Vol. 24., No. 12	January 21, 1999

Kandel Wins Wolf Prize

BY BOB NELSON

University Professor Eric R. Kandel, the biologist and Howard Hughes Medical Institute investigator who has devoted four decades to discovering what molecular changes take place in cells when an organism learns a new behavior, has been named to receive the 1999 Wolf Foundation Prize in Medicine.

The Wolf Prize, Israel's most prestigious award, is presented each year by the president of Israel for achievements in science and art. In the prize's 20-year existence, 17 recipients have gone on to win the Nobel Prize.

"I'm deeply honored," said Kandel, 69, who will accept the $100,000 award in a ceremony May 2 at the Knesset, Israel's parliament, in Jerusalem. "I have always felt very privileged to be at Columbia, with its outstanding neurobiology community. In a larger sense, I see this recognition as also reflecting on the intellectual life of that neurobiology community as a whole."

In its announcement, the Wolf Foundation said: "Kandel's contribution stands as the single most important advance in bridging molecular neurobiology to behavior. He has shown how the methods of psychology can be merged with those of biology to endow the study of behavior and learning with renewed vigor and explanatory power. His work has influenced the way both biologists and psychologists now think about these processes." Born in Vienna, Kandel fled Nazi-occupied Austria with his family in 1939. He received his B.A. degree from Harvard in 1952 and his M.D. degree from NYU in 1956. After holding faculty appointments at Harvard Medical School and the NYU School of Medicine until 1974, he joined Columbia's College of Physicians & Surgeons as professor of physiology and psychiatry and founded the Center for Neurobiology and Behavior. He directed the Center until 1984, when he became a senior investigator at the Howard Hughes Medical Institute.

In 1983, he was named University Professor, Columbia's highest academic rank. He maintains affiliations at the Departments of Biochemistry and Molecular Biophysics, Physiology and Cellular Biophysics, and Psychiatry, all at the College of Physicians & Surgeons. Kandel is a member of the National Academy of Sciences and several foreign academies and counts among his previous awards the Albert Lasker Basic Medical Research Award, the Dana Award, the Gairdner Award and the National Medal of Science.

What happens in the brain when a memory is formed or when learning takes place has been a major question for both neuroscientists and cognitive psychologists.

Until the late 1950s, investigations of these questions were dominated by behavioral approaches that tended to treat the brain as a black box, without any understanding of what took place within it.

To overcome the technical obstacles that previously kept the study of learning beyond the reach of biologists, Kandel and his collaborators turned to a simple invertebrate, the sea snail Aplysia, a large, shell-less, hermaphroditic, ink-squirting relative of the octopus, which has relatively few nerve cells. His research team was able to teach the animal to retract its gills in response to a stimulus, then analyzed which nerve cells were involved in the action and discovered that the snail's learning could change that circuit. The work provided the first evidence that learning and memory involve changes in the strength of synapses, connections between nerves and that learning could be traced as a specific series of biological signals.

Kandel went on to find that long-term memories cannot form without the activation of genes that promote the growth of new synapses between neurons, or nerve cells, in the brain. More importantly, the Columbia group traced the formation of long-term memory to the nucleus of the neuron and showed that the series of biological signals that leads to a memory ends with a molecule called CREB. CREB switches on dozens of genes that stimulate the growth of synapses, which lead to the formation of persistent, long-term memories. In 1990, Kandel's team found that by blocking CREB, all these events were halted, indicating that CREB was a key to the genetic basis of long-term memory.

Following on this success, the Kandel lab found that formation of long-term memories is normally restrained by a series of inhibitory processes that determine the ease with which short-term memory is converted to long-term. One particularly potent inhibitor is a molecule called CREB-2, which blocks the action of the first CREB, now termed CREB-1, and therefore blocks long-term memories from forming. Removing CREB-2 gives rise to immediate long-term memory. Thus, to activate memory in a sea snail, not only must CREB-1 be produced, but CREB-2 must be removed.

More recently, to extend this molecular approach from the simple learning demonstrated in species such as the sea snail to more complex learning of spatial tasks in mammals, Kandel has begun to study behavior in genetically modified mice. The work has demonstrated that long-term changes in the synapses of the hippocampus, the part of the brain believed to be responsible for memory formation, are critical for the storage of memory of spatial tasks.

Parallel genetic work by Caltech neurobiologist Seymour Benzer and his students has shown which signaling pathways are required for formation of short-term and long-term memories in fruit flies. Similar approaches have now been adopted by scientists who study behavior and learning in vertebrates as well as invertebrates. As a result, it is becoming clear that the CREB molecular switch for converting short- to long-term memory that Kandel identified in the sea snail is also important for memory storage in many species.