in Ann Arbor checking me out for the Michigan chapter of the Huntington’s organization, and once at a meeting in Los Angeles for the Hereditary Disease Foundation (her father’s foundation for HD). She was a strikingly beautiful woman with long blond hair, and she captivated all who were around her. Nancy had already been to Venezuela, and she was planning who would be on the team. She asked me to come along as the neurologist. We would have to go down to remote towns on stilts in lagoons along Lake Maracaibo and spend several days in the towns examining the cluster of HD patients. How exotic, I thought. I questioned my ability to function effectively in a remote environment. I decided that if Nancy could do it, so could I. I thought of hearing from Dick Johnson about his trips to Papua New Guinea to study kuru.

This trip with Nancy began 22 years of returning to Venezuela each year to study the very large HD family that exists there along the shores of Lake Maracaibo. Huntington’s disease first appeared there in the 1800s. Whether it was a new mutation or from an itinerant sailor is still unknown. Over the 22-year period, I saw thousands of people at risk for and with HD, some homozygous for the gene. For some people, we had up to 22 years of follow-up exams, with videos. After the second year of the study, Jack also began to take part in the trips. The two of us would go down at different times because we always wanted one parent at home. On a couple of occasions, the kids came down with us, and then we could all be together. Jack helped create a neurology database. Jack and I competed to see how many people we could examine each year.

Jack and I viewed our time in Venezuela as soldiers in the field. Many personal events took place during those 22 years of trips, including developing very strong and lasting friendships, mentoring young people, being held up by armed guards, and nearly dying when our boat began to sink during a storm. Despite the dangers, we all made it through unscathed. Our experiences gave us a much deeper sense about the challenges faced by the populations of the underdeveloped world.

Fig. 1.    Nancy Wexler with children in Venezuela.

Nancy Wexler proved to be the most hardworking, driven person imaginable (Figure 1). She taught herself Spanish so she could communicate effectively. She knew the pedigree inside out and backward. She knew the names and relatives of nearly everybody. She would listen to their stories and cajole them to participate in the study. Her blond hair flowing, she would walk through towns and neighborhoods, stopping at houses where an HD family lived and soon 10–20 people would arrive who were part of the family. They called her La Catira or “The Blond.” Nearly all volunteered, and Nancy would explain that her own mother had HD and so she knew how they all felt about the disease. Nancy would not hesitate to get in close to people despite the conditions. She hugged everyone, particularly the affected people. She went into their homes, attended to their troubles, asked about their families, and helped them get everything from medicines to mattresses. Nancy made the most of every waking hour—and for her, three to four hours of sleep was enough. We would be up at dawn and then work until 10 p.m. or 2 a.m. During trips on trucks or buses, we could sometimes catch a few winks.

In Venezuela, we all became adept at drawing blood, taking skin biopsies, doing neuro exams, and at videotaping exams. We persuaded the Venezuelan men to give sperm samples as well. We brought the samples and data we obtained back to the United States and distributed them to other laboratories. The samples became an important resource for many lab groups.

In 1983, two years into the Venezuela project, the samples helped find a marker that was closely linked to the Huntington’s gene. Jim Gusella, at Massachusetts General Hospital, found it by using immortalized lymphocytes from Venezuelan blood samples. Jim had come from David Housman’s lab at Massachusetts Institute of Technology (MIT) to Mass General, and David had been the one to conceive of screening the human genome with anonymous RFLP markers in a large family to find the gene. Jim was going to set up the experiment in a new HD center at Mass General run by Joseph Martin, who was head of the neurology service there. Nancy’s father’s organization, the Hereditary Disease Foundation, helped fund the project as did the National Institutes of Health (NIH). The discovery of the HD gene marker allowed the use of linkage analysis to determine who had inherited the HD gene. People who had living affected family members could have linkage analysis to determine presymptomatically whether they had inherited the mutant gene.

Geneticists in the United States and abroad mounted a huge effort to find the actual gene. The hunt depended in part on getting more genetic data from the pedigree. More cases could narrow the area in which the gene could reside. We worked furiously in Venezuela. Each year, Nancy would tell me that I had to see several people myself to see if they had HD. She told me that my exams were the gold standard. I was totally blind to the genotyping being done for the pedigree but clearly either somebody was “diagnosed” who should not have been (i.e., misdiagnosed) or else they had HD but had not been diagnosed yet. As before, I just did as Nancy said. I put down my opinion, and we would not talk about it further.

Nancy thought broadly. She recruited geneticists who brought yeast, flies, and worms to the hunt because they used different techniques than human geneticists to work with DNA. All the methods proved useful when narrowing the site for the mutation on chromosome 4. Nancy brought the team together several times a year to exchange data and to discuss the next steps.

Recruitment to Mass General

At Michigan, I was fortunate that our research went well and I was getting grants. I was promoted to associate professor and then full professor by the time I was 38. I put together a proposal for an Alzheimer’s Disease Research Center at Michigan, and it was awarded. I had to run the center, and I was doing other administrative work also. At that point, I began getting letters asking if I was interested in becoming chair of a department or a director of a program with an endowed professorship. I knew the requests came mostly because I was a woman and they needed women candidates. I looked at only a couple of positions because I loved my job at Michigan. Then one day I got a letter from Massachusetts General Hospital (MGH) asking if I would be a candidate for the position of their chief of neurology. This was the job that Joseph Martin had just left to become dean at UCSF. This was one of the all-time premier departments in the country and clearly the place to be if you were interested in HD.

