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J. Biol. Chem., Vol. 281, Issue 31, 25, August 4, 2006
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Binding and Degradation of Low Density Lipoproteins by Cultured Human Fibroblasts. Comparison of Cells from a Normal Subject and from a Patient with Homozygous Familial Hypercholesterolemia
(Goldstein, J. L., and Brown, M. S. (1974) J. Biol. Chem. 249, 5153–5162)
Joseph Leonard Goldstein was born in 1940 in Sumter, South Carolina. He attended Washington and Lee University in Lexington, Virginia and received a B.S. degree in chemistry in 1962. Goldstein then went to the Southwestern Medical School at the University of Texas Health Science Center in Dallas where he was inspired to pursue a career in academic medicine by the Chairman of the Department of Internal Medicine, Donald W. Seldin.
During Goldstein's last year in medical school, Seldin offered him a future faculty appointment if he agreed to specialize in genetics and return to Dallas to establish a division of medical genetics in the Department of Internal Medicine. Goldstein initially declined, and after receiving his M.D. in 1966, he moved to Boston where he was an intern and resident at the Massachusetts General Hospital. It was there that he first met and developed a friendship with Michael Stuart Brown, his long term scientific collaborator.
Brown, who was born in 1941 in Brooklyn, New York, graduated in 1962 from the University of Pennsylvania, with a major in chemistry. He received his M.D. degree from the University of Pennsylvania School of Medicine in 1966, after which he became an intern and resident at the Massachusetts General Hospital.
After they completed their training in 1968, both Brown and Goldstein obtained positions at the National Institutes of Health in Bethesda, Maryland. Brown joined the Laboratory of Biochemistry at the National Heart, Lung, and Blood Institute (NHLBI). Goldstein worked with Nobel laureate Marshall W. Nirenberg and also worked as a clinical associate at NHLBI, serving as physician to the patients of Donald S. Fredrickson, who was an expert on disorders of lipid metabolism. Several of these patients had homozygous familial hypercholesterolemia, a condition that causes severe elevations in cholesterol levels. Goldstein discussed these patients extensively with Brown and, in view of their common interest in metabolic disease, convinced Brown to join him as a faculty member at the University of Texas Health Science Center at Dallas, where they would work collaboratively on the genetic regulation of cholesterol metabolism.
In 1971 Brown joined the division of Gastroenterology in the Department of Internal Medicine at the University of Texas Southwestern Medical School. Before going back to Dallas, Goldstein spent 2 years with Arno G. Motulsky at the University of Washington in Seattle, studying human genetics. He returned to the University of Texas Health Science Center in 1972 and was appointed Assistant Professor in the Department of Internal Medicine and head of the medical school's first Division of Medical Genetics.
Together, Brown and Goldstein began to address the task of identifying the genetic defect in familial hypercholesterolemia. They started by observing tissue cultures of fibroblasts harvested from healthy individuals and individuals with familial hypercholesterolemia. They set up a microassay to measure the activity of 3-hydroxy-3-methylglutaryl coenzyme A reductase, the rate-determining enzyme of cholesterol biosynthesis, in the fibroblasts. Soon it became clear that the cholesterol transport protein, low density lipoprotein (LDL), suppressed the activity of 3-hydroxy-3-methylglutaryl coenzyme A reductase. Because high density lipoprotein (HDL) was unable to do this, Brown and Goldstein suspected that a receptor might be involved in the control of 3-hydroxy-3-methylglutaryl coenzyme A reductase.
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However, the question of how LDL generated the signal that suppressed 3-hydroxy-3-methylglutaryl coenzyme A reductase still remained. The answer to this question came from studies of surface-bound 125I-LDL. Brown and Goldstein found that the receptor-bound LDL remained on the cell's surface for less than 10 min. Within this time most of the surface-bound LDL particles entered the cell. Within another 60 min the protein component of 125I-LDL was digested completely. The only cellular organelle that could have degraded LDL so completely and rapidly was the lysosome. This was eventually confirmed, and Brown and Goldstein also showed that the cholesterol that was generated from lysosomal degradation of LDL acted as the second messenger responsible for suppressing 3-hydroxy-3-methylglutaryl coenzyme A reductase activity.
As is often the case with truly novel, groundbreaking discoveries, the work presented in this JBC Classic was not met with great enthusiasm by journal reviewers. The initial review of this paper by the JBC is presented in Fig. 1, and the decision letter from Associate Editor Eugene Kennedy is shown in Fig. 2. This paper, the basis of the Nobel Prizes awarded to Brown and Goldstein, was eventually accepted.
By 1974 Brown and Goldstein had merged their laboratories. They continued their work on the LDL receptor and eventually purified and sequenced it. In recognition of their work, they were awarded the 1985 Nobel Prize in Physiology or Medicine "for their discoveries concerning the regulation of cholesterol metabolism."
Goldstein eventually became Associate Professor of Internal Medicine at the University of Texas Southwestern Medical School (1974) and then Professor (1976). In 1977, he was made Chairman of the Department of Molecular Genetics at the University of Texas Health Science Center and Paul J. Thomas Professor of Medicine and Genetics, a position that he still holds today. In 1985, he was named Regental Professor of the University of Texas, and in 1983 he became a Non-resident Fellow of The Salk Institute for Biological Sciences.
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In addition to the Nobel Prize, Brown and Goldstein's work has been recognized by their receipt of numerous awards, including the Heinrich Wieland Prize for Research in Lipid Metabolism (1974), the American Chemical Society's Pfizer Award for Enzyme Chemistry (1976), the Passano Award (1978), the National Academy of Sciences' Lounsbery Award (1979), the Gairdner Foundation International Award (1981), the Lita Annenberg Hazen Award (1982), the Association of American Medical Colleges' Distinguished Research Award (1984), the American Heart Association's Research Achievement Award (1984), the FASEB 3M Life Sciences Award (1985), the Albert D. Lasker Award in Basic Medical Research (1985), the U. S. National Medal of Science (1988), the Albany Medical Prize in Biomedical Sciences (2003), and the Herbert Tabor/Journal of Biological Chemistry Lectureship (2005).
Both Brown and Goldstein were elected to the National Academy of Sciences and the American Academy of Arts and Sciences. Goldstein is, or has been, a member of the editorial board of several journals including the Annual Review of Genetics, Arteriosclerosis, Cell, the Journal of Biological Chemistry, the Journal of Clinical Investigation, and Science. Brown has served on the editorial boards of the Journal of Lipid Research, the Journal of Cell Biology, and Arteriosclerosis and Science.1,2
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1 All biographical information on Joseph L. Goldstein was taken from Refs. 1 and 2. 
2 All biographical information on Michael S. Brown was taken from Refs. 2 and 3.
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