Joseph Leonard Goldstein

1940-

American Geneticist

Nobel laureate Joseph Goldstein was the first person to describe the process by which cholesterol is metabolized and accumulates in the human body. The understanding of the relationship between cholesterol, blood lipids, and heart disease has been one of the most important health discoveries of the twentieth century, enabling the development of new drugs and diet regimens to lower blood cholesterol levels.

Goldstein was born April 18, 1940, in Sumter, South Carolina. His family owned a clothing store in Kingstree, South Carolina. Goldstein graduated from Washington and Lee University in Lexington, Virginia, in 1962. He received the doctor of medicine from Southwestern Medical School of the University of Texas Science Center in 1966. Goldstein was offered a faculty position by Donald Seldin, who was impressed by Goldstein, if he would study genetics and return to Dallas to establish a division of medical genetics in the department of internal medicine. Goldstein declined at that time and went on to do an internship at Massachusetts General Hospital in Boston, where he met Michael Brown (1941- ), another intern who became a life-long friend and future collaborator.

Moving to the National Institute of Health (NIH) in 1962, Goldstein worked in the laboratory of Marshall Nirenberg (1927- ), a biochemist whose great challenge was to decipher the genetic code. Goldstein also served as an associate at the National Heart Institute, where he described the action of several proteins related to protein synthesis. While at NIH he launched a study into cholesterol metabolism in the human body, a topic that would become a lifelong pursuit. Noting that cholesterol accumulation in the blood was related to heart attacks, he began a study of the risk factors, leading him to the idea of a genetic component.

From 1970-72 Goldstein worked at the University of Washington as a Special NIH Fellow in the laboratory of Dr. Arno G. Motulsky, who helped establish the relationship between medicine and human genetics. There Goldstein studied tissue culture techniques and population genetics strategies. He and his colleagues initiated and completed a study to determine the frequency of hereditary lipid disorders in heart attack survivors. They found that 20 percent of heart attack survivors have one of three single-gene types for hyperlipidemia, or the presence of excess fat and cholesterol in the blood. Familial hypercholesterolemia affects one out of 25 heart attack victims, and it is present in one out of every 500 people.

Taking up Dr. Seldin's earlier offer, in 1972 Goldstein returned to Southwestern Medical as an assistant professor in Internal Medicine and led the school's first Division of Medical Genetics. He also convinced them to bring Michael Brown, by then an expert in metabolic disease, to Dallas. The two combined their expertise in the study of genetic regulation of cholesterol metabolism.

Concentrating on the problem of accumulation of cholesterol, they discovered that lowdensity lipoproteins (LDLs) are the major carrier of cholesterol. Special receptors on the cell's surface take the LDLs out of the bloodstream. They wondered what would occur if these receptors were not present. They found that under such circumstances LDLs build up in the blood vessels, causing them to eventually clog. Absence of the LDL receptors are found in family hypercholesterolemia. The body cannot remove LDL from the bloodstream, allowing it to build up. This discovery led to the use of drugs to combat the buildup and new understanding of the importance of low cholesterol diets.

Goldstein was elected to the National Academy of Science in 1980 and has won numerous awards and lectureships. In 1985 he and Brown won the Nobel Prize for Physiology or Medicine. Goldstein has since continued his research at the Southwestern Texas Medical School in Dallas, where he has worked to unravel the mechanisms by which the sterol regulatory element binding proteins (SREBPs) pathway regulates cholesterol metabolism at the molecular, cellular, and whole body levels.

EVELYN B. KELLY