Joseph L. Goldstein Biography (1940-)

Nationality
American
Gender
Male
Occupation
molecular geneticist, physician

Joseph Leonard Goldstein, the only son of Isadore E. and Fannie (Albert) Goldstein, was born on April 18, 1940, in Sumter, South Carolina. He graduated from Washington & Lee University in 1962 with a B.S. degree in chemistry, and attended Southwestern Medical School of the University of Texas Health Science Center in Dallas. There, Donald Seldin, chairman of the Health Science Center's department of internal medicine, offered him a future faculty appointment, provided he would specialize in genetics and then return to Dallas to establish a division of medical genetics there. He received his M.D. degree in 1966.

Goldstein's internship and residency at Massachusetts General Hospital brought him to Michael Brown, who had arrived from the University of Pennsylvania,having also obtained his M.D. degree in 1966. The two served in the same internship and residency program, and both were interested in research. After finishing their training in 1968, they joined the National Institutes of Health (NIH) in Bethesda, Maryland.

At the NIH biochemical genetics laboratory, Goldstein studied under the leadership of Marshall Warren Nirenberg, who was awarded the 1968 Nobel Prize in physiology or medicine for unraveling the way in which the genetic codedetermines the structure of proteins. Here, he learned about the excitementand efficiency of biology on a molecular level. At the same time he worked under Dr. Donald S. Fredrickson, clinical director of the National Heart Institute, who was investigating people with hypercholesterolemia, or abnormally high cholesterol levels. In particular, Goldstein was interested in those patients with homozygous familial hypercholesterolemia. Familial hypercholesterolemia, identified as a genetically acquired disease by Carl Müller of Oslo, Norway, involved a genetic defect which caused a metabolic error resultingin high blood cholesterol levels and heart attacks. But it was Fredrickson and Avedis K. Khachadurian of the American University of Beirut, who identifiedtwo forms of the disease: a heterozygous form, involving a single defectivegene found in one in 500 people; and a homozygous form, in which two defective genes are present and which strikes about one in a million. Blood cholesterol levels reach four to eight times the normal amount with symptoms of atherosclerosis, or hardening of the arteries, beginning in childhood. Nearly every sufferer from the homozygous form dies from a heart attack before theage of 30.

In 1972 Goldstein left the National Institutes of Health for Seattle under atwo-year NIH fellowship in medical genetics. During this time he worked withArno G. Motulsky, an internationally recognized expert in the field of genetic aspects of heart disease, and devoted himself to a study investigating thefrequency of various hereditary hyperlipidemias (diseases of high blood-fat levels) in a random sampling of heart attack survivors. The samples were taken from 885 patients (who survived three months or more) out of 1,166 coronary victims admitted in an eleven-month period to thirteen Seattle hospitals from 1970 to 1971. Studying 500 of those survivors and 2,520 members of their families revealed that thirty-one percent of the survivors had high blood-fat levels, either high cholesterol, high triglycerides, or a mixture of both. Eleven percent had an inherited combination of high cholesterol and high triglycerides. Goldstein and his associates defined this disease as familial combined hyperlipidemia. He knew that due to its complexity, combined hyperlipidemia would be an arduous area in which to begin research. Patients with homozygous hypercholesterolemia--having no normal genes at the area of the unknown defect--might be easier to study regarding gene functioning and cholesterol level.

Returning to the University of Texas Health Science Center in 1972 as head ofthe medical school's first division of medical genetics, and assistant professor in the department of internal medicine which was still directed by Donald Seldin, Goldstein addressed the task of identifying the fundamental geneticdefect in familial hypercholesterolemia (FHC). Brown had joined the staff the previous year.

The idea of cell receptors was known, but it had never been studied in relationship to fat and cholesterol in the blood. Over 93% of the cholesterol in the human body is found inside cells. There, it participates in functions critical to cell development and cell membrane formation. Cholesterol also contributes to the essential production of sex hormones, corticosteroids andbile acids. The remaining seven percent is dangerous, however, if it is not absorbed into the cells as it courses through the circulatory system, and sticks instead to the walls of blood vessels disrupting the flow of blood to theheart and brain.

