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Sir John Vane FRS In 1955 John returned to the UK and When animal blood was used it could embarked upon what might be regarded be sampled from many different sites in 1927 – 2004 as the first of his three major creative the body and recirculated into the periods. He joined WDM Paton’s venous return enabling John to pinpoint Department of at the the organs responsible for the release Institute of Basic Medical Sciences and removal of hormones such as which was (after some time at Queens angiotensin and bradykinin. Working Square) located at the Royal College of on this problem with SH Ferreira, YS Surgeons of England in London. John Bakhle and others he observed that the rose quickly through the academic pulmonary circulation was a major site ranks gaining a personal chair himself for the destruction of bradykinin as in 1966. GVR Born, a friend of John well as for the conversion of from his Oxford days, had succeeded angiotensin I to angiotensin II. The Paton in 1961 and under the joint group speculated that both phenomena influence of Born and Vane, the were attributable to the same enzyme John Vane, who died peacefully of department at the Royal College and deduced that the ‘bradykinin pneumonia on 19 November 2004, was provided an astonishingly productive potentiating factor’ from Bothrops heir to the physiological tradition of intellectual environment which jararaca venom, which inhibited pharmacology and one of its greatest published much cutting edge science, bradykinin proteolysis, might also exponents. However, he became a nurtured many careers and rose to great block angiotensin I conversion and biological scientist essentially by prominence. furthermore, that this strategy could accident. His first choice of career, prove a useful therapy for hypertension. It was during these years that John stemming from a childhood hobby, was John took the idea to Squibb where perfected his signature ‘blood bathed chemistry and he graduated from the Welch, John’s mentor from Yale, was organ cascade’; a combination, and a University of with a by then Research Director. The development along extraordinary lines, Bachelors degree in that subject in outcome of this initiative was the of JH Gaddum’s parallel bioassay and 1946. But John, who was an development of the revolutionary ACE superfusion techniques of 1953. Blood experimentalist by nature, did not find inhibitors. from animals, or sometimes humans, the actual practice of chemistry as was passed continuously over a series A few years later, in 1971, John began rewarding as he had imagined. of isolated tissues chosen for their what is generally regarded as his finest Discussing his future with his head of exquisite sensitivity to, and ability to piece of work. was a drug that department, he was told that J H Burn differentiate between, hormones or had been around since the end of the in Oxford was seeking graduates to be other substances under investigation. th trained in pharmacology. John later 19 century, but for all its utility it had This technique enabled John to measure wrote ‘without hesitation I grasped the defied every attempt to unravel the instantaneously and with great opportunity and immediately went to underlying mechanism that linked specificity, the levels of one or more the library to find out what together its distinctive therapeutic and blood hormones. The dynamic nature pharmacology was all about!’ The side effects – a pharmacological profile of this technique suited his study of experimental pharmacology that was also shared by many other temperament for insights and ideas turned out to be exactly what he was ‘non-steroidal anti-inflammatories’. came quickly to him and he was looking for and he never forgot Burn’s John’s interest in had impatient to test them. inspirational early influence on his been kindled some years earlier and work and thinking.

After qualifying, John spent a short time at Sheffield University before returning to Oxford for postgraduate studies with G Dawes. In those days it was common for post doctoral scientists to do a stint in the USA and after receiving his DPhil John was invited by A Welch to join the Department of Pharmacology at Yale as an Assistant Professor. These early years were formative ones for John and one may trace the roots of much of his subsequent work back to these early influences and to the friendships he John Vane, pictured at the Royal College of Surgeons (then in Lincoln’s Inn Fields) in the late 1960s with an old­ forged at this time. fashioned kymograph.

