Sir John Robert Vane (1927–2004)

Sir John Robert Vane was born on 29th March 1927, a nutritient fluid (for example: Krebs’ buffer, or blood) in the family of several children, at Tardebigg, superfusing drop by drop several smooth muscle or- Worcestershire (England); died on 19th November gans, suspended in air downwards in the bioassay cas- 2004 in London. In 1982 he was awarded, together cade. When one of these biologically active sub- with Sune Bergstrom and Bengt Samuelsson of the stances appears in the fluid, organs in cascade per- Karolinska Institutet in Stockholm, the Nobel Prize form a dance of contractions and relaxations (some for achievements in their research on prostaglandins. organs stay still). This answer of the cascade, “the set- Many universities in the world bestowed on Sir John ting of ballet steps”, is characteristic for each one of the title of doctor honoris causa; the title received known biological mediators. However, when the cas- from the Jagiellonian University in Krakow was the cade shows an unknown dance setting – a bell is ring- first honorary doctorate in his life. Sir John was the ing – a new, hitherto unknown biological mediator has foreign member of the Polish Academy of Sciences been discovered. In this way we discovered prostacy- and Polish Academy of Sciences and Arts, and com- clin; nobody knew it existed until the Vane’s cascade mander of the Order of Merit for the Republic of Po- showed a record, which did not match dance setting land. He was a founder and the first director of the of any known biological mediators, especially none of William Harvey Research Institute in London. the known prostanoids. His death brought an end to the romantic, stimulat- The Vane’s method was – and still is – used in the ing era in history of experimental medicine, studded systems in vitro (e.g., Krebs’ buffer perfused isolated with such names like Claude Bernard, Louis Pasteur, guinea pig lungs), or in vivo (e.g., blood-superfused Oscar Langendorff, Paul Ehrlich, Napoleon Cybulski, cascade of detector-organs in dog’s extracorporal cir- Marceli Nencki, Henry Dale, Sir Howard Florey, Al- culation). This method was, for Sir John and some of bert Szent Gyorgy, Harold J. Burn, Sir Hans Krebs, his collaborators and pupils, a tool to accomplish cru- John Gaddum, Janusz Supniewski and many others. cial discoveries in medical sciences. These comprise: These names became the symbol of the epoch which discovery of the role of histamine and peptides in re- believed in global biological Script of Existence. This leasing of adrenalin and noradrenalin from superrenal attitude justified addressing the Nature with ques- glands, discovery of the importance of catecholamines tions, meaning – in practice – carrying out of the sim- in acute myocardial infarction, discovery of the mecha- plest experiments to obtain clear answers: “yes” or nism of antiinflammatory and anti-thrombotic activity “no”. This is why the scientists of that epoch not only of acetylsalicylic acid (aspirin), and of some other discovered unknown facts, not only they were authors non-steroid antiinflammatory drugs (e.g., naproxen), of new hypotheses and theories; they also invented discovery of the mechanism of action of steroid antiin- new, sometimes perversely simple research methods. flammatory drugs, i.e. hydrocortisone and dexametha- For example, Sir John invented “the Vane’s bioas- sone, on the release of arachidonic acid from cell mem- say cascade”, one may say: a new way to tease the brane phospholipides, discovery of unstable interme- Nature with subversive questions. The method con- diary products (RSC) in the biosynthesis of prosta- sists in biological designation of active substances glandins, discovery of prostacyclin, discovery of (such as adrenalin, serotonin, histamine, angiotensin, metabolic function of lungs, discovery of coupled re- bradykinin or prostaglandins), which might occur in lease of prostacyclin and nitric oxide from vascular

"#" Pharmacological Reports, 2010, 62, 454456 Sir John Robert Vane (19272004) Ryszard J. Gryglewski

