In Search of Memory: The Emergence of a New Science of Mind (15 page)

S
oon after I arrived at Columbia in 1955, Grundfest suggested that I work alongside Dominick Purpura, a young physician whom he had encouraged to change careers from neurosurgery to basic research on the brain (figure 7–1). When I met Dom, he had just made the decision to focus his research on the cerebral cortex, the most highly developed region of the brain. Dom was interested in mind-altering drugs, and the first experiments I helped him with concerned the role of the psychedelic agent LSD (lysergic acid diethylamide) in producing visual hallucinations.

LSD was discovered in the 1940s. By the mid-1950s it had become extremely well-known because of its widespread recreational use. Aldous Huxley had publicized its mind-altering properties in his book
The Doors of Perception
, in which he described how LSD enhanced his own awareness of visual experiences, giving rise to powerful, brightly colored images and a greater sense of clarity. The ability of LSD and related psychedelic drugs to alter perception, thought, and feeling in ways that are not ordinarily experienced except in dreams and exalted religious states makes them markedly different from other classes of drugs. People taking LSD often have the sense that their mind has expanded and split in two: one part is organized, experiencing the enhanced perceptual effects; the other part is passive, observing the events as a neutral outsider. Attention is typically turned inward, and the clear distinction between self and non-self is lost, giving the user of LSD a mystical sense of being part of the cosmos. In many people the perceptual distortions take the form of visual hallucinations; in some people LSD can even cause a psychotic reaction resembling schizophrenia. Because of these remarkable properties, Dom wanted to know how LSD worked.

7–1
Dominick Purpura (b. 1927) trained as a neurosurgeon but switched to full-time research and became a major contributor to the physiology of the cortex. I worked with him in 1955–56 during my first stay in the Grundfest laboratory. He later became an academic leader at Stanford University and then at the Albert Einstein School of Medicine. (From Eric Kandel’s personal collection.)

A year earlier D. W. Woolley and E. N. Shaw, two pharmacologists at the Rockefeller Institute, had found that LSD binds to the same receptor as serotonin, a substance that had recently been discovered in the brain and was thought to be a neurotransmitter. For their studies they used a preparation favored by experimental pharmacologists, the smooth muscle of the rat uterus, which they found would undergo spontaneous contractions in response to serotonin. LSD counteracted this effect of serotonin, and it did so by displacing serotonin from its receptor. This led Woolley and Shaw to suggest that LSD might counteract serotonin in the brain. They further suggested that since LSD can cause psychotic reactions, it might do so by preventing the normal action of serotonin in the brain. If that were so, they argued, serotonin might well be required for our sanity—for normal mental functioning.

Although Dom had no problem with the idea of using smooth uterine muscle to test ideas about chemicals in the brain, he thought a more relevant test about brain functioning in mental health and illness would be to look at the brain directly to see how psychedelic drugs act. Specifically, he wanted to know whether LSD affects synaptic activity in the visual cortex, the area of the cortex concerned with visual perception, where presumably the dramatic visual distortions and hallucinations occur. He asked me to help him explore the action of serotonin on a neural pathway in cats that ends in the visual cortex.

We anesthetized the animals, opened their skulls to expose the brain, and placed electrodes on the surface of the visual cortex. We found that in the visual cortex, serotonin and LSD did not act in opposition to each other, as they did in the smooth muscle of the uterus. Not only did both have the same action, inhibiting synaptic signaling, but each enhanced the other’s inhibitory activity. Thus our studies, and subsequent studies from other laboratories, seemed to disprove Woolley and Shaw’s notion that the disorienting visual effects of LSD were due to the drug’s blocking the action of serotonin in the visual system. (We now know that serotonin acts on as many as eighteen different types of receptors throughout the brain and that LSD seems to produce its hallucinatory action by stimulating one of these receptors, located in the frontal lobe of the brain.)

This was quite a nice result. In the course of these studies I learned from Dom how to set up experiments with cats and how to operate electrical recording and stimulating equipment. To my surprise, I found my first laboratory experiences to be absorbing, quite unlike the rather dry science I had been taught in college and medical school classrooms. In the laboratory, science is a means for formulating interesting questions about nature, discussing whether those questions are important and well formulated, and then designing a series of experiments to explore possible answers to a particular question.

The questions Grundfest and Purpura were asking were not immediately related to the ego, superego, or id, but they made me realize that neural science was beginning to be able to test ideas about aspects of major mental illnesses, such as the perceptual distortions and hallucinations of schizophrenia.

More important, I found discussions with Grundfest and Purpura fascinating—they were penetrating and sometimes marvelously gossipy about other scientists’ work, their careers, their sex lives. Dom was extremely bright, technically strong, and highly entertaining (I later called him the Woody Allen of neurobiology). I began to realize that what makes science so distinctive, particularly in an American laboratory, is not just the experiments themselves, but also the social context, the sense of equality between student and teacher, and the open, ongoing, and brutally frank exchange of ideas and criticism. Grundfest and Purpura admired each other and were involved together in the design of the experiment, but Grundfest would criticize Dom’s data as if he were a rival from another laboratory. Grundfest was at least as demanding about the experiments from his and Dom’s laboratory as he was about other people’s experiments.

In addition to learning about the important new ideas emerging from biological studies of the brain, I learned methodology and strategy from Grundfest and Purpura, and later from Stanley Crain, a young colleague of Grundfest’s. In a larger sense, much as the painful memories of my youth in Vienna in 1938 were to obsess me in later years, these early positive research experiences and the ideas to which I was exposed when I was twenty-five years old had a major impact on my thinking and my life’s work.

