Alfred G. Gilman

Alfred G. Gilman
Born	Alfred Goodman Gilman July 1, 1941
Birthplace	New Haven, Connecticut, U.S.
Died	December 23, 2015 Dallas, Texas, U.S.
Nationality	American
Occupation	Pharmacologist, biochemist
Known for	Discovery of G proteins and their role in cellular signal transduction
Education	MD–PhD, Case Western Reserve University (1969); BA, Yale University (1962)
Spouse(s)	Kathryn Hedlund
Children	3
Awards	Nobel Prize in Physiology or Medicine (1994), Albert Lasker Award for Basic Medical Research (1989), Louisa Gross Horwitz Prize (1989)

Alfred Goodman Gilman (July 1, 1941 – December 23, 2015) was an American pharmacologist and biochemist whose discovery of G proteins — the critical intermediary molecules that transmit chemical signals from the surface of cells to their interior — fundamentally transformed the understanding of cellular communication in biology and medicine. For this work, he shared the 1994 Nobel Prize in Physiology or Medicine with Martin Rodbell, who had earlier demonstrated the involvement of guanosine triphosphate (GTP) in cell signaling. Gilman's contribution was the identification and purification of the actual proteins that interacted with GTP to initiate signaling cascades, thereby giving them the name "G proteins." Born into a family with deep roots in pharmacology — his father, Alfred Gilman, co-authored the landmark textbook Goodman & Gilman's The Pharmacological Basis of Therapeutics — the younger Gilman built a distinguished career spanning more than four decades at institutions including the University of Virginia, the University of Texas Southwestern Medical Center, and the Cancer Prevention and Research Institute of Texas. His research laid the groundwork for understanding the molecular mechanisms underlying the action of numerous hormones, neurotransmitters, and drugs, with implications for the treatment of diseases ranging from cancer to heart disease. Gilman died in Dallas, Texas, on December 23, 2015, at the age of 74.

Early Life

Alfred Goodman Gilman was born on July 1, 1941, in New Haven, Connecticut. He grew up in a household steeped in the science of pharmacology. His father, Alfred Gilman, was a professor of pharmacology who, together with Louis S. Goodman, authored Goodman & Gilman's The Pharmacological Basis of Therapeutics, one of the most influential pharmacology textbooks in medical education. The younger Gilman's middle name, "Goodman," was given in honor of his father's collaborator and close colleague, Louis S. Goodman.

Growing up in the environment shaped by his father's academic career, Gilman was exposed to the world of biomedical research from an early age. The elder Gilman's work on the pharmacological basis of therapeutics helped establish the field of modern pharmacology, and this background provided the younger Gilman with both intellectual stimulation and a framework for understanding the mechanisms of drug action. The family's connection to the discipline would prove formative in shaping Alfred Goodman Gilman's own career trajectory, though he would go on to make discoveries that extended far beyond the traditional boundaries of pharmacology into the realm of molecular biology and cellular biochemistry.

Education

Gilman attended Yale University, where he earned a Bachelor of Arts degree in biology with a major in biochemistry in 1962. Immediately following his graduation from Yale, he worked with Allan Conney at Burroughs Wellcome & Company, a pharmaceutical firm. This early industrial research experience proved productive, resulting in the publication of his first two technical papers.

Gilman was subsequently persuaded by Earl Wilbur Sutherland Jr., the renowned biochemist who would himself win the Nobel Prize in Physiology or Medicine in 1971 for his discoveries concerning the mechanisms of hormone action, to enroll in the combined MD–PhD program at Case Western Reserve University School of Medicine. Sutherland's influence was instrumental in directing Gilman toward the study of signal transduction, the very field in which he would later make his most celebrated contributions. Gilman completed his MD–PhD degree at Case Western Reserve in 1969.

Following the completion of his doctoral training, Gilman undertook postdoctoral research at the National Institutes of Health (NIH), where he worked in the laboratory of Marshall Nirenberg between 1969 and 1971. Nirenberg, a Nobel laureate himself for his work on the genetic code, provided Gilman with rigorous training in molecular biology and biochemistry. This period at the NIH proved important in equipping Gilman with the technical skills and conceptual framework necessary for his subsequent research on signal transduction mechanisms.

Career

University of Virginia

In 1971, Gilman joined the faculty of the University of Virginia School of Medicine as an assistant professor of pharmacology. He rose through the academic ranks, becoming a full professor in 1977. It was during his decade at the University of Virginia that Gilman began the research program that would lead to his most significant scientific contributions. Building upon the earlier work of Martin Rodbell, who had demonstrated in the 1960s and 1970s that GTP played a role in cellular signaling processes, Gilman set out to identify and characterize the specific proteins that mediated signal transduction between cell-surface receptors and intracellular effector enzymes.

