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Remembrance of Things Past

Larry Squire

In Search of Memory. Eric R. Kandel. xvi + 510 pp. W. W. Norton, 2006. $29.95.

In the 1950s and early 1960s, neuroscience was not yet a coherent discipline and was not in the curriculum. Psychology was still under the strong influence of behaviorism, and the new discipline of cognitive science was just emerging. There was considerable interest in how the brain supported such fundamental processes as learning and memory, but the merger of biology and psychology that became neuroscience was still to occur. A good deal had been learned by the mid-20th century about the physiology of nerve cells and synapses, but the study of complex functions like learning and memory had not yet reached very far into biology.

It was during this period that the modern era of memory research can be said to have begun. In 1957, Brenda Milner, a neuropsychologist at McGill University, described the selective effects on memory of medial temporal lobe damage in a patient who became known as "H.M." These observations showed that acquiring new memories is a distinct cerebral function, separable from other perceptual and cognitive abilities. Following the successful development of an animal model of H.M.'s memory impairment, the structures of the medial temporal lobe important for memory were identified, including the hippocampus. Since 1957, an enormous amount has been learned about the physiology, anatomy and cell biology of these structures.

Today, the scope of research on learning and memory ranges from genes to cognition, from molecules to mind. We know that memory is not a single faculty of the mind but is composed of multiple systems that have different neuroanatomy and different operating principles. We know that simple forms of learning result in functional and structural changes at synapses between the neurons that support the behavior being modified. Short-term memory involves modifications of preexisting proteins and transient strengthening of preexisting synaptic connections. Long-term memory involves altered gene expression, protein synthesis and the growth of new and stronger synaptic connections within existing circuits. Intracellular signaling pathways convert short-lasting stimulus events to persistent changes in synaptic strength.

No one has done more to bring the study of memory to the cellular and synaptic level than Eric Kandel. His autobiographical volume, In Search of Memory, recounts the gradual transition of memory research from an endeavor rooted largely in psychology to a broad discipline in which the cells of the nervous system are understood to be connected by modifiable synapses and governed by universal biological principles.

Photographs capture the movement of AplysiaClick to Enlarge Image

A key point in Kandel's career was his bold but deliberate decision to study an organism that had been largely neglected by science, the large marine snail Aplysia. In 1965, after a fellowship in Paris, where Ladislav Tauc introduced him to the Aplysia nervous system, Kandel began his independent scientific work at New York University. Aplysia provided several advantages. It has a simple nervous system (about 20,000 neurons), large and identifiable neurons (some nearly 1 millimeter in diameter) that can be located in every individual, and a modest capacity for simple forms of learning like habituation and classical conditioning. The idea was to work out the wiring diagram for a simple behavior and then ask: Where in the circuit does change occur when the behavior is modified by learning?

Initially, there was considerable skepticism about this approach. One wondered first of all what could be learned from a lowly marine invertebrate about the rich phenomena of human memory. Another concern was that, early on, the kinds of behavioral change that were demonstrated in Aplysia were very short-lasting (less than 10 minutes). But Kandel was compelled by the idea, now widely accepted, that evolution is conservative and that even humans have probably retained some of the cellular mechanisms of memory found in simple animals. And in a landmark study, he and his colleagues drew on the historic principle of human learning that spaced training episodes are more effective than massed training to show that, with spaced training, Aplysia could exhibit a long-term memory lasting for weeks.

Before long, circuits underlying simple behaviors were identified, signaling pathways were described, and sites of synaptic plasticity were identified within the circuits. This work revolutionized the biology of memory. Science was scarcely ready for the idea that long-standing debates about memory could now be settled by direct evidence about mechanism. Does learning require new neural circuits or modifications within preexisting circuits? (Modifications.) Is forgetting a matter of interference, or is some of what was acquired actually lost? (Some is lost.) Independent work on memory in the fruit fly, Drosophila, soon identified some of the same biochemical pathways that had been discovered in Aplysia and reinforced the idea that many animal species, including humans, employ the same cellular mechanisms to record the effects of experience.

Soon after moving to Columbia University in 1974, Kandel was drawn to the power of genetics. So it was that after the age of 50 he mastered the tools of molecular biology. He and his colleagues established cell-culture systems of isolated Aplysiasensory and motor neurons, and they identified molecular steps by which synaptic events signal the nucleus to activate genes, which then send messenger RNAs and proteins back to the synaptic terminals. Although this material arrives at all the synapses made by the cell, only recently active synapses are strengthened and become the basis for long-term change.

Upon reaching the age of 60, Kandel stretched his horizons once again to exploit the new techniques in molecular genetics that could be applied to the mouse. He studied more complex forms of memory, including spatial memory, and his laboratory was among the first to study memory in genetically modified mice.

In Search of Memory is the success story of a creative, ambitious and energetic young man who came to be one of the most accomplished scientists of his time, recognized by the 2000 Nobel Prize in Physiology or Medicine. As is the case with many great scientists, there was little in his beginnings to suggest what would come. Perhaps the most compelling parts of the book cover Kandel's early years, before he decided on Aplysia at the age of 33 and set off for France. Born in Vienna to middle-class parents who ran a toy store, he writes chillingly of his recollections of Kristallnacht, when he was 9 years old. His family was forced from their home, robbed of their possessions, and humiliated and terrified in the ensuing months. After escaping to New York City in 1939, he attended public school and then, due solely to the urging of a supportive teacher, applied to Harvard. There he pursued an intense interest in Austrian and German history and might well have become an intellectual historian had his principal professor and mentor not died unexpectedly of cancer. At about that time Kandel came into contact with two prominent psychoanalysts from Freud's circle and, like many intellectuals in the 1950s, he developed a deep fascination with psychoanalysis. This led to medical school, internship and a residency in psychiatry with plans to practice psychoanalysis.

All this was to change when, during medical school, he entertained the vague idea that he should learn something about the biology of the mind and took a defining elective in the laboratory of the neurophysiologist Harry Grundfest. When Kandel explained that he wanted to discover the seat of the ego, superego and id, Grundfest famously countered that to understand the mind one would need to study the brain one cell at a time. Kandel never turned away from this reductionist outlook. In 1957, he found a research position at the National Institutes of Health, where he eventually conceived the idea of studying Aplysia, the most radically reductionist approach that had yet been brought to the problem of learning and memory.

There are two stories in this book: the history of research on memory and cognition since 1950, including the increasing promise of clinical application and the role of the pharmaceutical industry, and the story of Kandel's own life and career. It is a story of chance encounters, bold decisions and cherished colleagues. And it illustrates how deep knowledge of a field and its history lays the foundation for having good ideas for experiments and keen insights about the results. Kandel also writes about the importance of "chance influences and of the generosity of spirit that encourages young people to thrive," advising that "Young people, for their part, must strive to have an open mind and seek out places where they will be surrounded by first-rate intellects."

It would be only speculation to consider how Kandel's background in German literature, history and psychoanalytic theory might have been especially beneficial for his life in science. But there can be no doubt that it helped make the man. When the president of Austria wrote a congratulatory letter on the occasion of the Nobel Prize, Kandel responded by proposing to organize a symposium in Vienna "to compare Austria's response to the Hitler period, which was one of denial of any wrongdoing, with Germany's response, which was to try to deal honestly with the past." The symposium was held in June 2003, and Kandel returned to Vienna in 2004 with his wife, Denise, to celebrate the publication of the symposium volume.

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