I decided to look at the job. Jack did not think it would amount to anything, but his family was in Boston so he did not object. The first visit was memorable. I had very long hair that I wore in a ponytail on one side. I did not have any suits, so I wore a fairly casual dress. I had breakfast with the chair of the search committee, John Potts, the chief of medicine. He told me how much fun MGH was, and how you could have a vision and really carry it through at this institution. The rest of the day I saw all men, the whole search committee. I would see one person and then go to the lobby of another building to wait for the secretary of the next person. Because I did not look like the candidates they were used to, the secretaries never found me; I found the secretaries. The whole process seemed like an affirmative action pretense at being interested in a woman candidate, so I figured I did not have a chance. Therefore, I was completely blunt when I described my vision for the department in my final session with the search committee. I was shocked when I was asked back to MGH for a second look, and even more shocked when, in September 1990, John Potts called to actually offer me the job.

Then came the haggling over the agreement. I received help negotiating from Herb Pardes, Nancy’s partner. He told me to negotiate like Peter Falk in “Columbo.” Simply scratch your head and think out loud about how you cannot possibly make it the best department there is without so many new recruits, so much more for infrastructure support, and without funds for so many more fellows. I had never negotiated before, but I did my homework and asked for a lot. Nancy’s father, Milton Wexler, gave me a great piece of advice about how to decide whether to go to MGH or to stay at Michigan. He said that I should simply negotiate until it clearly felt good to go to MGH. If it ever got that far then I should go, but if it did not, I should stay at Michigan. Sid wanted me to stay but the one thing I wanted—an endowed chair—he did not have to offer me. Jack did not want to go at first because he had all his patients and also a very nice position as professor. I negotiated for a nice laboratory for us, a professor position for Jack at Harvard and MGH, and an instructor position for my laboratory manager, Zane Hollingsworth. The rest of the negotiations were for new positions in several undermanned areas and for fellows for many of the staff who were trying to do everything with little help and no infrastructure. I thought that the strengths for the department could be vastly enhanced by junior help for the more senior people. Eventually, I got everything I asked for, and I accepted.

I was the first woman chair of a department at MGH. When I arrived, I felt comfortable until someone leaned over and said: “Do you feel comfortable here?” Truthfully, I was always treated very nicely at MGH, but I was never part of the inner circle.

Nonetheless, I was able to get things done. One of my residents later told me that she had been told by another professor that I would probably be eaten alive by the old boys who ran MGH. The same professor told her a few years later that he had been completely wrong—that I had pushed through a change from a private inpatient service to a ward service that no previous chairman had been able to accomplish.

Moving the girls was a challenge. One wanted to go, and the other definitely did not. They had a series of demands themselves, so I had to negotiate with them as well as with MGH. One of their demands was a house with a yard where they could play. They were not being very forward thinking about that because, as it turned out, they became adolescents at just about the time of the move. I do not think they ever played in the yard; instead, they adapted themselves to their new lives as teenagers. We left Joan the babysitter behind in Ann Arbor, after living with her for 14 years. The girls were old enough to watch over themselves and Joan, by that point, had a significant other. She moved in with him as soon as we left. She later had two sons.

I started my new job at MGH on August 1, 1991. Zane took on the cumbersome job of moving the lab. His organization was outstanding, and we were up and working in no time. We helped most of our graduate students finish up and arrived in Boston with one graduate student, one technician, and two fellows (Leon Dure and Mara Catania). David Standaert joined the lab (as a fellow) just as we were starting up at MGH.

At that time, we were particularly interested in defining the receptor phenotypes of striatal neurons. We thought that differential cell death in illnesses such as Huntington’s disease could stem from the differential expression of different subtypes of NMDA, AMPA, and kainate receptors. We combined radioactive and immunochemical methods of measuring mRNA of various transmitter subtypes. The methods were challenging, but we perfected them in the lab. Postdoctoral fellows David Standaert, Bernhardt Landwehrmeyer, Christoph Kosinski, Ulrich Wullner, Clemens Scherzer, Josef Priller, and others all contributed important efforts into these studies.

One of the challenges for me was finding a good secretary. Unfortunately, the secretaries who came with the job were slow, passive aggressive, and prejudiced. I caught them being nice to all the Christians but rude and unfriendly to Jews and foreigners. I had to fire all of them. That instantly gave me the reputation as a bitch, and I could not find another secretary who would even apply for the job.

Finally, a woman named Beverly Mahfuz applied. Clearly, Bev was very smart. She said she was a fast reader and could read all my mail and summarize it for me. I hired her right away. She is wonderful, and we continue to work together to this day 21 years later!!! Bev has made my life much, much easier. The two of us work together almost seamlessly. Bev is my right hand. She is definitely the power behind my facade for the whole department. Eventually, she knew more about what people needed for promotions than anyone else, and she became an excellent advisor for junior faculty moving up the ladder. She not only reads my mail, she can read me like a book, and she knows how to make the same kind of decisions that I do. She also knows the people at all levels of the hospital so that if something needs to be done, she knows whom to call to make it happen.

Just two years into my tenure as chief, two important papers came out of MGH in the same month—March 1993. One reported the identification of the HD gene. Jim Gusella and Marcy Macdonald played key roles in the discovery. The second paper by Robert Brown and his group at MGH, identified the gene mutation in SOD1 (superoxide dismutase, type 1) that leads to some forms of familial amyotrophic lateral sclerosis (ALS). I was immensely proud of our department, although I knew I could not take credit for this good work. My predecessor Joe Martin’s efforts to put neurogenetics on the map at MGH had finally paid off on my watch.

