U.S. Geneticists Win Nobel Prize : 2 Cited for Findings on Cholesterol Circulation
Two American geneticists won the 1985 Nobel Prize for Medicine on Monday for key discoveries that “revolutionized knowledge” about cholesterol circulation in the body.
The research by Drs. Michael S. Brown and Joseph L. Goldstein of the University of Texas Health Science Center at Dallas helps explain why many people are at high risk from atherosclerosis, the buildup of fat deposits in the blood vessels that leads to heart attacks and strokes.
The two physicians were honored for their discovery of a protein, called the low-density lipoprotein (LDL) receptor, that controls the transfer of cholesterol from the blood to many cells in the body.
Malfunction of this protein is responsible for a disease affecting about one in 500 Americans. It can cause high blood-cholesterol levels and heart attacks in young people.
The research by Brown and Goldstein has advanced understanding of the relationship between diet and cholesterol levels and led to the development of medicines that reduce the risk of heart attacks by increasing the number of LDL-receptors on cells and thereby decreasing the amount of cholesterol in the blood.
Saying that the research could also lead to new treatment for cholesterol-related arteriosclerosis, the Nobel Institute, which made the announcement in Stockholm, said their discoveries have “revolutionized our knowledge about the regulation of cholesterol metabolism and the treatment of diseases caused by abnormally elevated cholesterol levels in the blood.”
Dr. Robert W. Mahley, director of the Gladstone Foundation Laboratories at UC Medical Center in San Francisco, said, “They are the best as scientists and people that I’ve seen.” Mahley has collaborated with the Texas physicians in cholesterol research for the last 10 years.
“They are helpful and open,” he said. “They are not the stereotype of the hard-driving, grab-as-much-credit-as-you-can scientists.”
Brown and Goldstein began their study of the disease called familial hypercholesterolemia while in training in internal medicine at Boston’s Massachusetts General Hospital in the late 1960s. They continued their work at the National Institutes of Health and later at the University of Texas.
‘Shocked and Surprised’
After discovering the LDL-receptor in 1973, the scientists isolated the protein, determined its exact structure and explained the role of the defective or absent protein in human disease. They continue to study the LDL-receptor and the genes which control its production.
“All I can say is that we’re both shocked and very surprised and it will be a time before it all sinks in,” Brown told United Press International in Cambridge, Mass., where he and Goldstein were attending a conference.
While cholesterol is often thought of largely as a contributing factor to disease, the fatty substance has many important functions in healthy individuals. All human cells need cholesterol to build their surface membranes, and specialized cells convert cholesterol into steroid hormones, such as cortisone and estrogen.
Excess cholesterol, however, cannot be digested by the body but must be eliminated in the bile.
Cholesterol Extracted
Much of the cholesterol in the body is carried in LDL particles. These particles can attach to LDL-receptors in the liver and other tissues. The receptors are constantly being swallowed by the cell and then returned to the cell surface; any LDL attached to the receptor is carried into the cell and the cholesterol extracted.
When the LDL-receptors do not work, the concentrations of cholesterol and LDL in the blood stream rise. In the mild form of this disease, individuals inherit half the normal number of receptors and may begin to have heart attacks by age 35. In the severe form, affecting about one person in a million, normal receptors are totally absent. Heart attacks among people with this condition often occur before the age of 20.
Understanding the receptor deficiency in familial hypercholesterolemia has helped physicians tailor diet and drug therapy for patients with this disease, as well as others with high cholesterol levels.
“The LDL-receptor hypothesis states that much of the atherosclerosis in the general population is caused by a dangerously high blood level of LDL resulting from failure to produce enought LDL receptors,” Brown and Goldstein wrote in Scientific American last November.
Because the buildup of cholesterol in the body slows the production of new LDL-receptors, researchers including Brown and Goldstein reasoned that depleting cholesterol from the blood stream would reverse this process.
Many people can achieve this goal by reducing dietary intake of cholesterol and animal fats, also known as saturated fats, as a panel of experts convened by the National Institutes of Health recommended last year.
Others have benefitted from a group of medicines, called bile-acid-binding drugs, that increase the number of LDL-receptors by eliminating more cholesterol in the bile. Medical researchers have found that one such drug, cholestyramine, can reduce the chance of suffering or dying from a heart attack for some individuals.
This year’s Nobel prizes each carry a cash award of about $225,000.