Dietary cholesterol, found only in animal foods, is not necessary to the human body since the body produces its own cholesterol in the liver. If no cholesterol is available in the bloodstream, individual cells will produce their own. The human liver excretes that cholesterol which is not used by cells or deposited on artery walls. Cholesterol is fat-soluble, but attaches itself to water-soluble proteins, or lipoproteins, manufactured in the liver, as a meansof moving through the bloodstream. The lipoproteins most favored by cholesterol are low-density ones, called LDLs, which are composed of much more fat than protein. Thus, high levels of LDLs are equated with the threat of heart disease.

Goldstein and Brown started their study by observing tissue cultures of the human skin cells known as fibroblasts, harvested from six FHC homozygotes, sixteen FHC heterozygotes and forty normal people. The cultured fibroblasts, like other animal cells, need cholesterol for the formation of the cell membrane. During this process, Goldstein and Brown were able to follow the manner inwhich the cells obtained cholesterol, and identify the process of cholesterolextraction from the lipoproteins in the serum of the culture medium, specifically LDLs. This discovery was made in 1973 with their demonstration of the presence of receptor molecules on the cells, which function to adhere LDLs andcarry them into the cell. Goldstein and Brown noted that each individual cell normally has 250,000 receptors that bind low-density lipoproteins, and further located LDL receptors on circulating human blood cells as well as cell membranes from assorted animal tissues.

The cells of individuals with the heterozygous form of FHC have forty to fifty percent of the LDL receptors that are typically present on normal cells. Cells of individuals with the homozygous form of FHC have no LDL receptors or avery small number. Cholesterol, manufactured by the liver and attached to LDLs, is passed into the blood, but is removed from the circulatory system rather slowly. Under normal circumstances an LDL molecule spends a day and a halfin the bloodstream, but in FHC heterozygotes this length of time is extendedto three days, and in FHC homozygotes to five days, providing increased opportunity for cholesterol to accumulate in the walls of the blood vessels.

Cholestyramine, a drug used to treat high cholesterol levels, had been synthesized over 20 years before Goldstein's and Brown's study, but had never beenfully understood. Goldstein and Brown discovered that cholestyramine works bymultiplying LDL receptors in the liver, which then converts cholesterol intobile acids and passes them into the intestines. However, in spite of this action, cholestyramine had only limited effect on levels of serum cholesterol.Goldstein and Brown determined the reason for this: The increased numbers ofLDL receptors in the liver signaled the need for more cholesterol and the liver responded by increasing cholesterol production. This increase in cholesterol level then shut down the production of LDL receptors in the liver. These findings indicated the need for a drug to impede the liver's synthesis of cholesterol that could be administered in tandem with cholestyramine. In 1976 Akiro Endo, a Japanese scientist, isolated compactin, an anticholesterol enzyme,from penicillin mold, and in the same year Alfred W. Alberts of Merck, Sharpand Dohme research laboratories isolated a structurally similar enzyme, mevinolin, from a different mold. Goldstein and Brown combined mevinolin and cholestyramine in animal experiments with good results, and in 1987 the Food and Drug Administration approved mevinolin, now called lovastatin, for marketing. The FDA made the recommendation with the stipulation that the drug should be used only when diet and exercise proved inadequate in treating high cholesterol. Goldstein anticipated a lapse of five to ten years before use ofthe drug would affect the nation's coronary death rate.

For revolutionizing scientific knowledge about the regulation of cholesterolmetabolism and the treatment of diseases caused by abnormally elevated cholesterol levels in the blood, Goldstein and Brown received the 1985 Nobel Prizein physiology or medicine. They also have received awards from the National Academy of Sciences, the American Chemical Society, the Roche Institute of Molecular Biology, the American Heart Association and the American Society for Human Genetics.

Goldstein's and Brown's research illuminating the activity of LDL receptors and their function in the management of cholesterol levels has had far-reaching effects. Not only has their work increased understanding of an important aspect of human physiology, but it has also had a practical impact on the prevention and treatment of heart disease. The National Institutes of Health, in part because of Goldstein's and Brown's work, recommended the lowering of fatintake in the U.S. diet.

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