The other illness receiving a great deal of attention in our department as well as nationally was Alzheimer’s disease (AD). Jim Gusella, Rudy Tanzi, and MGH were key in identifying the amyloid precursor protein gene and subsequently mutations in the presenilin gene. These genetic discoveries in HD, ALS, and AD (all made possible in part by the DNA from the Venezuelan HD family) set the stage worldwide for the next 10 years or more of mapping the human genome, collecting families with a variety of nervous system disorders.

After the discovery of the HD gene, the next few years of scientific advances were slow. A very wealthy donor, along with Nancy Wexler, David Housman, Richard Mulligan, Robert Horwitz, and I, began an effort to push toward a cure faster. We began a series of regular meetings at MIT to discuss important avenues of research that should be funded. We often targeted a particular investigator based on his or her known scientific skills and asked them to become involved in HD research. The donor was extremely wealthy and funded all our efforts. The targeting brought in many new scientists to the HD field. The Hereditary Disease Foundation (which Nancy’s father Milton had started in the 1960s and of which Nancy had assumed leadership) began a series of August meetings every other year in Boston to bring together HD researchers. Data blitzes were the highlight of the meetings because people would have five to seven minutes to tell only their latest results. Posters also became a vehicle for communication. These meetings continue to this day, and the numbers of researchers has expanded dramatically.

The donor eventually decided to form his own virtual nonprofit company to fund HD research. The Hereditary Disease Foundation continues to do well and funds key high risk–high payoff research and fellowships and conducts workshops on cutting-edge research. Work on HD continues unabated, and many new and exciting experiments have implications for patients, particularly gene silencing methods.

The Huntington’s Study Group

In 1993, after the Huntington’s genetic mutation was identified, long-time colleague and collaborator, Ira Shoulson, got together with Jack and decided to start the “Huntington’s Study Group” (HSG). This group was the final piece of the HD pie. The idea was to form a multicenter group that could mount clinical trials quickly and efficiently. Ira and Jack were co-directors of the HSG, and I was head of the scientific advisory committee of the HSG. To be part of the group, investigators had to agree to use common measurement scales of motor, cognitive, and behavioral function. Each site had to train investigators in the use of the scales. Protocols for drug studies were shared among the HSG sites. The HSG not only contracted with drug companies to do studies but also wrote grants to the NIH to fund observational and intervention studies. The HSG continues to this day and has run studies on the natural history of HD and on the efficacy of multiple drugs for HD including tetrabenazine, which is currently the only drug specifically marketed for the chorea of HD.

Jack and Ira became fast friends. Jack was a quiet man, but with Ira, he functioned as a solid and reliable sounding board. Jack was very ethical, which made him an excellent advisor when it came to conflict of interest or other organizational and scientific issues. Jack was also excellent at data analysis and worked closely with David Oakes, the statistician for the HSG. They would go over the large data sets from HSG studies and come up with observations about the natural history and the effects of certain agents on HD (Figure 2).

Fig. 2.    Jack Penney.

Women in Academic Medicine

As chief of the neurology service at MGH, I learned a great deal about men and women in academic medicine. The most important observation was that men had no hesitation asking for the moon from the chief, whereas the women rarely asked for anything. This observation was even true for women who were aggressive when it came to patient care or research. When it came to asking for themselves, it would not happen. I had to train the women in the department to stick up for themselves and to ask for resources and space when they needed it. Merit Cudkowicz (now chief of MGH neurology) was the first woman to ask me outright for a raise. Diana Rosas, Karen Furie, Natalia Rost, and Nicte Mejia have all benefited from my mentorship and have learned to negotiate appropriately.

The second most important thing I learned was that at least part of the challenge in getting women promoted was not that the leadership was bad per se. Rather, women either never got on or promptly fell off the radar screen of leadership because they would not complain or ask for things. Women were not in any inner circles of their departments. Promoting women at the medical school was not difficult once the department showed interest and support. Recognizing their accomplishments took active surveillance, however.

The third aspect of women in neurology was that having role models was very important for the young women coming into residency. They could join an inner circle of strong women who would teach them the ropes if they did not feel comfortable working in a man’s world.

Finally, more women than men choose to limit their academic efforts in favor of spending more time with their families. Fortunately for those of us in the clinical departments, there is no clock for promotions at the medical school. That means that women can take more time to get promoted without being penalized for spending more time with their families during critical times of their careers.

Partners Neurology

In 1994, MGH and Brigham and Women’s Hospital (BWH) decided to join forces in the health care arena and form Partners HealthCare. Suddenly, two rival hospitals were joined at the hip. Neurology was not a department at BWH, and so I lobbied that it become one so that our departments could partner together instead of compete. This was a foreign concept to the other chiefs. In the spirit of partnership, neurology was made a department at BWH. Martin Samuels became chief of neurology at BWH. He was known for his skills as a teacher and as a clinician. Together, Marty and I arranged for the longstanding Longwood Neurology Training Program to be dissolved and reconfigured such that the Beth Israel and Children’s would become independent and BWH would join in a Partners Neurology training program with the longstanding independent MGH program. The first class entered in 1996.

Our collaborative efforts allowed the MGH neurology department to apply for funding directly from the new Partners HealthCare. We got funding for an administrator, an access nurse, a residency coordinator, and funds to support technologies to assist the residents at the two hospitals. We began having joint faculty meetings so that people would get to know each other. Initially, we did not set up rival clinical programs so as not to compete for patients. MGH was strong in movement disorders and neurodegenerative diseases whereas BWH was strong in neuroimmunology. Marty and I decided that patients with multiple sclerosis would be seen at BWH and movement disorders would be seen at MGH. A limited number of faculty worked at both institutions. This division of labor was partly successful, but there were many patients who only wanted care at one institution. This eventually resulted in the need for limited neuroimmunology and movement disorders at both institutions.

