The Nobel Prize in Physiology or Medicine 1985

• Summary
• Press Release

Nobel Prize Award Ceremony

• Award Ceremony Speech

Michael S. Brown

• Biographical
• Nobel Lecture
• Banquet Speech

• Interview
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Joseph L. Goldstein

• Biographical
• Nobel Lecture

• Banquet Speech
• Interview
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Joseph L. Goldstein

Born: 18 April 1940, Sumter, SC, USA

Affiliation at the time of the award: University of Texas Southwestern Medical Center at Dallas, Dallas, TX, USA

Prize motivation: "for their discoveries concerning the regulation of cholesterol metabolism"

Biography

Joseph L. Goldstein was born on April 18, 1940, in Sumter, South Carolina, the only son of Isadore E. and Fannie Alpert Goldstein. The family owned and operated a clothing store in Kingstree, South Carolina, a town of 5000 people. After his education in the primary and secondary public schools of Kingstree, Goldstein attended Washington and Lee University in Lexington, Virginia, and received the B.S. degree in chemistry, summa cum laude, in 1962. He then attended Southwestern Medical School of the University of Texas Health Science Center in Dallas where he was inspired to pursue a career in academic medicine by Donald W. Seldin, then and now Chairman of the Department of Internal Medicine. During his last year in medical school, Seldin offered Goldstein a future faculty position if he would become trained in genetics and return to Dallas to establish a division of medical genetics in the Department of Internal Medicine. After receiving the M.D. degree in 1966, Goldstein moved to Boston where he was an Intern and Resident in Medicine at the Massachusetts General Hospital (1966-68).It was at the Massachusetts General Hospital that Goldstein first met and developed a friendship with Michael S. Brown, his long-term scientific collaborator.

After completion of his medical training, Goldstein spent two years (1968-70) at the National Institutes of Health, where he worked in the laboratory of Marshall W. Nirenberg and also served as a clinical associate at the National Heart Institute. The opportunity to work in a first-rate basic science laboratory while at the same time carrying a limited clinical responsibility proved highly influential in shaping Goldstein's career. In Nirenberg's laboratory, Goldstein and his colleague C. Thomas Caskey isolated, purified, and worked out the mechanism of action of several proteins required for termination of protein synthesis. Here he acquired scientific skills and taste, experienced the thrill of discovery and the excitement of science, and appreciated the power of a molecular biology approach to human disease. As a clinical associate, Goldstein served as physician to the patients of Donald S. Fredrickson, then Clinical Director of the National Heart Institute and an expert on disorders of lipid metabolism. His curiosity about hypercholesterolemia was aroused when he cared for patients with the striking clinical syndrome of homozygous familial hypercholesterolemia. These patients were intensively discussed with Brown. In view of his and Brown's common interest in metabolic disease, Goldstein convinced his colleague 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. While at the National Institutes of Health, Goldstein and Brown became avid duplicate bridge players. Their successful bridge partnership proved to be a valid testing ground for their future scientific partnership.

Before returning to Dallas, Goldstein spent two years (1970-72) as a Special NIH Fellow in Medical Genetics with Arno G. Motulsky at the University of Washington in Seattle. Motulsky was one of the creators of human genetics as a medical specialty. In Seattle, Goldstein initiated and completed a population genetic study to determine the frequency of the various hereditary lipid disorders in an unselected population of heart attack survivors. He and his colleagues discovered that 20% of all heart attack survivors have one of three single-gene determined types of hereditary hyperlipidemia. One of these disorders was the heterozygous form of familial hypercholesterolemia, which was found to affect 1 out of every 500 persons in the general population and 1 out of every 25 heart attack victims. During his fellowship in Seattle, he became conversant with tissue culture techniques, which proved to be invaluable in the subsequent studies with Brown.

In 1972, Goldstein returned to the University of Texas Health Science Center at Dallas, where he was appointed Assistant Professor in Seldin's Department of Internal Medicine and head of the medical school's first Division of Medical Genetics. He became Associate Professor of Internal Medicine in 1974 and Professor in 1976. In 1977, he was made Chairman of the Department of Molecular Genetics at the University of Texas Health Science Center at Dallas and Paul J. Thomas Professor of Medicine and Genetics, a position that he currently holds. In 1985, he was named Regental Professor of the University of Texas.

Goldstein was elected to membership in the National Academy of Sciences in 1980. He is also a member of the American Academy of Arts and Sciences, Association of American Physicians, American Society for Clinical Investigation (President, 1985-86), American Society of Biological Chemists, American Society of Human Genetics, American Society for Cell Biology, and the American Federation for Clinical Research (National Council, 1979-82). He is also a Fellow of the American College of Physicians and is a Diplomate of the American Board of Internal Medicine. Goldstein has served on study sections for the American Heart Association (1975-78) and the National Institutes of Health (1975-78). He served on the Scientific Review Board of the Howard Hughes Medical Research Institute (1978-84) and is presently a member of its Medical Advisory Board (1985-present). In 1983 he became a Non-resident Fellow of The Salk Institute for Biological Sciences. He is, or has been, a member of the Editorial Board of the following journals: Annual Review of Genetics (1979-84), Arteriosclerosis (1981-present), Cell (1982-present), Journal of Biological Chemistry (1980-85), Journal of Clinical Investigation (1977-82), and Science (1985-present).

