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Michael S. Brown

1996 AACC Lectureship Award

Michael S. Brown was born on April 13, 1941, in Brooklyn, NY. When Brown was 11, the family moved to Elkins Park, PA, a suburb of Philadelphia, where Brown attended Cheltenham High School. An amateur radio operating license obtained at age 13 led to a lifelong fascination with science. A serious interest in journalism also developed early. These two passions- science and writing- have remained paramount.

Brown graduated in 1962 from the University of Pennsylvania, with chemistry as his major subject. He spent most of his time at the headquarters of the student newspaper, the Daily Pennsylvanian, where he served as features editor and editor-in-chief. In 1964 he married Alice Lapin, a companion from childhood. They have two daughters: Elizabeth (born in 1973) and Sara (born in 1977). In 1966 Brown received the M.D. degree from the University of Pennsylvania School of Medicine. The next two years were spent as intern and resident in Internal Medicine at the Massachusetts General Hospital in Boston. Here Brown met Joseph L. Goldstein, a fellow intern, and the two established the friendship that led to their long-term scientific collaboration.

The years 1968–1971 were spent at the National Institutes of Health, where Brown served initially as clinical associate in gastroenterology and hereditary disease. He then joined the Laboratory of Biochemistry, headed by Earl R. Stadtman, a pioneer in the disclosure of the mechanisms by which enzymes are regulated.

In 1971 Brown joined the Department of Internal Medicine at the University of Texas Southwestern Medical School in Dallas. His selection of Dallas was strongly motivated by his friendship with Goldstein, who had graduated from the Southwestern Medical School. In Dallas, Brown came under the influence of Donald W. Seldin, chairman of the Department of Internal Medicine, an inspirational figure whose passion for medical science shaped the lives of a generation of Texas students.

Soon after his arrival in Dallas, Brown succeeded in purifying an enzyme that catalyzes the rate-controlling reaction in cholesterol biosynthesis. He and Goldstein had developed the hypothesis that abnormalities in the regulation of this enzyme were the cause of familial hypercholesterolemia, a genetic disease in which excess cholesterol accumulates in blood and tissues. The formal scientific collaboration with Goldstein began one year later, in 1972, just after Goldstein returned to Dallas from a postdoctoral fellowship in Seattle. The two young physicians initially maintained separate laboratories, but by 1975 the laboratories had been joined.

Together Brown and Goldstein elucidated the biochemical and genetic mechanisms that regulate the level of cholesterol in blood and cells. In 1974 the two young scientists discovered that human cells possess on their surfaces a protein that they called the low-density lipoprotein (LDL) receptor. This receptor binds a cholesterol-carrying protein called LDL, which circulates in blood. The receptor carries the LDL into the cell by a process called receptor-mediated endocytosis, a fundamental pathway that was also discovered by Brown and Goldstein. This uptake supplies cells with cholesterol and simultaneously lowers the level of LDL in plasma.

About 1 in 500 people has a mutation in the gene encoding the LDL receptor. The disease is called familial hypercholesterolemia. Affected individuals cannot produce a normal number of receptors, and they cannot remove LDL from blood at a normal rate. As a result, the cholesterol-rich LDL particle builds up to high levels in blood. Eventually, it deposits in arteries, producing atherosclerosis and heart attacks.
The work of Brown and Goldstein established the first cause of heart attacks that could be traced to the molecular level. Their work also provided a strong scientific foundation for the theory that cholesterol-carrying LDL particles are a major cause of heart attacks. Building upon their work, scientists in the pharmaceutical industry developed drugs that increase the activity of LDL receptors, lowering LDL-cholesterol. These drugs are now in widespread use throughout the world. Brown and Goldstein also discovered the fundamental process by which cells take up molecules from the blood. This discovery led to the realization that viruses, hormones, and nutrient molecules enter cells by the same route.

In recent years, Brown and Goldstein and their colleagues have isolated the gene for the LDL receptor and traced the mutations to the molecular level. As a result, familial hypercholesterolemia is among the best understood of all human genetic diseases, and it provides a framework for understanding a whole new class of genetic receptor diseases.

Throughout the 1970s, when their scientific work was most intensive, Brown and Goldstein continued to function as academic physicians, each performing clinical attending rounds on the general medicine wards of Parkland Memorial Hospital for six to twelve weeks per year. They also conducted frequent teaching rounds in medical genetics.

In 1974, Brown was promoted to associate professor of internal medicine at the University of Texas Southwestern Medical School. He became a professor in 1976. In 1977 he was appointed Paul J. Thomas Professor of Medicine and Genetics and director of the Center for Genetic Disease at the same institution. In 1985, Brown was appointed Regental Professor of the University of Texas, and he also holds the W.A. (Monty) Moncrief chair in Molecular Genetics.

Brown is a trustee of the University of Pennsylvania, the Lamplighter School, and the Science Place. He is on the Scientific Advisory Boards of the Salk Institute, the Scripps Clinic, and the Memorial Sloan-Kettering Cancer Center. He is a member of the governing Council of the National Academy of Sciences.

Brown received honorary degrees of Doctor of Science from the University of Chicago (1982), Renssalaer Polytechnic Institute (1982), the University of Pennsylvania (1986), the University of Paris (1988), the University of Buenos Aires (1989), and Southern Methodist University (1993). With his colleague Goldstein, Brown has shared the following awards: Heinrich Weiland Prize for Research in Lipid Metabolism (1974); Pfizer Award for Enzyme Chemistry of the American Chemical Society (1976); Albion O. Bernstein Award of the New York State Medical Society (1977); Passano Award (1978); Lounsbery Award of the U.S. National Academy of Sciences (1979); Gairdner Foundation International Award (1981); New York Academy of Sciences Award in Biological and Medical Sciences (1981); Lita Annenberg Hazen Award (1982); V.D. Mattia Award of the Roche Institute of Molecular Biology (1984); Distinguished Research Award of the Association of American Medical Colleges (1984); Research Achievement Award of the American Heart Association (1984); Louisa Gross Horwitz Award (1984); 3M Life Sciences Award of the Federation of American Societies for Experimental Biology (1985); William Allan Award of the American Society of Human Genetics (1985); Albert D. Lasker Award in Basic Medical Research (1985); Nobel Prize in Medicine or Physiology (1985); and the National Medal of Science (1986).

Dr. Brown was elected to membership in the following honorary societies: the US National Academy of Sciences (Washington), the American Academy of Arts and Sciences (Boston), and the American Philosophical Society (Philadelphia). He is a foreign member of the Royal Society (London). He is also a member of several scientific and medical societies, including the Association of American Physicians, the American Society for Clinical Investigation, the American Society of Biological Chemists, and the American Society for Human Genetics.