Portal de Periódicos da CAPES

John Robert Vane

2005; Lippincott Williams & Wilkins; Volume: 45; Issue: 3 Linguagem: Inglês

10.1097/01.fjc.0000158305.65838.1a

1533-4023

Alan M Edelson,

Sir John R. Vane, F.R.S., Nobel Laureate, and one of the world's pre-eminent pharmacologists, died on November 19, 2004, at the age of 77.FIGURE 1His notable scientific achievements covered a wide range of cardiovascular and pharmacological discoveries. It was during his 18 years at the Royal College of Surgeons, University of London, from 1955 to 1973, that he developed his powerful cascade superfusion bioassay technique for the detection and measurement of vasoactive hormones. He elaborated the technique over the years, and it served him and his colleagues well. Starting in the mid-1960s, he focused his attention on the prostaglandins. In studies with P.J. Piper, published in 1969, he detected a previously undescribed and highly unstable substance released from perfused lungs isolated from sensitized guinea pigs. Because this substance caused a strong contraction of strips of rabbit aorta, they tentatively named it rabbit aorta contracting substance (RCS). Its release during anaphylaxis was selectively prevented by aspirin and similar compounds. In 1971, Vane made his signal discoveries on the linkage between the prostaglandins and the effects of aspirin. He had been impressed by the effects of an infusion of aspirin into the hyperventilated dog: “Not only was the associated hypotension reduced, but there was also a strong inhibition of prostaglandin release,” he later wrote in the printed text of his Nobel lecture. ▪ It was this experiment that led me to the idea (over the weekend) that aspirin might be interfering with prostaglandin biosynthesis. On the Monday morning I said…‘I think I know how aspirin works’ and set about doing an experiment…I homogenized some guinea pig lungs, spun off the cell debris, divided the supernatant into test tubes, added arachidonic acid and measured by bioassay the amounts of PGE2 and PGF2alpha formed. By the end of that day I was convinced that aspirin and indomethacin (but not morphine) strongly inhibited the formation of prostaglandins from arachidonic acid. He developed the hypothesis that this biochemical intervention in prostaglandin formation by the aspirin-like drugs is the basis of their therapeutic action. During this time at the Royal College of Surgeons, he, together with coworkers S.H. Ferreira, Y.S. Bakhle, and others, also laid down the experimental evidence which persuaded him that inhibition of angiotensin would be a useful therapy for hypertension. As a consultant for Squibb in the U.S., he suggested angiotensin-converting enzyme as a target for research at the Squibb Institute, the end result of which was the first ACE inhibitor, captopril. In 1973, he accepted the position of Group Research and Development Director at what was then the Wellcome Foundation, bringing with him a nucleus of research colleagues. In his new role at Wellcome, he formed and expanded over the years a prostaglandin research department under the leadership of S. Moncada. It was in this group that prostacyclin was discovered and its pharmacology elucidated in work he first published in 1976 with Moncada, R. Gryglewski, and S. Bunting. Work by Bengt Samuelsson and others with the prostaglandin endoperoxides in the early 1970s had led Vane to the conclusion by 1977 that most of the activity associated with the substance he had called RCS was due to thromboxane. He and his group isolated the enzyme from the microsomal fraction of platelets and showed by his bioassay techniques that endoperoxides, when incubated with this fraction, were rapidly transformed into thromboxane, which potently contracted rabbit aorta and induced platelet aggregation. This enzyme, which Vane and his colleagues called thromboxane synthetase, became a major target for new drug development. Vane proposed the concept that a balance between the amounts of thromboxane formed by platelets and of prostacyclin formed by blood vessel walls might be critical for thrombus formation, a view now widely accepted. These insights, further developed with Moncada, Ferreira, R.J. Flower, and others, provided the key to understanding the action of many other anti-inflammatory drugs. They also strongly influenced the development of future anti-inflammatory agents, including the COX-2 inhibitors. It was with his signature cascade superfusion bioassay technique that Vane achieved enhanced specificity by using a combination of several different tissues, generally up to six, arrayed in cascade, and arranged in two banks. This takes advantage of the principle of parallel pharmacological assay to demonstrate a characteristic pattern of responses to the test substance or substances. Another important technical innovation was his use of blood as the superfusion medium, the “blood-bathed organ” technique. Bakhle, a former colleague and now a senior research