A Baltimore boyhood
Martin Rodbell was born in Baltimore, Maryland, on December 1, 1925, the son of Shirley (Abrams) and Milton Rodbell. His family was Jewish, and his father ran a neighbourhood grocery store that Rodbell later described as a focal point for contact between people in the area. He loved Baltimore all his life and remembered his childhood home and street as a wonderful atmosphere for a curious boy.
He attended public schools and graduated from the accelerated course at Baltimore City College, a selective public high school that taught Latin, Greek, German and French and treated the sciences as an afterthought. Its only chemistry teacher, Rodbell joked, seemed to know Lavoisier personally. His real scientific education came from two gifted neighbourhood friends, with whom he competed in mathematics and chemistry from elementary school until all three reached Johns Hopkins University.
War, French novels and a vocation
Rodbell entered Johns Hopkins in 1943 with interests in biology and French literature. A year later he was drafted into the United States Navy. “As a Jew, fighting Hitler was the highest priority,” he wrote, but the Navy sent him to the South Pacific, where he served as a radio operator attached to the Marine Corps until he caught malaria in the jungles of the Philippines. After recovering he served on ships that took him to Korea and China. Meeting so many kinds of people under hard conditions, he said, gave him a healthy respect for the human condition.
Back at Hopkins he became an avid reader of contemporary French writers, especially André Gide and the existentialists. His father hoped he would study medicine, but a small biology class taught by the graduate student James Ebert drew him toward science instead. On the advice of the geneticist Bentley Glass he chose biochemistry, spent an extra year taking every advanced chemistry course Hopkins offered, and received his bachelor’s degree in biology in 1949.
Barbara
In 1949 Rodbell met Barbara Ledermann, a young Dutch woman acting in a student production of Molière’s School for Wives. She had survived the Second World War in the Netherlands by joining the Dutch underground; her parents and sister were murdered at Auschwitz. As a girl in Amsterdam she had been a friend of Margot Frank, the older sister of the diarist Anne Frank. She was a dancer and photographer, and through her circle of friends Rodbell, who played classical piano, found himself immersed in theatre, art and music. They married in 1950 and had four children, Paul, Suzanne, Andrew and Phillip.
The couple moved to Seattle, where Rodbell earned his PhD in biochemistry at the University of Washington in 1954, studying how the liver makes the fatty molecule lecithin. A rival laboratory solved the problem first, showing that a compound called CTP, not ATP as Rodbell had assumed, drove the reaction. The lesson he drew, never to trust the purity of biological chemicals, would help him make his great discovery fifteen years later. After two years as a postdoctoral fellow at the University of Illinois, he joined the National Heart Institute in Bethesda in 1956, beginning a career of nearly four decades at the National Institutes of Health.
Fat cells and the question of hormones
At the NIH Rodbell first studied the proteins that carry fat in the blood, identifying several of the proteins on the surface of chylomicrons that later proved important in lipid diseases. After a year in Europe, in the laboratories of Jean Brachet in Brussels and Peter Gaillard in Leiden, he returned to the NIH and turned to the question of how hormones act on cells.
His breakthrough technique was simple. By digesting fat tissue with the enzyme collagenase, he freed individual fat cells, which floated to the top of the dish and could be collected. The Argentine Nobel laureate Bernardo Houssay, visiting the laboratory, demanded proof that the cells were alive and responded to insulin; when Rodbell showed him they did, Houssay predicted it would be a landmark in endocrinology. Rodbell’s 1964 paper on the metabolism of isolated fat cells became one of the most influential in the field, because it let researchers study hormone action on single cells rather than on whole tissues. He then made fat cell “ghosts”, emptied of fat but still responsive to hormones, to study the cell membrane itself.
Discovering the transducer
By the mid-1960s Earl Sutherland had shown that many hormones work by making a cell produce a “second messenger”, cyclic AMP, inside it. How a hormone outside the cell could switch on that machinery inside was a mystery. In November 1969, in a bar in Washington, Rodbell and the biochemist Oscar Hechter borrowed a term from computer science and engineering, signal transduction, to describe the problem. Rodbell proposed that a cell’s signalling system has three parts: a discriminator, the receptor that recognises a particular hormone; an amplifier, the enzyme that makes the second messenger; and, between them, a transducer that carries the message across.
