Tonegawa, Susumu

views updated May 29 2018

Susumu Tonegawa

Immunologist Susumu Tonegawa (born 1939) received the 1987 Nobel Prize in Physiology/Medicine for his discovery of the principle under which human genes rearrange to form the antibodies that fight disease. As a graduate student in 1968 he left Japan to earn his Ph.D. in molecular biology at the University of California at San Diego. He then traveled to the Basel Institute of Immunology in Switzerland where he conducted his Nobel winning research. After ten years, he returned to the United States to teach at the Massachusetts Institute of Technology's Center for Cancer Research. In 1998 as an investigator at the Howard Hughes Medical Institute, he used genetically engineered mice to research mechanisms used in learning and memory.

Interest in Chemistry Turned to Biology

Susumu Tonegawa was born in Nagoya, Japan, on September 6, 1939, the son of textile engineer Tsutomu and mother Miyoko. He had two brothers and a sister. His father needed to travel to various textile factories around the rural part of southern Japan, causing the family to move every few years. Staunch believers that parents owe their children a good education, Tonegawa's parents sent him and his elder brother to live with an uncle in Tokyo so the boys could easily commute to the topranking Hibiya High School. In high school, Tonegawa developed an interest in chemistry.

Expecting to pursue chemical engineering in college, Tonegawa took the entrance exams for the Department of Chemistry at the University of Kyoto. Although he failed the first time, he succeeded the second time and was admitted in 1959. At this time, Japan was one year away from renewing a 10-year defense treaty with the United States. College students rallied in with their opinions and demonstrations, some causing so many disturbances that classes at Kyoto University were often cancelled. When Japan decided to renew the treaty, Tonegawa and other students felt a sense of defeat. In this atmosphere, Tonegawa abandoned his original major and decided to pursue the academic life.

In his senior year at Kyoto University, Tonegawa read scientific papers by French biochemists Francois Jacob and Jacques Monod on the operon theory of immunology. So inspired by it was he that he changed his major to molecular biology and wanted to study it as a graduate student. He was accepted into Professor Itaru Watanabe's laboratory at the Institute for Virus Research at Kyoto University, a unique lab where US-trained molecular biologists conducted research. After only two months in the lab, Watanabe suggested that Tonegawa complete his graduate studies in the United States, which had more sophisticated graduate training programs than the ones available in Japan. Watanabe assisted Tonegawa in applications to US universities. In 1963, Tonegawa graduated from the University of Kyoto with a BS degree in chemistry.

Studied Molecular Biology in California

With Watanabe's help, Tonegawa was awarded a Fulbright travel grant to attend graduate school in the Department of Biology at the University of California at San Diego. The department had been newly established by Professor David Bonner in La Jolla, California. At the age of 23, Tonegawa left Japan for the US, and never returned to his native country as a resident. He would spend his scientific and academic career abroad from then on.

Tonegawa served as a research assistant at the University of California in 1963, then as a teaching assistant from 1964 to 1968. He also conducted research under the guidance of Professor Masaki Hayashi in genetic transcription in bacteriophages. In 1968, Tonegawa earned his Ph.D. in molecular biology.

Tonegawa remained in San Diego as a postgraduate fellow at the Salk Institute. Under the direction of Dr. Renato Dulbecco, the lab hosted a number of international postdoctoral students trained in prokaryotic molecular biology. At the lab, Tonegawa studied the morphogenesis of a phage. His task was aimed at defining the transcripts of SV40 during lytic infection and in transformed cells. Although this was a challenge in the days before experiments with recombinant DNA, Tonegawa was impressed with the excitement of the lab's scientific research and inspired by the stimulating atmosphere.

Proved the Theory of Antibody Diversity

Around the end of 1970, as a recipient of the Fulbright travel grant, Tonegawa could not renew his US visa, which was about to expire. He was required to leave the country for at least two years before re-applying for a visa. Just before he had to leave, Dulbecco sent him a letter from Europe saying that the new Basel Institute for Immunology in Switzerland had opened. Dulbecco suggested that the field of immunology might benefit from someone from a molecular biology point of view and encouraged Tonegawa to apply. Soon, Professor Niels Kaj Jerne in Basel offered Tonegawa a two-year contract to work in Switzerland.

In 1971, Tonegawa became a member of the Basel Institute and stayed for the next ten years. His first year was difficult, as he wanted to continue his work on SV40, but eased into immunology in order to find an interesting subject. The right topic for him was revealed when he learned of a question that had baffled scientists for more than one hundred years—what were the genetic origins of antibody diversity. By now scientists were using the techniques of restriction enzymes and recombinant DNA in molecular biology research, which Tonegawa used to attack the mysteries of antibodies.

Between 1974 and 1981, Tonegawa thrived at Basel under the direction of Professor Jerne in an atmosphere of freedom and cooperation. With Drs. Nobumichi Hozumi, Minoru Hirama, and Christine Brack, Tonegawa wrestled with two theories on how antibodies, or proteins, in the body fight disease. The "germline" theory hypothesized that all the genes needed to make an antibody were already part of the genetic code. The "somatic mutation" theory said that genes rearrange themselves to create various antibodies so that only a few genes are needed to generate many varieties of antibodies.

Tonegawa wrote an influential paper in 1976 explaining that he was able to scientifically prove the somatic mutation theory. He found that mutating DNA segments were separated by inactive, or noncoding, strands of DNA called introns, which contained a gene control called an enhancer. Antibody diversity was generated by somatic recombination of the inherited gene segments and by somatic mutation. This discovery laid the groundwork for future research in the causes of cancer, specifically blood cancers such as leukemia and lymphoma.

