A Bronx childhood
Robert Joseph Lefkowitz was born in the Bronx, New York, on April 15, 1943, the only child of Max Lefkowitz, an accountant in Manhattan’s garment district, and Rose, an elementary school teacher. All four of his grandparents were Jewish immigrants from Eastern Europe: his father’s parents came from towns in southeast Poland in 1903 and settled first on the Lower East Side, where his grandfather made caps, and his mother’s parents came from Russia. His maternal grandmother’s brother was Rabbi Solomon Polachek, a renowned Talmudic scholar who headed the rabbinical seminary of Yeshiva University.
The family lived in Parkchester, a large apartment complex in the Bronx. His mother was a perfectionist who made him redo homework at the slightest flaw; his father was easygoing and could do complicated sums in his head faster than his son could on paper. A lonely, bookish boy, Lefkowitz carted home the maximum six books at a time from the public library and, by thirteen, had read Churchill’s six-volume history of the Second World War, ordered through newspaper book-club coupons his surprised parents ended up paying for. He also played stickball, collected baseball cards and followed the New York Yankees.
Dreaming of being a doctor
By the third or fourth grade Lefkowitz had decided to become a physician like his family doctor, Joseph Feibush, whose house calls and stethoscope enthralled him. He never wavered. Once a month he joined the Associated Kremsdorf Descendants, a family society of his grandmother’s relatives who met for a meal, entertainment and a formal business meeting, a kind of organisation common among Eastern European Jewish immigrant families. From it, he wrote, he gained a sense of the importance of family and respect for the older generation who had come from Europe.
He entered the Bronx High School of Science in 1956 and graduated at sixteen, then studied chemistry at Columbia College, where he was inspired by the young chemist Ronald Breslow. Thanks to college credits earned in high school he graduated at nineteen and went straight to Columbia’s College of Physicians and Surgeons, where his classmates included the future Nobel laureate Harold Varmus. He married Arna Gornstein after his first year of medical school; their first two children were born while he was still a student.
Failure at the NIH
After graduating in 1966 and two gruelling years of residency, Lefkowitz avoided service in Vietnam by winning a highly competitive commission in the Public Health Service and was assigned to the National Institutes of Health in 1968. His mentors, Jesse Roth and Ira Pastan, gave him the task of developing a way to detect the receptor for the hormone ACTH. At the time many scientists doubted that such receptors even existed as real physical molecules; they were a convenient idea to explain how hormones and drugs could act on cells.
For a year almost everything he tried failed. At Thanksgiving in 1968 he told his father he was not cut out to be a scientist and would return to clinical medicine. Weeks later his father died of a heart attack at 63, and Lefkowitz felt bound to follow the plan they had made together. But in the summer of 1969 his experiments began to work, and the thrill of data surprised him. When he went to Massachusetts General Hospital for cardiology training, he found he missed the laboratory so much that, against hospital rules, he spent his elective months doing research in the lab of the cardiologist Edgar Haber.
Proving the receptor is real
In 1971 Lefkowitz chose his target: the beta-adrenergic receptor, which responds to adrenaline and noradrenaline and makes the heart beat faster and harder. As a cardiologist he wanted something relevant to the heart, and the first beta blocker had recently been approved in the United States, so dozens of drugs that act on the receptor were available to turn into tools. He worked on it, as he later wrote, for the next forty years.
In 1973 he moved to Duke University to build a programme in molecular cardiology, and he has stayed there ever since. In 1974, with Marc Caron, he developed a radioactive drug that bound tightly and specifically to the receptor, making it possible to measure receptors directly for the first time; Gerald Aurbach at the NIH and Alex Levitzki at the Hebrew University in Jerusalem developed similar methods. His group then built a toolkit of labelled drugs, affinity columns and computer analyses, purified the receptors, and in the early 1980s put the purified protein into cells that normally ignore adrenaline and showed that they began to respond. “That really did it for people,” he recalled. “They realized we had it.”
