Wednesday, March 01, 2006

In Search of Memory

The Emergence of a New Science of Mind

By: Eric R. KandelM.D.

Neuroscientist Eric Kandel’s new memoir covers more than six decades, beginning with his experiences as a nine-year-old child in Nazi-occupied Vienna. He considers those powerful memories the touchstone for a lifetime studying the processes in the brain that enable us to remember. Kandel first planned to become an intellectual historian, but, in college in the United States, became interested in science and trained in psychoanalysis. While in medical school, he encountered the revolution in biological science that began with the discovery of the structure of DNA, and he soon realized that the cells and molecules of the human brain were the key to understanding learning and memory. His retelling of those choices, the colleagues he sought out, and the stream of groundbreaking research that followed add up to what Booklist, the journal of the American Library Association, calls “an autobiography of exceptional substance.” Woven into this compelling tale of scientific discovery are delightful portraits of his family life, his passion for art and music, and his views on world affairs. In Search of Memory is the self-portrait of one of our time’s most important thinkers. In the final chapter of the book, excerpted here, Kandel reflects on the new biology of mind and the connections between modern neuroscience and his early interest in psychiatry. He also ponders some of the questions he might choose to study if he were now a young scientist just beginning his career.

Excerpted from In Search of Memory: The Emergence of a New Science of Mind by Eric R. Kandel, M.D. © 2006 Eric. R. Kandel. Published by W.W. Norton & Company, Inc. Rerinted with permission. This selection may not be reproduced, stored in a retrieval system, or transmitted in any form by any means without the prior written permission of the publisher. 

LEARNING FROM MEMORY: PROSPECTS

exc_0603kandel_1After fifty years of teaching and research, I continue to find that doing science at a university—in my case, Columbia University— .is unendingly interesting. I derive great joy from thinking about how memory works, developing specific ideas about how it persists, shaping those ideas through discussions with students and colleagues, and then seeing how they are corrected as the experiments play out. I continue to explore the science in which I work almost like a child, with a naïve joy, curiosity, and amazement. I feel particularly privileged to be working in the biology of mind, an area that—unlike my first love, psychoanalysis—has grown magnificently in the last fifty years. 

In reviewing those years, I am impressed with how little there was initially to suggest that biology would become the passion of my professional life. Had I not been exposed in Harry Grundfest’s laboratory to the excitement of actually doing research, of carrying out experiments to discover something new, I would have ended up with a very different career and, I presume, a very different life. In the first two years of medical school I took the required basic science courses, but until I had actually done research, I saw my scientific education as a prerequisite for doing what I really cared about—practicing medicine, taking care of patients, understanding their illnesses, and preparing to become a psychoanalyst. I was astonished to discover that working in the laboratory —doing science in collaboration with interesting and creative people— is dramatically different from taking courses and reading about science. 

Indeed, I find the process of doing science, of exploring biological mysteries on a day-to-day basis, deeply rewarding, not only intellectually but also emotionally and socially. Doing experiments gives me the thrill of discovering anew the wonders of the world. Moreover, science is done in an intense and endlessly engrossing social context. The life of a biological scientist in the United States is a life of discussion and debate—it is the Talmudic tradition writ large. But rather than annotate a religious text, we annotate texts written by evolutionary processes working over hundreds of millions of years. Few other human endeavors engender as great a feeling of camaraderie with colleagues young and old, students and mentors alike, as making an interesting discovery together. 

The life of a biological scientist in the United States is a life of discussion and debate—it is the Talmudic tradition writ large. But rather than annotate a religious text, we annotate texts written by evolutionary processes working over hundreds of millions of years. 

The egalitarian social structure of American science encourages this camaraderie. Collaboration in a modern biology laboratory is dynamic, extending not only from the top down but also, importantly, from the bottom up. Life at an American university bridges gaps in both age and status in ways that I have always found inspiring. François Jacob, the French molecular geneticist whose work so influenced my thinking, told me that what impressed him most about the United States on his first visit was the fact that graduate students called Arthur Kornberg, a world-famous DNA biochemist, by his first name. That was no surprise to me. Grundfest and Purpura and Kuffler always treated me and all their students as equals. Yet this would not—could not—have taken place in the Austria, the Germany, the France, or perhaps even the England of 1955. In the United States, young people speak up and are listened to if they have interesting things to say. Therefore, I have learned not only from my mentors, but also from my daily interaction with an extraordinary group of graduate students and postdoctoral fellows.

