Takashi Sugimura 1926‐2020

On Sunday, September 6, 2020, Takashi Sugimura, MD, President Emeritus of the National Cancer Center and former President of the Japan Academy, passed away in hospital in Tokyo from heart failure at the age of 94.

Graduating as an MD from the School of Medicine, the University of Tokyo in 1949, Takashi Sugimura began his professional career as a radiologist. He soon changed his focus to cancer biochemistry, receiving a Doctor of Medical Science degree from Department of Biochemistry, the University of Tokyo, in 1957. Then, he moved to the United States and trained his research as a visiting scientist with Dr J. P. Greenstein (NIH; 1957‐1959) and with Dr H. G. Wood (Case Western Reserve Univ; 1959‐1960) as a research associate. In 1960, Dr Sugimura came back to Tokyo and joined Cancer Institute, Japanese Foundation for Cancer Research, then joined the National Cancer Center Research Institute (NCCRI) in 1962. He had become Director of NCCRI (1974‐1984), reflecting his extraordinary energy, passion and enthusiasm for cancer research, and then President of National Cancer Center (1984‐1991). From 1970 to 1985, he was also a professor of molecular biology at the Institute of Medical Science, the University of Tokyo.

Dr Sugimura had long been a leading scientist in the field of basic cancer research in Japan and also was recognized as a symbolic authority among Japanese cancer researchers, being well acquainted worldwide as well. He was warm to and caring of all colleagues and friends, despite his strict and strong discipline in basic research.

One of Dr Sugimura's seminal and prominent achievements in the field of cancer research is that he played a key role in proving the multistep carcinogenesis model using animal models exposed to various environmental mutagenic and carcinogenic compounds. ¹ He initiated his work to clarify the carcinogenic potential in mutagenic compounds in the early 1960s and proved that most of the mutagenic chemicals in bacteria are carcinogenic in animals. Dr Sugimura proved that DNA damage caused by these environmental compounds is the key event, even in carcinogenesis, by discovery of the carcinogenicity of a mutagen, N‐methyl‐N’‐nitro‐N‐nitrosoguanidine (MNNG) in 1966, ² and succeeded in inducing stomach cancer in rats by its oral administration in 1967. ³ The close relationship between mutagenicity and carcinogenicity was demonstrated based on a considerable body of in vitro and in vivo experiments. Since 1976, he expanded his work to explore environmental human carcinogens in food, being inspired by cooking smoke from the kitchen drifting into his room, and he discovered numerous heterocyclic amines in cooked fish and meat which induce cancers in various organs of rodents. ⁴ Dr Sugimura's accomplishments have led to the recognition of the importance of naturally occurring environmental mutagens and carcinogens.

Dr Sugimura also pioneered the research field of ADP‐ribose metabolism. Triggered by the report of a new NAD‐dependent polyadenylic acid synthesizing nuclear enzyme by P. Mandel and P. Chambon (Strasbourg, France) in 1963, Dr Sugimura identified the structure of poly(ADP‐ribose) in 1967 ⁵ paralleled with the groups of P. Chambon and O. Hayaishi. This discovery led to the finding of poly(ADP‐ribose)polymerase (PARP), which catalyzes polymerization reaction of ADP‐ribose and modifies various proteins. ⁶ He and M. Miwa subsequently found a degrading enzyme poly(ADP‐ribose)glycohydrolase (PARG), which splits the ribose‐ribose bond of poly(ADP‐ribose), in 1971. ⁷ Dr Sugimura and Y. Kanai also identified naturally occurring antibodies to poly(ADP‐ribose) in patients with systemic lupus erythematosus in 1977. ⁸ More importantly, he demonstrated enhancement of anti‐tumor activity of bleomycin by a PARP inhibitor, benzamide, in vitro and in vivo. ⁹ This discovery consequently contributed to the development and possible utilization of PARP inhibitors in clinical settings. PARP inhibitors are now proved to confer synthetic lethality to cancer cells with BRCA1/2 dysfunction, including hereditary breast and ovarian cancers (HBOC). In line with the PARP/PARG research, Dr Sugimura made a considerable contribution in identifying another novel protein, pierisin, from the cabbage butterfly Pieris rapae, ¹⁰ and demonstrated for the first time that pierisin has mono‐ADP‐ribosylating activity and modifies the DNA guanine base at the N² amino group of deoxyguanosine, but not proteins, in 2001. ¹¹ The series of his research on pierisin was purely motivated by his scientific curiosity on mechanisms controlling metamorphosis, and he was strongly motivated by sheer serendipity, and inspiration and cooperation from sympathetic colleagues.

Dr Takashi Sugimura received a tremendous number of awards and honors not only from Japanese societies but also from foreign academic societies, which include the Charles S. Mott Prize of the General Motor Cancer Research Foundation and the Ernst W. Bertner Memorial Award in 1981.

Dr Takashi Sugimura was a very exacting person and requested of his colleagues precise interpretation, integrity, and reproducibility of data. There was no room for compromise when he conducted research. I was very fortunate to be able to learn how he felt, thought, took appropriate decisions and actions, and brought about a unique and attractive atmosphere in the surrounding environment. The lessons from Dr Sugimura will remain deeply inside the hearts of Japanese cancer researchers, and of course in mine, forever.