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Eric R. Kandel, M.D. The Biology of Memory By Steve Mirsky Remember your first day in high school? Or the first time you went to the theater? Or just learned how to ride your bicycle? Such seemingly simple learning tasks require a complex system of nerve cells, genes, and proteins, working together to maintain and retrieve old memories and to lay down new ones. Howard Hughes Medical Institute Investigator Eric Kandel decided in the mid-1950s to try to understand the biology of memory. It was an audacious decision—the tools of molecular biology that make it possible now to examine the genetic controls did not exist, and the biochemistry of the inner working of cells was just beginning to emerge. But as a result of decades of hard work, Kandel succeeded in unraveling the tapestry of memory. His early boldness and subsequent years of original and elegant research made him a recipient of the 2000 Nobel Prize in Physiology or Medicine. Eric Kandel was born in Vienna, Austria. His parents owned a toy store. Their quiet, modest lives changed on March 13, 1938 when the Nazis marched into Austria and were welcomed by the Austrians with open arms. Several weeks later in April 1938, Eric and all the other Jewish students were expelled from their school. On November 7, 1938, Eric’s ninth birthday, his parents gave him a remote-controlled model toy car. He played with it constantly for two days. On November 9, the day of Kristallnacht, or Crystal Night—the Night of Broken Glass—when Jewish homes and shops were vandalized and Jews were beaten and killed, Nazi police pounded on the door of the Kandel family apartment. The police told the Kandels they must leave until further notice. When allowed back several days later, they found most of their belongings—including the toy car—gone. The Kandels were comparatively fortunate, however. They were able to leave for the United States before their fellow Jews were sent to concentration camps. Settling in New York City, Eric continued his education first at a Yeshivah—a Hebrew parochial school—and then at Erasmus Hall High School, a public high school in Brooklyn where he was sports editor of the newspaper and co-captain of the track team. He then received a scholarship to attend Harvard College, where he majored in modern European history and literature. A Viennese friend’s parents who were prominent psychoanalysts, a discipline to this day associated with Vienna and Sigmund Freud, fired Kandel’s fascination with the workings of the mind. He entered New York University Medical School in 1952, intending to become a psychoanalyst. Freud’s attempts to understand how the brain works through observing and analyzing people’s behavior led him to divide the mind into three functional parts: ego, id, and superego. Kandel now wanted to connect psychology with the physical structure of the brain. In his second year in medical school, the students constructed a clay model of the brain. “It was hard to look at the brain, even a clay model of it, without wondering where Freud’s ego, id, and superego were located,” Kandel remembers in his autobiography, In Search of Memory. In order to gain more direct familiarity with the brain, Kandel took advantage of a six-month elective period in his senior year in medical school and did a research stint in the Columbia University neural science laboratory of Harry Grundfest. He told Grundfest of his desire to locate the ego, id, and superego—roughly the equivalent of telling a physics mentor that your goal is to go to Mars by the end of the semester. Grundfest gently informed him that the tools to do so were still decades away; the problem was beyond the reach of neuroscience at that time. “Rather, he told me, to understand mind we needed to look at the brain one cell at a time,” Kandel recalls. Kandel was initially dejected, but then remembered that Freud too had started by trying to tease out the brain’s secrets one cell at a time—one of his first studies, in 1882, was on the nerve cells of crayfish. By the late 1950s, researchers knew that memory lived in various brain regions—for example, memory for facts, people, and places is briefly stored in the prefrontal cortex, and when this short-term memory is converted to long-term memory, this occurs in the hippocampus. Heeding Grundfest’s advice, Kandel decided to try to get a handle on memory one cell at a time. He therefore spent 1957 to 1960 at the National Institute of Health (NIH). Working on humans was out of the question: we have over a hundred billion nerve cells in our brains. Kandel started on the hippocampus of the cat and made some important progress but soon decided that the hippocampus was too complex. “The approach was most likely to succeed if it focused on the simplest behavior of the simple animal,” he thought. While still at the NIH, Kandel happened to attend a number of lectures on various simple animals, and into his life walked, or rather slid, Aplysia. From these lectures he learned that the giant marine snail Aplysia (more than a foot long and weighing several pounds) was a good subject for studying nerve cells. It has only about 20,000 of them, some of which are 50 times as large as those in a mammal brain. Kandel decided to hitch his wagon to the snail. Friends and colleagues discouraged him—a prominent scientist even told Kandel that he was going to derail his career. But Kandel was confident. “I don’t go into projects impetuously,” he says. “I try to select important problems, and by reading about them and listening to scientific lectures, I try to develop a practical approach to the problem. But once I decide a problem is important, I really trust my judgment.” At the beginning of the 20th century, soon after Freud’s crayfish research, Ivan Pavlov famously showed that dogs quickly learn to associate a bell with food, so much so that the bell alone would cause salivation—the dog remembered that the bell meant food. Pavlov showed that memory, which is crucial to all behavior, can be studied successfully in the laboratory, not only in people but also in simple experimental animals. Aplysia engages in a very simple behavior that seemed ripe for study with Pavlov’s methods: when its gill is touched, it retracts. In the mode of Pavlov, Kandel taught the snail also to retract the gill when it received a mild shock to the tail. This simple system led to profound discoveries, first at New York University and for the last 34 years at Columbia University. Each nerve cell touches many other cells in a thicket of interactions, and they communicate with each other chemically at specialized contact points called synapses. Kandel found that short-term memory involves a functional strengthening of synapses. When activated by learning, a synapse gets stronger because one neuron increases its release of neurotransmitters, the chemical messengers by which one nerve cell communicates with its neighbor. Long-term memory, however, requires a deeper mechanism: genes must be activated that code for the synthesis of new proteins. These newly synthesized proteins allow the nerve cell to grow new synapses with its neighbors. As a result, more neurotransmitter chemicals are also released. An important insight is that the genes do not simply determine behavior and thus predestine it. Genetic controls respond to environmental conditions such as the organism’s need to learn new information. Genes thus are also, as Kandel wrote in an essay, “servants of the environment.” One additional fascinating finding: he discovered evidence for a gene that actually suppresses memory, probably so that the brain isn’t cluttered with trivia, and possibly even to make room for new memories should the brain’s capacity for memory storage become limited. In the past two decades, with techniques unimagined when Kandel started his work, he has returned once again to a more complex system—the hippocampus—now using the brain of the mouse, an animal whose genes can be readily modified. Aplysia has and continues to be incredibly fruitful for revealing molecules of memory. However, as Kandel told Scientific American Mind magazine, “It doesn’t have awareness or think great thoughts. But mice, in their own way, do.” He is therefore looking at the mouse’s little mammalian brain to examine the roles that individual nerve cells in the hippocampus play in learning and memory, and how the brain works as an organic whole—how the brain produces mind. “Once in a while,” he concludes his autobiography, “I find myself filled with wonder to be doing what I am doing. I entered Harvard to become a historian and left to become a psychoanalyst, only to abandon both of those careers to follow my intuition that the road to a real understanding of mind must pass through the cellular pathways of the brain. And by following my instincts, my unconscious thought processes, and heeding what then seemed an impossibly distant call, I was led into a life that I have enjoyed immensely.”
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