Published online before print February 7, 2005, doi: 10.1161/01.HYP.0000156754.39760.e6
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(Hypertension. 2005;45:319.)
© 2005 American Heart Association, Inc.
In Memoriam |
John R. Vane (1927–2004)
Jagiellonian Medical Center, Cracow, Poland
Department of Pharmacology, New York Medical College, Valhalla, New York
"Let us now praise famous men."1 John R. Vane died on November 26, 2004, marking the end of an era of pharmacological sciences that rested on global biological concepts and addressed nature’s grand design, the human body in motion, not in stasis.
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John Vane was born in Tardebigg, Worcestershire on March 29, 1927, the youngest of 3 children. His father was the son of Russian immigrants and his mother’s family farmed in Worcestershire. The Vane family lived in a suburb of Birmingham, where they weathered World War II, colored by the trappings of war: nights were frequently spent in an air-raid shelter at the bottom of the garden.
John Vane studied chemistry at Birmingham University, a subject that did not satisfy his native curiosity. On graduation in 1946, a letter arrived in the Department of Chemistry from Professor J. Harold Burn, Chairman of Pharmacology at Oxford, inquiring if any of the recent graduates would like to be trained in pharmacology. John Vane said "yes" while thinking "I’ll do anything but chemistry." At Oxford, Professor Burn recognized John’s driving curiosity to probe the undiscovered and channeled it into the area of experimental pharmacology. A telling remark is John Vane’s comment on being designated a pharmacologist, "the label hid the truth, as labeling tied one to a discipline." He preferred the label, "experimentalist."2
J. Harold Burn was a remarkable energizer of young scientists, as revealed in John Vane’s commentary on him. This is also a splendid recapitulation of John Vane’s own impact on biological sciences. "If anyone can be said to have molded the subject of pharmacology around the world, it is J. Harold Burn. He did this through his particular style of research, through the lucidity of his writings, but most of all through the school which he founded. His laboratory gradually became the most active and important center for pharmacological research in the U.K. and the main school for training of young pharmacologists. It was his energy and inspiration that set my career into one of adventure in the fields of bioassay and pharmacology. It was Burn who reinforced for me the essence of experimentation and that is, never to ignore the unusual."3 The past is prelude to the present as the disciple becomes the mentor. In his own laboratories, John Vane reproduced this hospitable environment for discovery and pursuing new directions in which young scientists maturated and thrived. One of his most famous pupils paid tribute to his mentor in a memorable phrase: "John’s unique personality sculpted my scientific life."
In a 1984 commencement address,2 John Vane urged young scientists "to be simplifiers and not complicators! Do simple experiments and make simple hypotheses—there are plenty of others who will come along and show how much more complicated the answer really is; but at least for a few years a concept will exist that is elegant and easily understood." John Vane then enumerated the preeminent attributes of a successful scientist: "flexibility, curiosity and intellectual endeavor. There is another element which some call luck and others call serendipity, or discovery through the ‘happy accident.’ I would urge you never to ignore the unusual."
An extraordinary example of pursuit of the unusual was the discovery of angiotensin-converting enzyme inhibitors (ACEI), which many regard as the most important drug discovery of the past half-century. In 1965, a young Brazilian scientist, Sergio Ferreira, joined John Vane’s laboratory as a postdoctoral fellow at the Royal College of Surgeons (RCS). Sergio had been working on the vasoactive properties of peptides isolated from the venom of a Brazilian pit viper, Bothrops jararaca (called the "mother-in-law" snake because it strikes unprovoked!).4 These peptides exhibited potent hypotensive properties, in part by inhibiting destruction of kinins and were so named "bradykinin potentiating factor". Down the hall at the RCS, Mick Bakhle was working on lung ACE;5 the peptides isolated from the snake venom were tested on lung ACE and were shown to inhibit conversion of angiotensin I to angiotensin II,4 in addition to potentiating bradykinin (kininase II=ACE). Thus was constructed the intellectual cradle for the development of ACEI that was hastened by John Vane’s serving as a consultant to Squibb, where captopril was conceived and synthesized by Ondetti and Cushman6 in response to the discoveries made by Vane, Ferreira, and Bakhle at the RCS.
The many discoveries of John Vane rested on the ingenious applications of bioassay methods incorporated in the principle of parallel pharmacological assays in which bioassay tissues are arranged in a cascade and superfused with either an organ’s perfusate or circulating blood. The tissues are selected to "detect biological activity," which are the unique fingerprints of "chemically unstable compounds whose activity would otherwise be lost in an extraction procedure."7 In this manner, thromboxane (rabbit aorta contracting substance [RCS!]) and prostacyclin (PGX) were first detected and characterized.8 These studies gave evidence of the triumph of intellect over technology.
