Alfred G. Gilman
Alfred Goodman Gilman
July 1, 1941
|Died||December 23, 2015 74) (aged|
Dallas, Texas, U.S.
|Alma mater|| Yale University (B.S., 1962)|
Case Western Reserve University (MD-Ph.D., 1969)
|Known for||G proteins|
|Awards|| John J. Abel Award (1975)|
Richard Lounsbery Award (1987)
Louisa Gross Horwitz Prize (1989)
Nobel Prize in Physiology or Medicine (1994)
|Fields|| Biochemistry |
Alfred Goodman Gilman (July 1, 1941 – December 23, 2015) was an American pharmacologist and biochemist.He and Martin Rodbell shared the 1994 Nobel Prize in Physiology or Medicine "for their discovery of G-proteins and the role of these proteins in signal transduction in cells."
Pharmacology is the branch of biology concerned with the study of drug or medication action, where a drug can be broadly defined as any man-made, natural, or endogenous molecule which exerts a biochemical or physiological effect on the cell, tissue, organ, or organism. More specifically, it is the study of the interactions that occur between a living organism and chemicals that affect normal or abnormal biochemical function. If substances have medicinal properties, they are considered pharmaceuticals.
Biochemistry, sometimes called biological chemistry, is the study of chemical processes within and relating to living organisms. Biochemical processes give rise to the complexity of life.
Martin Rodbell was an American biochemist and molecular endocrinologist who is best known for his discovery of G-proteins. He shared the 1994 Nobel Prize in Physiology or Medicine with Alfred G. Gilman for "their discovery of G-proteins and the role of these proteins in signal transduction in cells." According to a Plaque posted in Silver Spring Maryland, Dr. Martin Rodbell was a "Nobel Laureate in medicine for discovering that cells were like computer chips."
Gilman was the son of Alfred Gilman, who co-authored Goodman & Gilman's The Pharmacological Basis of Therapeutics with Louis S. Goodman, from whom his middle name came. He earned a BA in biology with major in biochemistry from Yale University. Immediately after graduation in 1962, he worked with Allan Conney at Burroughs Wellcome & Company, which resulted in the publication of his first two technical papers. Persuaded by Earl Wilbur Sutherland, Jr., he joined Case Western Reserve University School of Medicine for an MD-PhD course. He obtained his degree in 1969. He then went to the National Institutes of Health to work with Marshall Nirenberg between 1969 and 1971.
Goodman & Gilman's The Pharmacological Basis of Therapeutics, commonly referred to as the Blue Bible or Goodman & Gilman, is a textbook of pharmacology originally authored by Louis S. Goodman and Alfred Gilman. First published in 1941, the book is in its thirteenth edition, and has the reputation of being the "bible of pharmacology". The readership of this book include physicians of all therapeutic and surgical specialties, clinical pharmacologists, clinical research professionals and pharmacists.
Louis Sanford Goodman was an American pharmacologist. He is best known for his collaborations with Alfred Gilman, Sr., with whom he authored the popular textbook The Pharmacological Basis of Therapeutics in 1941 and pioneered the first chemotherapy trials using nitrogen mustard.
Yale University is a private Ivy League research university in New Haven, Connecticut. Founded in 1701, it is the third-oldest institution of higher education in the United States and one of the nine Colonial Colleges chartered before the American Revolution.
Gilman became assistant professor of pharmacology at the University of Virginia School of Medicine in 1971, and full professor in 1977. He chaired the Department of Pharmacology at the University of Texas Southwestern Medical Center at Dallas from 1981. Upon his retirement in 2009, he was appointed chief scientific officer of the Cancer Prevention and Research Institute of Texas. He resigned in 2012. He was the founder of Regeneron Pharmaceuticals company and the Alliance for Cellular Signaling. From 2005, he was also director of Eli Lilly and Company.
The University of Virginia School of Medicine is a medical school located in Charlottesville, Virginia. The tenth medical school to open in the United States, it has been part of the University of Virginia since the university's establishment in 1819 by Thomas Jefferson. The school's facilities are on the University of Virginia grounds adjacent to Academical Village, and it shares a close association with the University of Virginia Health System.
