In Search of Memory: The Emergence of a New Science of Mind (20 page)

9–3 The brain of
Aplysia
is very simple
. It has 20,000 neurons grouped into nine separate clusters, or ganglia. Since each ganglion has a small number of cells, researchers can isolate simple behaviors that are controlled by it. They can then study changes in particular cells as a behavior is altered by learning.

Arvanitaki-Chalazonitis had found that a few nerve cells in
Aplysia
are uniquely identifiable—that is, the same cells can easily be recognized by sight under the microscope in every single snail. In time I realized that the same thing is true of most other cells in its nervous system, heightening the prospect of mapping the entire neural circuitry controlling a behavior. As it turned out, the circuitry controlling
Aplysia
’s most elementary reflexes was quite simple. Moreover, I later found that stimulating a single neuron often produced a large synaptic potential in its target cells, a clear sign and measure of the strength of the synaptic connection between the two cells. These large synaptic potentials made it possible to map neural connections cell by cell and eventually enabled me to work out for the first time the precise wiring diagram of a behavior.

Many years later, Chip Quinn, one of the first scientists to conduct genetic studies of learning in the fruit fly, noted that the ideal experimental animal for biological studies of learning must have “no more than three genes, be able to play the cello or at least recite classical Greek, and learn these tasks with a nervous system containing only ten large, differently colored and therefore easily recognizable neurons.” I have often thought that
Aplysia
meets these criteria to a surprising degree.

At the time I decided to work on
Aplysia
, I had never dissected the snail or recorded the electrical activity of its neurons. Moreover, no one in the United States was working on
Aplysia
. The only two people in the world who were studying it in 1959 were Tauc and Arvanitaki-Chalazonitis. Both of them were in France, Tauc in Paris and Arvanitaki-Chalazonitis in Marseilles. Denise, ever the Parisian chauvinist, thought Paris the better choice. Living in Marseilles, she said, would be like living in Albany instead of New York City. So the decision was for Tauc. Before leaving NIH in May 1960, I visited Tauc and we arranged that I would join him in September 1962, as soon as I had completed my residency in psychiatry at Harvard Medical School.

AS I LEFT NIH IN JUNE 1960, I FELT A DEEP SADNESS, SOMEWHAT
similar to that which I experienced when I graduated from Erasmus Hall High School. I had come as a novice, and I left as a limited but nonetheless working scientist. At NIH I had walked the walk. I found that I liked it and that I was quite successful at what I tried. But I was genuinely surprised by my success. For a long time I felt that it was due to pure chance, my good fortune, my enjoyable and productive collaboration with Alden, the generous psychological support of Wade Marshall, and the youth-oriented scientific culture of NIH. I had had a number of ideas that proved to be useful, but I thought they were beginner’s luck. I was very much afraid that I would run out of ideas and would not last in science.

This insecurity about my ability to come up with new ideas was not helped by the fact that John Eccles and several other senior scientists whom I respected thought I was making a grave error in switching from a highly promising start in the mammalian hippocampus to a new beginning with an invertebrate whose behavior had not been well studied. But three factors drove me onward. First, there was the Kuffler-Grundfest principle of biological research: for every biological problem there is a suitable organism in which to study it. Second, I was now a cell biologist. I wanted to think about how cells functioned during learning, and I wanted to spend my time reading, thinking, and discussing ideas with others. I did not want to spend hours simply setting up an experiment time and again as Alden and I had done on the hippocampus, only to find an occasional good cell to study. I liked the idea of big cells and, despite the risks involved, I was convinced that
Aplysia
was the right system and that I had the tools to study behavior in this snail effectively.

Finally, I had learned something in marrying Denise. I had been reluctant and fearful of marriage, even to Denise, whom I loved much more than any other woman I had ever thought of marrying. But Denise was confident that our marriage would work, so I took a leap of faith and went ahead. I learned from that experience that there are many situations in which one cannot decide on the basis of cold facts alone—because facts are often insufficient. One ultimately has to trust one’s unconscious, one’s instincts, one’s creative urge. I did this again in choosing
Aplysia
.

