Named after a textbook
Alfred Goodman Gilman was born on July 1, 1941, in New Haven, Connecticut, into a family steeped in both music and science. His mother, Mabel Schmidt Gilman, was an accomplished pianist who gave lessons; one grandfather owned a music store in Bridgeport and the other was a professional trombonist. His father, Alfred Gilman, had turned to science and was a pharmacologist at Yale, where with his close friend Louis S. Goodman he wrote The Pharmacological Basis of Therapeutics, first published in 1941. It became the standard textbook of drug science, known to generations of medical students as “the blue bible.”
The baby born that same year was named Alfred Goodman Gilman in honour of his father’s co-author. His friend, the Nobel laureate Michael Brown, later joked that he was probably the only person ever named after a textbook. Gilman himself said he had been born with a scientific silver spoon in his mouth, “or perhaps a pestle (but not the mortar).”
From star-gazing to biochemistry
Gilman grew up mainly in White Plains, a suburb of New York City, while his father taught at Columbia University and then became founding chairman of pharmacology at the new Albert Einstein College of Medicine. Trips with his parents and older sister, Joanna, to the city’s museums and the Hayden Planetarium convinced him for a while that he would be an astronomer; in the early 1950s he even made a reservation for a trip to the moon. Visits to his father’s laboratory, with its vivid demonstrations for medical students, pulled him toward biology instead.
In 1955 his parents sent him to the Taft School in Connecticut, which he found strict and joyless but academically superb: he learned how to learn, and was made to write an essay every week. At Yale University he majored in biochemistry, was inspired by the lectures of Henry Harbury, and did his first research in the laboratory of Melvin Simpson, where he met his future wife, Kathryn Hedlund. They married in 1963 and had three children, Amy, Anne and Edward.
A scientist in training
After graduating from Yale in 1962, Gilman spent a summer in the laboratory of Allan Conney at the drug company Burroughs Wellcome and published his first two papers. He was lured to Case Western Reserve University in Cleveland by Earl Sutherland, who had discovered cyclic AMP, the “second messenger” that carries hormone signals inside cells, and who persuaded him that pharmacology was “just biochemistry with a purpose.” Gilman entered the combined MD-PhD programme there and completed it in 1969 under Sutherland’s colleague Theodore Rall.
From 1969 to 1971 he worked at the National Institutes of Health with Marshall Nirenberg, a Nobel laureate. Assigned a project he found dull, he instead developed, against advice, a simple and sensitive assay for measuring cyclic AMP. Published in 1970, it made second messengers accessible to laboratories everywhere, and made his name.
Finding the missing link
In 1971 Gilman joined the University of Virginia in Charlottesville. The question that absorbed him was how a hormone such as adrenaline, binding to a receptor on the outside of a cell, switches on the enzyme inside that makes cyclic AMP. At the NIH, Martin Rodbell had shown that the message needed GTP, an energy-rich molecule, and proposed that a separate “transducer” linked the receptor to the enzyme. No one knew what it was.
Gilman’s group, joined in 1975 by the postdoctoral fellow Elliott Ross and later by Paul Sternweis and John Northrop, used a line of cancerous mouse white blood cells and a mutant strain whose receptors and enzyme were normal but which failed to respond to hormones. By adding back extracts from normal cells, they showed that the mutant was missing a protein. Between 1977 and 1980 they tracked it down and, in 1980, purified it: the first G protein, so called because it binds guanine nucleotides such as GTP. It works as a molecular switch, turned on when a receptor is activated and turned off again when it breaks down its GTP.
How the switch works
The discovery completed a picture first sketched by Martin Rodbell at the National Institutes of Health in the late 1960s and early 1970s. Rodbell showed that passing a message through the cell membrane takes three cooperating parts: a receptor that recognises a particular hormone, an amplifier that makes large amounts of a second messenger such as cyclic AMP, and, between them, a transducer driven by GTP. Gilman found what that transducer actually is.
G proteins are made of three separate chains, called alpha, beta and gamma, each existing in several forms, so that combinations can produce something like a hundred different G proteins. When a receptor is activated, the alpha chain swaps a molecule of GDP for GTP and the G protein switches on, triggering the amplifier inside the cell. When it converts the GTP back to GDP, it switches itself off again. Different G proteins stimulate or inhibit different processes, changing how cells use energy, how ions cross their membranes, how they divide and how they specialise. Specific G proteins in the retina turn light into nerve signals for vision, and others make possible our senses of smell and taste.