Regeneron Pharmaceuticals, Inc. is an American biotechnology company headquartered in Eastview, near Tarrytown, New York. The company was founded in 1988. Originally focused on neurotrophic factors and their regenerative capabilities, it branched out into the study of both cytokine and tyrosine kinase receptors.
Eli Lilly and Company is an American pharmaceutical company headquartered in Indianapolis, Indiana, with offices in 18 countries. Its products are sold in approximately 125 countries. The company was founded in 1876 by, and named after, Col. Eli Lilly, a pharmaceutical chemist and veteran of the American Civil War.
G proteins are a vital intermediary between the extracellular activation of receptors (G protein-coupled receptors) on the cell membrane and actions within the cell. Rodbell had shown in the 1960s that GTP was involved in cell signaling. It was Gilman who actually discovered the proteins that interacted with the GTP to initiate signalling cascades within the cell, and thus, giving the name G proteins.
The cell membrane is a biological membrane that separates the interior of all cells from the outside environment which protects the cell from its environment consisting of a lipid bilayer with embedded proteins. The cell membrane controls the movement of substances in and out of cells and organelles. In this way, it is selectively permeable to ions and organic molecules. In addition, cell membranes are involved in a variety of cellular processes such as cell adhesion, ion conductivity and cell signalling and serve as the attachment surface for several extracellular structures, including the cell wall, the carbohydrate layer called the glycocalyx, and the intracellular network of protein fibers called the cytoskeleton. In the field of synthetic biology, cell membranes can be artificially reassembled.
Guanosine-5'-triphosphate (GTP) is a purine nucleoside triphosphate. It is one of the building blocks needed for the synthesis of RNA during the transcription process. Its structure is similar to that of the guanine nucleobase, the only difference being that nucleotides like GTP have a ribose sugar and three phosphates, with the nucleobase attached to the 1' and the triphosphate moiety attached to the 5' carbons of the ribose.
Signal transduction is the process by which a chemical or physical signal is transmitted through a cell as a series of molecular events, most commonly protein phosphorylation catalyzed by protein kinases, which ultimately results in a cellular response. Proteins responsible for detecting stimuli are generally termed receptors, although in some cases the term sensor is used. The changes elicited by ligand binding in a receptor give rise to a biochemical cascade, which is a chain of biochemical events as a signaling pathway.
For his works, he received the Canada Gairdner Foundation International Award in 1984, Albert Lasker Award for Basic Medical Research and the Louisa Gross Horwitz Prize in 1989, in addition to Nobel Prize. He was elected member of the National Academy of Sciences and American Academy of Arts and Sciences, Fellow of the American Association for Cancer Research Academy, and, since 2013 (or earlier), member of the Advisory Council of the National Center for Science Education.
The Albert Lasker Award for Basic Medical Research is one of the prizes awarded by the Lasker Foundation for the outstanding discovery, Contribution and achievement in the field of medicine and Human Physiology. The award frequently precedes a Nobel Prize in Medicine: almost 50% of the winners have gone on to win one.
The Louisa Gross Horwitz Prize for Biology or Biochemistry is an annual prize awarded by Columbia University to a researcher or group of researchers who have made an outstanding contribution in basic research in the fields of biology or biochemistry.
The National Academy of Sciences (NAS) is a United States nonprofit, non-governmental organization. NAS is part of the National Academies of Sciences, Engineering, and Medicine, along with the National Academy of Engineering (NAE) and the National Academy of Medicine (NAM).
Gilman was born in New Haven, Connecticut, as he later commented, "with a scientific/academic silver spoon" in his mouth, "or perhaps a pestle (but not the mortar)."His parents were Mabel (Schmidt) and Alfred Gilman, a professor at the Yale School of Medicine and one of the authors of the classic pharmacology textbook Goodman & Gilman's The Pharmacological Basis of Therapeutics (nicknamed the "Blue Bible" of pharmacology). His middle name was in honor of the co-author Louis S. Goodman. The book was published in 1941, the year he was born. His friend Michael Stuart Brown (who was also born in 1941, and later the 1985 Nobel Prize in Physiology or Medicine laureate) joked that Gilman was "probably the only person who was ever named after a textboook." (Gilman later served as one of the textbook's editors from 1980 to 2000, first collaborating with, then succeeding his father and Goodman. ) He had an elder sister Joanna Gilman. He grew up in White Plains, New York, while his father worked at Columbia University and Albert Einstein College of Medicine.