During this time, our laboratory continued to focus on studies of various glutamate receptors in rodent and human brains. We found several areas of unique receptor distribution, and these have subsequently been found to have potential pharmacologic specificity in targeting certain clinical symptoms and behavioral effects. We also collaborated with Jim Gusella and Marcy MacDonald and examined the distribution of HD mRNA in human and rodent brains. Predominantly, though, we focused on glutamate receptors in rodent basal ganglia.

In 1998, mutations in alpha-synuclein were identified in familial PD. Jack figured that the expertise in our lab could be put to good use in studying PD and wrote a program project grant that included our lab and the labs of Ann Graybiel, Brad Hyman, and Xandra Breakefield. The grant was for a Udall Center for Excellence in Parkinson’s Research. Jack got the grant, and the center started in the fall of 1998. The MGH-MIT Morris Udall Center for Excellence in PD Research had the overall theme of understanding the mechanisms by which abnormalities in synuclein, parkin, torsinA, and related proteins lead to dopamine cell dysfunction and neurodegeneration. The center encompassed four projects: an in situ hybridization-based investigation into gene expression and selective vulnerability in Parkinson’s disease substantia nigra, led by the principal investigator (P.I.), Dr. Jack Penney. Dr. Hyman explored the expression of alpha-synuclein using then new fluorescence energy transfer techniques to examine its location in cells in vitro. Dr. Breakefield investigated the genetics of parkinsonism, dystonia, and rapid onset parkinsonism-dystonia with an emphasis on her studies of torsinA. Dr. Graybiel developed more sophisticated electrophysiologic approaches to studying the role of basal ganglia in learning and movement using tetrode arrays in mice and rats during acquisitions of novel behaviors. She also pursued experiments using changes in immediate early gene expression to assess the circuits involved in motor learning and adaptation following dopamine agonist treatment.

Creating the MassGeneral Institute for Neurodegenerative Diseases

Over the years, I had become convinced that in most drug companies, development of new treatments centered on compounds that had been discovered years before. To get modern discoveries more quickly to people, investigators needed to have the resources to set up an assay and to do high throughput screening for potential therapeutic candidates right there in the academic laboratory, rather than waiting for years before the drug company would consider them. To get compounds for proof of principle experiments and subsequently for partnering with industry, Jack and I thought that if we could put all the people working on neurodegenerative disease at MGH together in one place, and add a drug screening lab to the mix, we would have a unique center and a real powerhouse. All we needed was a building.

I was on a space committee, and I heard about an old Navy building in the Charlestown Navy Yard that had been gutted by fire but that was up for sale. The building was close to an already existing MGH research building. I asked my friends if any proposals for use of the space had been made, and the answer was “no.” I immediately put forward a plan to have it house an MGH Center for Aging, Genetics and Neurodegeneration (CAGN, or CAGn with its connection to Huntington’s disease). I wanted the whole building. It would have open laboratories, good communication between floors, and a collaborative atmosphere. I found a donor who was willing to give $2 million to help get it started; $2 million was not enough to rebuild the building—that would take much more. Therefore, the hospital administrators had to decide whether to invest in my vision. They liked my plan, in part because I proposed to free up other space they could then give to key researchers in other departments. It was to be win-win for a lot of people.

All was going well in the negotiations, but I had to present to several committees before any decision was made. A key presentation kept me from going to the Winter Brain Research meeting in Aspen that January 1999. Instead Jack went with my younger daughter, Ellen, who was then age 19. My presentation went well. The hospital administration approved my plan and said I could have two-thirds of the building. A coup! Although the whole building was my dream, two-thirds was more than enough space for us and would allow all the planned programs to go into the building.

That evening I called Jack to tell him. He was ecstatic. A few days later, he and Ellen returned after a day of skiing at the end of the conference. That night as we lay in bed, Jack suddenly gave a large gasp. And died. I gave him CPR for what seemed like hours until the ambulance came but with each chest compression I knew it was hopeless. A massive heart attack. He was just 51.

Nothing in my life could have been worse. Jack and I were together in every aspect of our lives. He was my husband and my best friend, my co-resident, my most important research collaborator. He told me when it was time to go home from a party and what was important in the latest journals. Every aspect of my life was instantly crushed. Even now, 14 years later, it is raw and bitter. Thank God for all my friends. Nancy was by my side in what seemed like just minutes, Zane, Jang-Ho, Sharin Sakurai, Alice Flaherty, and Diana Rosas were there quickly also. Jim Olson from Seattle came and spent a week trying to help. My daughter Ellen, who had had to watch me try hopelessly to revive Jack was with me too as was Jessica (our oldest daughter) who flew in immediately from Michigan. Our apartment was within walking distance of the hospital, and nearly everyone in the department came by and stayed for hours. For 12 days, my apartment was full of people and constant noise.

Remarkably, in the days following Jack’s death, several of my trainees decided to collaborate on new projects. In particular, Jim Olson, a pediatric neuro-oncologist, worked out a collaboration in my laboratory on gene expression studies in HD with Ruth Luthi-Carter. Jim was an expert from an oncology background and Ruth was a good molecular biologist. Jang-Ho Cha, a contemporary of Jim’s in the lab from Michigan joined the collaboration, too. Jang-Ho had done his neurology training at MGH and then worked in my lab again. (Jang-Ho had previously observed that in HD transgenic mice, neurotransmitter receptors were changed in a pattern that suggested altered gene transcription of certain receptors but not others.) This began the first gene expression studies in HD animal models and in the HD brain. It was found that in HD there are remarkable changes in subsets of genes suggesting that the mutant protein alters specific gene expression via altering transcription.

