Alfred W. Alberts, Arthur A. Patchett, and Georg Albers-Schönberg
Alfred Alberts in the laboratory in 1963. Courtesy Merck Archives, Merck & Co., Inc.
Cholesterol is a critical component of cell membranes, and steroid hormones and bile acids are synthesized from it in our bodies. Yet we are reminded daily by advertisements and items in the news about low-density lipoprotein (LDL), or “bad,” cholesterol and its harmful deposition in our arteries, which can lead to heart attacks and strokes. Only about 30 percent of the cholesterol in the human body comes from the food we eat; the remaining 70 percent is synthesized by the body itself. This synthesis takes place mainly in the liver, starting with acetic acid, which can be derived from a wide variety of sources. Clearly, modifying dietary intake of cholesterol can only partially alleviate the cholesterol problem that many people face—much of it owing to hereditary flaws in their biochemistries. In the 1970s researchers at Merck and Company discovered that lovastatin (trade named Mevacor), the product of a mold, could intervene effectively in the biosynthesis of cholesterol.
Arthur Patchett at the blackboard in 1962. Courtesy Merck Archives, Merck & Co., Inc.
When they began their research, the Merck scientists already knew a great deal about the steps of this synthesis because of previous research in the field. The synthesis begins with the condensation of acetic acid into isoprene units via the key intermediate of mevalonic acid; then the pathway, leaving out details, leads from squalene to lanosterol to cholesterol. It was Merck’s own Karl Folkers who discovered mevalonic acid in 1956. At every step of the way researchers found enzymes and also coenzymes—organic substances that are required, in addition to an enzyme and a substrate, for an enzymatic reaction to proceed.
They also knew from the work of other researchers that there were LDL receptors on the surface of cells that serve as conduits for cholesterol, which is taken out of the bloodstream and then used in the cell or excreted. And an early anticholesterol drug, cholestyramine (which Merck scientists had discovered in the 1950s), actually worked—for a while. It stimulated the increase of LDL receptors in the liver, thus increasing the amount of LDL excreted as bile acid, but unfortunately it also triggered an increase in the liver’s synthesis of cholesterol. An obvious target for researchers became the cholesterol synthesis itself.
Georg Albers-Schönberg, circa 1990. Courtesy Merck Archives, Merck & Co., Inc.
In pursuing this line of research, Merck sought the advice of P. Roy Vagelos, an expert on the metabolism of fats (lipids) and at the time a faculty member at Washington University in St. Louis. In 1975 Vagelos joined Merck as senior vice president in pharmaceutical research, a position from which he rose to become Merck’s chairman and CEO. He brought with him his longtime associate Alfred W. Alberts (b. 1931). Alberts, while still in graduate school, was originally hired to assist Vagelos at the National Institutes of Health (NIH). A native of Brooklyn, Alberts had completed a bachelor’s degree in biology at Brooklyn College in 1953, had served in the army, and was completing course work for a Ph.D. in zoology at the University of Maryland. One of his professors at Maryland, a noted enzymologist and Vagelos’s chief at NIH, announced in class that there were some openings for laboratory workers at NIH, and Alberts leaped at this opportunity. The work with Vagelos turned out to be so interesting that Alberts never returned to Maryland to complete his dissertation.
When Alberts arrived at Merck, he set about putting together an in vitro assay that focused on a key step early in the cholesterol synthesis. This reaction is, in turn, controlled by a feedback loop that is, in part, dependent on the level of LDL cholesterol in the bloodstream. Alberts planned to screen microbial extracts for substances that would inhibit the action of an enzyme critical to the synthesis of mevalonic acid.
Meanwhile Akira Endo at Sankyo Laboratories in Japan was working on a similar project. In 1976, after screening thousands of microbial extracts, Endo announced that he had discovered a substance—mevastatin, isolated from the mold Penicillium citrinum—that reduced cholesterol production by acting on the same step in the biosynthesis as Alberts’s target. Mevastatin (also known as compactin) was also isolated by scientists at Beecham Research Laboratories in England as a potential antifungal, compactin.
