A small town in South Carolina
Joseph Leonard Goldstein was born on April 18, 1940, in Sumter, South Carolina, the only son of Isadore E. Goldstein and Fannie Alpert Goldstein. The family owned and ran a clothing store in Kingstree, a town of about 5,000 people, and he went through Kingstree’s public primary and secondary schools.
He studied chemistry at Washington and Lee University in Lexington, Virginia, graduating summa cum laude in 1962, and then went to medical school at the University of Texas Southwestern Medical School in Dallas. There he came under the spell of Donald W. Seldin, the chairman of internal medicine, a teacher who believed that the best doctors should also be scientists. In Goldstein’s final year Seldin made him an unusual offer: if he would train in the new field of genetics, he could come back to Dallas and found a division of medical genetics. Goldstein accepted, and received his MD in 1966.
Meeting Mike Brown
From 1966 to 1968 Goldstein was an intern and resident at Massachusetts General Hospital in Boston. One of his fellow interns was Michael S. Brown, a Brooklyn-born doctor a year younger than him. The two became friends, and the friendship would grow into one of the longest and most productive partnerships in the history of medicine.
Both then went to the National Institutes of Health in Bethesda, Maryland. Goldstein worked from 1968 to 1970 in the laboratory of Marshall Nirenberg, a pioneer of the genetic code, and with C. Thomas Caskey he purified the proteins that tell a cell when to stop building a protein chain. He later wrote that this was where he experienced the thrill of discovery and learned the power of molecular biology for understanding disease. At the same time he served as a physician to the patients of Donald Fredrickson, an expert on fat disorders, and met children with homozygous familial hypercholesterolaemia, an inherited condition in which cholesterol levels are so high that heart attacks can strike in childhood. He and Brown discussed these patients at length. In their spare time they became avid partners at duplicate bridge, a partnership Goldstein called a valid testing ground for their scientific one.
Genes and heart attacks
Before returning to Dallas, Goldstein spent 1970 to 1972 in Seattle with Arno Motulsky, one of the founders of medical genetics. There he studied an unselected population of heart attack survivors and found that about 20 per cent had one of three single-gene inherited disorders of blood fats. The milder, single-copy form of familial hypercholesterolaemia (FH) affected about one person in 500 in the general population and one in 25 heart attack victims. Familial disease, in other words, was not a curiosity but a significant part of the heart disease epidemic. He also mastered cell culture, the technique that would let him study patients’ cells in a dish.
In 1972 he returned to Dallas as head of the medical school’s first division of medical genetics. Brown had arrived a year earlier and was already studying HMG-CoA reductase, the enzyme that controls how fast cells make cholesterol. Goldstein persuaded him to collaborate, and by 1974 their two laboratories had merged into one.
The LDL receptor
Most of the cholesterol in the blood travels in particles called low-density lipoprotein, or LDL. Goldstein and Brown grew skin cells from healthy people and from children with severe FH and asked why the patients’ cells kept making cholesterol even when surrounded by LDL. In 1973 they found the answer. Normal cells carry receptors on their surface that grab LDL particles and pull them inside, where the cholesterol is released and used; the incoming cholesterol then signals the cell to stop making its own and to make fewer receptors. Cells from children with the severe form of FH had no working receptors at all, and cells from people with the milder form had about half the normal number. The LDL stayed in their blood, building up in artery walls and causing early heart attacks.
In tracing how the receptor works, they discovered something even more general. The receptors cluster in small pits on the cell surface coated with a protein lattice; the pits pinch off into bubbles that carry the LDL inside, and the receptors are then recycled back to the surface. This process, receptor-mediated endocytosis, turned out to be one of the basic ways all cells take in nutrients, hormones and other large molecules.
The Nobel committee later spelled out what this meant for patients. The severe, double-gene form of FH is rare, about one person in a million, and in such patients cholesterol levels are five times normal and heart attacks can come in adolescence or earlier. The milder form, carried by one person in every few hundred, means two to three times the normal level and heart disease in middle age. In a city the size of Stockholm, the committee noted, several thousand people carry it. For the first time doctors knew exactly what was wrong in these families.