Because Jack ran through every aspect of my life, there was nowhere to go to escape the intense grief. His absence was everywhere. I had to take over direction of the Udall Center and write grant renewals that Jack had been working on. For the next two years, my students and colleagues all rallied around to help me through the most difficult time imaginable. My colleagues, particularly Jang-Ho Cha and David Standaert, helped write grant renewals that got funded.

I tried to channel my efforts into the new Center for Aging, Genetics and Neurodegeneration, the last project that Jack and I had started together. Three weeks after Jack’s death, I had one final hurdle to go through in front of the finance committee at Partners HealthCare to sell the idea and convince the committee to buy and renovate the new building. I dressed all in black and made a passionate plea based on my late husband’s and my concept for a center that could focus on accelerating new therapies for neurodegenerative disease by bringing fundamental discoveries more quickly to application. Although by no means unanimous, the motion passed and soon we began designing the center.

The center opened up lab space for Brad Hyman, Rudy Tanzi, David Standaert, Marian DiFiglia, Jang-Ho Cha, and Bob Brown and a host of more junior people. We had 36,000 square feet of prime research space on two floors with an open staircase that connected the two floors. The $2 million helped get people set up, to hire a person to be the executive director, and helped fundraise and maintain center infrastructure. I hired Janice Hayes Cha, Jang-Ho’s wife, to fill the position. She is the type of person who is self-motivated and just knows how to get things done. Zane was designated the center manager who coordinated the space moves and kept me abreast of space wars that existed between investigators. Each year, Janice brought in philanthropic support that allowed us to do the drug screening, to support young people, and to get new equipment. One of the donors said our name was too confusing and we should rename the center. We chose the MassGeneral Institute for Neurodegenerative Diseases (MIND).

Just as MIND was getting off the ground, I sent a summary of my plan to Dennis Selkoe over at BWH. Shortly after this happened, a large anonymous $37 million gift was made to Harvard Medical School with Dennis Selkoe and Joe Martin (who had returned from UCSF to become dean at Harvard Medical School) as the leaders to set up an almost identical center at the medical school. They had drug screening, fellowships, grants, and so on. They collaborated with us and one of their core facilities (the laser capture microdissecion core) is at MIND. It was a center without walls, so there was no building for it. Many people around the medical school were part of it including many of our investigators.

Novartis Collaboration

Shortly after MIND opened, David Housman from MIT and I decided to approach Novartis for a collaborative effort to solve Huntington’s disease. Two of David’s prior postdocs had junior faculty positions in MIND and one, Alex Kazantsev, was the head of the drug screening lab. Alex had found an interesting compound that seemed to block aggregation of proteins in HD. At MIND, he looked at analogs of the compound and found one that was very effective and potent. Novartis looked at the compound and found that it was orally bioavailable and was nontoxic.

In 2006, we put together a four-year, multi-lab project with Novartis to uncover agents to treat HD. The project supported five postdocs plus money for supplies and animal experiments at MGH and MIT, and Novartis contributed considerable resources on their side as well. The projects were to follow up on Alex’s drug and find agents that effected (1) huntingtin proteolysis, (2) huntingtin-induced abnormal transcription, and (3) huntingtin clearance.

The Novartis neuroscience team was located primarily in Basel, Switzerland, with a few people in Cambridge, Mass. The distance and the difficulty getting things in a timely fashion made the collaboration challenging. Although we did not find any drugs that altered HD gene transcription, we did find drugs that altered the proteasome breakdown of huntingtin. We also advanced the field by coming up with a good assay for the huntingtin protein. We looked hard for drugs that could simply lower HTT expression, but we found none. The one drug we found that had worked in aggregation and had the potent IC50 was not taken up by Novartis. After four years, the contract was not renewed; shortly thereafter, Novartis closed its neuroscience division. We are still working on our drug, and Alex has a grant from NIH to try to develop it to the point of an IND. Our experience with Novartis was a good one and all the investigators have stayed friends. It taught us however about the vast difference between being an investigator in a drug company and being an investigator in academics.

American Neurological Association

The American Neurological Association (ANA) is the oldest neurological association in the country, and its members have always been chosen by a membership committee that scrutinizes the individual’s academic contributions and then the membership votes on the candidates. Typically, people were not admitted before they attained the academic rank of associate professor. The ANA is comprised exclusively of academic neurologists.

In 2001, two years after Jack’s death, I was elected president of the ANA— the second woman to have held that position. It was a great honor and the work was fun not onerous. I held the position for two years, and during that time we had a wonderful meeting in New York and another in San Francisco. During the time of my presidency, a mentoring program for neurologists and neurosurgeons was developed by joint efforts of the ANA and NINDS. This one-and-a-half-day program still takes place on the day before the official onset of the annual ANA meeting. We also began a discussion about opening up the membership to a broader and younger group of academic neurologists.

Society for Neuroscience

In 2003, I was elected president of the Society for Neuroscience (SfN). I should have had a year as president-elect, but Story Landis who was in line to be president had to bow out because of her position at NIH. I stepped directly into the position of president. At the time, the SfN had made a decision to build a building for their organization in Washington, D.C. During my watch, we had to design the building. We decided to go for the top designation of environmentally friendly architecture. We chose all the materials for the various spaces as well as the lighting to keep the spaces open and friendly. It was a fun project and the resultant building is extremely cost-effective.