Named Professor at MIT Cancer Center

By the early 1980s, Tonegawa had made his major contribution to immunological research. He was ready to launch a new scientific project and wanted to return to the United States. Selecting from numerous offers, he accepted a position as professor of biology at the Center for Cancer Research at the Massachusetts Institute of Technology (MIT) in Cambridge. Tonegawa credits the assistance of Professor Salvador E. Luria, director of the center.

At MIT, Tonegawa decided to investigate the role of somatic rearrangement in the activation of the rearranged antibody gene and also to extend the research he did in Basel to include the antigen receptor of T cells. Both problems could be addressed if he could discover a tissue-specific transcriptional enhancer in the immunoglobulin heavy chain gene. One important development he made was identifying a gene that led to the discovery of a new T cell receptor, gamma delta, that could be involved in a new type of immunity.

Won Nobel Prize

The news was a surprise to Tonegawa when a reporter called him for his comments on being named 1987's sole winner of the Nobel Prize in Physiology/Medicine. The 48-year-old had not yet been informed by the Nobel committee that he had won. The committee had realized that Tonegawa's key to unlocking the way the immune system functions was the basis for all future research on fighting infectious disease.

The bulk of Tonegawa's work which won the Nobel was done in Switzerland when he discovered how only 10,000 genes in the human body could produce millions of diverse antibodies that fought off disease caused by viruses and bacteria. Tonegawa had used mouse cells to determine that when antibodies are produced, different segments of the gene are combined at random, resulting in a huge number of varying combinations. Tonegawa's research techniques were as notable as his results; they may lead other scientists to make more effective vaccines and to find ways to improve the body's immune system.

Tonegawa's findings had shattered the prevailing belief that genes could not change. He compared the way genes reshuffled to create a variety of antibodies to the way automobiles are built: "It's like when General Motors builds a car that they want to meet the specific needs of many customers. If they custom make each car, it is not economical, so they make different parts, then they assemble it in different ways, and therefore one can make different cars. It's a matter of how you assemble those pieces."

This discovery has implications for improving immunological therapy, treating autoimmune diseases, minimizing graft rejection, and inhibiting adverse reactions during transplantation.

Nancy Hopkins, a biology professor at MIT, commented on the type of scientist Tonegawa is, considering that immunology was not his field: "There are people who are brilliant and come upon things through analysis. He's the kind of person who moves by insight with enormous drive and passion."

Tonegawa himself credited his successful career to mentors and colleagues he met along the way: "When I look back on my scientific career, I am amazed at my good fortune. At every major turn, I met scientists who were not only at the very top in their own fields, but who also gave me insightful advice and generous help."

Investigated Neural Development and Memory

In 1988, Tonegawa was named an investigator at the Howard Hughes Medical Institute where he researched learning and memory. Using genetically engineered mice, he studied neural development and the molecular, cellular, and neuronal circuitry used in memory. His team was also deciphering mechanisms underlying neural activity-dependent development of sensory systems, and looked at specific brain areas to determine which deficits underlie learning, memory, and developmental impairments.

Tonegawa's work at the institute received support from the National Institute of Neurological Disorders and Stroke, the National Institute of Mental Health, the National Institute on Aging, and RIKEN (Institute of Physical and Chemical Research, Japan).

In 1994, he became Picower Professor of Biology and Neuroscience and director of the Picower Center for Learning and Memory at MIT. He holds a professorship at Amgen Inc., is a member of the American Academy of Arts and Sciences, and honorary member of the American Association of Immunologists and the Scandinavian Society for Immunology.

In 2002 at MIT a new complex for neuroscience was underway. The total cost of the new complex was $150 million. MIT received $50 million from a foundation which will go toward the learning and memory center directed by Tonegawa. The new complex will be completed by or before 2005.

In 2004 Tonegawa and his research team made a new discovery regarding memory. They discovered a mechanism in the brain which controls as quoted from Biotech Week, "the formation of lasting memories." They found that MAPK, an enzyme that stands for mitogen-activated protein kinase, was what initiated protein synthesis which is necessary for long-term memory. Memories could not be stored unless MAPK was stimulated first.

Critical of Japan's Educational System

Tonegawa attended the International Forum Commemorating the Centennial of the Nobel Prize held at Tokyo University and in Kyoto in 2002. The event was sponsored by the Science Council of Japan and supported by The Yomiuri Shimbun as a forum to discuss the lack of creativity in Japan's educational system.

In Japan, teachers typically ask students test questions that require one simple response, such as a historical date or factual answer, compared to the US where educators engage students in discussions that can yield a variety of views. Tonegawa, one of only five Nobel laureates in science to come from Japan, urged parents and teacher to encourage creativity and independent thought in Japanese children. "Imagination starts from copying," he said. "Creative people attract creative people."

When the 1987 Nobel Prize was given to Tonegawa, who had moved to the US so he could be inspired and free to carry on his research, Japanese academics took notice and some were humiliated. Tonegawa had asserted that if he had remained in Japan, he would have had to spend years courting favor with mentors and dealing with disinterested colleagues, lagging unchallenged and unmotivated, certainly never to attain Nobel laureate. The press labeled the phenomenon as "Tonegawa Shock" which described the actions of similar Japanese scientists, such as Leo Esaki, a 1973 laureate in physics, who left Japan to work at IBM in the US.


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