In Search of Memory: The Emergence of a New Science of Mind (50 page)

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.

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.

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 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.

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?

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.

I AM OFTEN ASKED, “WHAT DID YOU GAIN FROM YOUR PSYCHIATRIC
training? Was it profitable for your career as a neural scientist?”

I am always surprised by such questions, for it is clear to me that my training in psychiatry and my interest in psychoanalysis lie at the very core of my scientific thinking. They have provided me with a perspective on behavior that has influenced almost every aspect of my work. Had I skipped residency training and gone to France earlier to also spend time in a molecular biology laboratory, I might have worked on the molecular biology of gene regulation in the brain at a slightly earlier point in my career. But the overarching ideas that have influenced my work and fueled my interest in conscious and unconscious memory derive from a perspective on mind that psychiatry and psychoanalysis opened up for me. Thus, my initial career as an aspiring psychoanalyst was hardly a detour; rather, it was the educational bedrock of all I have been able to accomplish since.

Often, newly graduating medical students who want to do research ask me whether they should take more basic coursework or go into research right away. I always urge them to get into a good laboratory. Obviously, coursework is important—I continued to take courses throughout my years at the National Institute of Mental Health, and I continue to this day to learn from seminars and meetings, from my colleagues, and from students. But it is much more meaningful and enjoyable to read the scientific literature about experiments you are involved in yourself than to read about science in the abstract.

Few things are more exciting and stimulating to the imagination than making a new finding, no matter how modest. A new finding allows one to see for the first time a part of nature—a small piece of the puzzle of how something functions. Once I have gotten into a problem, I find it extremely helpful to get a complete perspective, to learn what earlier scientists thought about it. I want to see not only what lines of thought proved to be productive, but also where and why certain other directions proved to be unproductive. So I was very much influenced by the psychology of Freud and by the early workers in the field of learning and memory—James, Thorndike, Pavlov, Skinner, and Ulric Neisser. Their thinking, and even their errors, provided a wonderfully rich cultural background for my later work.

I also think it is important to be bold, to tackle difficult problems, especially those that appear initially to be messy and unstructured. One should not be afraid to try new things, such as moving from one field to another or working at the boundaries of different disciplines, for it is at the borders that some of the most interesting problems reside. Working scientists are constantly learning new things and are not inhibited from moving into a new area because it is unfamiliar. They follow their interests instinctively and teach themselves the necessary science as they go along. Nothing is more stimulating for self-education than working in a new area. I had no useful preparation for science before I began with Grundfest and Purpura; I knew very little biochemistry when I joined forces with Jimmy Schwartz; and I knew nothing about molecular genetics when Richard Axel and I began to collaborate. In each case, trying new things proved anxiety-provoking but also exhilarating. It is better to lose some years trying something new and fundamental than to carry out routine experiments that everyone else is doing and that others could do as well as (if not better than) you.

Most of all, I think it is important to define a problem or a set of interrelated problems that has a long trajectory. I was fortunate at the very beginning to stumble onto an interesting problem in my work on the hippocampus and memory and then to switch decisively to the study of learning in a simple animal. Both have an intellectual sweep and scope that have carried me through many experimental failures and disappointments.

As a result, I have not experienced the malaise that some of my colleagues have described when, in midlife, they become bored with the science they are doing and turn to other things. I have engaged in a variety of non-research-based academic activities, such as writing textbooks, serving on academic committees at Columbia and nationally, and helping to found a biotechnology company. But I never did any of those things because I was bored with doing science. Richard Axel talks about the reinforcing value of data—the playing in one’s head with new and interesting findings—as addictive. Unless Richard sees new data coming along, he becomes despondent, a feeling many of us share.

MY WORK IN SCIENCE HAS ALSO BEEN GREATLY ENRICHED BY THE
passion that Denise and I share for music and art. When we moved to New York from Boston in December 1964, we bought a hundred-year-old house in the Riverdale section of the Bronx with wonderful views of the Hudson River and the Palisades. Over the decades we have filled that house with etchings, drawings, and paintings—decorative art from the beginning of the twentieth century—a form with strong roots in Vienna as well as in France. We collect French art nouveau furniture, vases, and lamps by Louis Majorelle, Emile Gallé, and the brothers Daum, an interest that originated with Denise. Her mother got us started in this direction by giving us for a wedding present a beautiful tea table that Gallé had made for his first exhibit.

Once in New York, we began to focus our interest in graphic art on Austrian and German expressionists—Klimt, Kokoschka, and Schiele among the Austrians, and Max Beckmann, Emil Nolde, and Ernst Kirschner among the Germans. This interest originated with me. For almost every major birthday—and sometimes in between when we cannot wait—Denise and I buy each other something we think the other would like. Most of the time we select the pieces together. As I write this, I am beginning to suspect that our collecting may well be an attempt to recapture part of our hopelessly lost youth.

IN RETROSPECT, IT SEEMS A VERY LONG WAY FROM VIENNA TO
Stockholm. My timely departure from Vienna made for a remarkably fortunate life in the United States. The freedom I have experienced in America and in its academic institutions made the Nobel Prize possible for me, as it has for many others. Having been trained in history and the humanities, where one learns early on how depressing life can be, I am delighted to have ultimately switched to biology, where a delusional optimism still abounds.