In thinking about the students and postdoctoral fellows with whom I have collaborated in my laboratory, I am reminded of the painting workshop of the Renaissance artist Andrea del Verrocchio. In the period from 1470 to 1475, his workshop was filled with a succession of gifted young artists, including Leonardo da Vinci, who studied there and, while doing so, made major contributions to the canvases that Verrocchio painted. To this day, people point to Verrocchio’s Baptism of Christ, which hangs in the Uffizi Gallery, in Florence, and say, “That beautiful kneeling angel on the left was painted in 1472 by Leonardo.” Similarly, when I give talks and project giant drawings of Aplysia neurons and their synapses onto an auditorium screen, I tell my audience, “This new culture system was developed by Kelsey Martin, this CREB activator and repressor were found by Dusan Bartsch, and these wonderful prion-like molecules at the synapse were discovered by Kausik Si!”

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At its best, the scientific community is infused with a marvelous sense of collegiality and common purpose, not only in the United States but throughout the world. As pleased as I am about what my colleagues and I have been able to contribute to the emerging picture of memory storage in the brain, I am even more proud to be part of the accomplishments of the international community of scientists that has given rise to a new science of mind. 

As pleased as I am about what my colleagues and I have been able to contribute to the emerging picture of memory storage in the brain, I am even more proud to be part of the accomplishments of the international community of scientists that has given rise to a new science of mind.

Within the span of my career the biological community has advanced almost unerringly from understanding the molecular nature of the gene and the genetic code to reading the code of the entire human genome and unraveling the genetic basis of many human diseases. We now stand at the threshold of understanding many aspects of mental functioning, including mental disorders, and perhaps someday even the biological basis of consciousness. The total accomplishment— the synthesis that has occurred within the biological sciences in the last fifty years—is phenomenal. It has brought biology, once a descriptive science, to a level of rigor, mechanistic understanding, and scientific excitement comparable to that of physics and chemistry. At the time I entered medical school, most physicists and chemists regarded biology as a “soft science”; today, physicists and chemists are flocking into biological fields, along with computer scientists, mathematicians, and engineers. 

Let me give an example of this synthesis in the biological sciences. Soon after I began to use cell biology to link neurons to brain function and behavior in Aplysia, Sydney Brenner and Seymour Benzer began to look for genetic approaches to link neurons to brain function and behavior in two other simple animals. Brenner studied the behavior of the tiny worm C. elegans, which has only 302 cells in its central nerve cord. Benzer studied the behavior of the fruit fly, Drosophila. Each experimental system has distinct advantages and drawbacks. Aplysia has large, easily accessible nerve cells, but it is not optimal for traditional genetics; C. elegans and Drosophila are highly suitable for genetic experiments, but their nerve cells are small and not well suited to studies of cell biology.

The molecular conservation that has so powerfully characterized the biology of genes and proteins is now being seen in the biology of cells, neural circuits, behavior, and learning. 

For twenty years these experimental systems developed within different traditions and along largely separate lines. The parallels inherent in them were not apparent. But the power of modern biology has drawn them progressively closer. In Aplysia, first with recombinant DNA techniques and now with a nearly complete map of the DNA in its genome, we have the power to transfer and manipulate genes in individual cells. In a complementary way, new advances in cell biology and the introduction of more sophisticated behavioral analyses make possible cellular approaches to the behavior of the fruit fly and the worm. As a result, the molecular conservation that has so powerfully characterized the biology of genes and proteins is now being seen in the biology of cells, neural circuits, behavior, and learning.

