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Medicine: Brown, Goldstein honored.

This year's Nobel Prize in physiology or medicine goes to Michael S. Brown and Joseph L. Goldstein of the University of Texas Health Science Center at Dallas for their elucidation of a key step in cholesterol metabolism. The two researchers "revolutionized our knowledge about the regulation of cholesterol metabolism and the treatment of diseases caused by abnormally elevated cholesterol levels in the blood," said the Nobel Assembly of the Karolinska Institute in Stockholm, Sweden.

The body requires cholesterol for building cell membranes, certain steroid hormones and bile acids. Cells get the substance from ingested cholesterol that has been absorbed by the blood, and by manufacturing it themselves. In 1973 Brown and Goldstein discovered a protein on the surface of cells that grabs a cholesterol-carrying particle called low-density lipo-protein (LDL) from the blood and brings it into the cell where it can be used.

Finding the LDL receptor was the initial step in a cascade of research. Brown and Goldstein went on to discover that when cells have enough cholesterol they temporarily stop manufacturing the receptors. The high cholesterol levels left circulating in the blood wind up clogging arteries and causing potentially fatal heart and blood vessel diseases.

Complete absence of the receptors provided the explanation for why some children--about one in a million--get severe atherosclerosis at an early age, some of them having heart attacks at the age of 5 or 6. The disease, called familial hypercholesterolemia, "is a vivid experiment of nature," Brown and Goldstein wrote in the November 1984 Scientific American. "It demonstrates unequivocally the causal relation between an elevated circulating LDL level and atherosclerosis."

One such child, 8-year-old Stormie Jones of Dallas, received the first human heart/liver transplant last year after suffering a heart attack and having two bypass operations. The new liver has given her an organ capable of producing the much-needed receptors. Her cholesterol levels have dropped dramatically, and she is doing well.

With the exclusion of a few ethnic groups, about one in every 500 people are capable of manufacturing only low levels of the receptor. These people have plasma LDL levels twice the normal level--even before they are born--and begin to have heart attacks at the age of 35. People with normal ability to make LDL receptors are also at risk of atherosclerosis, Brown and Goldstein say, because eating a diet high in cholesterol and fatty acids suppresses receptor synthesis.

The two researchers have also looked closely at the basic genetics behind the LDL receptor. Recently, they and co-workers reported that the gene coding for the receptor is built of parts very similar to gene segments coding for unrelated proteins (SN: 5/18/85, p. 309). The finding is the first evidence supporting a theory that gene segments with no apparent function actually allow "meaningful" genetic segments to combine and form new genes.

Brown and Goldstein, in their Scientific American article, estimated that "more than half of all people in Western industrialized socieities, including the United States, have a level of circulating LDL that puts them at high risk for developing atherosclerosis." They are working with others on combining a cholesterol-reducing resin (SN: 1/2/84, p. 38) with a drug called mevinolin that inhibits a key step in cholesterol synthesis. The combination lowers blood LDL levels and increases the number of LDL receptors on cells. If drugs can be found to safely prevent suppression of the receptors, they say, "it may one day be possible for many people to have their steak and live to enjoy it too."
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Title Annotation:Nobel Prize, Michael S. Brown, Joseph L. Goldstein
Author:Silberner, Joanne
Publication:Science News
Date:Oct 19, 1985
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