Alfred Gilman (1941–2015) A Nobel laureate’s work on G proteins illuminated how signals are transmitted into cells By Melvin Simon
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lfred Goodman Gilman died on 23 December, after a protracted battle with pancreatic cancer. We lost an extraordinary scientist, academic leader, and “mensch.” Al pioneered our understanding of the biochemical mechanisms that drive signal transduction and (with Martin Rodbell) shared the 1994 Nobel Prize in Physiology or Medicine for his role in the discovery of heterotrimeric guanine nucleotide–binding proteins (G proteins). He went on to describe the basic design of G protein–mediated cellular signaling circuits that regulate an enormous number of physiological responses and are the targets of a large fraction of today’s drugs. Al was born into the scientific community. His father was an accomplished research pharmacologist, department chairman, and coauthor of a major pharmacology textbook. Al followed in his father’s footsteps. After receiving his BS in biochemistry from Yale University, Al pursued an MD-Ph.D. at Case Western Reserve University in Cleveland, Ohio, where he worked under Ted Rall and became intrigued with the mechanism of cellular signaling and the role of the enzyme adenylyl cyclase and its product cyclic adenosine 3',5'-monophosphate (AMP). As a postdoctoral fellow at the U.S. National Institutes of Health, he developed a sensitive assay for cyclic AMP and moved on to a faculty position at the University of Virginia Medical School in Charlottesville, where he returned to the issue of cellular signaling. The problem was that hormones were known to bind to specific receptors on the outside of the cell and to activate the enzyme adenylyl cyclase inside the cell. But how did the information regarding the receptor-binding event get communicated to the enzyme? Martin Rodbell showed that the connection between the two required the nucleotide guanosine 5'-triphosphate (GTP) and possibly a third protein component. However, the most straightforward resolution of the issue was to separate each of the possible components and to reconstitute the system. At the time, this was a herculean task, but it was accomDivision of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA 91125, USA. E-mail: [email protected]
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plished by Al and his postdoctoral fellow Elliot Ross. Other members of the lab, including Paul Sternweis and John Northrup, finished the job by purifying the G protein and studying its nucleotide-binding and GTPase activity. In 1981, Al moved to Texas to chair the pharmacology department at the University of Texas (UT) Southwestern Medical Center in Dallas and to understand the mechanism of information processing by G-protein circuits. The hypothesis was that the circuit was driven by a series of consecutive conformational changes in protein structure alternatively stabilized by GDP or GTP. Taking the most straightforward approach, Al’s group was amazingly successful in producing the proteins and complexes required for x-ray
diffraction analysis and in collaborating with outstanding crystallographers. Highly informative pictures of the structural changes in signaling intermediates at the atomic level emerged. Even the cantankerous adenylyl cyclase yielded some of its intimate secrets. During evolution, nature used elements and variations of the G-protein paradigm to solve a multitude of information processing problems by circuit design. Thus, there are hundreds of genes specifying G protein–coupled membrane receptors, dozens of homologous genes that code for the components of G proteins, and G-protein regulators that increase or decrease the amplitude of the signal, as well as many gene families representing targeted effectors. G-protein signaling circuits are integral to almost every physiological
function. In his Nobel lecture Al wrote, “The complexity of the cellular switchboard thus appears sufficiently vast to permit each cell (type) to design a highly customized signaling repertoire by expression of a relatively modest number of modular components.” He went on to predict that, “With this information in hand, we will be able to complete our understanding of the wiring diagram of the signaling switchboard in each type of cell.” In 1997, Al initiated the conversation about a project to deduce the nature of the wiring diagram. He called on me, Henry Bourne, and others working in various signaling systems. We spoke about a consortium of laboratories with an advisory group that would coordinate the research project and the development of analytical tools and reagents. The Alliance for Cellular Signaling was born in 2000. There were enormous problems, and Al was a remarkable leader and administrator. We