fellow at the Imperial College, London, credits these techniques as among Vane's greatest legacies: “I think people looked at it as some sort of medieval rite-it looks so non-scientific, but it was immensely powerful and I think it still is.” In Flower's opinion, the elegance, simplicity and efficiency of his bioassay techniques enabled Vane to test his ideas and make his discoveries quickly at a time when chemical methods for assessing hormone concentrations were slow and cumbersome and radioimmunoassay had not been fully developed. Later, when molecular biology and molecular genetics techniques were developed, he was content to leave their application to others, preferring his classic bioassay techniques. Vane himself wrote that “it is doubtful whether the biological significance of any of the unstable products of arachidonic acid metabolism would have been recognized without bioassay techniques. With extraordinary simplicity and convenience, by its very nature, bioassay distinguishes between the important biologically active compounds and their closely related but biologically unimportant metabolites.” According to Moncada, “Vane would say, ‘Go to the tissues; they will tell you what the answer is.’ He also believed that bioassay tissues never told you a lie-if they did, it's because you didn't interpret them well.” John Vane was born in Tardebigg, Worcestershire, U.K. At the age of 12, living in a suburb of Birmingham, U.K., his parents gave him a chemistry set for Christmas, and his passion for experimentation was born, but not without mishap. A minor explosion involving hydrogen sulfide altered the newly painted décor from blue to dirty green. His father moved his laboratory into a small wooden shed he erected for his son in the garden and equipped it with a bench, gas, and water. “This became my first real laboratory,” Vane wrote, “and my chemical experimentation rapidly expanded into new fields.” At the University of Birmingham he studied chemistry, but quickly found that experimentation in chemistry was nonexistent at university. When Maurice Stacey, Professor of Chemistry, asked him what he wanted to do when he graduated, he said, with his characteristic candor, “Anything but chemistry.” Professor Stacey must have been remarkably patient and perceptive. He told his student that he had received a letter that morning from Professor Harold J. Burn, in Oxford, asking whether he could recommend a young chemist to come to Oxford for training in pharmacology. “Without hesitation,” Vane later wrote, “I grasped the opportunity and immediately went to the library to find out what pharmacology was all about. That brief exchange with Stacey reshaped my whole career.” Working under Burn, he found inspiration and caught his enthusiasm for pharmacology. It was Burn who reinforced for him “the essence of experimentation, and that is, never to ignore the unusual.” And, crucially, it was Burn who taught him the principles and practice of pharmacology and bioassay. In addition to Burn, wrote Vane, Sir Henry Dale [1875-1968] “had a great influence…on my own scientific endeavors. Indeed, I can put forward a strong case for considering myself as one of Dale's scientific grandchildren.” His collaborators have testified to Vane's uncanny knack of putting his finger on the right question and devising the right experiment to answer it. Observed Flower: ▪ He was quite an impatient man, and he liked to see results appearing quickly. He found an old closed circuit TV camera in the lab and rigged it up so that it was focused on the chart recorder. The monitor was in his office on the other side of the department. He would watch the progress of the experiment through the closed circuit television monitor and phone me up on the lab telephone extension and tell me what doses to try next and so on. If I made a mistake then the bell used to ring immediately and I used to get a terse reminder that I was wasting time and money. Despite his impatience, recalls B. Whittle, who joined the group in 1976, Vane tempered his demands with a sharp wit and “could mix humor with a strong message-he knew how to tell us when he didn't think we were performing adequately, but always in an amusing way.” Vane managed to pass on his scientific expertise and to train numerous students while ignoring what are considered essential elements of laboratory management. At the Royal College of Surgeons, according to Flower, he almost never held any formal management meetings, conducted almost no departmental reviews, and performed no formal counseling of students, “yet most of his students have turned out to be stars. At the end of the day good management can't replace strong leadership, and I think that is where John triumphed.” To John Vane, science was a quintessentially international endeavor, and he took pride in gathering talented scientists to his laboratories from all parts of the world, including Australia, Belgium, Brazil, Canada, Holland, Honduras, Italy, Japan, Poland, Singapore, Taiwan, and