Lasker~DeBakey
Clinical Medical Research Award

Award Presentation by Joseph Goldstein

The human body produces tens of thousands of different molecules. Several of them — DNA, hemoglobin, insulin, estrogen — are household names. But none has captured the public's imagination like cholesterol. Cholesterol is the quintessential celebrity molecule: it appears regularly on the front pages of USA Today and The New York Times, on the covers of Time and Newsweek, and it's the subject of endless Jay Leno jokes, New Yorker cartoons, and cocktail party conversations. Many of you in the room know your cholesterol level, but can't remember your wedding anniversary.

In the last five years, cholesterol has achieved perhaps its greatest distinction: it is among the five most highly searched topics on the Web, joining an elite group that includes Albert Einstein, Michelangelo, Jesus Christ, and — Madonna.

Like Madonna, cholesterol has a good side and a bad side. It's a Dr. Jekyll and Mr. Hyde-type molecule; it's vital and lethal at the same time. Cholesterol's vital role is its essential function in maintaining the integrity of the membranes that surrounds every cell in our body. Cholesterol becomes lethal when it accumulates in the blood in the form of a lipoprotein particle called LDL. LDL is the toxic particle that initiates the atherosclerotic process in arteries, which leads after many years to coronary heart disease and heart attacks.

Coronary disease is responsible for more than one-third of all deaths in the developed world. It is the number one killer in the U.S. As many as 16 million Americans alive today have coronary disease, and 1.2 million will have a new or recurrent heart attack this year. An overwhelming body of evidence — genetic, experimental, epidemiological, and therapeutic — has established a causal link between the cholesterol-carrying LDL particle and coronary disease. Building on that knowledge, scientists and the pharmaceutical industry have successfully developed a remarkably effective class of drugs — the statins — that lower LDL-cholesterol levels in blood and reduce the frequency of heart attacks.

This year's Lasker~DeBakey Clinical Award is given to the scientist — Akira Endo — who discovered the first statin and demonstrated its clinical efficacy. As a child growing up on a farm in Northern Japan, Endo became fascinated with mushrooms and other molds, and as a young boy he read several biographies of Alexander Fleming and the discovery of penicillin in a mold. After obtaining his PhD in biochemistry in 1957, Endo joined the Sankyo Co. in Tokyo as a research scientist. His project was to identify enzymes produced by molds that make fruit juices less pulpy. After 12 years on this project, Endo's efforts led to several commercially successful products, and the Sankyo Co. rewarded him with two bonuses.

The first bonus was a two-year sabbatical in the U.S. where he worked on phospholipids in the department of a great biochemist, Bernard Horeker at the Albert Einstein Medical Center here in New York City. Sankyo's second bonus to Endo — one that is rarely if ever granted to a scientist in a pharmaceutical company — was the opportunity to work for two years on a project totally of his own choosing. So, in 1970 Endo and his colleague, Masao Kuroda, began a search for inhibitors of cholesterol synthesis, reasoning that a decrease in cholesterol production in the body would lower cholesterol levels in the blood and thus decrease coronary disease.

Inspired by Fleming's success with molds, Endo began searching fungal cultures for secreted natural products that would inhibit cholesterol synthesis in an homogenate of rat liver. Endo's assay was anything but simple: it was complicated, cumbersome, and capricious, involving the conversion of a radioactive 2-carbon precursor molecule into the final 27-carbon cholesterol, a sequence of reactions requiring the concerted performance of 25 different liver enzymes. For two years, Endo and Kuroda toiled day and night, screening through 6000 different fungal extracts, but with no success. Finally, as their deadline was approaching and the project was winding down, on March 15, 1972, Endo hit pay dirt — literally and figuratively — in a strain of Penicillium citrinum that grew in the rice fields near Kyoto. The extract from this 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. Atherosclerosis, beware!

Even though the Sankyo Co. in 1972 was not keenly interested in developing cholesterol-lowering drugs, they nonetheless permitted the project to continue. Endo spent the next several years purifying the inhibitor, working out its structure, and identifying HMG CoA reductase as the target enzyme in the cholesterol pathway that was inhibited by their drug, known today as compactin. In 1976 Endo published two papers reporting the discovery and characterization of compactin, the first statin.

The next chapter in the statin story involved a series of animal experiments in which Endo showed that compactin lowered the plasma cholesterol level in dogs and in monkeys. The success of these studies led Endo to a surreptitious clinical study in patients — a study that was neither sanctified nor sanctioned by Sankyo.