New Haven is a coastal city in the U.S. state of Connecticut. It is located on New Haven Harbor on the northern shore of Long Island Sound in New Haven County, Connecticut, and is part of the New York metropolitan area. With a population of 129,779 as determined by the 2010 United States Census, it is the second-largest city in Connecticut after Bridgeport. New Haven is the principal municipality of Greater New Haven, which had a total population of 862,477 in 2010.
The English language expression silver spoon is synonymous with wealth, especially inherited wealth; someone born into a wealthy family is said to have "been born with a silver spoon in their mouth". As an adjective, "silver spoon" describes someone who has a prosperous background or is of a well-to-do family environment, often with the connotation that the person does not appreciate or deserve his or her advantage, its having been inherited rather than earned.
The Yale School of Medicine is the graduate medical school at Yale University in New Haven, Connecticut. It was founded in 1810 as The Medical Institution of Yale College, and formally opened in 1813.
Gilman attended local elementary school in White Plains. Hoping for better education, in 1955 his parents sent him to The Taft School in Watertown, Connecticut, where he completed grades 10 to 12. The school was known for its sports activity, and he described it as "a strict, monastic, and frankly unpleasant environment in the 1950s: academic boot camp."He recalled that he was "the worst 120-pound lineman on the intramural tackle football team." He studied science at Yale University. His first research project was to test the adaptor hypothesis of Francis Crick. He worked in the laboratory of Melvin Simpson, where he met his future wife Kathryn Hedlund. (They were married in 1963.) He graduated in 1962 receiving a BA in biology with major in biochemistry. During summer break in 1962, he briefly worked at Burroughs Wellcome & Company in New York, under with Allan Conney. With Conney he published his first two research papers in 1963. He then entered a combined MD-PhD program at Case Western Reserve University School of Medicine in Cleveland, Ohio where he wanted to study under Nobel laureate pharmacologist Earl Sutherland, who was a close friend of his father. It was Sutherland who had introduced the combined MD-PhD course, and invited Gilman to join course. But to Gilman, a seven-year program was like "an eternity in purgatory" and that he preferred not to have a degree in pharmacology, so he refused. Sutherland later persuaded him by explaining that pharmacology was "just biochemistry with a purpose." However, Sutherland was departing for Vanderbilt University, so Gilman studied with Sutherland's collaborator, Theodore Rall. Gilman graduated from Case Western in 1969, then did his post-doctoral studies at the National Institutes of Health with Nobel laureate Marshall Nirenberg from 1969 to 1971. Nirenberg assigned him to work on the study of nerve endings (axons from cultured neuroblastoma cells), which he considered as "a truly boring project." Instead, against the advice of Nirenberg, he worked on a new method for studying protein binding. After six weeks of working, he showed his result to Nirenberg, who immediately communicated it and get it published in 1970. The work was a simple and vital biochemical assay for studying cyclic AMP.
In 1971, Gilman was appointed Assistant Professor of pharmacology at the University of Virginia, School of Medicine, in Charlottesville, Virginia. He became full professor in 1977. In 1981, he became chairman of the Department of Pharmacology at the University of Texas Southwestern Medical Center at Dallas.From 2004 he became the dean, and between 2006 and 2009 he was Executive Vice President for Academic Affairs and Provost. He retired from university in 2009 to hold the office the chief scientific officer of the Cancer Prevention and Research Institute of Texas. He, however, resigned after three years as he felt that the administration was under commercial and political pressures. His resignation was followed by seven senior scientists.
In addition to mainstream academic position he held other key positions. He was one of the founders of Regeneron, a biotechnology company headquartered in Tarrytown, New York.He was also the founder and Chair of the Alliance for Cellular Signaling, a global collaboration for the study of cell signalling. He became its director from 1990. In 2005, he was appointed director of the drug company, Eli Lilly & Co.