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Although deeply satisfying, a career in science is by no means easy. I have experienced many moments of intense pleasure along the way, and the day-to-day activity is wonderfully invigorating intellectually. But the fun of doing science is to explore domains of knowledge that are relatively unknown. Like anyone who ventures into the unknown, I have at times felt alone, uncertain, without a well-trodden path to follow. Every time I embarked on a new course, there were well-meaning people, both social friends and scientific colleagues, who advised against it. I had to learn early on to be comfortable with insecurity and to trust my own judgment on key issues. My experience is hardly unique. Most scientists who have tried to pursue even slightly new directions in their research, with all the difficulty and frustration these paths entail, tell similar stories of cautionary advice urging them not to take risks. For most of us, however, cautions against going forward only kindle the spirit of adventure.

The most difficult career decision of my life was to leave the potential security of a practice in psychiatry for the uncertainty of research.

The most difficult career decision of my life was to leave the potential security of a practice in psychiatry for the uncertainty of research. Despite the fact that I was a well-trained psychiatrist and enjoyed working with patients, I decided in 1965, with Denise’s encouragement to devote myself to full-time research. In an upbeat frame of mind, having put this decision behind us, Denise and I took a brief holiday. We accepted an invitation from my good  friend Henry Nunberg to spend a few days at his parents’ summer home in Yorktown Heights, New York. Henry was then pursuing a residency in psychiatry at my hospital, the Massachusetts Mental Health Center. Denise and I knew his parents moderately well. 

Henry’s father, Herman Nunberg, was an outstanding psychoanalyst and an influential teacher whose textbook I much admired for its clarity. He had a broad, albeit dogmatic interest in many aspects of psychiatry. At our first dinner together, I enthusiastically outlined my new career plans of learning in Aplysia. Herman Nunberg looked at me in amazement and muttered, “It sounds to me as if your psychoanalysis was not fully successful; you seem never really to have quite resolved your transference.”

I found that comment both humorous and irrelevant—and typical of many American psychoanalysts of the 1960s, who simply could not understand that an interest in brain research need not imply a rejection of psychoanalysis. If Herman Nunberg were alive today, it is almost inconceivable that he would pass the same judgment on a psychoanalysis-oriented psychiatrist who moved into brain science. 

This theme recurred periodically throughout the first twenty years of my career. In 1986, when Morton Reiser retired as chairman of the department of psychiatry at Yale University, he invited several colleagues, including me, to give a talk at a symposium held in his honor. 

One of the invitees was Reiser’s close associate Marshall Edelson, a well-known professor of psychiatry and director of education and medical studies for the department of psychiatry at Yale. In his lecture, Edelson argued that efforts to connect psychoanalytic theory to a neurobiological foundation, or to try to develop ideas about how different mental processes are mediated by different systems in the brain, were an expression of a deep logical confusion. Mind and body must be dealt with separately, he continued. We cannot seek causal connections between them. Scientists will eventually conclude, he argued, that the distinction between mind and body is not a temporary methodological stumbling block stemming from the inadequacy of our current ways of thought, but rather an absolute, logical, and conceptual barrier that no future developments can ever overcome. 

When my turn came, I gave a paper on learning and memory in the snail. I pointed out that all mental processes, from the most prosaic to the most sublime, emanate from the brain. Moreover, all mental illness, regardless of symptoms, must be associated with distinctive alterations in the brain. Edelson rose during the discussion and said that, while he agreed that psychotic illnesses were disorders of brain function, the disorders that Freud described and that are seen in practice by psychoanalysts, such as obsessive-compulsive neurosis and anxiety states, could not be explained on the basis of brain function. Edelson’s views and Herman Nunberg’s more personal judgment are idiosyncratic extremes, but they are representative of the thinking of a surprisingly large number of psychoanalysts not so many years ago. The insularity of such views, particularly the unwillingness to think about psychoanalysis in the broader context of neural science, hindered the growth of psychoanalysis during biology’s recent golden age. In retrospect, it was probably not that Nunberg, or perhaps even Edelson, really thought that mind and brain were separate; it was rather that they did not know how to join them.

Since the 1980s the way in which mind and brain should be joined has become clearer. Consequently, psychiatry has taken on a new role. It has become a stimulus to modern biological thought as well as a beneficiary of it. In the last few years I have seen significant interest in the biology of mind within the psychoanalytic community. We now understand that every mental state is a brain state and every mental disorder is a disorder of brain function. Treatments work by altering the structure and function of the brain.