He has received honorary Doctor of Science degrees from the University of Chicago (1982) and Rensselaer Polytechnic Institute (1982). His other academic honors include membership in Phi Beta Kappa and Alpha Omega Alpha. He was also the recipient of the Ho Din Award for Outstanding Medical School Graduate of the University of Texas Southwestern Medical School (1966) and of a Research Career Development Award from the National Institutes of Health (1972-77).

In addition to the 1985 Nobel Prize for Physiology or Medicine, Goldstein and his colleague Brown have been jointly honored for their research with the following awards: Heinrich Wieland Prize for Research in Lipid Metabolism (1974); Pfizer Award for Enzyme Chemistry of the American Chemical Society (1976); Albion O. Bernstein Award of the New York State Medical Society (1977); Passano Award (1978); Lounsbery Award of the U.S. National Academy of Sciences (1979); Gairdner Foundation International Award (1981); New York Academy of Sciences Award in Biological and Medical Sciences (1981); Lita Annenberg Hazen Award (1982); V.D. Mattia Award of the Roche Institute of Molecular Biology (1984); Distinguished Research Award of the Association of American Medical Colleges (1984); Research Achievement Award of the American Heart Association (1984); Louisa Gross Horwitz Award (1984); 3M Life Sciences Award of the Federation of American Societies for Experimental Biology (1985); William Allan Award of the American Society for Human Genetics (1985); and the Albert D. Lasker Award in Basic Medical Research (1985).

Goldstein and his colleague Brown have shared the podium for a number of distinguished lectureships, including the Harvey Lecture (1977), Christian A. Herter Lectures at Johns Hopkins University (1979), Harry Steenboch Lectures at the University of Wisconsin at Madison (1980); Smith, Kline, and French Lectures at the University of California, Berkeley (1981); Duff Memorial Lecture of the American Heart Association (1981); Doisy Lectures at the University of Illinois at Urbana-Champaign (1983); the first Pfizer Lecture in Honor of Konrad Bloch at Harvard University (1985); and the Berzelius Lecture at the Karolinska Institute, Stockholm (1985).

From Les Prix Nobel. The Nobel Prizes 1985, Editor Wilhelm Odelberg, [Nobel Foundation], Stockholm, 1986

This autobiography/biography was written at the time of the award and later published in the book series Les Prix Nobel/Nobel Lectures. The information is sometimes updated with an addendum submitted by the Laureate.

Addendum, October 2012

Since receiving the Nobel Prize in 1985, I have continued hands-on involvement with research, electing to pass up opportunities for positions in scientific administration. Michael Brown and I continue to work together, and our most significant discovery in the post-Nobel era has been the purification and molecular identification in 1993 of a family of membrane-bound transcription factors called SREBPs (Sterol Regulatory-element Binding Proteins). Since 1993, we and our students and postdoctoral fellows have delineated the complex machinery that proteolytically releases the SREBPs from membranes, thus allowing their migration to the nucleus where they activate all the genes involved in the synthesis of cholesterol and fatty acids. The machinery for generating active SREBPs is tightly regulated by a negative feedback mechanism, which explains how human and animal cells maintain the necessary levels of cholesterol and fats in the face of varying environmental conditions.

The SREBP feedback system also explains the mechanism of action of the statin drugs, the LDL-cholesterol lowering compounds that are taken by millions of people for reducing the risk of coronary heart disease and stroke. Inhibition of cholesterol synthesis in the liver by a statin drug leads sequentially to feedback activation of the SREBP pathway, increased expression of LDL receptors in liver, and reduction of LDL-cholesterol in the blood.

For our research on the SREBP pathway, Michael Brown and I have been honored with several awards, including the Warren Alpert Foundation Prize, Harvard Medical School (2000); the Albany Medical Center Prize in Medicine and Biomedical Research (2003); and the Stadtman Distinguished Scientist Award, American Society for Biochemistry and Molecular Biology (2011). In 1991, we were elected as Foreign Members of The Royal Society of London.

Michael Brown and I have worked together as scientific partners since 1972. Our 40-year collaboration is now the longest such scientific partnership in Nobel history. Other long-term Nobel partnerships include those of Cori and Cori (34 years, Nobel Prize in 1947); Stein and Moore (33 years, 1972); Cournand and Richards (30 years, 1956); Hubel and Wiesel (20 years, 1981); and Bishop and Varmus (19 years, 1989).

Brown and I have recently written three articles that summarize the highlights of our 40-research scientific partnership. One article deals with the discovery of the LDL receptor (http://atvb.ahajournals.org/content/29/4/431.full.pdf+html). A second article describes how we discovered the SREBP pathway (http://www.jlr.org/content/50/Supplement/S15.full.pdf+html). And a third article reflects on six scientific side trips that we have made over the last 40 years, telling about our research excursions off the beaten path of the LDL receptor and the SREBP pathway (http://www.jbc.org/content/287/27/22418.full.pdf+html).

In addition to my research activities, I am currently a member of the Boards of Trustees of the Howard Hughes Medical Institute and The Rockefeller University. Since 1996, I have served as Chairman of the Albert Lasker Medical Research Awards Jury. In this role, I have written a series of essays connecting creativity in science with creativity in the arts. These essays, which deal with questions such as “How does a series of scientific experiments come to be regarded as ‘elegant’ or a body of research deemed as ‘beautiful’?”, have been published in Nature Medicine (beginning in 2001) and are collected on the Lasker Foundation web site (http://www.laskerfoundation.org/awards/artofscience.htm).