Gilman died after a long battle with pancreatic cancer in Dallas, Texas on December 23, 2015 at the age of 74. He was survived by his wife and three children, Amy Ariagno and Anne Sincovec, both of Dallas, and Edward Gilman of Austin.
In the 1960s, Earl Sutherland and Theodore Rall discovered that cyclic AMP (the second messenger in signal transduction) was a responsible for activating enzymes in the cell, and that cyclic AMP is produced only when hormones (the first messengers) bind on the cell surface.Cyclic AMP is formed from ATP by the enzymes adenylyl cyclase. In 1970 Martin Rodbell found that hormones did not directly influence cyclic AMP, but there existed other molecules, the third messengers. Rodbell discovered that cyclic AMP is activated when guanosine triphosphate (GTP) is released from the cell membrane. He, however, did not know how the GTP molecules were produced. Gilman pursued the mystery in the signalling process. He found that in lymphoma (cancer) cells, hormones lost their activity to activate adenylyl cyclase, thereby losing their ability to produce cyclic AMP. This was due to loss of proteins in these cancer cells. When he introduced the missing protein from normal cells into the cancer cells, normal hormone action was produced. This showed that the missing membrane protein was responsible for mediating hormonal signal to cyclic AMP by producing GTP. His findings were published in a series of papers between 1977 and 1979. In 1980, he succeeded in identifying and isolating the new protein, which he named G protein, as it specifically bind GTP molecules.
Gilman played active roles in defending science education, and opposing creationism. He opposed the Texas state board of education in 2003 when the board tried to remove evolution from science curriculum. He was the leader of scientists of the US National Academy of Sciences, including Nobel laureates, to publicly criticize the board in The Dallas Morning News . He eventually became member of the Advisory Council of the National Centre for Science Education. He also opposed the Institute for Creation Research on its application for certification of its graduate course. He commented: "How can Texas simultaneously launch a war on cancer and approve educational platforms that submit that the universe is 10,000 years old?" He was also one of the signatories on the petition against the Louisiana Science Education Act of 2008.
Gilman was given the Canada Gairdner International Award in 1984 "For elucidating the mechanism by which peptide hormones act across cell membranes to influence cell function."He received the Albert Lasker Award for Basic Medical Research as well as the Louisa Gross Horwitz Prize from Columbia University in 1989 together with Edwin Krebs. In 2005, he was elected as Dean of University of Texas Southwestern Medical School, Dallas. He served on the board of advisors of Scientists and Engineers for America, an organization focused on promoting sound science in American government. He was elected as a member of the National Academy of Sciences in 1986. He was elected Fellow of the American Association for Cancer Research Academy in 2013. He was elected member of American Academy of Arts and Sciences. He received honorary doctorates from Case Western Reserve University, Yale University, University of Chicago, and University of Miami.
Adenylyl cyclase is an enzyme with key regulatory roles in essentially all cells. It is the most polyphyletic known enzyme: six distinct classes have been described, all catalyzing the same reaction but representing unrelated gene families with no known sequence or structural homology. The best known class of adenylyl cyclases is class III or AC-III. AC-III occurs widely in eukaryotes and has important roles in many human tissues.
Cyclic adenosine monophosphate is a second messenger important in many biological processes. cAMP is a derivative of adenosine triphosphate (ATP) and used for intracellular signal transduction in many different organisms, conveying the cAMP-dependent pathway. It should not be confused with 5'-AMP-activated protein kinase.
G protein-coupled receptors (GPCRs), also known as seven-(pass)-transmembrane domain receptors, 7TM receptors, heptahelical receptors, serpentine receptor, and G protein–linked receptors (GPLR), constitute a large protein family of receptors that detect molecules outside the cell and activate internal signal transduction pathways and, ultimately, cellular responses. Coupling with G proteins, they are called seven-transmembrane receptors because they pass through the cell membrane seven times.