In the last few years I have seen significant interest in the biology of mind within the psychoanalytic community. We now understand that every mental state is a brain state and every mental disorder is a disorder of brain function.

I encountered a different type of negative reaction when I turned from studying the hippocampus in the mammalian brain to studying simple forms of learning in the sea snail. There was a strong sense at the time among scientists working on the mammalian brain that it was radically different from the brain of lower vertebrates like fish and frogs and incomparably more complex than that of invertebrates. The fact that Hodgkin, Huxley, and Katz had provided a basis for studying the nervous system by studying the giant axon of the squid and the nerve-muscle synapse of the frog was seen by these mammalian chauvinists as an exception. Of course all nerve cells are similar, they conceded, but neural circuitry and behavior are very different in vertebrates and invertebrates. This schism persisted until molecular biology began to reveal the amazing conservation of genes and proteins throughout evolution. 

Finally, there were continued disputes about whether any of the cellular or molecular mechanisms of learning and memory revealed by studies of simple animals were likely to be generalizable to more complex animals. In particular, there were arguments about whether sensitization and habituation are useful forms of memory to study. The ethologists, who study behavior in animals in their natural environments, emphasized the importance and generality of these two simple forms of memory. But the behaviorists emphasized primarily associative forms of learning, such as classical and operant conditioning, which are clearly more complex. The disputes were eventually resolved in two ways. First, Benzer proved that cyclic AMP, which we had found to be important for short-term sensitization in Aplysia, was also required for a more complex form of learning in a more complex animal–namely, classical conditioning in Drosophila. Second, and even more dramatic, the regulatory protein CREB, first identified in Aplysia, was found to be an important component in the switch from short- to long-term memory in many forms of learning in various types of organisms, from snails to flies to mice to people. It also became clear that learning and memory, as well as synaptic and neuronal plasticity, represent a family of processes that share a common logic and some key components but vary in the details of their molecular mechanisms.

It became clear that learning and memory, as well as synaptic and neuronal plasticity, represent a family of processes that share a common logic and some key components but vary in the details of their molecular mechanisms. 

In most cases, by the time the dust had settled, these disputations proved beneficial for science: they sharpened the question and moved the science along. That was the important thing for me, the sense that we were moving in the right direction.

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Where is the new science of mind heading in the years ahead? In the study of memory storage, we are now at the foothills of a great mountain range. We have some understanding of the cellular and molecular mechanisms of memory storage, but we need to move from these mechanisms to the systems properties of memory: What neural circuits are important for various types of memory? How are internal representations of a face, a scene, a melody, or an experience encoded in the brain? 

To cross the threshold from where we are to where we want to be, major conceptual shifts must take place in how we study the brain. One such shift will be from studying elementary processes—single proteins, single genes, and single cells—to studying systems properties—mechanisms made up of many proteins, complex systems of nerve cells, the functioning of whole organisms, and the interaction of groups of organisms. Cellular and molecular approaches will certainly continue to yield important information in the future, but they cannot by themselves unravel the secrets of internal representations in neural circuits or the interactions of circuits—the key steps linking cellular and molecular neuroscience to cognitive neuroscience. 

To study how we perceive and recall complex experiences, we will need to determine how neural networks are organized and how attention and conscious awareness regulate and reconfigure the actions of the neurons in those networks

To develop an approach that can relate neural systems to complex cognitive functions, we will have to move to the level of the neural circuit, and we will have to determine how patterns of activity in different neural circuits are brought together into a coherent representation. To study how we perceive and recall complex experiences, we will need to determine how neural networks are organized and how attention and conscious awareness regulate and reconfigure the actions of the neurons in those networks. Biology will therefore have to focus more on nonhuman primates and on human beings as the model systems of choice. For this, we will need imaging techniques that can resolve the activity of individual neurons and of neuronal networks.

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These considerations have caused me to wonder what questions I would take on were I to start anew. I have two requirements of a scientific problem. The first is that it allow me to open a new area that will occupy me for a very long time. I like long-term commitments, not brief romances. Second, I enjoy tackling problems at the border of two or more disciplines. With those predilections in mind, I have found three questions that appeal to me. 