To recognize John Vane’s most important contributions, which may overshadow or rival the elucidation of the mechanism of action of aspirin,9 we cite: (1) the circulatory dynamics of the renin-angiotensin system;10 (2) the metabolic and endocrine function of the lung whereby circulating hormones are degraded (kinins), generated (prostacyclin), and transformed (angiotensin I 
II);11 and (3) the endothelium as a generator of biological mediators, particularly prostacyclin, that act as guardians of the integrity of the blood–endothelial interface.12
The discovery of the mechanism of action of aspirin9 looms large because it serves as the basis of a paradigm ripe with therapeutic implications. The most pervasive is the use of low-dose aspirin to prevent thrombotic events by inhibiting platelet cyclooxygenase, thereby preventing generation of the pro-thrombotic eicosanoid, thromboxane A2, while sparing the platelet anti-aggregatory, dilator vascular hormone, prostacyclin (PGI2). (Is there anyone out there older than 60 not taking 1 baby aspirin per day?)
We grieve the passage of our colleague and friend but rejoice in his legacy in which we are all beneficiaries. Beyond the ideational legacy is the William Harvey Institute, which stands as a beacon and reminder of the life and achievements of John Vane. The succession is secure because the William Harvey Institute is directed by a distinguished scientist, Rod Flower, a former student and lifetime colleague of John Vane.
Milestones
- 1948: Married Elizabeth Daphne Page. They had two daughters, Mandy and Nikki
- 1953: DPhil, University of Oxford
- 1955: Assistant Professor in Pharmacology, Yale
- 1966: Professor of Experimental Pharmacology, London University
- The Royal College of Surgeons of England
- 1973: Group Research and Development Director
- The Wellcome Foundation
- 1974: Fellow of the Royal Society
- 1982: Nobel Prize in Physiology and Medicine
- 1983: Knight Bachelor in New Year Honors List for services to pharmaceutical research
- 1986: Founded William Harvey Research Institute
- Chairman and Director
- 1995: Director General, William Harvey Research Institute
- St. Bartholomew’s and The Royal London School of Medicine and Dentistry
- 1997: Honorary President, William Harvey Research Foundation
- 1953: DPhil, University of Oxford
References
- Agee J, Evans W. Let Us Now Praise Famous Men. Boston, Mass: Houghton Mifflin; 1960:F326.A17.
- Vane JR. Finding the Right Road. Commencement Address. Valhalla, NY: New York Medical College; 1984.
- John R. Vane—Autobiography. Available at: http://nobelprize.org/medicine/laureates/1982/vane-autobio.html. Accessed January 18, 2005.
- Ferreira SH, Greene LJ, Alabaster VA, Bakhle YS, Vane JR. Activity of various fractions of bradykinin potentiating factor against angiotensin I converting enzyme. Nature. 1970; 225: 379–380.[CrossRef][Medline] [Order article via Infotrieve]
- Bakhle YS. Conversion of angiotensin I to angiotensin II by cell-free extracts of dog lung. Nature. 1968; 220: 919–992.[CrossRef][Medline] [Order article via Infotrieve]
- Ondetti MA, Rubin B, Cushman DW. Design of specific inhibitors of angiotensin-converting enzyme: new class of orally active antihypertensive agents. Science. 1977; 196: 441–444.
[Abstract/Free Full Text] - Les Prix Nobel 1982. Almqvist & Wiksell International. Stockholm, Sweden.
- Gryglewski RJ, Bunting S, Moncada S, Flower RJ, Vane JR. Arterial walls are protected against deposition of platelet thrombi by a substance (prostaglandin (PG) X) which they make from PG endoperoxides. Prostaglandins. 1976; 12: 685–713.[CrossRef][Medline] [Order article via Infotrieve]
- Vane JR. Inhibition of PG synthesis as a mechanism of action for aspirin-like drugs. Nature New Biol. 1971; 231: 232–235.[Medline] [Order article via Infotrieve]
- Ng KKF, and Vane JR. Fate of angiotensin I in the circulation. Nature. 1968; 218: 144–150.[CrossRef][Medline] [Order article via Infotrieve]
- Vane JR. Release and fate of the vasoactive hormones in the circulation. 2nd Gaddum Memorial Lecture, Edinburgh. Br J Pharmacol. 1942; 35: 209–242.
- Bunting S, Moncada S, Vane JR. The prostacyclin-thromboxane A2 balance: pathophysiological and therapeutic implications. Br Medical Bulletin. 1983; 39: 271–276.
[Free Full Text]
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