From discovery to statins
Their work explained, for the first time, how the body sets the level of cholesterol in the blood: the liver’s LDL receptors act as a drain, and the more receptors there are, the lower the LDL. That suggested a strategy. If a drug could block cholesterol production inside liver cells, the cells would respond by making more receptors and pulling more LDL out of the blood. The Japanese biochemist Akira Endo had discovered the first statin, a compound that blocks HMG-CoA reductase, in the 1970s, and Merck isolated lovastatin, first marketed in 1987 as Mevacor. Goldstein and Brown’s research provided the scientific framework for how such drugs lower cholesterol, and the Nobel committee noted in 1985 that they had already shown that increasing the number of LDL receptors with drugs lowered cholesterol in patients with the milder form of FH.
Statins are now among the most widely prescribed medicines in the world and are on the World Health Organization’s list of essential medicines. By lowering LDL cholesterol they reduce the risk of heart attack and stroke for many millions of people. In 1993 the Goldstein-Brown laboratory added the final piece of the puzzle by discovering SREBPs, proteins that sit in cell membranes and switch on the genes for making cholesterol and fat when levels fall. That feedback system, Goldstein wrote, explains exactly how statins work: blocking cholesterol synthesis in the liver activates SREBPs, which increase LDL receptors and draw LDL out of the blood.
Nobel Prize
On October 14, 1985, Goldstein and Brown were awarded the Nobel Prize in Physiology or Medicine for their discoveries concerning the regulation of cholesterol metabolism. The Nobel Assembly said they had revolutionised knowledge of how the body handles cholesterol and how diseases caused by high blood cholesterol are treated. It was the first Nobel Prize in medicine awarded for research carried out entirely in Texas, and UT Southwestern celebrated it as proof of the collaborative culture that had kept the two scientists in Dallas despite attractive offers elsewhere.
The same year they received the Albert Lasker Award for Basic Medical Research, and in 1988 the National Medal of Science. Goldstein has been elected to the US National Academy of Sciences and as a Foreign Member of the Royal Society of London.
Jewish roots in the South
Goldstein comes from a Jewish family, one of the small Jewish merchant families who kept clothing and dry-goods stores in the towns of the American South. When the prize was announced, the Jewish Telegraphic Agency reported it under the headline that three American Jewish scientists had won Nobel Prizes for 1985: Goldstein, Brown and the economist Franco Modigliani. It noted that Goldstein had travelled to Israel several times in connection with the cholesterol research he and Brown were doing.
He is counted among Jewish Nobel laureates in medicine by the Jewish Virtual Library and other lists. He has spoken little in public about religious practice, and this profile makes no claim about it.
Scientist, teacher and essayist
After the Nobel Prize, Goldstein, like Brown, turned down offers to run large scientific institutions in order to keep doing research with his own hands. Since 1977 he has chaired the Department of Molecular Genetics at UT Southwestern. The partners have trained more than 145 graduate students and postdoctoral fellows; among them, Thomas Südhof won the Nobel Prize in 2013 and Helen Hobbs won the Breakthrough Prize in Life Sciences in 2015.
Goldstein has also been a leading figure in American science policy and philanthropy. Since 1996 he has chaired the jury of the Albert Lasker Medical Research Awards, and for that role he began writing essays connecting creativity in science with creativity in art, asking why a set of experiments comes to be called elegant or a body of research beautiful. They were collected in 2023 as The Art of Science. He has served as a trustee of the Howard Hughes Medical Institute and of Rockefeller University, chaired the scientific advisers of the Broad Institute, and sat on the board of the biotechnology company Regeneron.
Legacy
Goldstein and Brown’s partnership, which began in 1972, is the longest in Nobel history, longer than those of Carl and Gerty Cori or David Hubel and Torsten Wiesel. Its legacy is visible in almost every doctor’s office: the cholesterol test, the target LDL number, and the statin prescription all rest on their explanation of how the body handles cholesterol.
Before their work, high cholesterol was a number linked to heart disease with no clear mechanism. They showed exactly where the cholesterol goes, why it builds up in some families, and how the body can be persuaded to clear it.
Sources & further reading
Joseph L. Goldstein, Biographical, NobelPrize.org · Press release: The Nobel Prize in Physiology or Medicine 1985, NobelPrize.org · 3 U.S. Jewish Scientists Awarded Nobel Prizes for 1985, Jewish Telegraphic Agency · Nobel Prize 1985: Michael S. Brown, M.D., and Joseph L. Goldstein, M.D., UT Southwestern · Joseph L. Goldstein, Wikipedia · Researched from the sources above and checked against them. Spotted an error? Tell us.
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