endothelium, of the role of superoxide anion in selec- whole truth about his vocation, as – above all – he feels tive destruction of nitric oxide free radical – and many himself an “experimentator”, a person who – using in- others. vented by himself experimental systems – asks the An important achievement was the discovery of Nature his personal questions. He joked that his ap- a new group of drugs applied in arterial hypertension, preciation of the journal “Nature” was connected with so-called angiotensin-converting enzyme inhibitors its title suggesting what should be published inside. (ACE-I). First, Sergio Ferreira found in the venom of Collaborators and pupils knew well Sir John’s sev- a viper bothrops jararaca a peptide that intensified eral original sayings and a specific choice of quota- biological action of bradykinin (bradykinin potentiat- tions from other authors, matching his personal atti- ing factor, BPF). Quite soon later, Mick Bakhle ob- tude towards Science. served that BPF – in perfused guinea pig lungs – inhibits He had a special respect for William Harvey, the conversion of angiotensin 1 to blood vessel-contracting Court Physician to the King Charles Stuart the First. angiotensin 2, meaning that BPF “additionally” acts William Harvey was the author of the most famous as ACE-I. This important discovery was made at John medical dissertation of all times: “De motu cordis et Vane’s labortory, with the use of his classic cascade. sanguinis in animalibus” (1628). So it is symbolic As for John Vane, his merit was his persistent demand that John Vane crowned his scientific career and activ- from the American chemists of the Squibb farmaceu- ity founding the William Harvey Institute in that very tical firm to perform chemical synthesis of orally ac- place in London (Charterhouse Square) where his great tive compounds derived from the proline-rich struc- countryman worked and discovered the central role of ture of venom peptide BPF/ACE-I. Sir John believed the heart in blood circulation. Nowadays, the John that these compounds might become the drugs effec- Vane Centre has been erected besides this Institute. tive in the treatment of arterial hypertension. He was According to Sir John, the attributes of a good sci- right again. In fact, the first such drug from the ACE-I entist were readiness to instantaneous change of any group was captopril and Sir John’s expectations found conception in view of undeniable facts and intellec- confirmation in clinical practice. tual curiosity to continue research on a new way su- Even more, newer lipophilic ACE-I – like china- perimposed by these facts. He considered persever- pril, perindopril or ramipril (“The Three Musketeers”) ance an important condition of research success, but not only exert hypotensive activity, but they also im- he did not deny the importance of the element called prove endothelial dysfunction, showing their proper- “an ounce of luck”, although he preferred to describe ties of BPF. This is because – as we proved – their this element with an English-Hindu” term “serendip- second function is due to their ability to accumulate ity”, more applying to imagination. bradykinin within endothelium, and that triggers the It is worthy to pay attention to Sir John’s relations release of prostacyclin and nitric oxide. It is why with our country. For the first time he visited Poland nowadays clinicians administer these drugs to patients in 1963, invited by the Division of Medical Sciences not only with arterial hypertension but also with coro- of the Polish Academy of Sciences and it was then nary insufficiency, stroke and diabetic retinopathy. that he demonstrated his new “cascade” research tech- Let us not forget that many elderly people owe to nique, a year after he had invented it, while dr. Janina Sir John their every day ingestion of aspirin at low Staszewska-Barczak (presently Woolley) offered him doses (50–150 mg) for protection against myocardial the assistance. Later she, her colleague dr. Krystyna infarction. To many others, physicians administer ACE-I Herbaczyñska-Cedro (from the Institute of Experi- in aim to control arterial hypertension or to prevent mental Medicine of the Polish Academy of Sciences, atherosclerotic or diabetic angiopathies. in Warsaw) and the Warsaw cardiologist dr. Leszek Sir John studied chemistry (University of Birming- Ceremu¿yñski were engaged in scientific cooperation ham), but having finished his studies he at once de- with Sir John, in Warsaw, and in the Department of clared that he would engage in anything except chem- Pharmacology of the Royal College of Surgeons in istry. Thus he happened to come across an outstanding London. In 1967, Sir John started his collaboration British pharmacologist, Harold J. Burn of the Oxford with the Chair of Pharmacology of the Medical Acad- University. It was his strange way to becoming the top emy (presently Jagiellonian University Medical Col- British pharmacologist, although he himself used to lege) in Kraków and in the next years nine researchers say that the label “pharmacologist” does not say the of that Chair (dr. dr. Emilia Mikoœ, Aldona Dembiñska-

Pharmacological Reports, 2010, 62, 454456 "## Kieæ, Ryszard Korbut, Marek Radomski, Artur Zem- are able to duly appreciate Sir John’s generosity and bowicz, Waldemar Radziszewski, Maciej Trybulec, help and understand our feelings of deepest gratitude. Tomasz Œwierkosz, and myself) had a chance to work From the moment of funding in 1992 in Kraków of with John Vane. Most of us were staying several times JMRC (Jagiellonian Medical Research Centre) till in laboratories under Sir John’s direction working 2003, Sir John was taking part in our annual Interna- there for a period of a few weeks to the whole year, tional JMRC Symposia. He delivered unforgettable not only in the Royal College of Surgeons, but also in lectures and participated vividly in discussions on the the Borrough Wellcome Research Laboratories and results of research of young scientists, especially the William Harvey Institute. In those very hard times those from Poland, Czech Republic, Slovakia, Hun- for Poland we received also from Sir John generous gary, Ukraine, Belarus and Lithuania. Sir John’s per- sonality attracted many excellent scientists from and precious help, as test kits, reagents and laboratory Europe, USA and Japan who came to Kraków to par- equipment. ticipate in our meetings and who became – and are – At first, big two-cylinder brass Palmer’s kymographs, our “friends in science”, among them Jack McGiff, factory-mounted on heavy, oak tables came by sea to Robert Furchgott, Kenneth Wu, Garry FitzGerald, Gdynia, beautiful monsters remembering the begin- Randy Sprague, Fujio Numano, Rod Flower, Jim Par- ning of the 20th century. Then, at the Warsaw Airport, ratt, Renia and Jack Botting, Sir Arnold Burgen, Eric we collected modern, chromium-glistening six-channel Anggaard, Paola Patrignani, Flavio Coceani, Jean- polygraphs, donation from the Wellcome Trust, of- Pierre Dupin, Michael Mulvany, Gunther Stock, fered to us by Sir John’s pledge, not speaking about Sylvester Vizi, Valeria Kecskemeti, Radoslav Stoika, meters of silicone piping, polyethylene cannules and Valery Kozlovski, Frantisek Kolar, Ivan Stepuro, bathes, electronic transducers and the Gustav Born’s Zygmunt Mackiewicz, and many, many others. blood platelet aggregometers made by Zygmunt In our memory John Vane will forever stay as Sabikowski. In this way John Vane simply enabled us a symbol of an unforgettable epoch in history of Sci- to continue in Kraków research, which we carried out ence, our friend and protector, and – above all – our with him in London. Only those who remember piti- Guide to “the Nature’s beautiful gardens”. ful standards of equipment of the Polish biological laboratories of sixties and seventies of the last century Ryszard Jerzy Gryglewski

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