Akira Endo, a Japanese biochemist whose fascination with the internal workings of fungi underpinned research that discovered cholesterol-lowering statins in blue mold, a find that revolutionized cardiovascular care and became one of the world’s most widely used drugs, died June 5 at age 90.
The death was announced by Tokyo University of Agriculture and Technology, where Dr. Endo was a professor emeritus. No cause was given. Japan’s public broadcasting network NHK reported that Dr. Endo died at a nursing facility in Tokyo, citing “sources close” to the scientist.
Dr. Endo’s breakthrough in 1973 was the first step toward statin drugs that reduce the body’s production of so-called “bad” cholesterol LDL, a major contributor to diseases such as arteriosclerosis that can lead to heart attacks or strokes. Statins also serve to boost the liver’s ability to scrub the bloodstream of even more LDL and act as important anti-inflammatory agents that can improve vascular health.
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His work also became part of an international scramble between pharmaceutical giants. U.S.-based Merck pushed ahead with its own statin drug that hit the market first in 1987 — capturing the world’s attention and somewhat obscuring Dr. Endo’s foundational research in Japan.
More than 200 million people around the world take some form of statin drugs, according to Johns Hopkins Medicine, under brand names such as Lipitor and Crestor.
The beginnings trace back to a lab at the Japanese pharmaceutical company Sankyo, where Dr. Endo was a researcher in the 1960s assigned to look for enzymes in fungal extracts for use in the food industry. The biochemical wonders of fungi had intrigued Dr. Endo since he was a boy, learning from his grandfather how to boil poisonous mushrooms to remove the toxins.
In 1966, Dr. Endo took a two-year leave of absence to take a research position at the Albert Einstein College of Medicine in New York. He also received a crash course in America’s health problems, including learning the connection between high cholesterol and cardiovascular disease.
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“I often saw ambulances coming to take elderly people who had suffered a heart attack to hospital,” he recalled from his years living in the Bronx. (He was also stunned by the large portions in American restaurants.)
Yet even as scientific evidence mounted in the 1960s linking elevated low-density lipoprotein, or LDL, to clogged arteries and other problems, there was not much in the way of treatment. The only consensus at the time was common sense advice that was not always followed: eating lower-cholesterol diets and exercising to improve metabolism. (According to the most current World Health Organization statistics, an estimated 17.9 million people died from cardiovascular disease in 2019, representing 32 percent of all global deaths.)
Dr. Endo was captivated by the research on cholesterol by Harvard University’s Konrad Bloch, who received the Nobel Prize in Medicine in 1964, along with West German researcher Feodor Lynen, for studies into how cholesterol and fatty acids metabolize in the body. Dr. Endo wondered how he could put on the biological brakes.
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Fungi, he believed, held the answer. Some species could inhibit enzymes to help kill invading bacteria. Dr. Endo hoped to find a way to use those enzyme-blocking powers to block the human cholesterol-production process.
A painstaking trial-and-error run started in 1971 at his lab in Japan. For two years, Dr. Endo grew more than 6,000 cultures, aiming to find a compound that could safely block a liver enzyme involved in cholesterol production. None hit the mark.
The compound from pythium ultimum, a plant fungus, appeared to work in rats, but ravaged their livers.
Then in 1973, Dr. Endo ran tests on penicillium, or blue mold, growing on rice. He was close to giving up on the research, he said. But the blue mold produced promising results in chickens, which had replaced rats as the initial test subject. One strain proved effective in shutting down the cholesterol-triggering enzyme with no liver damage. The compound was later renamed compactin, or mevastatin.
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“The discovery … was like a seesaw,” he recalled, noting the rivalry with Merck that was ahead.
While Dr. Endo moved ahead with more tests — first on dogs and then human trials in 1975 — a research group at Merck had started its hunt for a cholesterol-fighting drug. Merck’s leadership was surprised to learn that Dr. Endo had already hit on mevastatin.
“'I said, ‘Oh, my God, we are behind already,’'' P. Roy Vagelos, a biochemist who later became chairman of Merck, recounted to the New York Times in 2018. “'Then I said: ‘The hell with it. We are a lot faster than they are. Let’s go ahead.’''
The Merck team, led by researcher Alfred Alberts, soon found a compound secreted by the common soil fungus aspergillus with lab results similar to Dr. Endo’s mevastatin. Merck dubbed Alberts’s discovery lovastatin.
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Suddenly, Dr. Endo’s company halted the mevastatin trial. Media reports carried speculation that some of the dogs in the test developed intestinal tumors, but no details were made public. “Rumor … is all that we have to this day,” American Scientist magazine reported in a 2008 account of statin development.
Even Dr. Endo said he never received a clear answer. He had left Sankyo in late 1978 to teach and conduct research at the Tokyo University of Agriculture and Technology. Merck put lovastatin temporarily on hold, but determined it posed no cancer risks. The drug hit the U.S. market as the first statin in a new and booming field of drug research.
“In my opinion, this is the second-most important discovery of the century after penicillin,” Joseph Wu, a cardiologist and president of the American Heart Association, said in an interview. “It is the cornerstone of cardiovascular medicine.”
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For decades, Dr. Endo’s name was mentioned as part of speculation for the Nobel Prize. He displayed no bitterness in public. He once looked back on his career and said he had a “pleasant feeling like after I exercise.”
“Thanks to my success with statins, the dream from my boyhood was realized and I received appreciation from a large number of people from all over the world,” he said. “This is a source of immeasurable joy for me.”
Farming family
Akira Endo was born Nov. 14, 1933, in Yurihonjō, a town in the northern part of Japan’s main island, Honshu. His parents operated a farm and the young Akira often spent long stretches with his grandfather, who was an amateur naturalist and the area’s de facto doctor using herbs and other natural treatments.
After Akira’s grandmother died of an apparent tumor when he was in fourth grade, he decided on a career in medicine, he once wrote.
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His family couldn’t afford university and proposed to buy him a new suit if he abandoned plans for college study, he recalled. He flatly refused the deal. “I don’t need any clothes, let me go to the university. Cut me off from your money,” he said he replied, basically threatening to disown his family. In the end, his high school principal helped arrange a scholarship.
He graduated from Tohoku University in 1957 with a degree agricultural studies and was hired by Sankyo to work in food research, including identifying an enzyme from a parasitic fungus that ended up being used to remove residue pectins from wines and ciders. He received a doctorate in biochemistry at Tohoku in 1966.
Dr. Endo in 2008 received the Lasker Award, commonly known as the American Nobel. He received the Canada Gairdner International Award in 2017 for his contributions to medical science.
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Complete information on survivors was not immediately available.
Throughout his career, Dr. Endo often recounted the story of Alexander Fleming, the doctor who returned to his London lab after a holiday in 1928 and noticed a mold in a petri dish that appeared to block the growth of bacteria. The chance discovery became known as penicillin.
Dr. Endo said one of his favorite titles was being known for finding the “penicillin for cholesterol.”
