Tadashi Inagami, PhD, DSc, Stanford Moore Professor Emeritus of Biochemistry at Vanderbilt University, died in Pittsburgh on March 13 after a brief illness. He was 92 years old. Dr. Inagami was among the most prominent basic scientists in the field of cardiovascular medicine, known internationally for his contributions to understanding the basic biology of hypertension (high blood pressure), heart failure and vascular disease.
Dr. Inagami was born in Kobe, Japan in 1931. His father moved his young family to Kyoto for better educational opportunities for his children after his son had been accepted into a prestigious middle school in Kyoto.
A few years later, Japan’s entry into World War II, however, would impact the family and Dr. Inagami’s education for many years. The war interrupted his education at the age of 14, in April of 1945, when he was conscripted to work in a munitions factory working as a machinist grinding to micrometer accuracy pistons for oil pumps. This experience developed a life-long interest in scientific instrumentation used in his future seminal scientific discoveries. When the war ended 8 months later, Dr. Inagami would resume school in an educational system that the Occupation had redesigned. He navigated through the changing school system and graduated from Kyoto University with a BS in agricultural/nutritional chemistry in 1953.
After the war in 1946, President Truman established the Fulbright Program to promote mutual understanding between the United States and other countries through educational exchange. In 1952, Fulbright Japan was founded. Dr. Inagami came to the United States as a Fulbright Scholar in 1954, at the urging of his professors due to the lack of resources in scientific education in post-war Japan. He chose to attend Yale University and completed his PhD in biophysical chemistry at Yale in 1958 and remained another year as a post-doctoral fellow. Upon returning to Japan, realizing a Japanese degree would be needed for employment in Japan and that his stipend would be helpful in supporting his family, he completed his Doctor of Science degree in nutritional sciences from Kyoto University in 1963. Despite the degree, there were still no position available in Kyoto, and so newly married, he and his wife, Masako, returned to Yale to work with his former mentor, Dr. Peter Sturtevant, who offered him a multi-year post-doctoral position.
While at Yale, he developed his expertise in protein chemistry. As a research associate, he worked on understanding the catalytic properties of the proteases, trypsin and chymotrypsin, made protein crystals and obtained detailed molecular structures of the enzyme, Ribonuclease S, using the X-ray diffractometer, a machine requiring adjustments every ½ hour. In 1966, he was recruited to Vanderbilt University’s Department of Biochemistry, where he remained until his retirement. He was quoted as being joyful at leaving the machine that had tried and nearly succeeded at killing his patience.
He and his wife, now with daughters Sanae and Mari, arrived in Nashville, a city with a population 1/3 of the population today, with a handful of Japanese families, no Japanese restaurants and no Japanese food stores. The city was undergoing significant changes during the civil rights movement, but he arrived to a department renowned for its warm, collegial and cooperative spirit “where the haves shared with the have-nots,” enabling young investigators to advance.
Dr. Inagami and his colleagues were the first to purify renin and to determine the primary structure of renin, a key protein in blood pressure regulation. Renin had been described 70 years earlier but had eluded purification. At the time, it was noted that pepstatin, a protease inhibitor, had remarkable affinity for binding to renin. This knowledge led to using pepstatin in the efforts to purify renin, but because pepstatin could only be obtained in small amounts, progress was slow. It was serendipity when a research investigator from the pharmaceutical company that owned the patent for pepstatin wanted to collaborate; when asked what Dr. Inagami might want from Japan as a gift (typically a bottle of Japanese whiskey), the reply was “pepstatin.” The provided amount allowed the lab to greatly accelerate experiments leading to renin’s purification. This work laid the foundation for the development of ACE inhibitors, a major class of anti-hypertensive medicines used today.
Dr. Inagami’s experiences in proteases at Yale proved invaluable in his work identifying renin’s role as a protease, digesting the precursor protein angiotensinogen to angiotensin I.
Dr. Inagami remained a protein chemist throughout his research career, but he added molecular biology to his skill set with the development of scientific techniques analyzing DNA and RNA. In 1983, he encouraged his daughter now attending college to take molecular biology classes and wanted copies of the syllabus and texts from those classes, and in 1984, his team published their first paper using molecular biology techniques. Dr. Inagami’s lab later went on to clone and characterize two types of receptors for angiotensin II, a peptide with many effects on blood pressure, which have been used by pharmaceutical companies to develop a new class of anti-hypertensive drugs that block these receptors, known today as Angiotensin Receptor Blockers (ARBs).