A
fter visiting Ladislav Tauc briefly in Paris, Denise and I went to Vienna in May 1960 so I could show her the city where I was born. This was the first time I had returned since I left in April 1939. We walked around the beautiful Ringstrasse, the major boulevard where many of the most important public buildings of the city—the opera house, the university, the parliament—are located. We enjoyed our visit to the Kunsthistorisches Museum, a richly baroque building with its beautiful marble staircase and a superb art collection first put together by the Habsburg royal family. One of the high points of this great museum is a room containing Pieter Bruegel the Elder’s paintings of the seasons of the year. We visited the Oberes Belvedere and enjoyed the world’s best collection of the Austrian expressionists—Klimt, Kokoschka, and Schiele, the three modern painters whose images are indelibly impressed in the minds of most Viennese art lovers of my generation.

Most important, we went to the apartment in Severingasse 8 where my family and I had lived. We found it occupied by a young woman and her husband. She allowed us to enter and look around. Despite the fact that legally the apartment still belonged to my family, since we had never sold it, I felt awkward imposing on this nice person. We stayed only a short time, but it was long enough for me to be surprised at how tiny the apartment was. I remembered the space as being rather small—the living room and dining room in which I had steered my shiny blue remote-controlled car on my ninth birthday all those years ago—but I was astonished at how small it was in reality a common trick of memory distortion. We then walked to Schulgasse to visit my elementary school, only to find that it had been replaced by a government agency. The walk, which I remembered from my school days as being a bit of a hike, took us all of five minutes. It was a similarly short walk to Kutschkergasse, where my father’s store had been.

Denise and I were standing across the street from the store and I was pointing it out to her when an older man I did not know came up and said, “You must be Hermann Kandel’s son!”

I was dumbfounded. I asked him how he could possibly have inferred that, since my father had never returned to Vienna and I had left it as a child. He identified himself as living three buildings away and then said simply, “You look so much like him.” Neither he nor I had the courage to discuss the intervening years—and in retrospect I am sorry not to have done so.

I was quite moved by the visit. Denise was interested, but she later told me that were it not for my deep and continuing fascination with Vienna, she would have found the city boring compared with Paris. Her comment reminded me of an evening early in our friendship, when Denise first invited me to her mother’s house for dinner. Joining us that evening was Denise’s imposing Aunt Sonia, a large, intellectually powerful, and slightly arrogant woman who worked for the United Nations and who had been secretary of the Socialist party in France prior to World War II.

As we sat down for a drink before dinner, she turned to me inquisitorially and asked in her strong French accent, “Where do you come from?”

“Vienna,” I replied.

Without changing her overall condescending expression, she forced a small smile and said, “That’s nice. We used to call that little Paris.”

Many years later my friend Richard Axel, who introduced me to molecular biology, was preparing for his first trip to Vienna. Before I could prime him on its virtues, one of his other friends passed on to Axel his pronouncement about Vienna: “It’s the Philadelphia of Europe.”

It is clear to me that neither of these people really understood Vienna—its lost grandeur, its enduring beauty, or its present-day complacency and latent anti-Semitism.

UPON RETURNING FROM VIENNA, I BEGAN MY RESIDENCY
training in psychiatry at the Massachusetts Mental Health Center of Harvard Medical School. I had actually committed to starting it a year earlier, but because work on the hippocampus was moving along so well, I had written to Jack Ewalt, director of the mental health center and professor of psychiatry at Harvard Medical School, asking if it were possible to have a one-year extension. He replied immediately that I should stay as long as necessary. That third year at NIH proved crucial, not only for my collaborative work with Alden, but also for my maturation as a scientist.

With this beginning in mind and a subsequent exchange of cordial letters, I visited Ewalt upon my arrival. I asked him if it might be possible to have some space and modest resources to set up a laboratory. Suddenly, the atmosphere was transformed. It was as if I were having a conversation with a completely different person. He looked at me and then pointed to the pile of résumés of the twenty-two other residents who were about to begin their training and bellowed, “Who do you think you are? What makes you think that you are better than any one of these?”