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implement this vision he took Ferreira, Moncada, Flower, GA Higgs and others with him to form a nucleus of his personal research group. In 1976, working mainly through Moncada, R Gryglewski and S Bunting, John’s group discovered the potent vasodilator and anti-aggregatory ‘X’. The mystery substance was characterised in collaboration with Upjohn and renamed

(PGI2). Analogues were later approved for the treatment of pulmonary hypertension and antithrombotic indications. Under John’s management, John Vane in 1982, shortly after the announcement of his , in front of one of his famous cascades. Wellcome produced several other important drugs including Zovirax, over a weekend he conceived the pharmaceutical company whose profits Tracrium and Lamictal. notion that perhaps aspirin worked by were gifted to the charitable Wellcome inhibiting the generation of these multi­ Trust. Perhaps John was encouraged to By now, John’s contributions to his faceted mediators. He turned again to accept this post by the thought that Sir discipline were increasingly recognised. his bio-assay system for the answer and Henry Dale, one of his intellectual In 1974 he was made a Fellow of the within a few days he had convinced heroes, was recruited by Henry Royal Society, in 1977 he won the himself and his colleagues that this Wellcome and was crucial to the early Albert Lasker Basic Medical Research indeed was the missing mechanism of development of the company. Award and in 1982 he shared with B action. This concept, which he further Samuelsson and S Bergström, the expanded mainly with Ferreira, S The 13 years that John spent at Nobel Prize for or Medicine Moncada and RJ Flower, profoundly Wellcome presented him with a new for his work on aspirin. In 1984 he was influenced the field including (in the and different set of challenges. He had knighted in the New Years Honours list 1990s) the development of Cox-2 no more time for lab work as such but for services to pharmaceutical science. inhibitors. continued to exert his influence on Over 50 other honorary degrees and research in different ways. John had fellowships followed over the years. 1973 saw a change in John’s very definite views about drug circumstances. Born had taken a chair discovery believing that if you recruited In 1986, aged 59, John left the in Cambridge and John was offered the the most motivated scientists and Wellcome Foundation but the idea that position of Group Research and allowed them to work on problems of he might simply retire and enjoy the Development Director of the (then) their own choice in a well supported fruits of a life’s work was simply not an Wellcome Foundation, in Beckenham, environment, then new ideas about option for him. An invitation from St Kent. In those days ‘The Foundation’ disease mechanisms and ultimately new Bartholomew’s Hospital Medical was a unique institution; a drugs would inevitably ensue. To School, brokered by another old friend D Willoughby, coupled with an offer of some start-up funding from Glaxo Group Research, gave John the opportunity to start up a new lab; he accepted this challenge with alacrity thereby initiating the third major phase of his career. As always when starting a fresh venture, John’s technique was to surround himself with colleagues that he trusted and respected and to work together with them to build up a critical mass of talented researchers. Groups headed by E Änggård, N Benjamin, I MacIntyre, D Tomlinson, B Whittle and Willoughby, as well as old colleagues Schematic diagram of the blood-bathed organ cascade. This diagram first appeared in John Vane’s 1968 Born and Flower, joined with John to Gaddum Memorial Lecture to the Pharmacological Society* and was later reproduced by Vane in his Nobel promote his vision of a free-standing lecture. The cascade can also be seen in the picture of John Vane, above. Institute devoted to excellence in (*Reprinted by permission from Br J Pharmacol. Vane JR (1969). Br J Pharmacol 35, 209-242. Macmillan Publishers Ltd). inflammation and cardiovascular