I made neurodegenerative disease my theme for the meeting when I was president. I had a presidential symposium featuring lead researchers in four prominent neurodegenerative diseases: Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, and Lou Gehrig’s disease (ALS). I had short, five-minute videos made introducing the clinical aspects of disease for the audience of basic neuroscientists. Everybody at the meeting could then get a copy of the videos for their use in classes back at their institutions.

The added bonus to my year as president was that the Boston Red Sox were in the World Series that year and on one of the nights at the meeting in San Diego, the Red Sox played their final game. We had a big party up in the presidential suite and watched them win the championship!

Getting My Life Back Together

In 2005, I received an e-mail from Stetson Ames, a high school boyfriend who I had not seen in 35 years. I was busy and I did not answer back for a month. Once I did, we reconnected easily. It was as if no time had passed. I invited him out for a visit, and because he was retired from his career in law enforcement, he was able to come. His wife had passed away as well. We hit it off and soon got married. He had spent his summers near Boston as a child and so he liked the idea of moving there. He is completely different from Jack, so I do not spend any time comparing the two. Stets was completely comfortable with me as head of a department. Because he knew me from childhood, I could not expect any special treatment. On the other hand, because I am still working, he is very tolerant and takes good care of me.

My oldest daughter, Jessica, teaches science and math to seventh graders in Manhattan. She and her husband have a son who is now four. My other daughter, Ellen, finished an MD/PhD at Columbia University School of Medicine. She is now a resident in neurology in the Partners training program.

MassGeneral Institute for Neurodegenerative Diseases

Collaborations within MIND grew. As researchers were successful, though, their reputations grew and other institutions recruited them away. Bob Brown became the chair of neurology at the University of Massachusetts. David Standaert was recruited to run a new similar center at the University of Alabama. Jang-Ho Cha went to Merck. Although I always regretted losing a friend and colleague, I also encouraged my junior colleagues to interview at other institutions—they owed it to their own careers to know their value elsewhere.

Many people chose to stay, however, and I worked hard to get them the best possible situations within our institutions. I got two endowed chairs funded, which I gave to Rudy Tanzi and Brad Hyman. (I then obtained funding for five additional chairs for other key faculty members in various areas of the department.) Researchers continue to find MIND to be a most stimulating place and so it has continued to thrive. Now, after 12 years, we have drugs in animal trials or in human trials for each of the neurodegenerative diseases. Furthermore, several of the agents are being tried in more than one neurodegenerative disorder—supporting the initial notion that the similarities of these diseases might lead to common mechanisms of neurodegeneration and therefore common means of treatment.

My laboratory gradually decreased in size. This was partly because the many jobs I had taken on meant that I could not really keep up with the literature. I missed having Jack to bounce ideas off. My graduate student Lianna Orlando stayed on for a postdoctoral fellowship and for a junior faculty position, and we worked together on experiments that indicated an interaction of huntingtin with mGluR5 receptors. A postdoctoral fellow of David Standaert’s, Ippolita Cantuti-Castelvetri, joined the lab to work on Parkinson’s disease. She had found two very interesting results. First, gene expression changes in dopamine neurons are strikingly different between men and women, and second, women seem to process alpha-synuclein differently than men. Time will tell whether this holds up in future investigations. In work with Ann Graybiel in mice with l-DOPA-induced dyskinesias, we found that thyrotropin-releasing hormone (TRH) was massively increased in the striatum and in striatal output areas in relation to the degree of dyskinesia. This becomes a new and novel target for treating dyskinesias.

Stepping Down as Department Chair

In 2010, I notified the president of MGH, Peter Slavin, that I would like to step down as chair of neurology. I had made the mark I had wanted on my department and on my field. I left the department nearly at its peak. We were moving all our inpatients to a spectacular new building with three neurology floors including a new neuro-ICU that had its own PET scanner and magnetic resonance imaging (MRI) scanner. The department was bringing in more money than ever before, and our patient load and admissions were at an all-time high. I figured it would take a year to find my replacement and then I would have been chief for 20 years. As it was, it took two years and in May 2012, I gave up my position and my replacement, a wonderful woman from MGH, Merit Cudkowicz, took over. She was an internal candidate but by far the best. She had trained in our residency program and started the first MGH Neurology Clinical Trials Unit. She was the first woman in my department to spontaneously ask me for a raise. I was so proud of her at the time that I quickly gave her a hug.

Post-Chief Era

The first thing I did after I stepped down as chief was to rent a boat in the Galapagos and invite all my friends for a vacation of a lifetime. Chief of these was Nancy Wexler, who has been so important to me at every stage of my life.

Since May 2012, I have given up my lab because I think younger people need the space and resources more than I do and because I would have to take a sabbatical to learn the new techniques that have been developed before really setting up my lab for the future. I decided that I would be better off giving up the lab and spending time on mentoring others. I continue to see my patients who depend on me.

In 2010, my mother died at the age of 90. I inherited more money than I expected due to the lack of taxes that year. I decided to give $1 million as a charitable annuity to MGH. It was very amusing to write a check for one million and 00/100 dollars as a personal check. That gift made me the first chief to have made such a contribution to MGH. It also brought forward the need for philanthropy in these days of limited NIH resources. I decided to become a fundraiser for the department as one of my main goals since resigning as chief. I find the job fun and rewarding because I am fundraising not for myself but for others in the department. It is very fulfilling work.