First, I would like to understand how the unconscious processing of sensory information occurs and how conscious attention guides the mechanisms in the brain that stabilize memory. Only then can we address in biologically meaningful terms the theories about conscious and unconscious conflicts and memory first proposed by Freud in 1900. I am much taken by Crick and Koch’s argument that selective attention is not only essential in its own right but also one of the royal roads to consciousness. I would like to develop a reductionist approach to the problem of attention by focusing on how place cells in the hippocampus create an enduring spatial map only when an organism is paying attention to its surroundings. What is the nature of this spotlight of attention? How does it enable the initial encoding of the memory throughout the neural circuitry that is involved in spatial memory? What other modulatory systems in the brain besides dopamine are recruited when an animal pays attention, and how are they recruited? Do they use a prion-like mechanism to stabilize place cells and long-term memory? It obviously would be good to extend such studies to people. How does attention allow me to embark on my mental time travel to our little apartment in Vienna? 

From this perspective, most of our mental life is unconscious; it becomes conscious only as words and images. 

A second, related issue that fascinates me is the relation of unconscious to conscious mental processing in people. The idea that we are unaware of much of our mental life, first developed by Hermann Helmholtz, is central to psychoanalysis. Freud has added the interesting idea that although we are not aware of most instances of mental processing, we can gain conscious access to many of them by paying attention. From this perspective, to which most neural scientists now subscribe, most of our mental life is unconscious; it becomes conscious only as words and images. Brain imaging could be used to connect psychoanalysis to brain anatomy and to neural function by determining how these unconscious processes are altered in disease states and how they might be reconfigured by psychotherapy. Given the importance of unconscious psychic processes, it is reassuring to think that biology can now teach us a good bit about them. 

Finally, I like the idea of applying molecular biology to link my area, the molecular biology of mind, to Denise’s area, sociology, and thus develop a realistic molecular sociobiology. Several researchers have made a fine start here. Cori Bargmann, a geneticist now at Rockefeller University, has studied two variants of C. elegans that differ in their feeding patterns. One variant is solitary and seeks its food alone. The other is social and forages in groups. The only difference between the two is one amino acid in an otherwise shared receptor protein. Transferring the receptor from a social worm to a solitary worm makes the solitary worm social. 

Male courtship in Drosophila is an instinctive behavior that requires a critical protein, called fruitless. Fruitless is expressed in two slightly different forms: one in male flies, the other in female flies. Ebru Demir and Barry Dickson have made the remarkable discovery that when the male form of the protein is expressed in females, the females will mount and direct the courtship toward other females or toward males that have been engineered to produce a characteristic female odor, or pheromone. Dickson went on to find that the gene for fruitless is required during development for hardwiring the neural circuitry for courtship behavior and sexual preference. 

Giacomo Rizzolatti, an Italian neuroscientist, has discovered that when a monkey carries out a specific action with its hand, such as putting a peanut in its mouth, certain neurons in the premotor cortex become active. Remarkably, the same neurons become active when a monkey watches another monkey (or even a person) put food in its mouth. Rizzolatti calls these “mirror neurons” and suggests that they provide the first insight into imitation, identification, empathy, and possibly the ability to mime vocalization—the mental processes intrinsic to human interaction. Vilayanur Ramachandran has found evidence of comparable neurons in the premotor cortex of people. 

In looking at just these three research strands, one can see a whole new area of biology opening up, one that can give us a sense of what makes us social, communicating beings. An ambitious undertaking of this sort might not only discern the factors that enable members of a cohesive group to recognize one another but also teach us something about the factors that give rise to tribalism, which is so often associated with fear, hatred, and intolerance of outsiders.



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Scientific Advisory Board
Joseph T. Coyle, M.D., Harvard Medical School
Kay Redfield Jamison, Ph.D., The Johns Hopkins University School of Medicine
Pierre J. Magistretti, M.D., Ph.D., University of Lausanne Medical School and Hospital
Robert Malenka, M.D., Ph.D., Stanford University School of Medicine
Bruce S. McEwen, Ph.D., The Rockefeller University
Donald Price, M.D., The Johns Hopkins University School of Medicine

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