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 fungal extracts. Endo believed – and eventually proved – that fungi could yield a substance to block cholesterol production.
Known as “bad” cholesterol, LDL cholesterol narrows the arteries, raising the likelihood of a heart attack or stroke. First licensed in 1987, statins were a game-changer in the treatment of heart disease. Today, approximately 200 million people take them daily and they are the most commonly prescribed drugs in the UK.
Endo, who received no plaudits at the time, and never any royalties, was nevertheless much 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 through statin therapy owe it all to Akira Endo and his search through fungal extracts.”
In the early 60s the link between LDL cholesterol and heart disease was well known, and safe, effective anti-cholesterol medicines were urgently needed: in 1961, half of all deaths in the UK were attributable to heart and circulatory disease. But attempts to create a drug to lower cholesterol were in the doldrums: the drug Triparanol, for example, introduced in 1960, had to be swiftly withdrawn due to it causing cataracts and other issues.
Endo grew up learning about the properties of plants and fungi from his grandfather, a herbalist. He was also inspired by the Scottish scientist Alexander Fleming, who isolated the first antibiotic, penicillin, from a mould he found in a petri dish in 1928. The natural world, it seemed, could yield important medicines.
In the 60s Endo was working for the Japanese pharmaceutical company Sankyo in Tokyo. He knew the enzyme HMG-CoA reductase in the liver was vital to making cholesterol. He wanted to target it and in 1971 had his chance
, when Sankyo offered him two years to work on a “blue sky” project of his choosing.
Endo spent that time analysing about 6,000 fungal extracts. He reckoned there might be fungi with chemicals that interfered with cholesterol production as a defence against predatory microbes requiring cholesterol to grow.
On 15 March 1972 he struck lucky with a strain of Penicillium citrinum. He said: “My team and I shouted with joy and toasted our success.” The blue-green mould that grows naturally on rice and fruit stopped the enzyme HMG-CoA reductase in its tracks. Endo extracted the active compound – citrinin – to create a statin drug named compactin. In 1976 he published a paper announcing 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 Centre 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 halted them in 1980 over concern about a side-effect it had in animals. However, by then his research was in the hands of a competitor. In 1976 Sankyo had signed an agreement with Merck Research Laboratories in the US, which gave Merck access to some of Sankyo’s data, including Endo’s. Merck swiftly spotted the commercial potential, and raced to produce a statin from another fungus, which differed chemically from compactin by just four atoms. They began large-scale trials and brought their drug, lovastatin, to market under the brand name Mevacor in 1987 as the first statin licensed for use.
Disenchanted at Sankyo, Endo had accepted a professorship at Tokyo University of Agriculture and Technology at the end of 1978. He did not leave on the best of terms and claimed Sankyo had even instructed colleagues not to help him carry out boxes of papers.
Despite not being recognised at the time, in 2006 Endo was honoured with the Japan prize and in 2008 he received a Lasker award, sometimes described as “the American Nobel”.
Born near Yurihonjo in the Akita prefecture of Japan, Endo grew up in a farming family. While his parents tended 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 college of agriculture in Sendai in 1953 to study biochemistry, and in 1957 joined Sankyo, where his main project was a pectinase enzyme that broke down cloudiness in apple juice, wines and ciders. For his research in this area, he received a PhD in 1966 from Tohoku University.
Endo had become interested in cholesterol in the mid-60s. He wrote to the American scientist Konrad Bloch, who had won the 1964 Nobel prize for his work on the substance. However, Bloch’s class was full, so Endo became a student of the biochemist Bernard Horecker at the Albert Einstein College of Medicine in New York in 1966. While he was there, he was astonished at seeing so many Americans “the size of sumo wrestlers”, and seeing ambulances ferrying heart attack patients to hospital. “My experience in New York made me realise the importance of developing an effective cholesterol-lowering agent,” he said.
Endo returned to Japan in 1968 to continue working for Sankyo. At Tokyo University from 1978, he continued to research 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.