The findings regarding serotonin and LSD encouraged Dom to carry his analysis to the edge of what was technically possible in the mammalian cortex. We had used flashes of light to activate the visual cortex. Those stimuli activated a pathway that ended on the dendrites of neurons in the visual cortex. Very little was known about dendrites. In particular, it was not known whether they could generate action potentials like those in the axon. Based on their studies, Purpura and Grundfest proposed that dendrites have limited electrical properties: they can produce synaptic potentials, but they cannot generate action potentials.

In reaching this conclusion Grundfest and Purpura were tentative, however, because they were uncertain that the experimental methods they were using were adequate to the task of studying dendrites. To detect changes in synaptic transmission produced by LSD, Grundfest and Purpura ideally needed to obtain intracellular recordings from the dendrites of the neurons in the visual cortex one dendrite at a time. This required using small glass electrodes of the sort used by Katz in single muscle fibers and by Eccles in single motor neurons. After some discussion they concluded that intracellular recordings were unlikely to succeed, because the neurons in the visual cortex were much smaller than the cells studied by Katz and Eccles. The slender dendrites, which are only one-twentieth the size of the cell body, seemed impossibly difficult recording targets.

IT WAS IN THE CONTEXT OF THESE DISCUSSIONS THAT I ONCE
again encountered Stephen Kuffler. One evening Grundfest threw into my lap an issue of the
Journal of General Physiology
that contained three papers by Kuffler based on his work with single nerve cells and their dendrites in the crayfish. I found the idea of a contemporary neurophysiologist working on crayfish simply remarkable: one of Freud’s first scientific papers, published in 1882, when he was only twenty-six, was on the nerve cells of the crayfish! It was in the course of this study that Freud almost discovered, independently of Cajal, that the nerve cell body and all of its processes are a single unit, the signaling unit of the brain.

I read Kuffler’s papers as best I could. Even though I did not understand them fully, one thing popped out immediately: Kuffler was doing what Purpura and Grundfest aspired to do but could not achieve in the mammalian brain. He was studying the dendrites of a single, isolated nerve cell. Here, without any other nerve cells present, Kuffler could actually see the individual branches of the dendrites and could record the conseqences of electrical changes in them.

Kuffler’s papers drove home the point that selecting an anatomically simple system is crucial to the success of an experiment and that invertebrate animals are a rich source of simple systems. The papers also reminded me that the choice of an experimental system is one of the most important decisions a biologist makes, a lesson I had learned earlier from Hodgkin and Huxley’s work on the squid’s giant axon and Katz’s work on the squid’s giant synapse.

These insights had a great impact on me, and I was eager to test the new research strategies directly for myself. I had no specific idea in mind, but I was beginning to think like a biologist. I appreciated that all animals have some form of mental life that reflects the architecture of their nervous system, and I knew I wanted to study nervous system function at the cellular level. All I knew at this point is that someday I might want to test an idea with an invertebrate animal.

AFTER GRADUATING FROM MEDICAL SCHOOL IN
1956,
I SPENT A
year as a medical intern at Montefiore Hospital in New York City. In the spring of 1957, during a brief elective period in my internship, I returned to Grundfest’s lab and spent six weeks with Stanley Crain, a master of simple systems. I sought out Crain because he was a cell biologist who had searched for appropriate experimental systems to solve important problems. He was one of the first to study the properties of single, isolated nerve cells removed from the brain and grown in tissue culture apart from all other cells. It doesn’t get much simpler than that!

Knowing of my growing curiosity about invertebrate animals, particularly about the crayfish, Grundfest suggested that I set up an electrophysical recording system with Crain’s help. I could use the system to replicate Hodgkin and Huxley’s experiment by recording from the large axon of the crayfish, which controls the animal’s tail and thus its escape from predators. This crayfish axon is smaller than that of the squid but nonetheless very large.

Crain showed me how to manufacture glass microelectrodes for insertion into individual axons and how to obtain and interpret electrical recordings from them. It was in the course of those experiments—which were almost laboratory exercises, since I was not exploring new ground scientifically or conceptually—that I first began to feel the excitement of working on my own. I connected the output from the amplifier I was using to record the electrical signal to a loudspeaker, as Adrian had done thirty years earlier. Whenever I penetrated a cell, I, too, could hear the crack of an action potential. I am not fond of the sound of gunshots, but I found the bang! bang! bang! of action potentials intoxicating. The idea that I had successfully impaled an axon and was actually listening in on the brain of the crayfish as it conveyed messages seemed marvelously intimate. I was becoming a true psychoanalyst: I was listening to the deep, hidden thoughts of my crayfish!

The beautifully straightforward results I obtained from early experiments on the simple nervous system of the crayfish—measurements of the resting membrane and action potentials, confirmation that the action potential is all-or-none and that it does not simply nullify the resting membrane potential but overshoots it—made a profound impression on me and confirmed the importance of selecting just the right animal for my studies. My results were completely unoriginal, but to me they were wonderful.

Based on my two brief periods in his laboratory, Grundfest offered to nominate me for a research position at the National Institute of Mental Health (NIMH), the psychiatric component of NIH, as an alternative to being drafted into the armed forces. During the years following the Korean War, physicians were drafted to provide medical care for members of the armed services and their families. The Public Health Service, then part of the Coast Guard, was an alternative form of active duty for those who were deemed eligible, and NIH was one of the installations that belonged to the Public Health Service. With Grundfest’s recommendation, I was accepted by Wade Marshall, chief of the Laboratory of Neurophysiology at NIMH, and was slated to arrive in July 1957.