I was completely taken aback by the content of his remarks and even more by the tone. In all my years as an undergraduate at Harvard and a medical student at NYU, none of my professors had ever talked to me like that. I assured him that while I had no illusions about my clinical skills compared with those of my peers, I did have three years of research experience that I did not want to lie dormant. Ewalt told me to go to the wards and take care of patients.

I left his office confused and depressed, and I briefly entertained the idea of switching to the Boston Veterans Administration Hospital residency training program. Jerry Lettvin, a neurobiologist and friend to whom I described the conversation with Ewalt, urged me to take the position at the Veterans Administration, stating, “Working at the Massachusetts Mental Health Center is like swimming in a whirlpool. It’s impossible to change things or to make progress.” Nevertheless, because of the excellent reputation of its residency program, I decided to swallow my pride and stay.

It proved a wise decision. A few days later, I went across the street to the medical school and discussed my situation with Elwood Henneman, a professor of physiology. He offered me space in his laboratory. Within several weeks, Ewalt approached me and said that he gathered from his colleagues at the medical school, referring to Henneman and Stephen Kuffler, that I was a good person to invest in. “What do you need?” he said, “How can I help you?” He then made available all the resources necessary to continue my research in Henneman’s laboratory throughout the two years of residency training.

The residency training turned out to be at once stimulating and a bit disappointing. My fellow residents were a gifted group who remained my friends over the years. Many of them went on to have major careers in academic psychiatry. The group included Judy Livant Rappaport, who became a leading researcher in the mental disorders of children; Paul Wender, who pioneered the modern era of genetic studies of schizophrenia; Joseph Schildkraut, who developed the first biological model of depression; George Valliant, who helped outline some of the factors predisposing people to physical and mental illness; Alan Hobson and Ernst Hartmann, important contributors to the study of sleep; and Tony Kris (Anna’s brother), a leading psychoanalyst who wrote an influential book on the nature of free association.

The clinical supervision was outstanding, if somewhat narrow in scope. In the first year we treated patients who were sufficiently ill to require hospitalization, some of whom were suffering from schizophrenia. We saw only a limited number of patients, and we had the rare opportunity to work with those very ill patients intensively in psychotherapy, seeing them for one-hour sessions two or even three times a week. Although we did not really improve their mental functioning, we learned a great deal about schizophrenia and depressive illnesses by simply listening to them. Elvin Semrad, the head of clinical services, and most of our supervisors were heavily oriented toward psychoanalytic theory and practice. Few of them thought in biological terms, few were familiar with psychopharmacology, and most discouraged us from reading the psychiatric or even the psychoanalytic literature because they thought we should learn from our patients and not from our books. “Listen to the patient, not the literature” was the prevailing pedagogical motto.

To a degree they had a point. Our patients taught us a great deal about the clinical and dynamic aspects of severe mental illness. We learned, above all, to listen very carefully and intelligently to what the patients told us about themselves and their lives. Most important, we learned to respect patients as individuals with distinctive assets and distinctive problems.

But we learned next to nothing about the fundamentals of diagnosis or the biological underpinnings of psychiatric disorders. We received only a rudimentary introduction to the use of drugs in the treatment of mental illness. In fact, we often were discouraged from using drugs in treatment because Semrad and our supervisors feared it would interfere with psychotherapy.

In response to this weakness in the program, the other residents and I organized a discussion group on descriptive psychiatry that met monthly at the house Kris and Hartmann shared. We took turns presenting original essays prepared for the occasion. I presented a paper on a group of acute mental disorders called the amentias, which follow head trauma and chemical intoxication. In some of these disorders, such as acute alcoholic hallucinosis, patients suffer from a psychosis that resembles schizophrenia but is completely reversible as the alcohol wears off. My point was that a psychotic reaction is not unique to schizophrenia but can be an end point for a number of disorders.