Members of his team worked in clarifying the signaling pathways coupled to this receptor leading not only to hypertension but also to the overgrowth of cells, in the heart, blood vessel walls and kidney. This understanding has led to the use of ARBs in heart failure, vascular and kidney disease.
Dr. Inagami early in his research career assisted Vanderbilt’s Dr. Stanley Cohen, mentor and the future Nobel Laureate, in sequencing Epidermal Growth Factor (EGF) using the department’s newly acquired automated Edman degradation protein sequencer, cutting-edge science at the time (and another machine requiring significant patience and care). In sequencing EGF, Dr. Cohen was able to understand EGF’s structure and function. When Dr. Inagami’s team later discovered that Angiotensin II transmits growth signals through pathways used by the Epidermal Growth Factor (EGF) receptor, he was quoted, “I feel like I’ve come back to where I started.”
The collaboration with Dr. Cohen was bi-directional; when it was learned that renin was found in salivary glands, Dr. Cohen provided the same submandibular glands used to isolate EGF to Dr. Inagami. Using this tissue, his team was the first to purify renin from any source. These two seminal publications on EGF sequencing and renin purification (#29 and #30 on Dr. Inagami’s CV) list each other as co-authors.
Though Dr. Inagami’s research is most identified with the Renin-Angiotensin system, he continued to explore other newly discovered peptide hormones, such as Atrial Natriuretic Peptide (ANP), identifying, characterizing these factors and receptors and their role in blood pressure and blood volume through natriuresis and diuresis, interacting with the renin and aldosterone systems.
Dr. Inagami served as director of Vanderbilt’s interdepartmental Specialized Center of Research in Hypertension for 17 years beginning in 1979. While serving, center investigators participated in some of the initial trial of blood pressure medications, now widely used. In 2000, at the age of 70 Dr. Inagami was honored with a MERIT (Method to Extend Research in Time) award from the National Institutes of Health, which provides 10 years of continuous funding without competitive review.
He authored more than 500 scientific papers, over 100 review articles, and contributed to chapters in many books.
Dr. Inagami’s research achievements were recognized at Vanderbilt with his appointment as the Stanford Moore Professor of Biochemistry, the creation in August 2013 of the endowed Tadashi Inagami Professor of Biochemistry chair and the awarding in 1990 of the Earl Sutherland Prize for Achievement in Research, named for Vanderbilt’s first Nobel laureate in Medicine.
He received the 2004 Award for Excellence in Teaching at Vanderbilt by mentoring more than 100 graduate students and postdoctoral fellows, many becoming leaders in science, industry and academia both in the United States and in Japan. The trainees were not only students from the United States, but also from many foreign countries, the majority arriving from Japan as post-doctoral fellows, as the Japanese universities encouraged their scientists to train abroad for a period of time.
He was an elected member of the American Association for the Advancement of Science, a recipient of the American Heart Association/American Stroke Association Distinguished Scientist Award, the Bristol-Myers-Squibb Award for Distinguished Achievement in Cardiovascular Research, the CIBA Award from the High Blood Pressure Research Council of the AHA, the Humboldt Foundation Award, the Japan Vascular Disease Research Foundation’s Okamoto International Award, the Japan Society for Cardiovascular Endocrinology and Metabolism’s Jokichi Takamine Memorial Award, and the Japan Academy Prize.
Dr. Inagami retired in 2012. He and Masako moved to Pittsburgh, where his eldest daughter, Sanae Inagami, MD MPH, lives, in order to support her family during her husband’s illness. He spent his retirement watching his grandson play baseball, his granddaughter’s dance recitals, both their violin recitals and practices during weekly dinners and walking through and exploring Squirrel Hill, Frick Park and the Japanese restaurants in the city.
In addition to his wife of 61 years and his eldest daughter, Dr. Inagami is survived by daughter, Mari Inagami, MD; son-in-law; and five grandchildren. He was predeceased by his son-in-law, Manley David Witten; mother, Yoshi Inagami; father, Yoshio Inagami; and brothers, Akhisa and Takehiro Inagami.
During a private memorial service, his ashes will be interred later at Saiko Ji Temple in Kyoto, where his family is buried. Donations may be made in Dr. Inagami’s name to the American Heart Association.
VUMC Reporter 3/17/2023, 6/30/2006, 8/30/2001, 9/25/1998
Cunningham, Leon Biochemistry at Vanderbilt 1953-2004 Professional services trusted to D’alessandro Funeral Home & CrematoryLtd., Pittsburgh. www.dalessandroltd.com