Why G proteins matter for medicine
Gilman and Rodbell’s work opened a new field. Scientists soon found that there are many different G proteins and that they relay signals not only for hormones but also for sight, smell, taste and the chemical messengers of the brain. The family of receptors that work through them, called G-protein–coupled receptors, is the largest family of drug targets known. When the Nobel Prize in Chemistry was awarded in 2012 for research on those receptors, the Nobel committee noted that about half of all medications achieve their effect through them. They include the receptors for adrenaline, histamine, dopamine and serotonin, the targets of many familiar medicines.
G proteins also explain disease. The 1994 Nobel committee pointed out that cholera kills by poisoning a G protein so that it is stuck in the “on” position, causing catastrophic loss of salt and water, that whooping cough toxin blocks other G proteins, and that faulty G proteins are found in some tumours and inherited hormone disorders. Understanding the switch has helped doctors and drug developers understand how medicines and toxins work, and why some treatments fail.
Dallas, the Nobel Prize and a famous textbook
In 1981 Gilman moved to the University of Texas Southwestern Medical Center in Dallas as chairman of pharmacology, recruited by Donald Seldin and joined by friends including the future Nobel laureates Michael Brown and Joseph Goldstein. He built a department he was proud of and later served as dean of the medical school and as the institution’s provost. In 1994 he shared the Nobel Prize in Physiology or Medicine with Martin Rodbell “for their discovery of G-proteins and the role of these proteins in signal transduction in cells.” Before the Nobel Prize he had received the Canada Gairdner International Award in 1984, for explaining how hormones act across cell membranes, and in 1989 both the Albert Lasker Award for Basic Medical Research and Columbia University’s Louisa Gross Horwitz Prize. He was elected to the National Academy of Sciences in 1986.
He also carried on his father’s work. From 1980 to 2000 Gilman was an editor of Goodman & Gilman’s The Pharmacological Basis of Therapeutics, first with his father and Goodman and then succeeding them, keeping the book that taught much of the world how drugs work up to date. He co-founded the biotechnology company Regeneron, founded and chaired the Alliance for Cellular Signaling, a large collaborative study of how cells process signals, and sat on the board of Eli Lilly.
A defender of science
Gilman spoke out when he believed science was being misused. In 2003, when the Texas State Board of Education considered weakening the teaching of evolution, he led a group of National Academy of Sciences members, including Nobel laureates, in publicly criticising the board, and he later served on the advisory council of the National Center for Science Education. He also opposed the certification of a creationist graduate programme in Texas.
After retiring from UT Southwestern in 2009 he became chief scientific officer of the Cancer Prevention and Research Institute of Texas, a large state-funded cancer research programme. In 2012 he resigned in protest after a large grant was approved without proper scientific review, warning that commercial and political pressures were undermining the agency. Seven senior scientists followed him in resigning.
Jewish background and legacy
Gilman is counted among Jewish Nobel laureates by the Jewish Virtual Library and by JINFO, which bases its listing on his own account in an interview; Wikipedia states that his family was Jewish. In his Nobel autobiography he wrote mainly about the family’s music and science, about his father’s career, and about the compulsory religion of his New England boarding school, which he did not enjoy. He did not write publicly about religious practice.
Alfred Gilman died of pancreatic cancer in Dallas on December 23, 2015, at the age of 74, survived by his wife and three children. He left behind a basic piece of human biology, the molecular switch that turns outside signals into action inside our cells, and a textbook and a generation of scientists that carried that knowledge into medicine. Every time a patient takes a medicine that acts on a G-protein–coupled receptor, the switch he discovered is at work.
Sources & further reading
Alfred G. Gilman, Biographical, NobelPrize.org · Press release: The Nobel Prize in Physiology or Medicine 1994, NobelPrize.org · Press release: The Nobel Prize in Chemistry 2012, NobelPrize.org · Alfred Gilman, Jewish Virtual Library · Jewish Nobel Prize Winners in Medicine, JINFO.ORG · Alfred G. Gilman, Wikipedia · Researched from the sources above and checked against them. Spotted an error? Tell us.
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