Prior to our arrival, the mental health center had almost never invited outside speakers to address the residents or the faculty. This was a reflection of the vaunted self-confidence of Harvard and Boston at large, which is best represented by the canard of the Boston matron who, when asked about her travels, responded, “Why should I travel? I’m already here.”

Kris, Schildkraut, and I initiated academic grand rounds, conferences that brought together all of the researchers and physicians of the hospital as well as important people from other institutions. While at NIH, I had been spellbound by a lecture in which Seymour Kety, the former intramural director at the National Institute of Mental Health and the person who had recruited Wade Marshall, reviewed the contributions of genes to schizophrenia. I thought we might kick off our lecture series with that topic. But in 1961 I could not find a single psychiatrist in all of Boston who knew anything about genetics and mental illness. Somehow, I learned that Ernst Mayr, the great evolutionary biologist at Harvard, had been a friend of the late Franz Kallman, a pioneer in the genetics of schizophrenia. Mayr generously agreed to come and give us two splendid lectures on the genetics of mental illness.

I had entered medical school convinced that psychoanalysis had a promising future. Now, with my NIH experience behind me, I found myself questioning my decision to become a psychoanalyst. I also missed being in the laboratory. I yearned for new data and was eager to have findings to discuss with other scientists. But most of all I questioned the usefulness of psychoanalysis in the treatment of schizophrenia, an area that even Freud was not optimistic about.

In those days, residents did not work very hard: from 8:30
A.M
. to 5:00
P.M
., with only a rare shift on evenings or weekends. As a result, I was able to follow up on an idea first suggested to me by Felix Strumwasser, namely, that I study hypothalamic neuroendocrine cells. These are atypical and fairly rare cells in the brain. They look like neurons, but instead of signaling other cells directly through synaptic connections, they release hormones into the bloodstream. Neuroendocrine cells were particularly interesting to me because some research hinted that the neuroendocrine cells of the hypothalamus are disturbed in major depressive illnesses. I had learned that goldfish have very large neuroendocrine cells, and during my spare time I carried out a somewhat original series of experiments showing that those cells generate action potentials and receive synaptic signals from other nerve cells, just as ordinary neurons do. Denise helped me set up the tank for the goldfish, and she made me a nice net for catching them from a dishrag and a wire hanger.

My studies provided direct evidence that neuroendocrine cells that release hormones are in fact both fully functioning endocrine cells and fully functioning nerve cells. They have all the complex signaling capability of nerve cells. The studies were well received because they showed something new. More important for me, I had done them completely on my own in a back room in Henneman’s laboratory, working at odd hours when other people were not usually there. After completing these studies, I began to feel more assured about my competence. But moving from the hippocampus to a project on neuroendocrine cells was not wildly original for me. I applied much of the same thinking here as I had at NIMH. How long would this limited burst of creativity last? I wondered, as I continued to worry that I would soon run out of ideas.

That was the least of my worries, however. Shortly after our son, Paul, was born, in March 1961, Denise and I had a serious crisis, by far the most serious of our life together. I thought we had an unusually harmonious relationship. She had strongly supported me as I was struggling to define my career, and she was working as a postdoctoral fellow at the Massachusetts Mental Health Center in a program designed to train research sociologists in issues related to mental health. We saw each other in passing during the day as well as at night.

But one Sunday afternoon she showed up as I was working in the lab and simply exploded on me. Carrying Paul in her arms, she screamed, “You can’t go on like this! You are only thinking of yourself and your work! You are just ignoring the two of us!”

I was startled and deeply hurt. I was so transfixed by my science, both enjoying it and also worrying about it when experiments failed, as they often did, that it never dawned on me that I was neglecting or in any way devaluing Denise and Paul or withdrawing my love from them. I was upset and angry about being confronted so harshly and so suddenly. I sulked, pouted, and took days to recover. Only gradually did I come to realize what my actions must have seemed like from Denise’s point of view. In response, I decided to spend more time at home with her and Paul.