Around the turn of 1970, Rodbell and his team, including Lutz Birnbaumer, Stephen Pohl and Michiel Krans, were studying how the hormone glucagon binds to membranes from rat liver. They found that ATP seemed to loosen glucagon from its receptor, but that tiny traces of another energy molecule, GTP, did so about a thousand times more powerfully. Remembering his student lesson about impure chemicals, Rodbell concluded that GTP contaminating the ATP had been the real actor. In papers published in 1971 he showed that GTP was required for the hormone to turn on the amplifier, and that the transducer was a separate component driven by GTP. He later found that there could be several transducers, some stimulating and some inhibiting.
Alfred Gilman, at the University of Virginia, then hunted down the molecule itself, and by 1980 his group had purified it: a protein that binds GTP, which became known as a G protein. The two men shared the 1994 Nobel Prize in Physiology or Medicine. Rodbell, the Nobel committee said, had been one of the first to realise that the receptor and the amplifier were distinct, and his major discovery was the transducer that links them.
Why G proteins matter
G proteins turned out to be one of life’s master switches. When a signal arrives, a G protein swaps one molecule for GTP and switches on; when it breaks the GTP down, it switches off. Hundreds of different G proteins relay messages from hormones and nerve signals, and specialised ones turn light into nerve signals in the eye and carry the senses of smell and taste. They help regulate the heartbeat, blood pressure, mood, metabolism and cell growth.
Understanding them explained several diseases. Cholera toxin locks a G protein in the “on” position in the gut, causing a massive loss of water and salt that can lead to fatal dehydration; pertussis toxin, from whooping cough bacteria, blocks other G proteins. Faulty G proteins cause certain hormone disorders, such as McCune-Albright syndrome, and some tumours. The receptors that feed signals into G proteins, studied by Robert Lefkowitz and others, became the targets of a huge share of modern medicines, from beta blockers for heart disease to antihistamines; the Nobel committee in 2012 estimated that about half of all medications act through them. Rodbell’s three-part model gave pharmacology a way to think about how those drugs work.
Later career
Rodbell spent his working life within the NIH, moving between institutes, with a long love affair with Europe and especially Geneva, where he ran a clinical biochemistry institute for a year in 1967–68 and was a professor at the university from 1981 to 1983. In 1985 he became scientific director of the National Institute of Environmental Health Sciences in Research Triangle Park, North Carolina, where he served until he retired in 1994. He was also an adjunct professor at Duke University and the University of North Carolina.
In his later research he came to see cells as programmable messengers, with signalling systems far more complex than his original three boxes. He thought of endocrinology, he wrote, as imbued with existentialism: hormones were not single-minded agents but could do many different things by separate routes.
A scientist of letters
Rodbell was remembered as a Renaissance man. He kept his love of French literature, wrote verses for important occasions, and said that his life as a scientist had been joyful largely because of his wife and four children. He believed that his wartime experience, his father’s shop and his marriage into a family of artists all fed his science, and that a scientist’s life could not be separated from everything else in it.
His Jewish identity ran through his story in quieter ways: the grocery his father ran in Baltimore, his eagerness to fight Hitler, and his marriage to a Holocaust survivor whose family had been destroyed. He died of multiple organ failure in Chapel Hill, North Carolina, on December 7, 1998, six days after his 73rd birthday. The following year the National Library of Medicine added his papers, including laboratory notebooks, letters and poems, to its Profiles in Science collection.
Legacy
Thirty years after the conversation in the Washington bar, the director of that collection observed that signal transduction was no longer merely a theory but one of the fundamental ideas of twentieth-century molecular biology. Today every biology textbook explains how receptors, G proteins and second messengers work together, and drug developers use that map daily.
Rodbell’s discovery began with a contaminated chemical and a scientist humble enough to suspect it. The result was a new way of understanding how the trillions of cells in the human body talk to each other, and how cholera, hormone diseases and countless medicines act on that conversation.
Sources & further reading
Martin Rodbell, Biographical, NobelPrize.org · Press release: The Nobel Prize in Physiology or Medicine 1994, NobelPrize.org · Private Papers of Nobelist Martin Rodbell Added to Profiles in Science, National Library of Medicine · Press release: The Nobel Prize in Chemistry 2012, NobelPrize.org · Martin Rodbell, Wikipedia · Researched from the sources above and checked against them. Spotted an error? Tell us.
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