Rodbell had proposed the existence of a "transducer" molecule that coupled hormone receptors on the cell membrane to intracellular enzymes such as adenylyl cyclase, and had shown that guanine nucleotides were required for this coupling. However, the actual proteins responsible for this transduction had not been isolated or characterized. Gilman's laboratory undertook the painstaking biochemical work of identifying, purifying, and characterizing these proteins, which he named G proteins due to their interaction with guanine nucleotides, specifically GTP and GDP.

Using a genetic approach, Gilman employed mutant cell lines — particularly a variant of the S49 lymphoma cell line that lacked functional adenylyl cyclase stimulation by hormones — to dissect the components of the signaling pathway. By reconstituting the signaling system with purified proteins, his laboratory was able to demonstrate that a specific GTP-binding protein acted as the intermediary between the receptor and the effector enzyme. This work provided the first direct biochemical evidence for the existence of G proteins as distinct molecular entities.

University of Texas Southwestern Medical Center

In 1981, Gilman moved to the University of Texas Southwestern Medical Center at Dallas, where he assumed the chairmanship of the Department of Pharmacology. Under his leadership, the department became one of the preeminent pharmacology programs in the United States. Gilman continued and expanded his research on G proteins during his tenure at UT Southwestern, further elucidating the molecular mechanisms by which these proteins regulated cellular responses to external signals.

At UT Southwestern, Gilman's research group made a series of contributions that deepened understanding of the G protein signaling system. The laboratory characterized the subunit structure of G proteins, demonstrating that they consisted of alpha, beta, and gamma subunits. When a hormone or neurotransmitter binds to a G protein-coupled receptor on the cell surface, the receptor activates the G protein by promoting the exchange of GDP for GTP on the alpha subunit. This activation causes the alpha subunit to dissociate from the beta-gamma complex, and both the free alpha subunit and the beta-gamma dimer can then interact with downstream effector proteins to propagate the signal within the cell. The alpha subunit possesses intrinsic GTPase activity, which hydrolyzes GTP back to GDP, thereby terminating the signal and allowing the G protein to reassemble in its inactive form.

This work revealed that G proteins constituted a large and diverse family of signaling molecules. Different classes of G proteins were found to regulate different effector systems, including adenylyl cyclase, phospholipase C, and ion channels. The discovery that G proteins served as a universal mechanism of signal transduction had profound implications for pharmacology and medicine, as it became clear that G protein-coupled receptors represented the largest family of cell-surface receptors in the human body and that an estimated 30 to 50 percent of all marketed drugs acted through G protein-coupled receptor pathways.

Gilman served as chairman of the Department of Pharmacology at UT Southwestern for nearly three decades before his retirement in 2009.

Alliance for Cellular Signaling

Gilman founded the Alliance for Cellular Signaling (AfCS), an ambitious collaborative research initiative aimed at understanding the complexities of cellular signaling networks in a systematic and comprehensive manner. The project sought to map the entirety of signaling pathways in specific cell types using a combination of experimental and computational approaches. The AfCS represented one of the early efforts in systems biology, bringing together researchers from multiple institutions to tackle problems that were beyond the capacity of any single laboratory.

Regeneron Pharmaceuticals

Gilman was a founder of Regeneron Pharmaceuticals, a biotechnology company that would grow to become one of the major pharmaceutical companies in the United States. The company, which focuses on the development of medicines for serious medical conditions, was established in the late 1980s and has since developed multiple approved therapies. Gilman's involvement in the founding of Regeneron reflected his interest in translating basic scientific discoveries into therapeutic applications.

Cancer Prevention and Research Institute of Texas

Upon his retirement from UT Southwestern in 2009, Gilman was appointed chief scientific officer of the Cancer Prevention and Research Institute of Texas (CPRIT), a state agency established by Texas voters in 2007 to fund cancer research and prevention programs. In this role, Gilman was responsible for overseeing the scientific review and evaluation of research grant applications submitted to the institute.

Gilman resigned from CPRIT in 2012 amid a controversy involving grants that had bypassed the normal peer review process. His departure highlighted his commitment to scientific integrity and the rigorous evaluation of research proposals. The controversy at CPRIT led to broader reforms in the agency's governance and grant-making procedures.