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research. From this confluence of John Vane's speech at the scientists the opportunity to visit the research groups arose The William Nobel Banquet West and to work in his laboratory. He Harvey Research Institute. Major December 10, 1982 made many close friends there and funding from Ono Pharmaceuticals in visited the country each year, invariably ‘Your Majesties, Your Royal Highnesses, Japan enabled the institute rapidly to Ladies and Gentlemen... accompanied by Daphne, to attend expand and it soon became a veritable scientific meetings. In 2003, John was powerhouse with a staff of over 120 It is sometimes said that the major accorded a rare honour in recognition people. discoveries have already been made and of his contributions to the Anglo-Polish that there is nothing important left to find. scientific collaboration when he was John himself, whilst rarely doing lab awarded the Polish Order of Merit at a work, continued to influence the This attitude is altogether too pessimistic. ceremony in Warsaw. direction of the science focusing again There are plenty of ideas and plenty of mainly upon hormones influencing the things left to discover. The trick is to find As in many fields of medical research, heart and blood vessels as well as on the right path from one to the other. The John’s own studies often depended medicines of today are based upon the pharmacology of the Cox-2 upon laboratory animals. This drew thousands of years of knowledge inhibitors. He even found time to start unwelcome attention from the animal accumulated from folklore, serendipity rights extremists who, being up (with Änggård) a new company, and scientific discovery. The new Vanguard Medica Ltd (now Vernalis). medicines of tomorrow will be based on humanitarians, pursued a particularly He retired as full-time Director of the the discoveries that are being made now, vindictive campaign against him. Hate Institute in 1995 but still maintained his arising from basic research in laboratories mail was sent; fire bombs thrown at his office and continued to influence the around the world. Fundamental house; graffiti was daubed on out­ course of research and to direct young discoveries can and should be made in buildings. These terror tactics did not people. Following the merger of the industry or academies, but to carry that deter him from his work and he was knowledge forward and to develop a new Institute with the medical school in always an eloquent advocate for the drug to the market has to depend on the 2000 John took over the role of responsible use of animals in scientific resources of industry. In many countries research and a source of moral support Honorary Chairman of the charitable now, research in universities is under Research Foundation. severe financial restraint. to others who had suffered in a similar way. He would have been very In getting to know John, there This is a short-sighted policy. Ways have gratified by the efforts now being made inevitably came a point when one was to be found to maintain university by the BPS, the Physiological Society introduced to his family. John had research untramelled by requirements of and the pharmaceutical industry to married Daphne during their Oxford forecasting application or usefulness. promote training in in vivo techniques. days where their two daughters, Nikki Those who wish to study the sex-life of butterflies, or the activities associated John Vane was a towering figure in the and Miranda, had also been born. with snake venom or seminal fluid should physiological tradition of Although by nature rather a shy man, be encouraged to do so. It is such pharmacology. He watched the John was immensely sociable and, improbable beginnings that lead, by molecular biology revolution unfold together with Daphne and his convoluted pathways, to new concepts from the sidelines and his confidence in daughters, frequently entertained and then, perhaps some 20 years later, to bioassay as an engine for the generation friends and colleagues at their home, in new types of drugs.’ of new ideas and discoveries remained restaurants and at scientific meetings (Reprinted with permission from the Nobel Foundation) undiminished throughout his life. around the world. Such parties were Though he is gone, his students, his legendary and always carried off with Science, with its uncompromising research style, his extensive enormous panache. Close colleagues regard for facts and evidence rather publications and his institute are a were adopted by the Vanes as a sort of than beliefs, is one arena where people continuing testimony to his enormous extended family which burgeoned as can truly work together unhindered by influence as a scientist and as a man. they made many life-long friends. considerations of race, colour, creed or Whenever scientists get together they gender. Like most scientists John was a R J Flower like to discuss data, experiments and committed internationalist in this William Harvey Research Institute, St Bartholomew’s ideas which often make dull listening respect. His labs were full of and the Royal London School of Medicine and Dentistry, London, UK for others. But if this bothered Daphne, researchers from around the world and with her background in the liberal arts, UK scientists usually constituted a This article is a shortened version of an obituary which first appeared in pA2, the Members’ magazine of the she never showed it and always treated minority. Of particular significance British Pharmacological Society and is reproduced here John’s colleagues with great grace and was John’s relationship with the Polish with permission. charm. John was devoted to his ‘girls’, scientific community which began in as he called them, and they provided the late ‘60s during the cold war era. Members may like to know that over the strongly supportive base from John made many trips to Poland during £2,500 has been raised for Cancer which he was able to launch his those difficult times, often taking hard­ BACUP in memory of Rob Clarke frequent and punishing schedules of to-obtain scientific equipment and who died last August (Physiology work and travel. reagents with him and offering Polish News 2004, 57, 49)

Physiology News | No. 59 | Summer 2005 | www.physoc.org