the United States. Some returned to his laboratories several times. Others started as technicians and remained with him as PhD's. He strove mightily to assist his colleagues behind the Iron Curtain during the Cold War. Beginning in the 1960s, he made many trips to Poland, taking to the laboratories equipment and reagents that might otherwise be unobtainable, and he offered Polish scientists the opportunity to visit the West and to work in his laboratories. For his dedicated efforts in this regard, he was awarded the Polish Order of Merit in 2003. One of those with whom he developed a close international collaboration was R.J. Gryglewski of the University of Cracow, who gratefully noted, “Each stay with him was my refuge from the totalitarian communistic system which overshadowed my country.” He has described how it was to live and work in Poland during the Solidarity period, the first organized resistance movement: ▪ Everybody knew that the storm was approaching. I made an agreement with John that if I needed his help I would cable him the following text: ‘Please send me 5 ampoules of prostacyclin.’ It was his idea. He explained, ‘There is no prostacyclin solution in ampoules, so I will know that there is something wrong with you.’ When in December 1981 the Martial Law was introduced in Poland and I was in trouble, I cabled him the text we had agreed upon. His reply was immediate: ‘Silly, there are no prostacyclin ampoules.’ Eventually we sorted out the problem, and via our embassy in London he succeeded to bring me to England. In 1985, at the age of 59, Vane left the Wellcome Foundation, but not active research. He accepted an invitation from St. Bartholomew's Hospital Medical School of London to start a new laboratory for research in cardiovascular and inflammatory disease-the William Harvey Research Institute-funded initially by the Glaxo Group Research and Ohno Pharmaceuticals. It was an offer he found irresistible. Having moved from academia to pharmaceutical industry research in 1973, he confounded convention by returning to academia. Again, he gathered 130 talented scientists from around the world, and in a relatively few years built the institute into one of the top 20 U.K. research establishments. Vane published some 900 original articles, wrote or edited 20 books, received more than 50 medals, prizes, awards, and honorary degrees, was made a Fellow of the Royal Society of England (in 1974), and was a member of about 30 other societies or institutions. In 1977, he won the Albert Lasker Basic Medical Research Award. In 1982, he shared the Nobel Prize in Physiology or Medicine with Sune K. Bergstrom and Bengt I. Samuelsson. In 1984, he was knighted in the New Year's Honors List for services to pharmaceutical science. There were interesting contrasts in Sir John's complex personality. He was understated in conversation, always preferring a pithy sentence to a paragraph, but he was fond of wearing his collection of whimsical floral and paisley patterned neckties. He never sought to draw attention to himself in a crowd, yet he radiated great personal warmth and charm, and showed unfailing courtesy to people from all stations in life, the surest mark of a true gentleman. An extremely social man, he loved to surround himself with the companionship of his colleagues and friends from around the world, of which he had a great many. Yet he never sought to dominate the conversation, preferring instead to interject an insightful or humorous remark when it seemed worth saying. With his wife, Daphne, and daughters, Nikki and Miranda, he frequently entertained people at their home in Kent near London, in restaurants, and at their Caribbean villa. I recall vividly the scene in his suite at the Grand Hotel in Stockholm in 1982 on the day before he was to receive his Nobel Prize, in what is surely the grandest academic ceremony on Earth, followed by a gala banquet of eleven hundred guests presided over by Swedish royalty. His hotel sitting room was crowded with his family and close friends, who were understandably excited about the upcoming event. Seated on the sofa, surrounded by the hubbub of which he was the focal point, he chatted quietly, appearing completely relaxed and confident, as if nothing very extraordinary was about to happen to him. John Vane's dry wit had a way of poking unexpectedly through his quiet demeanor. I recall our sitting together on the patio of his Caribbean vacation home watching yet another spectacular tropical sunset unfolding before us. It was a house tradition that we all sip champagne while rating each sunset on a scale of one to ten. (That evening was a ten.) We settled into appreciative silence. He then said that he had been thinking about someday retiring to California and its mild climate. I reminded him of the joke that those who do so may lose several points off their IQ. “I can afford it,” he said, with a twinkle in his eyes. Alan M. Edelson, PhD