Michael S. Brown

1941-

American Geneticist

One of America's leading experts on cholesterol metabolism in the human body, geneticist Michael S. Brown shared the 1985 Nobel Prize in physiology or medicine with Joseph Goldstein (1940- ). Brown and Goldstein, who began working together in the 1970s, discovered the LDL receptor, a protein in the membranes of a cell that plays a central role in the body's ability to regulate cholesterol levels.

Brown was born on April 13, 1941, in New York City. He performed his undergraduate studies at the University of Pennsylvania, graduating in 1962, and went on to enroll in the university's medical school. There his research work earned him the Frederick Packard Prize in Internal Medicine. After earning his M.D. in 1966, he served as an intern and resident at Massachusetts General in Boston, where he first met Goldstein.

In 1968 Brown became clinical associate at the National Institutes of Health (NIH) in Bethesda, Maryland, where he worked in the biochemistry lab alongside Earl Stadtman, head of the laboratory for the National Heart, Lung, and Blood Institute. Brown focused on research in gastroenterology, particularly on the function of enzymes in digestive chemistry.

In 1971 Brown was appointed assistant professor at Texas Southwestern Medical School in Dallas. Goldstein joined the school's faculty in 1972, and soon afterward the two began working together. Their study involved familial hypercholesterolemia, an inherited disorder that causes dangerously elevated levels of cholesterol in the blood. To discover the genetic causes of this condition, they studied skin samples from a variety of patients.

Of particular interest to Brown and Goldstein were those rare subjects who had not one, but two defective genes. From childhood, they discovered, these people had exhibited extremely high levels of low-density lipoprotein (LDL), which carries cholesterol to the cells. In large quantities LDL can clog arteries and encourage heart disease. These patients, Brown and Goldstein observed, were missing a crucial type of protein known as a receptor, which binds with and regulates the levels of LDL. Without these receptors the body is unable to break down LDL, which then accumulates in the blood.

Having located the LDL receptor, Brown and Goldstein soon identified the gene responsible for its production. They then sequenced and cloned the gene, enabling them to isolate the genetic mutations that cause familial hypercholesterolemia and other inherited disorders involving cholesterol metabolism. By giving their patients specific combinations of drugs that inhibited their livers' ability to synthesize cholesterol, Brown and Goldstein increased their need for cholesterol from outside sources. The patients' bodies produced more LDL receptors, which in turn lowered their cholesterol levels.

Brown and Goldstein later performed a series of experiments that tracked the body's processing of cholesterol from first production to final dissolution. They noted that a liver transplant could correct genetic deficiencies in the production of LDL receptors, and demonstrated the means whereby a combination of low-fat diet and regular exercise could decrease cholesterol levels. In addition, they genetically engineered a mouse with an abnormally high number of LDL receptors, which allowed it to eat a high-fat diet without a significant rise in LDL.

Brown and Goldstein, in the words of the Nobel Prize Committee, "revolutionized our knowledge about the regulation of cholesterol metabolism and the treatment of diseases caused by abnormally elevated cholesterol levels in the blood." Brown has received a number of other awards in addition to the Nobel Prize, including the National Medal of Science in 1988. He has served as Paul J. Thomas Professor of Genetics and director of the Center for Genetic Diseases at the University of Texas Southwestern Medical School since 1977. Brown married Alice Lapin in 1964, and they have two daughters.

JUDSON KNIGHT