The Japanese biochemist Akira Endo, who has died aged 90, was the creator of the first statin, a drug that lowers low-density lipoprotein (LDL) cholesterol, through his pioneering work with mushroom extracts. Endo believed – and eventually proved – that fungi could produce a substance to block cholesterol production.
Known as “bad” cholesterol, LDL cholesterol narrows the arteries, increasing the likelihood of a heart attack or stroke. First licensed in 1987, statins have been a game-changer in the treatment of heart disease. Today, around 200 million people take them daily and they are the most widely prescribed drugs in the UK.
Endo, who received no praise at the time, and never any royalties, was nonetheless highly respected in scientific circles. Michael Brown and Joseph Goldstein, who won a Nobel Prize in 1985 for their own work on cholesterol, said: “The millions of people whose lives will be extended by statin therapy are all thanks to Akira Endo and his search through mushroom extracts .”
In the early 60s, the link between LDL cholesterol and heart disease was well known, and safe, effective anti-cholesterol drugs were urgently needed: in 1961, half of all deaths in the UK were attributable to cardiovascular disease. But efforts to create a drug to lower cholesterol have been at a standstill: the drug Triparanol, for example, introduced in 1960, had to be quickly withdrawn because it caused cataracts and other problems.
Endo grew up learning about the properties of plants and fungi from his grandfather, an herbalist. He was also inspired by the Scottish scientist Alexander Fleming, who isolated the first antibiotic, penicillin, from a mold he found in a petri dish in 1928. The natural world, it seems, can yield important medicines.
In the 60s, Endo worked for the Japanese pharmaceutical company Sankyo in Tokyo. He knew that the enzyme HMG-CoA reductase in the liver is essential for making cholesterol. He wanted to target it and in 1971 he had his chance
when Sankyo offered him two years to work on a “blue sky” project of his choosing.
Endo spent that time analyzing approximately 6,000 mushroom extracts. He figured there might be fungi with chemicals that interfere with cholesterol production as a defense against predatory microbes that need cholesterol to grow.
On March 15, 1972, he struck lucky with a strain of Penicillium citrinum. He said: “My team and I shouted for joy and toasted our success. The blue-green form that grows naturally on rice and fruit has stopped the enzyme HMG-CoA reductase in its tracks. Endo extracted the active compound – citrinin – to create a statin drug called compactin. In 1976, he published a paper that announced it to the world as the first statin.
Compactin was effective in laboratory tests and on animals, but Sankyo did not want to take it forward to human trials, preferring to refine their existing drugs. So Endo secretly reached out to Akira Yamamoto, a physician at the National Cerebral and Cardiovascular Center in Osaka. In 1978, Yamamoto gave compactin to 11 patients with very high cholesterol levels and was impressed with the results.
Endo showed the results to Sankyo, who agreed to put compactin into human trials, but stopped it in 1980 over concerns about a side effect it had in animals. By then, however, his research was in the hands of a competitor. In 1976, Sankyo signed an agreement with Merck Research Laboratories in the US, which gave Merck access to some of Sankyo’s data, including Endo’s. Merck quickly saw the commercial potential and raced to produce a statin from another fungus, chemically different from compactin by only four atoms. They began large-scale trials and brought their drug, lovastatin, under the brand name Mevacor in 1987 as the first statin licensed for use.
Disillusioned with Sankyo, Endo accepted a professorship at the Tokyo University of Agriculture and Technology in late 1978. He didn’t leave in the best way, claiming Sankyo even instructed colleagues not to help him carry out boxes of papers.
Despite not being recognized at the time, Endo was honored with the Japan Prize in 2006 and in 2008 he received a Lasker Award, sometimes described as “the American Nobel”.
Endo, who was born near Yurihonjo in Japan’s Akita Prefecture, grew up in a farming family. While his parents looked after the farm, Endo spent time with his herbalist grandfather, who lived with the family.
After high school in Akita, Endo went to Tohoku University’s agricultural college in Sendai in 1953 to study biochemistry, and in 1957 he joined Sankyo, where his main project was a pectinase enzyme that broke down turbidity in apple juice, wines and ciders has. For his research in this area, he received a PhD from Tohoku University in 1966.
Endo became interested in cholesterol in the mid-60s. He wrote to the American scientist Konrad Bloch, who won the Nobel Prize in 1964 for his work on the substance. However, Bloch’s class was full, so Endo hired a student from the biochemist Bernard Horecker at Albert Einstein College Medicine in New York in 1966. While there, he was amazed to see so many Americans “the size of sumo wrestlers” and to see ambulances transporting heart attack patients to the hospital. “My experience in New York made me realize the importance of developing an effective cholesterol-lowering drug,” he said.
Endo returned to Japan in 1968 to continue working for Sankyo. At the University of Tokyo from 1978 he continued to investigate fungi for their use in cosmetics, chewing gum and other products. He also became a director of Biopharm Research Laboratories.
He is survived by his wife, Orie, daughter, Chiga, and son, Osamu.
