June 30, 2006

VUMC Reporter Profile — Beyond borders: Inagami’s global scientific odyssey

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Tadashi Inagami, Ph.D., internationally recognized for his decades of hypertension research, has been a cornerstone of Vanderbilt’s biochemistry program for 40 years.
Photo by Anne Rayner

VUMC Reporter Profile — Beyond borders: Inagami’s global scientific odyssey

Tadashi Inagami, Ph.D., and his wife of 45 years, Masako.
Photo by Anne Rayner

Tadashi Inagami, Ph.D., and his wife of 45 years, Masako.
Photo by Anne Rayner

Inagami with his two oldest granddaughters, Emi and Miya.

Inagami with his two oldest granddaughters, Emi and Miya.

Inagami’s extended familly, circa 1938. Tadashi is the young boy at the far right. Next to him is his mother, Yoshi, holding his brother, Takehiro. Next to her is his father, Yoshio, holding his other brother, Akihisa.

Inagami’s extended familly, circa 1938. Tadashi is the young boy at the far right. Next to him is his mother, Yoshi, holding his brother, Takehiro. Next to her is his father, Yoshio, holding his other brother, Akihisa.

Tadashi and Masako Inagami stroll through Radnor Lake State Park.

Tadashi and Masako Inagami stroll through Radnor Lake State Park.

As little girls, Sanae and Mari Inagami asked their father for the kinds of gifts all little girls wish for — pretty clothes and dolls, maybe even a dollhouse to put them in.

But what they received outlasted any plastic doll or frilly, pink dress.

“I asked him once for stilts, and he bought me bamboo plants,” Sanae recalls with a chuckle. “He said that once the plants grow, we could make stilts.”

The bamboo grew, and from that raw material they fashioned a pair of bamboo stilts — takeuma — a traditional toy for children in Japan.

With that simple gift, Tadashi Inagami relayed to his daughters not only the value of working hard to attain a goal, but also a sense of their culture and of the country where he grew up — more than 6,000 miles away.

Chemistry sets, microscopes, crystal growing kits and sea monkeys followed. With these, he conveyed his love of science and discovery.

Whether or not the gifts steered Sanae and Mari down the scientific road their father has traveled for more than 50 years, both went to on to medical school and became physicians.

“Our daughters are like their father. They like science and research,” said their mother Masako, Inagami's wife of 45 years. “He was very glad he could give them a medical school education. He thought that was the best gift.”

Half a world away

Tadashi Inagami, Ph.D., was born in the port city of Kobe, Japan, in 1931. After leaving Kobe when he was 5, the Inagami family settled in Japan's cultural center of Kyoto after Inagami had finished grade school. World War II was in full swing.

Kyoto was spared the devastation that Hiroshima and Nagasaki endured, reportedly due to its rich history and the thousands of ancient shrines and temples. But, in the midst of the escalating conflict, the citizens of Kyoto lived with fear and uncertainty.

“We knew that atom bombs were coming, and maybe the next target would be Kyoto,” said Inagami. “We got instructions on how to cover our heads and go under the desk.”

In April of 1945, just as Inagami was entering eighth grade, schoolwork was suspended and he and his classmates were sent to work in munitions factories to build aircraft engines.

Though the technical and precise work and around-the-clock schedule might seem like a harsh situation for a young boy, it fostered in Inagami a fledgling interest in mechanics and science.

“We liked working with the sophisticated machine tools. I was grinding to micrometer orders of accuracy one of the pistons for oil pumps,” he said proudly.

Fortunately, his tenure in the munitions factory ended along with the war in August that year and life slowly began to return to “normal.”

After finishing junior high school in Kyoto, Inagami was accepted into the prestigious and highly selective Third National High School. “This was probably the most 'relieving' time in my life because it guaranteed a good career,” Inagami said.

During the war, Inagami's interests had been mechanics and electronics. But the post-war period had brought reports of exciting “new” sciences from the west — and new opportunities for Inagami. By reading the American science journals, Inagami's interest took a turn toward life sciences.

“I was interested in the biological sciences and biochemistry which was written up in popular science journals after the war,” Inagami said.

In 1953, he received his bachelor's degree in nutritional chemistry from Kyoto University, one of Japan's top public universities. He began graduate school there, but quickly realized that educational opportunities in Japan were limited.

There and back again

The war had taken its toll on Japan's universities. “When we went into the laboratories, we realized there is nothing going on — there were no instruments, no chemicals,” Inagami recalls. Even the professors encouraged their students to make their way to the United States to seek training.

After the war, the United States established the Fulbright Program to promote mutual understanding between the United States and other countries through educational exchange. Inagami passed the program's exam on his second attempt and was accepted. As a Fulbright scholar, he could choose the American university he wished to attend.