Acknowledgments

I would like to thank NIH for all their support over the years. I have otherwise tried to credit people in the text for their meaningful interactions with me.

Index

Adelman, J., 173

Aglioti, S., 132–33

Agranoff, B., 44, 45, 47

Akert, K., 477–78

Akil, H., 1, 4, 5–8, 11–15, 17–27, 30–56

Albin, R., 567–68

Allfrey, V., 193, 216

Altman, J., 343

Alvarez-Buylla, A., 346–47, 471

Alves, S., 199–200

Alvord, E., 424

Ancona, N., 133, 92

Andrew, R., 240, 241, 242, 245–46

Anokhin, P. K., 461, 471

Anselmi, F., 404

Antonini, A., 124, 125

Arbib, M., 370

Arduini, A., 107

Ariely, D., 545

Arnold, A. P., 338, 340–41

Ascher, P., 67–93

Azmitia, E., 196

Baltimore, D., 381

Barbel, S., 169

Barchas, J. D., 34, 36–37, 39–40

Barnea, A., 351

Barron, D. H., 477

Baust, W., 108–9

Bentivoglio, M., 112

Benzer, S., 156–58, 158–60, 162

Berlucchi, G., 97–137

Bertero, M., 384

Beymer, D., 392

Biswal, B., 448

Bizzi, E., 397

Blochlinger, K., 174

Bloom, F., 34, 41, 42

Bodmer, R., 174

Bogen, J., 115

Borsellino, A., 367

Bottjer, S., 338

Bouvier, S., 547

Brakefield, X., 578

Bréchot, C., 89

Bregestovski, P., 81

Brenman, J., 179

Broadbent, D. E., 519–20

Bromberg, M., 564

Brooks, V., 467, 468, 483

Bronk, D., 469

Brown, B., 574, 580, 583

Brown, T. G., 445

Brunelli, R., 389, 391

Bruner, J., 526

Buchtel, H., 123, 124

Buelthoff, H., 388

Bueno, G., 498–99

Bulloch, K., 212

Burgen, A., 76

Burke, R., 481, 482–83, 484, 485, 487

Burrell, C. M., 300

Buser, P., 70–72

Busettini, C., 261, 262–66, 267

Bush, G., 261–62

Buskirk, D., 346

Cadieu, C., 402

Callahan, R., 16

Cameron, H. A., 198, 204

Cangiano, A., 133

Cantuti-Castelvetri, I., 583

Cardona, A., 487

Carli, G., 470

Carpenter, C., 425

Carpenter, D., 486

Casado, M., 85

Cha, J-H., 579–80, 583

Chaplin, E., 563

Chelazzi, L., 132

Cherry, C., 519, 527

Chong, S-C., 545

Cohen, J., 543

Collett, T., 241, 242, 246

Collewijn, H., 279

Corballis, M., 133

Corbetta, M., 132

Corteen, R. S., 521

Coryell, C. D., 453

Cox, J., 435

Cresse, I., 34

Crick, F., 379–80, 394–95, 531

Crick, W., 16

Cudkowicz, M., 576, 584

Cumming, B., 255, 263

D’Incamps, B. L., 88–89

Dambly-Chaudiere, C., 169, 170

Darlymple-Alford, E., 13

Dasparian, S., 342, 344

Dauth, G., 564

Dehaene, S., 523

Delbrück, M., 151–53, 154, 155–56, 368

DeLong, M., 247, 568

Dennis, M., 158–60

DeSchepper, B., 541

Desplan, C., 171

Deutch, T., 518

Deutsch, E., 464

Deutsch, J. A., 318

DeValois, K., 536

DeValois, R., 536

DeVoogd, T. J., 341

Dhabhar, F. S., 212

DiCarlo, J., 402

Dieudonné, S., 84, 85, 88

DiFiglia, M., 580

DiNardo, S., 171

Dreyfus, B., 536

Dumitriu, D., 202

Dutton, H., 476–77, 478, 485

Eberstadt, P., 464

Eccles, J., 112–13, 315, 370, 478, 479, 488–89

Echeverría, L., 497–98

Edelman, G., 369, 394

Edelman, S., 388

Eflij, D., 464

Eichling, J., 434

Eiland, L., 209–10

Ellison, J., 29

Emmanouil, T. A., 545

Engberg, I., 490

Enna, S., 562

Enríquez, M., 493

Eriksen, C. W., 524

Erlij, D., 464

Estes, W., 194

Evans, K., 544–45

Evarts, E., 246, 247–48, 249

Ezzat, T. G., 397

Fahle, M., 380, 388

Falck, B., 24, 29

Fee, M., 349

Ferster, D., 396–97

Filion, M., 568

Finkelstein, S., 563

Fisher, C. M., 563

FitzGibbon, E. J., 255, 268, 272–79

Flores, E., 491

Flores, J., 500

Foster, J. S., 308

Fox, P. T., 442–43

Fox, S. S., 18, 19

Frank, K., 481, 483

Fuller, J., 250–51

Fuortes, M., 370

Fuxe, K., 29

Galanter, E., 526

Galindo, J., 487

Ganong, F., 168

Gao, F-B., 179

Gazzaniga, M., 118–19

Gee, C., 51

Geiger, G., 370

Gerlach, J., 197, 203

Gerschenfeld, H. M., 72–74, 78

Ghysen, A., 160, 168, 170, 175

Gianaros, P. J., 211, 213

Giese, M. M., 397

Gilman, S., 563–64

Girosi, F., 387, 392–93

