Brooklyn, ham radio and newsprint
Michael Stuart Brown was born in Brooklyn, New York, on April 13, 1941, the elder child of Harvey Brown, a textile salesman, and Evelyn Brown, a homemaker. His sister Susan was born three years later. When he was 11 the family moved to Elkins Park, a suburb of Philadelphia, and he went to Cheltenham High School.
Two passions took hold early and, as he wrote in his Nobel autobiography, never left him. At 13 he earned an amateur radio operator’s license, which led to a lifelong fascination with science. He also fell in love with journalism. At the University of Pennsylvania, where he majored in chemistry and graduated in 1962, he spent most of his time at the offices of the student newspaper, the Daily Pennsylvanian, as features editor and briefly as editor-in-chief. He then went to the University of Pennsylvania School of Medicine, receiving his MD in 1966. In 1964 he married Alice Lapin, whom he had known since childhood.
A partnership begins
From 1966 to 1968 Brown was an intern and resident in internal medicine at Massachusetts General Hospital in Boston. A fellow intern was Joseph L. Goldstein, a year older, from a small town in South Carolina. The two established a friendship and a mutual respect that would carry them through more than half a century of joint work.
Both moved on to the National Institutes of Health. From 1968 to 1971 Brown was first a clinical associate in gastroenterology and hereditary disease and then joined the Laboratory of Biochemistry headed by Earl Stadtman, a pioneer in understanding how enzymes are switched on and off. There Brown learned enzymology and the principles of metabolic regulation, and with a colleague he discovered that a key enzyme in the bacterial pathway for making the amino acid glutamine was controlled by the attachment of a nucleotide. In the evenings he and Goldstein played duplicate bridge together, and talked about patients.
To Dallas
In 1971 Brown joined the gastroenterology division at the University of Texas Southwestern Medical School in Dallas. His choice was strongly influenced by his friendship with Goldstein, a Southwestern graduate who had promised its chairman of medicine, Donald Seldin, to return and found a division of medical genetics. Seldin, an inspirational figure who shaped a generation of Texas doctors, became a mentor to Brown too.
Soon after arriving, Brown managed to dissolve and partly purify HMG-CoA reductase, a hard-to-handle enzyme that controls the rate at which the body makes cholesterol. He and Goldstein had a hypothesis: that a fault in the regulation of this enzyme was the cause of familial hypercholesterolaemia (FH), an inherited disease in which cholesterol accumulates in the blood and tissues and causes early heart attacks. Their formal collaboration began in 1972, when Goldstein returned from Seattle, and by 1974 their two laboratories had become one.
The discovery
Brown and Goldstein grew skin cells from healthy people and from patients with FH. In normal cells, adding blood serum containing LDL, the particles that carry most cholesterol in the blood, shut down the cells’ own cholesterol factory. In cells from children with the severe form of FH, it did not. The enzyme itself was normal; the problem was getting the cholesterol in. In 1973 the two found that normal cells carry specific receptors for LDL on their surface. The receptors bind LDL, carry it inside the cell and release its cholesterol, which then tells the cell to make less cholesterol and fewer receptors. Patients with the severe form of FH had no functioning receptors; patients with the milder form, about one person in 500, had roughly half the normal number.
Following the receptor’s journey, they described how it gathers in coated pits on the cell surface that pinch off and carry their cargo inward, after which the receptor returns to the surface to be used again. This process, receptor-mediated endocytosis, proved to be a fundamental part of cell biology, used by cells to take up many substances besides cholesterol. Throughout the 1970s, when the research was most intense, Brown and Goldstein still served each year as attending physicians on the general medicine wards of Dallas’s Parkland Memorial Hospital and taught genetics on teaching rounds.
Saving hearts
The LDL receptor explained how the body sets its cholesterol level, and why that level rises when receptors are few. It also showed a way to lower it. When liver cells are prevented from making their own cholesterol, they respond by making more LDL receptors and pulling more LDL out of the blood. Statins, drugs that block HMG-CoA reductase, work in exactly that way. The first statin was discovered by Akira Endo in Japan in the 1970s, and Merck’s lovastatin was first marketed in 1987; Brown and Goldstein’s research provided the framework that explained why such drugs lower blood cholesterol, and they publicly championed Endo’s contribution.
