Like many newcomers to New York, Akira Endo was struck by the vivid sights and sounds of the bustling metropolis. In Endo’s case, it was not the tourist hotspots but the shapes of the people and the shrieking ambulance sirens that made a lasting impression.
The Japanese biochemist moved from Tokyo in 1966 for a two-year stint working on lipids and enzymes at the Albert Einstein College of Medicine. From a public health perspective it was a culture shock.
“I was very surprised by the large number of elderly and overweight people, and by the rather rich dietary habits of Americans compared to those of the Japanese,” he recalled. “In the residential area of the Bronx where I lived, there were many elderly couples living by themselves and I often saw ambulances going to take an elderly person who had suffered a heart attack to the hospital. At that time, coronary heart disease was the main cause of death in the United States.”
When he returned to Tokyo in 1968 with a renewed appreciation of the relationship between cholesterol levels and heart disease, his employer, the pharmaceutical company Sankyo, allowed Endo to choose his next research project.
As more studies showed a link between “bad” LDL cholesterol levels and coronary heart disease the race was on to find a drug that blocked an enzyme involved in cholesterol regulation, HMG-CoA reductase, and could be tolerated by humans. Harnessing his passion for moulds and mushrooms and operating on a hunch, Endo began searching for such a substance in fungi.
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This quest led to Endo discovering the first statin, a breakthrough that ultimately led to the creation of widely available cholesterol-lowering drugs that transformed cardiovascular treatment and saved countless lives by cutting the risk of heart attacks and strokes.
Endo and his colleague, Masao Kuroda, began cultivating fungal samples in broths in 1971 and tested their enzyme-blocking abilities using rat livers. “It was a bet, just like the lottery,” Endo said.
After more than two years of drudgery and more than 6,000 broths, Endo had his winning ticket: Penicillium citrinum, a fungus related to the mould that grows on old oranges, which he had isolated from a rice sample sourced from a shop in Kyoto. The compound would become known as mevastatin or compactin.
The problem was that it worked only fleetingly in rats. A frustrated Endo had a lucky break one night when he met a colleague at a bar who offered him some hens. He fed them chicken feed laced with mevastatin and found their blood cholesterol levels dramatically decreased. The same held true for dogs and monkeys. However, his worries were not over.
Endo felt that senior management at Sankyo did not fully appreciate the potential of his work and preferred to refine existing drugs. In 1978 he secretly collaborated with a doctor for a clinical study in humans that was not sanctioned by the company. Endo said that his bosses discontinued clinical trials in 1980 amid rumours that dogs had developed lymphoma after being given massive doses. But word of Endo’s success reached Merck, the US-headquartered pharmaceutical giant, and with some help from Sankyo it embarked on its own fungal statin search.
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Lovastatin was approved by the US regulator in 1987 and other companies eagerly leapt into a lucrative market. By one estimate, global sales of statins approached £800 billion by 2020. But Endo said he did not receive any financial reward for his discovery beyond his modest company salary.
One of six siblings, Akira Endo was born to impecunious farmers in Yurihonjo, Akita Prefecture, and formed an interest in mycology and medicine through his grandfather, who taught him about the remarkable properties of the local fungi.
Aged ten he resolved to become a scientist and follow in the footsteps of the Japanese bacteriologist Hideyo Noguchi, who studied syphilis in New York. Endo considered becoming a doctor when his grandmother died of cancer and after he suffered a serious leg burn, but realised he could also save lives through laboratory work.
After working in the fields during the day and attending a rural school in the evening — against the wishes of his parents, who wanted him to focus on farming — he went to senior high school in the city of Akita then attended the Tohoku University College of Agriculture in Sendai. There he read a biography of Alexander Fleming and was spellbound by the life of the Scottish physician and scientist who accidentally discovered penicillin in mould in 1928.
Following graduation in 1957 he joined Sankyo, worked on enzymes in wine and cider and grew interested in cholesterol biosynthesis while earning a PhD in biochemistry from Tohoku in 1966. The company was pleased with his efforts after he tested 250 varieties of fungi to find an enzyme that decreased the pulp in fruit juice, and supported his desire to research cholesterol in America.
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Endo left Sankyo under a cloud: he told a reporter that the firm instructed colleagues not to help him carry his boxes of papers from the laboratory to the removals van. Between 1979 and 1997 he worked at the Tokyo University of Agriculture and Technology, becoming a professor and applying fungal by-products to chewing gum and cosmetics.
After his formal retirement he was a director at a pharmaceutical company and worked as a visiting professor at several Japanese universities, living modestly in Tokyo. He was logical, calm and an enthusiastic teacher of young people who never forgot the challenges he faced pursuing his early education. Endo planted watermelon on land near his home and climbed mountains both for enjoyment and to collect plant and soil samples. He is survived by his wife, Orie, a former Japanese language professor, daughter, Chiga, and son, Susumu, an engineer at a car company. Another son died in a car accident.
He told The Wall Street Journal that at a medical check-up in 2004 he learnt that he had high cholesterol. “We have good drugs for that,” the unwitting doctor reassured him. Yet Endo preferred to lower his cholesterol through diet and exercise rather than take a statin. By way of explanation he cited a Japanese proverb: “The indigo dyer wears white trousers.”
Endo was perhaps unfortunate not to be honoured with a Nobel prize, not least since two American scientists, Michael S Brown and Joseph L Goldstein, did receive one in 1985 for their work on the regulation of cholesterol metabolism. They were influenced by Endo, who had visited Philadelphia to give a talk about drugs affecting lipid metabolism.
“We invited him to stop in Dallas on his way back to Tokyo and when … we met him he was really dejected,” Brown said in a 2012 interview. “He said, ‘No one came to my talk. Why is that? Nobody seems to think it’s important that you can stop cholesterol production.’ But we were very interested and so we arranged a collaboration and we worked together.”
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Still, Endo won other prestigious awards. And especially since Fleming was one of his heroes, it was no small matter for Endo to be hailed by peers as the man who unearthed a “penicillin for cholesterol”.
Akira Endo, statins pioneer, was born on November 14, 1933. He died of pneumonia on June 5, 2024, aged 90