Glaser, D., 383, 388, 389, 390–91, 395

Glucksberg, S., 543

Glusman, S., 486

Goldberg, M., 255

Goldman, S., 342–44

Goldstein, A., 31, 42

Goldwater, D. S., 207

González, H., 488

Gopnik, A., 536

Gormican, S., 539

Gould, E., 198, 204

Grafstein, B., 195–96

Graybiel, A., 578, 583

Greenamyre, J. T., 566

Gregory, R., 517–18

Griffin, J., 562, 563

Grimson, E., 383

Gross, C., 543

Gruber, W. B., 179

Guillemin, R., 39

Gusella, J., 571, 574, 578

Guze, S., 432

Haberman, J., 546

Hafter, E., 536

Hagbarth, K. E., 472

Hamburg, D., 30, 34, 36

Hamburger, V., 344

Harris, C., 526

Harvey, J., 18, 19

Hassenstein, B., 368

Hayes, A., 542

Heartline, K., 469

Hebb, D. O., 307–8, 309, 310, 314–16, 319

Heimburger, L., 368–69

Herbert, E., 43

Herbert, S, 177

Hernández-Peón, R., 472

Heroles, R., 500

Heron, W., 110–12, 126

Heuser, J., 160

Hick, W. E., 518

Hikosaka, O., 255

Hildreth, E., 378, 384

Hilgard, E., 27

Hillyard, S. A., 523

Hochstein, S., 547, 549

Hodgkin, A., 69, 72, 74, 77

Hoffman, E., 436

Hökfelt, T., 29, 40

Hollingsworth, Z., 565, 573, 580

Horwitz, R., 574

Hounsfield, G., 434–35

Housman, D., 574, 581

Hubel, D. H., 320, 370

Hughes, J., 38

Hultborn, H., 493–93

Hung, C., 402

Hurlbert, A., 386, 388

Hutchinson, J. M., 389–91

Hyden, H., 193

Hyman, B., 578, 580, 583

Hyman, R., 126

Ingvar, D., 438

Inoue, Y., 269, 270–71

Ito, M., 248, 252

Iverson, L., 35

James, J. D., 524

Jan, L., 146–83

Jan, Y-N., 145, 147–83

Jankowska, E., 488–89, 490

Jarvis, E. D., 340

Jerne, N., 368

Jiménez, I., 488, 489

Jobs, S., 381

Johnson, J. W., 81–83

Johnson, M., 543

Johnson-Laird, P., 543

Jones, G. M., 248

Judge, S. J., 254

Julesz, B., 370, 526

Julius, D., 180–81

Kahneman, D., 533–36, 542–43

Kasparian, S., 342, 344

Kastner, S., 543

Kawano, K., 255–59, 269

Kazantsev, A., 581

Kehoe, J., 73, 74, 75, 76, 87, 88, 90

Kelley, D. B., 336

Kessler, B., 387

Kety, S., 417, 427

Khachaturian, H., 41, 49

Kinsbourne, M., 130

Kim, A., 181

Kimmig, H., 259

Kirn, J., 349–50

Knoblich, U., 402

Koch, C., 382, 384, 388

Kodaka, Y., 274

Köhler, W., 319

Konishi, M., 332, 333, 339, 345, 348, 354

Kornberg, T., 170

Kosinski, C., 574

Kosterlitz, H., 26–27

Kouh, M., 402

Krasne, F., 19–20

Krauzlis, R. J., 262

Kreiman, G., 402

Krevans, J., 425

Kubo, Y., 176–77

Kuffler, S. W., 162, 163–64, 183

Kuhn, T., 123, 388, 445

Kuno, M., 475–76

Kunze, D., 78

Kupper, J., 84

Kutt, H., 426

Lampl, I., 397

Land, E., 386

Landwehrmeyer, B., 574

Lansdell, H., 309

Lashley, K., 113, 321, 336

Lasley, B. L., 195, 209

Lassen, N. A, 438

Lauterbur, P., 443

Lavie, N., 521–22

Lee, D., 256

Lee, S. W., 376

Lee, T. D., 149, 150, 173–74

Leibo, J., 404

Leonard, C., 335, 340

Leonard, R. B, 488

Lepore, F., 124, 125

Lewis, M. E., 52–53

Lewis, S., 426

Li, C. H., 38–39, 40, 42

Li, F., 544

Librande, S., 389, 397

Liebeskind, J. C., 19, 20–22, 23, 24, 31

Lisberger, S. G., 252, 253–54

Liu, W-C., 339–40

Llinás, R., 478, 479–80

Lo, A., 390

Logan, B., 379

Logothetis, N., 388, 390, 396

Lothman, E. W., 490

Luo, L., 179

Luthi-Carter, R., 579

MacDonald, M., 574, 578

Macintosh, H., 313

MacPherson, L., 472

Madrid, J., 485

Madsen, P. L., 449

Magarinos, A. M., 203–4, 206

Magistretti, P., 449

Mahfuz, B., 574

Malliani, A., 470

Manjarrez, E., 495

Marchiafava, P. L., 104, 121

Margoliash, D., 345, 348

Marler, P., 194, 330–31, 332

Marr, D., 369–70, 372–75, 377–80

Marroquin, J., 385

Martin, J., 572, 574

Marty, A., 79–80, 87, 88

Marzi, C. A., 123, 128, 129, 133, 136–37

Mascetti, G., 124

Masson, G. S., 264–66, 267, 271

Matthews, B. H. C., 477

Matthysse, S., 34

Maxwell, D. J., 489

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