Corporate and Advisory Roles

From 2005, Gilman served as a member of the board of directors of Eli Lilly and Company, one of the world's largest pharmaceutical companies. This role allowed him to bring his deep expertise in pharmacology and molecular biology to bear on strategic decisions regarding drug development and research priorities in the pharmaceutical industry.

Goodman & Gilman's The Pharmacological Basis of Therapeutics

Following in his father's footsteps, Gilman served as editor of Goodman & Gilman's The Pharmacological Basis of Therapeutics, the landmark pharmacology textbook that his father and Louis S. Goodman had first published in 1941. The textbook, often referred to simply as "Goodman & Gilman," remained one of the standard references in pharmacology and medical education for decades. Gilman's editorship helped ensure the continued relevance and scientific rigor of the work through multiple editions.

Personal Life

Gilman married Kathryn Hedlund, and the couple had three children. He lived in Dallas, Texas, during the latter decades of his life, in close proximity to the University of Texas Southwestern Medical Center where he spent the majority of his career.

Gilman was a member of the advisory council of the National Center for Science Education, an organization dedicated to promoting the teaching of science, including evolution and climate science, in public schools.

Alfred G. Gilman died on December 23, 2015, in Dallas, Texas, at the age of 74. His death was reported by multiple major news outlets and scientific journals, reflecting his stature in the biomedical research community. The Washington Post noted his contributions as a Nobel Prize-winning scientist in its coverage of his passing.

Recognition

Gilman received numerous awards and honors throughout his career in recognition of his contributions to biomedical science. His most prominent award was the 1994 Nobel Prize in Physiology or Medicine, shared with Martin Rodbell, "for their discovery of G-proteins and the role of these proteins in signal transduction in cells." The Nobel Assembly at the Karolinska Institute cited the fundamental importance of G proteins in understanding how cells communicate and respond to external signals.

Prior to receiving the Nobel Prize, Gilman was honored with several other major awards. In 1984, he received the Canada Gairdner Foundation International Award, one of the most prestigious prizes in biomedical research. In 1989, he received both the Albert Lasker Award for Basic Medical Research, often considered a precursor to the Nobel Prize, and the Louisa Gross Horwitz Prize from Columbia University, another award with a strong record of preceding Nobel recognition.

Gilman was elected to membership in several of the most distinguished scientific societies. He became a member of the National Academy of Sciences and a member of the American Academy of Arts and Sciences. He was also elected a Fellow of the American Association for Cancer Research (AACR) Academy, which recognized his contributions to cancer research and the broader biomedical sciences.

Case Western Reserve University, his alma mater, recognized Gilman as one of its most distinguished alumni, noting his pioneering contributions to both education and research.

Legacy

Alfred G. Gilman's discovery and characterization of G proteins represented one of the foundational advances in the field of cell biology and molecular pharmacology in the twentieth century. G proteins are now understood to be central to the function of G protein-coupled receptors (GPCRs), which constitute the largest superfamily of cell-surface receptors in the human genome. The signaling pathways mediated by G proteins regulate virtually every physiological process, including vision, taste, smell, neurotransmission, immune function, and cardiovascular regulation. The pharmaceutical significance of this discovery is substantial, as a large proportion of therapeutic drugs in clinical use target GPCRs or components of G protein signaling pathways.

Gilman's work built directly upon the earlier contributions of Martin Rodbell, who had established the conceptual framework for signal transduction involving GTP-binding proteins. While Rodbell proposed the model, it was Gilman who provided the definitive biochemical proof by purifying the G proteins and demonstrating their function in reconstituted systems. The complementary nature of their contributions was recognized by the joint award of the 1994 Nobel Prize.

Beyond his research accomplishments, Gilman made significant contributions to scientific education through his stewardship of Goodman & Gilman's The Pharmacological Basis of Therapeutics, ensuring that generations of medical students and pharmacologists had access to a comprehensive and authoritative reference work. His founding of the Alliance for Cellular Signaling represented an early and influential effort to apply systems-level approaches to understanding cell biology, prefiguring the growth of systems biology as a discipline.

Gilman's departure from CPRIT in 2012, prompted by concerns about scientific integrity in the grant review process, underscored his commitment to maintaining rigorous standards in the evaluation and funding of scientific research. His stance contributed to subsequent reforms at the agency and served as a reminder of the importance of peer review in the allocation of public funds for research.

The AACR recognized Gilman's lasting contributions by including him among the Fellows of the AACR Academy, an honor reserved for individuals who have made significant contributions to the field of cancer research or to the AACR's mission to prevent and cure cancer.