“I picked Yale…not so much for its reputation, but the meals were pretty good,” he said, laughing. He was only supposed to stay one year, but one year turned into four. After completing his doctoral degree in biophysical chemistry at Yale in 1958, he stayed another year as a postdoctoral fellow.

But his time in the United States was coming to an end. As a condition of the Fulbright award, grantees had to return to their country of origin to disseminate what they had learned abroad. Also, Inagami's former professor in Japan was pressuring him to come back to complete the degree he had started some five years before.

“I thought that was unfair, but they paid a reasonable salary,” Inagami said. The Japanese economy had still not rebounded from the war, and Inagami's father had lost his job, so his stipend from the university would help support the family. “And in order to get a job in Japan, it is better to have a degree from a Japanese university.”

So, Inagami agreed to return to Kyoto University and finish his degree. He soon realized that he was ready to move on in another aspect of his life — starting a family of his own.

“I wanted to get married, and no woman would marry a penniless man,” he said.

While working on his second doctoral degree, Inagami was introduced to Masako, the daughter of a close friend of Inagami's mother. They married in 1961.

But jobs were still scarce, and Inagami finally realized there was little hope of finding a good position in Japan. So in 1962, after completing his second doctorate in nutritional chemistry, Inagami returned to America — and to Yale — with his new bride. Within a few years, their family was complete with the birth of two daughters, Sanae in 1963 and Mari in 1966.

As a research associate at Yale, Inagami went back to his work on enzyme chemistry with his postdoctoral mentor. Using a new instrument being tested by his mentor, the X-ray diffractometer, he made protein crystals and obtained detailed molecular structures of ribonuclease S, an enzyme that degrades RNA. His experience with machines in the munitions factory would come in handy, he found.

“Because this was a test instrument, it kept breaking down every half hour.” The constant fiddling with the instrument became more than he could bear, and after two years, Inagami knew it was time to move on again.

“Vanderbilt offered the lowest salary, but looked to be the most exciting and most interesting (in the area of protein chemistry),” Inagami said. “Also, compared with New England, the atmosphere was more cooperative, very warm.” So he accepted the position, and the Inagami family headed south to what would become their lifelong home in Nashville.

“We drove an old car which conked out a number of times on our way,” said Inagami. “Finally, we got here on a frozen day in 1966.”

Scientific journey

Although the weather outside may have been frigid, Inagami soon realized that he had arrived in the Department of Biochemistry at a particularly “hot” time.

Just a few years prior, Stanley Cohen, Ph.D., had made his seminal discovery of epidermal growth factor (EGF). But one of the next crucial steps in Cohen's research was to determine how the protein works.

“If you don't know a protein's structure, then you won't know how it works,” said Cohen, distinguished professor of Biochemistry, emeritus. And Inagami's expertise in protein chemistry proved a perfect complement to the research going on in Cohen's lab and in the biochemistry department in general.

Leon Cunningham, Ph.D., former chair of Biochemistry and a close colleague and friend of Inagami, had earlier helped the department acquire a protein sequencer that provided an automated method of determining a protein's amino acid sequence. This process, called Edman degradation, was cutting-edge science at the time — and a special skill of the department's newest faculty member. It also required the patience and perseverance that Inagami knew so well from his mechanical exploits with the instrument at Yale and in the munitions factory.

“(The instrument) takes real attention to get excellent data from it,” said Cunningham, now professor of Biochemistry, emeritus. “It took just the kind of care and attention that Tad could give, and he made it available for other people.”

“He helped me immensely because he was the first to bring automated Edman degradation technique, which was very new at the time, to Vanderbilt,” Cohen said. “Using that technology, we were able to get the structure of EGF.”

Recently, the Journal of Biological Chemistry recognized Cohen's work on EGF and Inagami's contribution to it by reprinting the original research papers, accompanied by brief biographies of both researchers, as part of the centennial anniversary of the journal.

Inagami feels honored to have contributed to Cohen's Nobel Prize-winning research and considers Cohen one of his most important mentors.

“He never tried to be a mentor; he led by example,” Inagami said. “I gained an awful lot by working with him, from seeing his conscientious, very well-thought-out approach to research.”

But the collaboration turned out to be mutually beneficial. In the mouse salivary gland — the tissue from which Cohen had isolated EGF — researchers had identified another protein, called renin, which would become a central figure in Inagami's career.

Renin had been reported in 1898 by researchers at Karolinska Institute as a substance secreted by the kidney with the ability to increase blood pressure (or pressor activity). But for decades, researchers had been unsuccessful in isolating it.