were making headway, but all of the necessary technology wasn’t yet available. We were just too early. Today, the process is beginning again in a more dispersed fashion with better tools under the rubric of systems biology. Al Gilman did it all. As chairman, he built an outstanding department of pharmacology in Dallas. His research opened the cellular signaling field. His work on the mechanism of signal transduction continues to provide a basis for new drug design and development. He was Dean of the medical school at UT Southwestern Medical Center in Dallas and a member of the Board of Directors of the Eli Lilly pharmaceutical company. His students populate some of the best pharmacology and biochemistry departments in the country, and he was a founder, together with his former student Leonard Schleifer, of Regeneron, which is on its way to becoming a major pharmaceutical company. Al even published his own retrospective (Annual Review of Pharmacology and Toxicology, 2012). It is a wonderful review written in his engaging style. I didn’t get to know Al’s family well. However, I admired how his wife Kathy cared for him in the last months of his life. She and Al set up, in their home, what Al called the “off-shore faculty club annex.” Once or twice a week at a designated hour, friends and former students would drop by, make themselves a drink, and visit with Al. He loved engaging in conversation about science, sports, or the ways of the world with a congenial, mildly lubricated group of colleagues. In addition to his scientific prowess, intellectual acuity, administrative ability, and fierce integrity, Al was a charming and delightful friend. We will sorely miss him. ■ 10.1126/science.aaf2848
sciencemag.org SCIENCE
5 FEBRUARY 2016 • VOL 351 ISSUE 6273
Published by AAAS
PHOTO: TIM SHARP/AP PHOTO
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Alfred Gilman (1941−2015) Melvin Simon Science 351, 566 (2016); DOI: 10.1126/science.aaf2848
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A
lfred Goodman Gilman died on 23 December, after a protracted battle with pancreatic cancer. We lost an extraordinary scientist, academic leader, and “mensch.” Al pioneered our understanding of the biochemical mechanisms that drive signal transduction and (with Martin Rodbell) shared the 1994 Nobel Prize in Physiology or Medicine for his role in the discovery of heterotrimeric guanine nucleotide–binding proteins (G proteins). He went on to describe the basic design of G protein–mediated cellular signaling circuits that regulate an enormous number of physiological responses and are the targets of a large fraction of today’s drugs. Al was born into the scientific community. His father was an accomplished research pharmacologist, department chairman, and coauthor of a major pharmacology textbook. Al followed in his father’s footsteps. After receiving his BS in biochemistry from Yale University, Al pursued an MD-Ph.D. at Case Western Reserve University in Cleveland, Ohio, where he worked under Ted Rall and became intrigued with the mechanism of cellular signaling and the role of the enzyme adenylyl cyclase and its product cyclic adenosine 3',5'-monophosphate (AMP). As a postdoctoral fellow at the U.S. National Institutes of Health, he developed a sensitive assay for cyclic AMP and moved on to a faculty position at the University of Virginia Medical School in Charlottesville, where he returned to the issue of cellular signaling. The problem was that hormones were known to bind to specific receptors on the outside of the cell and to activate the enzyme adenylyl cyclase inside the cell. But how did the information regarding the receptor-binding event get communicated to the enzyme? Martin Rodbell showed that the connection between the two required the nucleotide guanosine 5'-triphosphate (GTP) and possibly a third protein component. However, the most straightforward resolution of the issue was to separate each of the possible components and to reconstitute the system. At the time, this was a herculean task, but it was accomDivision of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA 91125, USA. E-mail: [email protected]
566
plished by Al and his postdoctoral fellow Elliot Ross. Other members of the lab, including Paul Sternweis and John Northrup, finished the job by purifying the G protein and studying its nucleotide-binding and GTPase activity. In 1981, Al moved to Texas to chair the pharmacology department at the University of Texas (UT) Southwestern Medical Center in Dallas and to understand the mechanism of information processing by G-protein circuits. The hypothesis was that the circuit was driven by a series of consecutive conformational changes in protein structure alternatively stabilized by GDP or GTP. Taking the most straightforward approach, Al’s group was amazingly successful in producing the proteins and complexes required for x-ray