A family of a thousand receptors
In the mid-1980s Lefkowitz’s team, including a young cardiology fellow named Brian Kobilka, cloned the gene for the beta-adrenergic receptor. Its sequence held a surprise: the protein snaked back and forth through the cell membrane seven times, exactly like rhodopsin, the light receptor in the eye. The match revealed that receptors for light, hormones and nerve signals were members of a single family, now called G protein-coupled receptors because they pass their messages to the G proteins discovered by Martin Rodbell and Alfred Gilman. Using the sequence as a guide, laboratories around the world soon found many more. About a thousand human genes code for such receptors, including those for smell, taste, adrenaline, histamine, dopamine and serotonin.
Lefkowitz also discovered how cells switch these receptors off. His group identified two families of proteins, the receptor kinases and the beta-arrestins, that desensitise a receptor after it has been stimulated, explaining, for example, why some drugs lose their effect with repeated use. He later showed that beta-arrestins also send signals of their own, and that some drugs can be designed to trigger one pathway but not another, an idea known as biased signalling. In 2011 Kobilka, by then at Stanford, captured an image of the receptor at the very moment it is activated by a hormone and passes its signal into the cell. In 2012 the two men shared the Nobel Prize in Chemistry.
Medicines for millions
The practical reach of this work is enormous. The Nobel committee estimated that about half of all medications act through G protein-coupled receptors. They include beta blockers that relieve high blood pressure, angina and coronary disease, antihistamines for allergies, and drugs for stomach ulcers. Lefkowitz has written that his radioligand binding methods fundamentally changed the way drug candidates were screened and developed, and that the cloning of the receptors led others to discover many new “orphan” receptors as drug targets.
To pursue safer drugs based on biased signalling, he co-founded the company Trevena with his Duke colleague Howard Rockman. His work also illuminated disease: mutant receptors that are switched on all the time, which his laboratory first described, are now known to cause a growing number of inherited and acquired disorders.
Jewish roots and family
Lefkowitz has written warmly of his Jewish roots. In his Nobel autobiography he noted that he was one of a remarkable group of Jewish Nobel laureates educated in New York City public high schools, nearly all descended from Eastern European Jews who came to America during the great migration between 1881 and 1924. His family circle, his rabbinical great-uncle and his parents’ devotion to education all shaped him.
He has five children, David, Larry (now Noah Jordan), Cheryl, Mara and Joshua, with his first wife, Arna, and has been married since 1991 to Lynn Tilley of Durham. With a strong family history of heart disease, he developed angina at fifty and had quadruple bypass surgery in 1994; he has since kept to daily exercise and a vegetarian diet. In 2021 he published a memoir, A Funny Thing Happened on the Way to Stockholm, written with his former fellow Randy Hall.
The mentor
Colleagues at Duke say Lefkowitz’s proudest achievement may be his trainees. More than 200 students and postdoctoral fellows have passed through his laboratory, including Kobilka and R. Sanders Williams, who later became his dean, and many have become leaders in academia and the pharmaceutical industry. One of the longest-serving investigators of the Howard Hughes Medical Institute, he has been known for close attention to young scientists, encouraging them to keep a tight focus while asking big questions.
He continued to care for patients and to make teaching rounds at Duke for thirty years after arriving there. His other honours include the National Medal of Science in 2007, the Shaw Prize in Life Science and Medicine in 2007, and membership of the National Academy of Sciences.
Legacy
When Lefkowitz began, receptors were an abstraction that many scientists doubted. He made them real molecules that could be measured, purified, cloned and understood, and in doing so he gave medicine a map of the most important family of drug targets in the body. Anyone who has taken a beta blocker for the heart or an antihistamine for hay fever has benefited from that map.
His career also shows how much a single physician-scientist can do: a doctor who nearly quit research after a year of failure, and who instead spent fifty years at one bench, training hundreds of others and turning a question about adrenaline into medicines for millions.
Sources & further reading
Robert J. Lefkowitz, Biographical, NobelPrize.org · Press release: The Nobel Prize in Chemistry 2012, NobelPrize.org · Duke’s Robert Lefkowitz Wins Nobel Prize in Chemistry, Duke Today · Robert Lefkowitz, 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.