Kagaku to Seibutsu 56(3): 139 (2018)
Tribute to Dr. Akira Endo
© 2018 Japan Society for Bioscience, Biotechnology, and Agrochemistry
© 2018 公益社団法人日本農芸化学会
Coronary disease causes one-third of all deaths in the developed world. The knowledge that low-density lipoprotein (LDL) causes coronary disease led to development of a class of drugs—called statins—that lower LDL in blood and reduce heart attacks.
The first stain was discovered by Akira Endo, who received the 2017 Gairdner Prize and the 2008 Lasker Award. As a child growing up on a farm in Japan, Endo became fascinated with mushrooms and other molds, and he read stories of how Alexander Fleming discovered penicillin in a mold. After obtaining his PhD in biochemistry in 1957, Endo joined the Sankyo Co. in Tokyo as a research scientist. Sankyo recognized his biochemical expertise and allowed him to take a 2-year postdoctoral fellowship (1966–68) in the United States at the Albert Einstein College of Medicine where he worked with Professor Bernard Horecker on enzymes involved in phospholipid synthesis.
Inspired by Fleming’s success with molds, Endo screened fungal cultures for natural products that would inhibit cholesterol synthesis in rat liver. For two years, Endo toiled day and night, screening 6000 different fungal extracts, but with no success. Finally, on March 15, 1972, he hit pay dirt—literally and figuratively—in a mold that grew in the rice fields near Kyoto. Endo’s magic mold produced a powerful inhibitory activity. Historians of science will come to view the Ides of March, 1972 as the day that cholesterol was assassinated.
Endo spent the next several years purifying the inhibitor and identifying HMG CoA reductase as the target enzyme in the cholesterol pathway that was inhibited by his drug, known as compactin. In 1976 Endo published two papers reporting the discovery of compactin, the first statin. He and his collaborators then carried out animal experiments and one human study showing that compactin reduced LDL, the bad cholesterol, but did not lower HDL, the good cholesterol.
By 1978, many pharmaceutical companies jumped into the game, feverishly screening microorganisms for HMG CoA reductase inhibitors. In 1987, Merck’s molecule, called lovastatin (Mevacor®), became the first statin to be approved for human use. Today, more than a half a dozen statins are available for patients, the most popular being atorvastatin (Lipitor®).
Statins have now been tested in at least 27 randomized placebo-controlled trials, involving more than 170,000 middle- aged adults followed for 5 years. The results in all studies are remarkably consistent: statins lower LDL levels by 30%, reduce heart attacks by 30%, and extend life.
How do the statins lower LDL without major side effects? When a statin is ingested, it is absorbed by the intestine and routed to the liver where it inhibits HMG CoA reductase and lowers cholesterol production. This decrease in liver cholesterol triggers a compensatory feedback loop that increases receptors on the liver cell membrane that grab onto LDL, remove it from the blood, and deliver it to the interior of the cell. Once inside the cell, LDL is digested and its cholesterol becomes available for metabolic purposes. The net effect is that cholesterol in the liver is restored to normal, while LDL in the blood is kept low—a beautiful system of homeostasis. Today, an estimated 30 million people worldwide take statins every day. The millions whose lives are extended through statin therapy owe their good fortune to the revolutionary discovery of Akira Endo.
What other miracle drugs lie in the fungi of Japan? Tragically, we may never know. Pharmaceutical companies have largely stopped screening fungi. Instead, they now rely on vast libraries of chemicals synthesized in the laboratory. These libraries cannot compare with the complexity and diversity that Nature has produced over 4 billion years of evolution. The world needs more Endos and more Sankyos with the courage and the conviction to identify the useful chemicals that Nature has created.