diffraction analysis and in collaborating with outstanding crystallographers. Highly informative pictures of the structural changes in signaling intermediates at the atomic level emerged. Even the cantankerous adenylyl cyclase yielded some of its intimate secrets. During evolution, nature used elements and variations of the G-protein paradigm to solve a multitude of information processing problems by circuit design. Thus, there are hundreds of genes specifying G protein–coupled membrane receptors, dozens of homologous genes that code for the components of G proteins, and G-protein regulators that increase or decrease the amplitude of the signal, as well as many gene families representing targeted effectors. G-protein signaling circuits are integral to almost every physiological
function. In his Nobel lecture Al wrote, “The complexity of the cellular switchboard thus appears sufficiently vast to permit each cell (type) to design a highly customized signaling repertoire by expression of a relatively modest number of modular components.” He went on to predict that, “With this information in hand, we will be able to complete our understanding of the wiring diagram of the signaling switchboard in each type of cell.” In 1997, Al initiated the conversation about a project to deduce the nature of the wiring diagram. He called on me, Henry Bourne, and others working in various signaling systems. We spoke about a consortium of laboratories with an advisory group that would coordinate the research project and the development of analytical tools and reagents. The Alliance for Cellular Signaling was born in 2000. There were enormous problems, and Al was a remarkable leader and administrator. We were making headway, but all of the necessary technology wasn’t yet available. We were just too early. Today, the process is beginning again in a more dispersed fashion with better tools under the rubric of systems biology. Al Gilman did it all. As chairman, he built an outstanding department of pharmacology in Dallas. His research opened the cellular signaling field. His work on the mechanism of signal transduction continues to provide a basis for new drug design and development. He was Dean of the medical school at UT Southwestern Medical Center in Dallas and a member of the Board of Directors of the Eli Lilly pharmaceutical company. His students populate some of the best pharmacology and biochemistry departments in the country, and he was a founder, together with his former student Leonard Schleifer, of Regeneron, which is on its way to becoming a major pharmaceutical company. Al even published his own retrospective (Annual Review of Pharmacology and Toxicology, 2012). It is a wonderful review written in his engaging style. I didn’t get to know Al’s family well. However, I admired how his wife Kathy cared for him in the last months of his life. She and Al set up, in their home, what Al called the “off-shore faculty club annex.” Once or twice a week at a designated hour, friends and former students would drop by, make themselves a drink, and visit with Al. He loved engaging in conversation about science, sports, or the ways of the world with a congenial, mildly lubricated group of colleagues. In addition to his scientific prowess, intellectual acuity, administrative ability, and fierce integrity, Al was a charming and delightful friend. We will sorely miss him. ■ 10.1126/science.aaf2848
sciencemag.org SCIENCE
5 FEBRUARY 2016 • VOL 351 ISSUE 6273
Published by AAAS
PHOTO: TIM SHARP/AP PHOTO
R E T R O S P E CT I V E
Downloaded from on February 4, 2016
INSIGHTS | P E R S P E C T I V E S
Alfred Gilman (1941−2015) Melvin Simon Science 351, 566 (2016); DOI: 10.1126/science.aaf2848
This copy is for your personal, non-commercial use only.
If you wish to distribute this article to others, you can order high-quality copies for your colleagues, clients, or customers by clicking here. Permission to republish or repurpose articles or portions of articles can be obtained by following the guidelines here.
Updated information and services, including high-resolution figures, can be found in the online version of this article at: /content/351/6273/566.full.html
Science (print ISSN 0036-8075; online ISSN 1095-9203) is published weekly, except the last week in December, by the American Association for the Advancement of Science, 1200 New York Avenue NW, Washington, DC 20005. Copyright 2016 by the American Association for the Advancement of Science; all rights reserved. The title Science is a registered trademark of AAAS.
Downloaded from on February 4, 2016
The following resources related to this article are available online at www.sciencemag.org (this information is current as of February 4, 2016 ):