UT Southwestern describes their discovery as one that led to the development of statins, which help regulate cholesterol, improve the quality of life for millions and save lives. Statins have become some of the most widely prescribed medicines in the world and are on the World Health Organization’s list of essential medicines, reducing the risk of heart attack and stroke for many millions of people. For families with FH, who once faced heart attacks in early middle age or even childhood, the discovery identified the cause of their disease and the principle of its treatment.
By 1985 the Nobel committee could already point to new principles of treatment that came straight from the discovery. In patients with the milder form of FH, drugs such as cholestyramine and mevinolin, an early statin, increased the number of LDL receptors and lowered blood cholesterol. For the rare children with no working receptors at all, drugs could not help, but a liver from a donor could: a severely ill six-year-old girl who had already suffered several heart attacks received a new liver and heart, and her cholesterol fell from about 12 grams per litre to about 3.
Nobel Prize
In October 1985 the Nobel Assembly at the Karolinska Institute awarded the Nobel Prize in Physiology or Medicine to Brown and Goldstein for their discoveries concerning the regulation of cholesterol metabolism. It said they had revolutionised knowledge of the subject and of the treatment of diseases caused by abnormally high cholesterol, and called the discovery of the LDL receptor a milestone. Brown was 44. He told reporters he would use his share of the prize money for his daughters’ college education.
The prize capped a remarkable run of shared honours, including the Louisa Gross Horwitz Prize in 1984 and the Albert Lasker Award for Basic Medical Research in 1985. In 1988 Brown received the National Medal of Science. He was elected to the US National Academy of Sciences in 1980 and as a Foreign Member of the Royal Society in 1991.
Jewish family life in Dallas
Brown comes from a Jewish family in Brooklyn. When the Nobel Prize was announced, the Jewish Telegraphic Agency reported it as one of three Nobel Prizes won that year by American Jewish scientists. The agency noted that Brown and his wife, Alice Lapin Brown, belonged to Shearith Israel, a Conservative synagogue in Dallas, where their young daughters, Elizabeth and Sarah, attended Hebrew school.
Brown has described science and writing as the two passions of his life. The writer in him never left: he and Goldstein have published joint accounts of the history of their own discoveries, from the LDL receptor to the SREBP pathway and the scientific side trips they took along the way.
After the prize
Like Goldstein, Brown chose to keep doing hands-on research rather than move into scientific administration. Their team also showed how proteins are modified by attaching fatty chains, a process called prenylation that matters in cancer. In 1993 their trainees Xiaodong Wang and Michael Briggs purified the SREBPs, proteins anchored in cell membranes that, when cholesterol runs low, are cut free and travel to the nucleus to switch on every gene needed to make cholesterol and fatty acids. Brown, Goldstein and their colleagues spent the following decades working out this elaborate machinery, which explains how cells keep their fat and cholesterol levels steady and also explains exactly how statins raise LDL receptors.
Brown holds the W. A. (Monty) Moncrief Distinguished Chair in Cholesterol and Arteriosclerosis Research at UT Southwestern and is a Regental Professor of the University of Texas. He and Goldstein have trained more than 145 graduate students and postdoctoral fellows, several of whom have become leading scientists, including the 2013 Nobel laureate Thomas Südhof.
Legacy
The partnership of Brown and Goldstein, which began formally in 1972, is the longest scientific collaboration in Nobel history. For decades they have run a single laboratory, shared credit on their papers and given lectures together, from the Harvey Lecture in 1977 to the Berzelius Lecture in Stockholm in 1985.
Their work turned cholesterol from a vague risk factor into a mechanism that doctors could understand and treat. Every routine LDL cholesterol test, every statin prescription and every family screened for inherited high cholesterol draws on what a Brooklyn-born radio enthusiast and his bridge partner found by studying the skin cells of children with a rare disease.
Sources & further reading
Michael S. Brown, 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 · Michael Stuart Brown, Wikipedia · Researched from the sources above and checked against them. Spotted an error? Tell us.
A life of tikkun olam. This is part of tikkun olam, the Jewish idea of repairing the world, and every one of us can add to it.