Osamu Hayaishi (1920—2015)

Published May 4 2016

Osamu Hayaishi gives a lecture at the University of Tokyo in 2012. TAKAO SHIMIZO

Osamu Hayaishi, emeritus professor of Kyoto University, died in December at the age of 95. A leading international figure in biochemistry, Hayaishi discovered oxygenase, ADP-ribosylation and the sleep-inducing action of prostaglandin D2.

Hayaishi was born on Jan 7, 1920, in Stockton, Calif., where his Japanese father, who had studied medicine in the U.S., ran a clinic. The family moved from California to Germany and then settled in Osaka, Japan, where Hayaishi grew up. He graduated from Osaka University Medical School in 1942, served as a medical officer in the Japanese navy during the war and joined the lab of microbiologist and virologist Tenji Taniguchi at Osaka University.

Living conditions in severely damaged, postwar Osaka were miserable, and the university’s laboratory facilities were hopeless. Hayaishi spent much of his time in Taniguchi’s employ reading scientific literature until the day he received an unexpected visit from Yashiro Kotake, a biochemist known for his study of tryptophan metabolism in mammals. Kotake gave Hayaishi a bottle of tryptophan purified from casein lysates — a precious gift at the time. Hayaishi had read about an enrichment culture technique to isolate soil bacillus with adapted enzymes for added organic compounds and began culturing soil samples with tryptophan. He enriched a strain of pseudomonas, which degrades tryptophan completely to carbon dioxide, water and ammonia via kynurenine, anthranilic acid and catechol. He prepared bacterial extracts and found in them an enzyme that catalyzed conversion of catechol to cis,cis-muconic acid as the reaction product. He named it pyrocatechase. Using Warburg’s manometer, Hayaishi found a concomitant consumption of equimolar molecular oxygen with the conversion. At this point he suspected that consumed molecular oxygen was incorporated directly to the substrate, but experimental proof of his assumption was years away.

Hayaishi published his findings in 1949, attracting the attention of David Green at the University of Wisconsin. Green invited Hayaishi to be a postdoctoral fellow, and Hayaishi crossed the Pacific to join him in Madison. Hayaishi spent eight months with Green before moving to the laboratory of Roger Stanier at the University of California, Berkeley. Stanier also studied tryptophan metabolism in pseudomonas, and the two men struggled together in vain to extract tryptophan-metabolizing enzymes. One rainy evening in Berkeley, Hayaishi met National Medal of Science winner H. A. Barker, who advised him to use alumina to grind the bacteria. It worked. Hayaishi was able to extract enzymatic activities that reconstituted metabolism of tryptophan to catechol and consumed molecular oxygen concomitantly. After four months with Stanier, Hayaishi joined the lab of Nobel Prize-winner Arthur Kornberg. Kornberg, whom Hayaishi had first heard speak at a Federation of American Societies for Experimental Biology meeting, had offered him a position before Hayaishi moved to Berkeley. Hayaishi worked with Kornberg at the National Institutes of Health as a postdoctoral fellow and later at Washington University as an assistant professor.

Appointed chief of the toxicology section of the National Institute of Arthritis and Metabolic Diseases in 1954, Hayaishi led a team that tested his long-held hypothesis on pyrocatechase. Using O-18 isotopes, he found that oxygen atoms incorporated in the product came entirely from O2 and not at all from H2O. His discovery and a concurrent independent discovery by Howard Mason at the University of Oregon Medical School of incorporation of an atom of molecular oxygen into a substrate by mushroom phenolase were milestones in the understanding of how oxygen is utilized in biological systems. Until then, scientists believed that biological oxidation occurred exclusively through the dehydrogenation process that German Nobelist Henrich Wieland had discovered decades earlier. Hayaishi named the group of enzymes catalyzing incorporation of molecular oxygen into organic substrates “oxygenases.”

In 1958, Hayaishi returned to Japan and became a professor and chairman of the Department of Medical Chemistry at Kyoto University Faculty of Medicine. He said of the move, “My salary in Kyoto was one-thirteenth of that (at) NIH. More(over), the experimental facilities were miserably shabby.”

As Hayaishi got to work reconstructing the department, a flood of young people eager to learn modern biochemistry joined him. Hayaishi was as gifted a mentor as he was a scientist. He organized a lunchtime seminar where all members in the laboratory gathered and critically discussed papers. Hayaishi called the seminar a dojo and trained those in attendance through serious discussion. He still loved being close to the bench and made a daily round in his laboratory. When writing a paper, Hayaishi invited the authors to his office and carried out several rounds of review by examining the paper’s findings and logical flow and correcting his researchers’ English word by word.

Hayaishi inspired and trained several hundred people during his 25-year tenure in Kyoto and his several years of joint-appointments at Osaka University and the University of Tokyo. More than 130 of them became university professors or department heads.

Hayaishi and his researchers extensively studied structures and properties of oxygenases and came to a conclusion about the presence of the enzymatically activated form of oxygen in the ternary complex of the enzyme heme—oxygen—substrate. The study of oxygenase initiated by Hayaishi has developed enormously, and we now know that oxygenases are involved in the formation of various bioactive substances, cytochrome P450-catalyzed xenobiotic disposition, and the sensing of oxygen tension.

Hayaishi’s study on oxygenase also led him to create new fields of research, including work on ADP-ribose, a discovery derived from his study on the oxygenase-driven tryptophan metabolism to nicotinamide adenine dinucleotide, or NAD, and made in parallel with Paul Mandel at the University of Strasbourg and Takashi Sugimura at the National Cancer Center of Japan. Hayaishi also discovered the diphtheria toxin-catalyzed ADP-ribosylation of aminoacyl transferase 2 and thus clarified the toxin’s action mechanism. He was the first to demonstrate that the bacterial toxin is an enzyme. Hayaishi also discovered indoleamine 2, 3-dioxygenase and its induction by interferon, which is now known as one of the major immunosuppression mechanisms.

The last area of Hayaishi’s research, sleep induction by PGD2, began a few years before his retirement from Kyoto University. By characterizing enzymes in PG biosynthesis, Hayaishi found that PGD synthase and PGD2 are enriched in the brain. He unexpectedly found that intracerebroventricular injection of PGD2 induced sleep in animals. His subsequent works revealed that PGD2 acts on its receptor in the leptomeninges surrounding the brain and transmits its signal from there to the sleep-regulation center in the hypothalamus. This mechanism of sleep induction by PGD2 fascinated Hayaishi. He maintained an active group to pursue the topic and enjoyed discussing it with the lab members up until two years ago, when he fell ill.

Hayaishi retired from Kyoto University in 1983 and founded the Osaka Bioscience Institute. Hayaishi served as the president of the International Union of Biochemistry from 1973 to 1976, received numerous awards and prizes and was a member of several academies, including the U.S. National Academy of Sciences.

The principles discovered by Hayaishi are known now to operate in many physiologically important processes, and the science he created has influenced nearly all areas of bioscience and medicine.

A man of great charm, Hayaishi leaves behind his wife of 69 years, Takiko; their daughter, Mariko; two grandsons and six great-grandchildren. The academic community, his friends, colleagues and students, have lost an inspiring scientist who embodied the spirit of the field.

Shuh Narumiya is a professor and the director of Medical Innovation Center of Kyoto University School of Medicine.