Obituary for Akira Endo

Japanese biochemist Akira Endo has died aged 90; through his groundbreaking work using fungal extracts as precursors he invented the first statin drug used to reduce low-density lipoprotein cholesterol levels (LDL cholesterol). Endo hypothesized and eventually demonstrated that fungi could produce an inhibitor to LDL cholesterol production – more commonly referred to as “bad” cholesterol because it narrows arteries, increasing risk for heart attacks or stroke. Starting their release into circulation in 1987, statins revolutionized heart disease treatment. Today, approximately 200 million people use them daily and they are the most commonly prescribed drug in the UK. Endo, though he never received accolades or royalties himself, was greatly revered among scientists at his time and afterwards. Michael Brown and Joseph Goldstein, recipients of a Nobel prize in 1985 for their own research into cholesterol, noted: “Millions of lives who will benefit from statin therapy owe it all to Akira Endo’s investigation of fungal extracts. Early 1960s studies highlighted a correlation between LDL cholesterol and cardiovascular disease and safe, effective anti-cholesterol medications – specifically half of UK deaths were attributable to heart and circulatory illness at this time! In 1961 alone. However, attempts at creating an anticholesterol medication were futile: Triparanol introduced in 1960 was quickly pulled due to causes including cataracts. Endo learned the properties of various plants and fungi from his grandfather – who himself was an herbalist – growing up as part of an herbalist family. “He was also inspired by Scottish scientist Alexander Fleming, who discovered penicillin from mold growing on a petri dish in 1928. ” Endo recognized that nature could provide crucial medicines. Working for Japanese pharmaceutical company Sankyo in Tokyo in the 1960s, Endo realized HMG-CoA reductase enzyme in liver was vital in producing cholesterol. He set his sights on it, and in 1971 was granted an opportunity by Sankyo: two years to work on any “blue sky project” of his choosing; during which Endo conducted extensive analysis on roughly 6,000 fungal extracts. On 15 March 1972 he made an important discovery: Penicillium citrinum strain PC1130! He predicted this bacteria might produce chemicals which blocked cholesterol production as protection from predatory microbes requiring cholesterol for their own survival. On that fateful day he discovered it! Endo’s team and himself exclaimed with joy as the blue-green mould found naturally on rice and fruit stopped HMG-CoA reductase from functioning, and Endo extracted its active compound – citrinin – to formulate compactin as a statin drug. In 1976 he published a paper to announce Compactin as the world’s inaugural statin drug. Though effective in laboratory and animal tests, Sankyo decided not to move ahead with human trials because their existing products needed refining rather than expanding upon this one. Endo reached out in secret to Akira Yamamoto, an Osaka physician at the National Cerebral and Cardiovascular Centre. In 1978, Yamamoto administered compactin to 11 patients with extremely high cholesterol levels and was highly impressed by the results. Endo showed these to Sankyo who agreed to start human trials but discontinued these midway due to concerns regarding side-effects seen with animal trials. However, his research had already fallen into another competitor’s hands by then: in 1976 Sankyo signed an agreement with Merck Research Laboratories in the US that permitted access to some of their data including that belonging to Endo. Merck quickly identified its commercial potential, and set about producing another statin derived from another fungus with only four differences chemically between it and compactin. Starting large-scale trials and eventually marketing their drug under the name Mevacor in 1987 as the world’s first licensed statin drug was made easier when Endo took on a professorship position at Tokyo University of Agriculture and Technology nearing the end of 1978 after becoming disenchanted at Sankyo. Unable to leave on good terms with Sankyo, Endo claimed they instructed his colleagues against helping carry his boxes of papers out the door. Although not recognized at first glance, Endo would later receive both the Japan Prize in 2006 and Lasker award, sometimes known as “the American Nobel”, in 2008. Born near Yurihonjo in Akita prefecture of Japan into a farming family background; Endo now works for Sankyo. As his parents tended the farm, Endo spent time with his herbalist grandfather who lived with the family. Following high school in Akita in 1953, Endo enrolled at Tohoku University’s college of agriculture in Sendai to study biochemistry; upon completion he joined Sankyo to work on creating a pectinase enzyme to remove cloudiness in apple juice, wines, and ciders. Endo was awarded his PhD by Tohoku University for his studies of cholesterol in 1966. Beginning his interest in it during the mid-60s, Endo wrote to American scientist Konrad Bloch (winner of a 1964 Nobel prize in Biomedicine/Chemotherapy/Physiology or Medicine), who had written extensively on its effects and implications. Endo was initially accepted into Bloch’s class; however, due to limited spaces he eventually studied biochemist Bernard Horecker at Albert Einstein College of Medicine in New York in 1966. Whilst in Japan, he was amazed to witness so many Americans “the size of sumo wrestlers”, as well as ambulances transporting heart attack patients directly into hospitals. “My experience in New York helped me understand the critical nature of creating an effective cholesterol-reducing agent,” Endo noted. Afterward, he returned to Japan where he continued working for Sankyo. Beginning his research at Tokyo University in 1978, Akira Endo researched fungi used for cosmetics and chewing gum products; later becoming director of Biopharm Research Laboratories. Survived by wife Orie; daughters Chiga and Osamu;