Not being a clinician, Endo procured the collaboration of Akira Yamamoto, an astute physician at the National Cardiovascular Centre in Osaka. Yamamoto gave oral compactin to 11 patients with genetic forms of hypercholesterolemia, all of whom had been poorly responsive to available cholesterol-lowering drugs. A dramatic result was observed: compactin was extremely effective in lowering plasma cholesterol. Yamamoto had never seen such an effective response. Endo and Yamamoto published their pioneering studies in an obscure journal in 1980, one year after Endo had left Sankyo for an academic position at Tokyo Noko University. One year later, in 1981, the second clinical study on compactin was published in a not-so-obscure journal, the New England Journal of Medicine, and the world took note. A Japanese team, led by Hiroshi Mabuchi of Kanazawa University, reported that compactin reduced LDL, the bad cholesterol, but did not lower HDL, the good cholesterol. I'll come back to the significance of this key observation in a moment.

By early 1978, many pharmaceutical companies, although originally skeptical about the safety of inhibiting cholesterol synthesis in the body, had learned of Endo's results and jumped on the statin bandwagon, feverishly searching microorganisms for HMG CoA reductase inhibitors. The race to the finish line was won by the Merck Sharp & Dohme Research Laboratories. Led by biochemist Alfred W. Alberts, Merck scientists in 1979 identified a molecule, secreted by an Aspergillus mold, that differed from compactin by only 4 atoms. Merck's molecule, called lovastatin (Mevacor®), became the first statin to be approved for human use 8 years later in 1987. Today, more than a half a dozen statins (both natural products and totally synthetic versions) have been developed and commercialized, the most popular being Pfizer's atorvastatin (Lipitor®) and Merck's simvastatin (Zocor®).

Statins have now been tested in 14 large randomized multicenter trials, involving an unprecedented 90,000 middle-aged adults who were followed for 5 years. The results in all 14 studies have been astonishingly consistent: treatment with statins lowers plasma LDL levels by 25-35% and reduces the frequency of heart attacks by 25-30%. The percentage reduction in coronary events would be even more dramatic if the treatment were longer — say 10 or 15 years — and if statin therapy were started 20 years earlier — say age 30 or 40 — when clinically silent atherosclerotic plaques are fewer and smaller.

A noteworthy aspect of the 14 statin trials is that no major harmful effects of lowering cholesterol were observed in any of the studies. The remarkable safety of statins derives from their unique mechanism of action. When a statin is ingested, the drug is absorbed by the intestine and routed primarily to the liver where it binds and inhibits HMG CoA reductase, lowering cholesterol production. This decrease in liver cholesterol triggers a compensatory feedback loop that increases the number of LDL receptors displayed on the liver cell membrane. These LDL receptors grab onto LDL, remove it from the blood, and deliver it to the interior of the cell where the LDL is digested and its released cholesterol becomes available for metabolic purposes. The net effect is that the amount of cholesterol in the liver is maintained at a normal level while at the same time the level of LDL-cholesterol in blood is kept low. As an added dividend, the elevated LDL receptors don't grab HDL and the blood level of the good cholesterol doesn't drop. If all drugs worked in such a perfect way, the drug industry would be in perpetual pharmaceutical heaven.

The statins are the largest selling class of drugs currently taken by patients throughout the world. Sales for this one class of drugs in 2007 were $34 billion — $34 billion. That's a hell of a lot of money — even by Mayor Bloomberg's standards. Today, an estimated 30 million people worldwide are taking statins, including 30% of all Medicare patients in the US. The millions of people whose lives will be extended through statin therapy owe their good fortune to the immense contributions of Akira Endo. Without the exuberant unpredictability of Endo's hunt through 6000 fungal extracts 38 years ago, statins might never have been discovered. Moreover, statins might never have become approved drugs were it not for the pharmaceutical clout of Merck, which in those days was under the leadership of Roy Vagelos and his talented team of colleagues that included, in addition to Al Alberts, Jonathan Tobert, Richard Monaghan, George Albers-Schonberg, James MacDonald, and Edward Scolnick.

Despite the triumphant success of Endo's approach to drug discovery, the major pharmaceutical companies have largely abandoned the screening of natural products created by evolution in favor of the screening of synthetic chemical libraries created by modern-day chemical biologists. No random man-made library, no matter how large, would ever be expected to yield an HMG CoA reductase inhibitor with the potency and selectivity of Endo's first statin. The complex structure of compactin, containing seven asymmetric carbon atoms, evolved over billions of years of evolution to target HMG CoA reductase's catalytic site by mimicking its natural substrate (HMG CoA). To paraphrase the second law of Leslie Orgel, the great British chemist, evolution is smarter than any chemical biologists.

So now for the $34 billion question. Does Dr. Endo take a statin? In an interview with the Wall Street Journal 3 years ago, Endo told the reporter that his LDL-cholesterol was elevated at 155 (a normal level being under 100), but he was not taking a statin at that time. In offering an explanation for why the discoverer of statins would dismiss his own discovery, Endo invoked a Japanese proverb: "The indigo dyer wears white trousers." But, as you'll see in a moment, Dr. Endo is now wearing black trousers. I'll leave it to him to tell us whether he's now taking a statin and which one.