Alfred Goodman Gilman (1941–2015) Pharmacologist Who Won a Nobel Prize for His Discovery of G Proteins

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COMMENT OBITUARY Alfred Goodman Gilman (1941–2015) Pharmacologist who won a Nobel prize for his discovery of G proteins.

lfred Goodman Gilman discovered sensitivity on the adenylyl cyclase. heterotrimeric G proteins, which Using their reconstitution assay, they help to usher chemical signals into purified the protein and determined its DNA Acells. For this work, which reshaped our sequence. Their discovery, published in a understanding of hormone and drug action, series of papers in 1977–78 (E. M. Ross and he shared the 1994 Nobel Prize in Medicine A. G. Gilman J. Biol. Chem. 252, 6966–6969; or Physiology with Martin Rodbell. 1977; and E. M. Ross et al. J. Biol. Chem. Gilman’s impact on biomedical research 253, 6401–6412; 1978) confirmed Rodbell’s

and education extended much further. He prediction of the existence of such an inter- GRESHAM/UTSOUTHWESTERN DAVID edited several editions of the definitive text- mediate protein linking a cell’s hormone book The Pharmacological Basis of Therapeu- receptors to adenylyl cyclase and intracel- tics (or ‘Goodman and Gilman’), which has lular signalling. Over the next 15 years the served generations of medical and graduate family of heterotrimeric G proteins grew to students. At the University of Texas South- about 20, and their roles expanded to include western Medical Center in Dallas, he chaired almost all physiological processes in species the pharmacology department from 1981 from yeast to mammals. Gilman’s subse- to 2004, became dean in 2004 and provost quent work with Stephen Sprang focused in 2006. And in 2009, he was appointed first on the detailed characterization by X-ray chief scientific officer of the Cancer Preven- crystallography of several of the G proteins tion and Research Institute of Texas (CPRIT), the 1970s, evidence was mounting that the and the adenylyl cyclases that they regulate. established to disburse US$3 billion in state hormone receptors involved in cell signal- Gilman’s writing and speaking style were funding. He died on 23 December 2015. ling were independent entities in the plasma distinctive. He was critical not just of others’ Gilman was born in July 1941 in New membrane. Gilman and his postdoc Elliott work but also of his own. His wit could bor- Haven, Connecticut, with, in his words, a Ross were investigating this problem using der on the acerbic if he felt that the highest “scientific silver spoon” in his mouth. His membranes from a lymphoma cell line standards were not being met. He was beloved father was the eminent pharmacologist called cyc–. These cells seemed to lack the by his trainees, to whom he was fiercely loyal. Alfred Gilman Sr, who wrote the aforemen- key enzyme adenylyl cyclase, which cataly- They remember him as a hands-off mentor tioned textbook with his close colleague ses formation of cAMP. The cells retained who was nonetheless approachable and inspi- Louis Goodman. Gilman Sr, in tribute to the β-adrenergic receptor that binds a class rational, and who instilled in them a sense of his friend, gave his son the middle name of molecules called catecholamines, which rigour and integrity. Gilman displayed this Goodman. As a child, young Gilman includes the hormone adrenaline. This bind- personal integrity when, in 2012, he resigned enjoyed trips to his father’s labs at Columbia ing stimulates adenylyl cyclase, increasing from the CPRIT over concerns that political University and the Albert Einstein School of the formation of cAMP. and commercial factors were exerting undue Medicine in New York. To these cyc– membranes, Gilman and influence on its awarding of grants. After completing a degree in biochemistry Ross added an extract of another cell line, Al’s offbeat sense of humour occasion- at Yale University in New Haven in 1962, he mouse L cells, which retained enzyme ally made its way into his published work. enrolled in one of the first MD–PhD pro- activity but lacked the hormone receptors. For instance, he designated the irreversibly grammes in the United States, at Case West- To their delight, this ‘reconstitution’ system activated state of adenylyl cyclase induced by ern Reserve University in Cleveland, Ohio. worked and yielded hormone-sensitive a certain guanine nucleotide as the ‘P state’ The programme was run by Nobel laureate adenylyl cyclase activity. However, control (for priapic) because “the enzyme’s rate of Earl Sutherland, the discoverer of cyclic experiments indicated that extracts in which catalysis was persistently elevated”. AMP, a key intracellular messenger mol- the cyclase activity had been inactivated, by Reflecting on the role of serendipity in ecule. Here, Gilman solidified his interest in heat for example, still led to a fully reconsti- scientific discovery, Al once commented: cell-signalling mechanisms. A postdoc at the tuted hormone-sensitive enzyme. “The trick is to recognize good luck when US National Institute of Health in Bethesda, Through ingenious experiments they it happens, embrace it, and then commit Maryland, with Marshall Nirenberg, another demonstrated that these extracts contained whatever it takes to extract its full value.” He Nobel laureate, followed. In 1970, in Niren- a heat-stable, hitherto unknown regulatory certainly extracted the full value of his lucky berg’s lab, Gilman independently developed component required for activity of the ade- start as a scientific blueblood. ■ a sensitive technique for detecting cAMP nylyl cyclase and that the cyc– cells actually that was immediately widely adopted. did contain the catalytic unit of adenylyl Robert J. Lefkowitz is a Howard Hughes But it was his discovery of a family of cyclase (and hence had been misnamed). Medical Institute investigator and professor G proteins made up of three different subu- They called the new component Gsα — the of medicine at Duke University in Durham, nits (known as heterotrimeric G proteins) α subunit of the stimulatory guanine nucleo- North Carolina, USA. His scientific interests as a junior faculty member at the Uni- tide regulatory protein (G protein), because overlapped with Al Gilman’s, and they were versity of Virginia in Charlottesville, that it bound guanosine triphosphate (GTP) colleagues and friends for more than 40 years. transformed the field of cell signalling. In and conferred both hormone and GTP e-mail: [email protected]