For many scientists, winning the Nobel Prize is the crowning achievement of their life's work. Susumu Tonegawa, who won science's biggest award nearly two decades ago for discovering how the immune system generates a diverse repertoire of antibodies, has continued to make important contributions to science but in an entirely different field: neuroscience. Using advanced techniques of gene manipulation, Tonegawa is now unraveling the molecular, cellular, and neural circuit mechanisms that underlie learning and memory. His studies have broad implications for the understanding of human memory and learning, and of the ways that deficits in these abilities are linked to psychiatric and neurologic diseases.
Tonegawa was born and raised in Japan and came to the United States in 1963 to pursue a Ph.D. degree in molecular biology. By the time he finished a postdoctoral fellowship at the Salk Institute for Biological Studies in San Diego, his visa was about to expire, and he took the best job he could find outside the country, at the Basel Institute for Immunology in Switzerland. Tonegawa had little knowledge of immunology, but he soon became intrigued by a question that had long puzzled immunologists: how does the body with its limited number of genes generate a diverse army of antibodies to attack virtually any virus, bacterium, and other microorganism, even before the body encounters an assault? He was only in his 30s when he explained the mystery, demonstrating that the antibody diversity is achieved by the shuffling of genes that are used to produce specific antibodies. For this work, Tonegawa was the sole winner of the Nobel Prize in Physiology or Medicine in 1987.
Tonegawa's scientific interest switched to neurobiology in the early 1990s, when he began exploring the effects of missing or altered genes on learning and memory in mice in his laboratory at MIT. In his earlier antibody studies, Tonegawa had often used genetically engineered "knockout" mice that lacked the gene for a particular protein. He has since pioneered a way to make the technology more specific, so that a gene can be turned off only in a highly restricted area of the brain and only in the adult animal—an achievement that has proved critical to studying learning and memory.
One strain of mice Tonegawa developed lacks the enzyme calcineurin, which is active both in the immune system and in synapses between nerves. Without calcineurin, the mice exhibit severe short-term memory problems and are socially withdrawn. Such deficits also are common in patients with schizophrenia. Genetic studies of families with this devastating disease have shown a link between schizophrenia and the gene that codes for calcineurin. Tonegawa's mouse model could lead investigators to develop a new class of drugs for schizophrenia that target calcineurin. "With this mouse and our human studies, we have implicated an entire biochemical signaling pathway—the calcineurin pathway—that had not been implicated in schizophrenia before," Tonegawa said.
In other studies, he has uncovered genes and signaling pathways involved in long-term memory storage. For example, a gene for the N-methyl-D-aspartate (NMDA) receptor, which is important for nerve cell communication, also plays a crucial role in retrieving long-term memories. Mice without the gene in a tiny area within the hippocampus, called area CA3, can form long-term memories but require many more cues to retrieve them than mice with the gene. In another study, he has shown that eliminating a key enzyme called calcium/calmodulin-dependent kinase IV (CaMKIV) in the forebrains of mice has profound effects on signaling pathways in the brain and learning behavior. Mice without the enzyme can learn a simple task but have problems remembering it over the long term. These studies may aid in the development of drugs to counter the memory loss that occurs in Alzheimer's disease and other forms of dementia.
More recently, Tonegawa has developed a new genetic technology that permits a temporal and reversible cessation of synaptic transmission at a specific neuronal circuit. This technique, dubbed Dice-K, for doxycycline-inhibited circuit exocytosis-knockdown, allows scientists to identify the functions of specific neuronal circuits from various parts of the brain that may underlie cognition and behavior in both health and disease.