Joseph Goldstein American molecular geneticist Date of Birth: 18.04.1940 Country: USA

1. Early Life and Education
2. Internship and Research
3. Cholesterol and Atherosclerosis
4. Discovery of LDL Receptors and Cholesterol Regulation
5. Treatment and Impact on Understanding Cholesterol Metabolism
6. Nobel Prize and Legacy

Early Life and Education

Joseph Leonard Goldstein was born in Sumter, South Carolina to Isadore E. and Fannie A. Goldstein. He earned his Bachelor of Science degree from Washington and Lee University in Lexington, Virginia in 1962, and four years later, his Doctorate of Medicine from the University of Texas Southwestern Medical School in Dallas. Goldstein's exceptional intellect was recognized early on when he received an offer to join the medical school faculty from Dr. Donald Seldin, the head of the medical department, even before graduating.

Internship and Research

From 1966 to 1968, Goldstein completed his internship at the Massachusetts General Hospital in Boston, where he met and collaborated with Michael S. Brown, the hospital's house officer. After his internship, Goldstein spent two years as a research fellow in Marshall W. Nirenberg's laboratory for clinical genetics at the National Institutes of Health. From 1970 to 1972, Goldstein pursued a fellowship in medical genetics at the University of Washington in Seattle. It was there, under the mentorship of Arno G. Motulsky, that he discovered a novel condition called familial combined hyperlipidemia.

Return to Southwestern Medical School and Collaboration with Michael Brown

In 1972, Goldstein returned to Southwestern Medical School to head the division of medical genetics and become an assistant professor in the department of internal medicine. He received the title of associate professor two years later, followed by that of senior attending physician in Parkland Memorial Hospital (1974), professor in the department of internal medicine (1976), professor and director of the molecular genetics program, professor of medicine and genetics (1977), and an adjunct member of the board of the Salk Institute in San Diego, California (1983). By this time, Michael Brown had also joined Southwestern Medical School, and the two scientists began their groundbreaking collaboration on cholesterol metabolism.

Cholesterol and Atherosclerosis

Cholesterol, a vital compound for humans, is the primary building block of cell membranes and serves as a precursor for bile acids and steroid hormones. However, excess cholesterol can accumulate in the walls of blood vessels, obstructing blood flow and leading to heart attacks and strokes. Cholesterol is acquired both from dietary fats and synthesized within the body. The main carrier of cholesterol in the blood is low-density lipoprotein (LDL) particles.

Familial hypercholesterolemia is an inherited condition characterized by extremely high levels of cholesterol and LDL in the blood. Approximately 1 in 500 Americans and Europeans have the less severe heterozygous (one abnormal gene) form of this disorder and are at high risk of heart attacks between the ages of 30 and 50. In 85% of this group, primarily men, heart attacks will inevitably occur by age 60. Individuals with the more severe homozygous form of the disease, which results from inheriting two mutant genes and occurs approximately 1 in 1 million people, develop cardiovascular complications from childhood.

Discovery of LDL Receptors and Cholesterol Regulation

To study cholesterol formation and regulation, Goldstein and Brown employed tissue culture methods to grow skin cells from individuals with familial hypercholesterolemia. They discovered that these cells harbored excessive amounts of 3-hydroxy-3-methyl-glutaryl-coenzyme A-reductase (HMG-CoA reductase), the enzyme that controls the rate of cholesterol synthesis. Due to the overactivity of the enzyme, the cells produced far more cholesterol than they could utilize.

Goldstein and Brown then found that the surface of cells, particularly liver cells, possesses receptors for the LDL-cholesterol complex. Together with their colleague Richard G. Anderson, they determined that LDL receptors cluster in depressions on the cell surface known as clathrin-coated pits. Through a process called receptor-mediated endocytosis, the LDL-carrying cell membrane invaginates and pinches off, forming vesicles that transport the particles into the cell. The receptor then dissociates from the LDL and recycles back to the cell surface. Within the cell, the LDLs are broken down, releasing the cholesterol. Excess cholesterol inhibits the activity of HMG-CoA reductase (and thus the synthesis of new cholesterol) and activates acyl-CoA or cholesterol-acyltransferase (ACAT), an enzyme responsible for intracellular storage of cholesterol. The production of new LDL receptors is also halted as the intracellular cholesterol content increases. In this way, a healthy cell maintains a balance between dietary cholesterol and the intracellular production of the compound. However, when there is an excess of cholesterol, atherosclerotic deposits form in blood vessels.

In patients with familial hypercholesterolemia, the LDL receptors are abnormal and unable to clear sufficient cholesterol from the bloodstream. In 1984, Goldstein and Brown described several mutations in the gene responsible for the LDL receptors. Familial hypercholesterolemia can result from a defect in receptor synthesis, faulty LDL binding, inadequate endocytosis or translocation of the receptor within the cell, and failure of the surface receptor to migrate to the clathrin-coated pits.

Treatment and Impact on Understanding Cholesterol Metabolism

For some patients with heterozygous familial hypercholesterolemia, who have one functional gene for LDL receptors, treatment with drugs such as compactin or mevinolin increases the number of LDL receptors produced by the single functioning gene, thereby lowering LDL and cholesterol levels in the blood. However, this form of therapy is ineffective in homozygous patients who lack a functioning gene for LDL receptors. In 1984, a six-year-old girl with homozygous familial hypercholesterolemia underwent a liver transplant, and according to predictions based on Goldstein and Brown's theory, the presence of normal LDL receptors in the transplanted organ led to a marked reduction in blood cholesterol levels.

Nobel Prize and Legacy

Goldstein and Brown were awarded the 1985 Nobel Prize in Physiology or Medicine for their research, which, according to the Karolinska Institute in Stockholm, "fundamentally deepened our understanding of cholesterol metabolism and has increased the possibilities for prevention and treatment of atherosclerosis."

Goldstein, who remained unmarried, enjoys listening to classical music in his spare time. Along with Brown, he has received numerous other awards, including the American Chemical Society's Pfizer Award for Enzyme Chemistry Research (1976), the National Academy of Science's Lounsbery Award (1979), the Gardner Foundation International Award (1981), the Molecular Biology Institute's W.D. Mattia Award (1984), and the Louisa Gross Horwitz Prize from Columbia University (1984). Goldstein is a member of numerous medical and scientific societies, and he has actively participated in the American Federation for Clinical Research, the National Advisory Committee on Mammalian Cell Lines, the American Heart Association's Physiology Section, the American Society for Clinical Investigation (president, 1985-1986), and the medical advisory Committee for the Howard Hughes Medical Institute. He is on the editorial boards of Atherosclerosis Reviews, Arteriosclerosis, Cell, Molecular Biology and Medicine, and Science, and is a co-editor of The Metabolic Basis of Inherited Disease.