Discoverer Of Cholesterol Lowering Drugs Receives Lasker Award
Akira Endo wins The Lasker award for the discovery of the statins - drugs with remarkable LDL-cholesterol-lowering properties that have revolutionized the prevention and treatment of coronary heart disease.
The 2008 Lasker~DeBakey Award for Clinical Medical Research honors a scientist who discovered statins—drugs with remarkable LDL-cholesterol-lowering properties that have revolutionized the prevention and treatment of coronary heart disease (CHD). Akira Endo (Biopharm Research Laboratories, Inc., Tokyo) sifted through thousands of organisms, hunting for natural substances that block a key enzyme in the biochemical pathway that produces cholesterol, a major contributor to CHD. Remarkably, the compound that Endo found lowers concentrations of LDL (the bad cholesterol) but not HDL (the good cholesterol) in the bloodstream of animals and humans. His work stimulated Merck, Sharp & Dohme Research Laboratories (Merck) to launch a drug-development program that led, 20 years ago, to the first statin approved for medical use. This advance paved a path for other pharmaceutical companies to follow.
LDL in the bloodstream can form fatty deposits that narrow blood vessels. When this process occurs in arteries that deliver blood to the heart, it can lead to CHD, the major cause of chest pain and heart attack and the top killer in the industrialized world. In the US, more than 450,000 people died from CHD in 2004. In 2005, the American Heart Association estimated that 16 million Americans had CHD and 1.2 million would have a new or recurrent heart attack that year. Statin use is increasing—30 million people worldwide are taking them—and has begun to make a dent in those numbers. The drugs dramatically reduce the risk of CHD and its associated life-threatening events. Furthermore, studies with statins have erased long-standing doubt about the possibility of safely reducing cholesterol quantities with pharmaceutical agents.
Promising Early Results
In the 1950s and 1960s, epidemiological studies suggested a link between LDL cholesterol in the blood and CHD. Reducing LDL would shrink the incidence of this illness, some experts reasoned. However, many scientists and clinicians questioned whether doing so would stir trouble. Cholesterol is a crucial component of the membranes that encase our cells, and it serves as a raw material for other essential molecules, including some hormones and the sheath that insulates nerves. Further exacerbating uncertainty, most early agents that reduced cholesterol quantities in the blood cut concentrations only modestly and triggered unwelcome side effects. Therefore, skepticism simmered about the wisdom of lowering cholesterol concentrations.
Despite the concerns, efforts pushed forward. Humans acquire cholesterol from food and we also make it in our bodies, mostly in the liver. Dietary interventions to limit cholesterol intake had met with poor success and the idea of short-circuiting our ability to produce the compound seemed attractive. An enzyme called HMG-CoA reductase plays a central role in the manufacture of cholesterol. In the biochemical pathway that generates cholesterol, it converts a precursor molecule, HMG-CoA, into the next compound, mevalonate.
By 1971, when Endo began his work (at Sankyo Company in Tokyo), thwarting the reductase seemed like a possible way to keep the body's cholesterol production in check. Endo had a novel idea about how to find substances that block the reductase. Aware that organisms can secrete compounds with powerful biological activities—presumably to kill their competitors—Endo proposed that some creatures might spit out chemicals that foil the reductase and thus impede a vital activity of their neighbors.
Over the next two years, Endo and colleagues grew more than 6000 fungi, harvested the broth in which each had grown, and tested whether the material could interfere with an early step of cholesterol synthesis in a test tube. They then separated its components from one another, keeping track of the active material. By this and additional methods, he purified a substance from the fungus Penicillium citrinum, called mevastatin or compactin, that blocks the reductase.