GTPases are a large family of hydrolase enzymes that bind to the nucleotide guanosine triphosphate (GTP) and hydrolyze it to guanosine diphosphate (GDP). The GTP binding and hydrolysis takes place in the highly conserved G domain common to many GTPases.
G proteins, also known as guanine nucleotide-binding proteins, are a family of proteins that act as molecular switches inside cells, and are involved in transmitting signals from a variety of stimuli outside a cell to its interior. Their activity is regulated by factors that control their ability to bind to and hydrolyze guanosine triphosphate (GTP) to guanosine diphosphate (GDP). When they are bound to GTP, they are 'on', and, when they are bound to GDP, they are 'off'. G proteins belong to the larger group of enzymes called GTPases.
Adenosine monophosphate (AMP), also known as 5'-adenylic acid, is a nucleotide. AMP consists of a phosphate group, the sugar ribose, and the nucleobase adenine; it is an ester of phosphoric acid and the nucleoside adenosine. As a substituent it takes the form of the prefix adenylyl-.
In cell biology, protein kinase A (PKA) is a family of enzymes whose activity is dependent on cellular levels of cyclic AMP (cAMP). PKA is also known as cAMP-dependent protein kinase. Protein kinase A has several functions in the cell, including regulation of glycogen, sugar, and lipid metabolism.
Second messengers are intracellular signaling molecules released by the cell in response to exposure to extracellular signaling molecules—the first messengers. Second messengers trigger physiological changes such as proliferation, differentiation, migration, survival, and apoptosis.
"G protein" usually refers to the membrane-associated heterotrimeric G proteins, sometimes referred to as the "large" G proteins. These proteins are activated by G protein-coupled receptors and are made up of alpha (α), beta (β) and gamma (γ) subunits, the latter two referred to as the beta-gamma complex.
Guanine nucleotide-binding protein G(i), alpha-1 subunit is a protein that in humans is encoded by the GNAI1 gene.
Adenylyl cyclase type 3 is an enzyme that in humans is encoded by the ADCY3 gene.
Adenylyl cyclase type 5 is an enzyme that in humans is encoded by the ADCY5 gene.
Adenylyl cyclase type 1 is an enzyme that in humans is encoded by the ADCY1 gene.
Adenylyl cyclase type 2 is an enzyme typically expressed in the brain of humans, that is encoded by the ADCY2 gene. It belongs to the adenylyl cyclase class-3 or guanylyl cyclase family because it contains two guanylate cyclase domains. ADCY2 is one of ten different mammalian isoforms of adenylyl cyclases. ADCY2 can be found on chromosome 5 and the "MIR2113-POU3F2" region of chromosome 6, with a length of 1091 amino-acids. An essential cofactor for ADCY2 is magnesium; two ions bind per subunit.
Adenylyl cyclase type 9 is an enzyme that in humans is encoded by the ADCY9 gene.
Adenylyl cyclase type 8 is an enzyme that in humans is encoded by the ADCY8 gene.
In the field of molecular biology, the cAMP-dependent pathway, also known as the adenylyl cyclase pathway, is a G protein-coupled receptor-triggered signaling cascade used in cell communication.
The G beta-gamma complex (Gβγ) is a tightly bound dimeric protein complex, composed of one Gβ and one Gγ subunit, and is a component of heterotrimeric G proteins. Heterotrimeric G proteins, also called guanosine nucleotide-binding proteins, consist of three subunits, called alpha, beta, and gamma subunits, or Gα, Gβ, and Gγ. When a G protein-coupled receptor (GPCR) is activated, Gα dissociates from Gβγ, allowing both subunits to perform their respective downstream signaling effects. One of the major functions of Gβγ is the inhibition of the Gα subunit.
In enzymology, diguanylate cyclase, also known as diguanylate kinase, is an enzyme that catalyzes the chemical reaction:
Eva Julia Neer (1937–2000) was an American physician, biochemist, and cell-biology scientist who gained U.S. national research awards for her discoveries on G-protein subunit structure and function. She described the physiological roles of these subunits as an integrated and versatile molecular system of signal transduction for membrane-receptor regulation of cell function. Her research concepts turned her into a world leader in G-protein studies and impinged widely on the general understanding of cell behavior.
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