Shigekazu Nagata Is Better Known for His Work on Apoptosis
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© 2001 Nature Publishing Group http://medicine.nature.com NEWS Having originally researched the activities of the potent hematopeotic stimulator of bone-marrow cells, granulocyte colony stimulating factor, Shigekazu Nagata is better known for his work on apoptosis. Here, one of Japan’s most renowned biomedical scientists outlines the path that has taken him full circle: from stimulating cells to grow, to finding out how they die, to tying the two processes together. Shigekazu Nagata For a man who spends most of his time clusively activated in apoptosis. He says Charles Weissmann. He took the job be- thinking about death, Shigekazu Nagata is there are several questions left to be an- cause at that time, “almost no one was remarkably upbeat. For over a decade, he swered concerning the Fas pathway. using recombinant DNA technology in has been making a name for himself with Central among them is, how does the onco- Japan.” He credits his experience in research on apoptosis, the mechanism of gene product Bcl-2 block apoptosis? Weissman’s lab with forming the basis for programmed cell death, and during that However, he has no personal plans to work his future studies and teaching him an “or- time he has watched the field come alive. on an answer to that question, perhaps be- derliness and logical procedure” to re- “Medline publications on apoptosis have cause he has become a victim of his own search. In 1982, he returned to IMS for a risen from only a couple of hundred in success at propagating interest in cell death. short time before moving to the OBI in 1990 to over 10,000 this year,” he says with “There are so many other 1987 and then to taking up a satisfied nod. good researchers working on his current position at Osaka Nagata spoke to me in his office at Osaka this, I’ll leave it to them.” University. He encourages University, where he has been a professor Apoptosis is an area of basic this kind of mobility, which in the Department of Genetics for five research filled with promise is quite unusual in Japan years. “Apoptosis is fun. It’s like fireworks,” of therapeutic application. where researchers often re- he says, pointing to a screen full of magni- Where cell death leads to dis- main at their alma mater for fied cells that bulge, contract, fragment ease, such as in hepatitis or most of their career. and change colors, before shrinking and Alzheimer disease, the apop- Nagata is also unusual in disappearing into oblivion. totic pathway could be his eschewal of the institute He is credited with elucidating some of blocked. When cancerous directorships and administra- the basic cellular machinery that propels cells are proliferating uncon- tive positions that usually the process of apoptosis, such as the cell- trollably, the apoptotic sys- Shigekazu Nagata come with senior research po- surface receptor, Fas. Early work with his tem could be activated. sitions in Japan. “If you’re the colleague at the Osaka Bioscience Institute Nagata, however, says he has little interest boss, you can’t be productive anymore,” he © http://medicine.nature.com Group 2001 Nature Publishing (OBI), Shin Yonehara, who had shown that in trying his hand at more applied studies laughs. That said, he currently holds the a mouse antibody to Fas was involved in within a biotechnology company. In fact, post of director of the Japanese Biochemical the cytolytic pathway, revealed that the Japanese scientists are often criticized for Society. “No one ever turns [the antibody worked as an agonist; that is, that their lack of interest in applied research— Biochemical Society] down,” he admits. it contributed actively to the death of the giving rise to Japan’s stumbling efforts to Present efforts outside of apoptosis re- cell rather than merely blocking prolifera- promote biotech. But Nagata says the rea- search are directed at establishing a tion. Nagata further characterized the func- son he and his peers are reluctant to take ‘nanobiology’ graduate program at the tion of Fas by showing that mice with a part in commercial ventures is because pri- University. “This is re-construction of the mutation in this receptor develop lympho- vate investment is insufficient. “The gov- Institute of Molecular and Cellular Biology proliferation, a condition in which lymph ernment is the one that is pouring money that was established here 20 years ago. cells lose the ability to undergo apoptosis into biotech, but it’s a huge gamble. Even in Several professors from the Medical School and accumulate. the United States, 90% of companies fail. I and the Department of Engineering Science The next step was to discover exactly don’t want to gamble with the taxpayer’s would join together in an effort to apply how Fas caused apoptosis in natural, non- money.” nanotechnology to medicine,” he explains. stimulated conditions. During this period This doesn’t mean that others haven’t In the meantime, Nagata is taking his of investigation, Nagata received a fax from picked up on the value of Nagata’s re- apoptosis research in new directions. He’s Pierre Golstein at France’s CNR’s “cyto- search. Mochida Pharmaceuticals, for one, investigating parallels between apoptosis toxic T-cell with Fas-specific properties,” has licensed a patent from OBI, where and hemopoesis. “When a macrophage asking him whether he was interested in a Nagata did much of his Fas research, for use recognizes a cell undergoing apoptosis, it collaboration. “Of course I was interested!” of the Fas ligand system in developing clin- separates and fragments the nuclei. he remembers. Together they set about ical treatments. Similarly, during differentiation, precursors cloning and characterizing the Fas ligand. What sets Nagata apart from most to red blood cells undergo enucleation, by Nagata has since migrated from this lig- Japanese researchers is his willingness to which their nuclei are transferred to and–receptor surface interaction to study move between different laboratories. After macrophages where they are consumed. cell death from inside the cell, and has con- receiving a PhD from Tokyo University’s There must be parallels in how the tinued to do groundbreaking work charac- Institute of Medical Sciences (IMS) in macrophage is able to recognize and take terizing proteins that promote apoptosis. In 1977, he traveled to Zurich, Switzerland, out the nucleus in these two processes,” en- 1998 he published his discovery of a novel where he worked on cloning the gene en- thuses Nagata. DNase and its inhibitor, ICAD, which is ex- coding interferon-α in the laboratory of David Cyranoski, Tokyo NATURE MEDICINE • VOLUME 7 • NUMBER 7 • JULY 2001 759.