With the exciting possibility that renin could be found in the mouse salivary gland, Cohen offered to help Inagami in his search. In 1972 — some 74 years after the initial report of renin's pressor activity — Inagami became the first researcher to purify and identify renin as a specific enzyme as it is presently known. He later purified renin and its precursors from pig and human kidneys and several other tissues.

In determining renin's sequence, Inagami realized that it was a protease, an enzyme that “chews up” proteins. He found that renin acts only on a very specific target, a hormone precursor called angiotensinogen. Renin cleaves this precursor to form angiotensin I, which is again cleaved to produce angiotensin II — a peptide hormone with numerous effects on blood pressure.

Over the years, Inagami's dogged pursuit of the mechanism of blood pressure regulation has identified and characterized many pieces of this pathway — including the cloning and characterization of angiotensin receptors and the identification of renin's active site, the spot on the protein that interacts with its substrate and to which renin-inhibiting drugs are targeted. His basic research on the structure and function of renin helped lay the foundation for the development of renin inhibitors to treat hypertension — drugs that have only recently become viable.

In 1979, Inagami became director of the Specialized Center of Research (SCOR) in Hypertension, a large, interdisciplinary research center funded by the National Institutes of Health. As a basic scientist coordinating a rather clinically-based research center, he entered this new role with some trepidation.

However, during his 17 years as director, center investigators participated in some of the initial clinical trials of blood pressure medications which suppress renin-based hormones like angiotensin II — some of the first medications to be widely used as anti-hypertensive drugs.

Inagami has amassed more than 500 papers in scientific journals and a long list of prestigious accolades, including the Bristol-Myers-Squibb Award for Distinguished Achievement in Cardiovascular Research, the Research Achievement Award from the American Heart Association (AHA), and the Japan Academy Award — Japan's highest academic honor awarded by that nation's equivalent of the United States National Academy of Sciences.

He is particularly proud of the Ciba Award from the High Blood Pressure Research Council of the AHA, which he received in 1985. The highly selective award recognizes the most original research in the hypertension field.

“(Receiving that award) meant you had really established something,” Inagami said.

Building bridges

Vanderbilt has also honored Inagami with the Earl Sutherland Prize for Achievement in Research — the school's highest research award named for Vanderbilt's first Nobel laureate — and the 2004 Award for Excellence in Teaching for his training of more than 100 postdoctoral fellows, a large percentage from Japan.

“Tad takes very seriously what happens to his trainees,” said Michael Waterman, Ph.D., chair of Biochemistry. Many of his former postdocs are now established independent researchers in Japan, where Inagami is a revered figure in his field.

“I've been fortunate to go to a meeting in Japan with him. People say 'wow, that's the famous Dr. Inagami. You are so lucky to be working with him,'” said Gerald Frank, Ph.D., research assistant professor in Biochemistry and one of Inagami's former trainees.

“He's a kind of grandfatherly figure with a gentle temperament that, naturally, one feels deserves respect,” Frank said. “Some postdocs may call their mentors by their first name, but it's hard to call him 'Tadashi' or 'Tad.'

“From our standpoint, he is always 'Dr. Inagami.'”

The cultural exchange that began with his Fulbright scholarship continues in Inagami's mentoring of students from Japan — mentoring that extends well beyond the laboratory walls. He and Masako provided non-academic support to help the international postdocs transition to life in Nashville.

“When I first came to the U.S., he and his wife helped me with almost everything you can imagine — car shopping, banking, Social Security, trips to Target,” said Satoru Eguchi, M.D., Ph.D., a former postdoc who is now an associate professor of physiology at Temple University in Philadelphia, Pa. “We were like his children.”

His oldest daughter Sanae remembers vividly the constant stream of Japanese trainees the family welcomed into their home. “It provided a kind of Japanese network,” she said. That cultural network helped provide moral support to those postdocs entering a new and unfamiliar country.

“I miss (his support) when I am facing issues that are not limited to science,” Eguchi said.

The road ahead

After all of the awards and volumes of original contributions to the hypertension field, many folks might start winding down their research. But not Inagami. In 2000, at the age of 70, Inagami was honored with a MERIT — Method to Extend Research in Time — award from the National Institutes of Health. The award provides 10 years of continuous funding without competitive review.

“The MERIT award is remarkable recognition of his great accomplishments during his truly outstanding career,” said Waterman.

“You cannot ask for a MERIT award,” notes Waterman. “The NIH awarded him because they thought he deserved it and that he would continue to be productive throughout that period of time.”

And Inagami's research is, indeed, still going strong. Although his friends and family may plead with him to retire, Inagami still feels compelled to carry out the research to some sort of conclusion.

“I probably should have retired five or six years ago. I didn't do it because other research areas began to show up related to renin and angiotensin,” Inagami said. “I just want to settle it.”