Information arriving from both the Japanese and the English researchers confirmed Alberts’s belief that he had taken the right track, which inspired the Merck team to redouble their efforts. Alberts then turned to Arthur A. Patchett (b. 1929), director of Merck’s New Lead Discovery department, to provide microbial broths maintained in Merck’s fermentation products for screening (FERPS) system that could be submitted to the assay he had designed to find an appropriate enzyme inhibitor. Patchett had been at Merck for 20 years, having joined the company soon after receiving a Ph.D. from Harvard University in organic chemistry. At Harvard he had worked with Robert Burns Woodward on synthesizing lanosterol and understanding its role in the biosynthesis of cholesterol. Almost simultaneously with the work that he was doing with Alberts, Patchett was working on enalapril (Vasotec), Merck’s angiotensin-converting enzyme (ACE) inhibitor (see Miguel Ondetti).
In late September 1978, Alberts was ready to begin his assay. His assistant prepared special glass tubes containing mixtures of the enzyme that Alberts wanted to inhibit and its radioactively tagged substrate—reactants that would normally produce mevalonic acid. The microbial extracts were then placed in the tubes—a single extract in each one. If an extract had no effect on the reaction, radioactive mevalonic acid would appear and could be separated out. If, however, the extract inhibited the reaction, little or no radioactive mevalonic acid would be found. First Alberts’s group tested some hundred samples from FERPS that had been used in other assays, and mevalonic acid was produced in the presence of each of them. Next Patchett’s group sent over 20 or so new extracts, and surprisingly the tube with the 18th sample produced no mevalonic acid whatsoever. After ruling out accidents—such as leaving out the enzyme—Alberts was delighted to conclude that there was indeed a substance in this extract that would interrupt the body’s synthesis of cholesterol.
But was it the same substance that the Japanese and English investigators had already discovered? To determine this, Alberts needed the assistance of expert analytical chemists. Carl Hoffman from Patchett’s laboratory isolated the active principle from the extract, and Georg Albers-Schönberg (b. 1929) set to work determining the molecular structure of the isolated substance from its mass spectra and nuclear magnetic resonance (NMR).
The child of a German father and a Swiss mother, Albers-Schönberg received his secondary and higher education in Switzerland during and shortly after World War II. After earning a doctorate in organic chemistry from the University of Zurich, he accepted a postdoctoral fellowship at the Massachusetts Institute of Technology. At MIT he carried out the synthesis of natural products, deploying the new physical methods of structural determination, including NMR techniques. At the end of this fellowship, in 1965, Albers-Schönberg accepted a position at Merck Research Laboratories. Among the projects at Merck to which he contributed shortly before his work on lovastatin was the development of ivermectin, an effective treatment for river blindness, a disease that used to infect and blind millions of people living in tropical countries around the world.
Albers-Schönberg was given the newly isolated active principle that prevented the production of mevalonic acid on a Friday afternoon. He and his associates were scheduled to make a report on the material’s structure at a meeting on the following Monday, so they worked furiously through the weekend. Mass spectra showed right away that the structure was very similar to that of mevastatin. Indeed, NMR techniques showed that the Merck molecule differed from mevastatin by only a single additional methyl group. But as subsequent studies showed, that group had a big effect on potency, making Merck’s substance, which they named lovastatin, two to three times more powerful than mevastatin in reducing cholesterol levels.
The long weekend in the laboratory paid off. Although Endo also discovered this more powerful molecule, a U.S. patent for lovastatin was granted to the Merck scientists in 1980. The drug was approved by the U.S. Food and Drug Administration in 1987 after rigorous clinical testing. Since that time other anticholesterol drugs have come on the market, and Merck itself has produced a semisynthetic version of lovastatin, trade named Zocor.