Autobiography

I have never wanted to check out the family folklore that we could be traced back to a dominie at the hamlet of Balquhidder in the Scottish highlands. The romantic notion that I might have tenuous roots with two great traditions - with the political rebelliousness of Rob Roy McGregor and with the Scottish tradition of rural education, arguably one of the best anywhere - was too enjoyable to be seriously tested. The outcome, the fourth in an issue of five boys born into a staunch Baptist home, meant that from the beginning I was taught to be respectful of others no less than myself, influencing ever since both my political and administrative attitudes. My father, a mining engineer and colliery manager, gave his brood many advantages not least of which, for me, was his love of singing which gave music a central place in our lives.

Apart from two periods of intense study, of music between the ages of 12 and 14 and of mathematics between the ages of 14 and 16, I coasted, daydreaming, through most of my school years. The imprinting mathematical influence was Dr Waterson at Beath High School, a brilliant and rumbustious teacher, who more or less man-handled me into sitting the competitive entrance examination for St Andrews University. This led to an interview with the Vice-Chancellor, the redoubtable Sir James Irvine, flanked by elderly academic worthies, all poking into the mind of a nervous 15 year old boy. I was awarded the Patrick Hamilton Residential Scholarship, mercifully unaware at the time that the family budget couldn't otherwise have stretched to yet another university student.

As a condition of the Patrick Hamilton Residential Scholarship I spent my undergraduate years in St Salvator's Hall, a fine new building modelled on the Oxbridge colleges. The young aficionados of St Salvator's Hall in my day were culled from every imaginable class and state from the United Kingdom and overseas. The few intimate years I spent in this company were an extraordinarily mind-broadening experience for the country boy from the coalfields of Fife, no doubt much as the scholarship architects had intended.

I chose to study Medicine mainly under the influence of an elder brother, William, a graduate in Medicine at St Andrews some years earlier. In the cold, forbidding, greyness of St Andrews - with its dedication to "causes purely spiritual and intellectual, to religion and learning" (Andrew Lang) - I learned, for the first time, the joys of substituting hard, disciplined study for the indulgence of day-dreaming. Undergraduate prizes seemed to confirm that I was working harder than my colleagues in a new-found love affair with knowledge. An important catalyst in my conversion to scholarship was my first year encounter with Professor D'Arcy Wentworth Thompson, last of the great Victorian polymaths, author inter alia of the classic allometric study "On Growth and Form", and an intellectual giant if ever there was one.

I met Hilary Vaughan at a Student Ball in 1944 and we married in the summer of 1946, as soon as I graduated. I joined the Physiology Department under Professor R.C. Garry in October 1946 and Hilary, completing her degree in Biochemistry, was the best student I ever had. Had she chosen a sectarian approach to study she would have become a visible star but her eclectic pursuit of knowledge and her unwavering support for her family led her to study law and choose poetry as a distillate of her wisdom. Intellectually she was the most exciting person I have ever known and, quite simply, the mainspring of my life until she died in 1986.

My first year of research in Garry's laboratory introduced me to some simple ideas which, in a variety of ways, have dominated my thinking ever since. Garry was trying to find out how the intestine was able to absorb sugars selectively. Na iodoacetate treatment eliminated selective absorption and Verzar had deduced that the selectivity was based on phosphorylation. Learning that Garry's research student was showing that iodoacetate destroyed the intestinal epithelium, I wondered if iodoacetate was a general poison. What did it do to blood pressure, for example? When I developed the technology to show that, in rats, iodoacetate rapidly and irreversibly reduced the blood pressure to about 40 mm Hg, I was faced with the question which has influenced my thinking ever since: when and to what extent does local blood flow act as a metabolic throttle?

We went to Singapore at the end of 1947 - an inevitable result of marriage, debts accumulated to pay for the completion of my medical studies, and pitiful academic prospects. As a Lecturer at the King Edward VII College of Medicine I experimented with learning how to teach Physiology; and I learned that experimenting in Physiology was too difficult if the inspiration was no more than wishful thinking. Nevertheless, I made some progress in relating mucosal blood flow to rates of intestinal absorption to use in my carpet-bagging efforts later in London.

We paid off our debts, we learned some, made friends and returned in 1950 with a larger view of life. I had, however, no home, no income of any kind and no prospects whatsoever. I knocked on the doors of Physiology Departments all over London and met more sympathy than I expected; then a chance encounter with Professor Garry in Oxford Street led me to William Weipers, subsequently knighted, Director of the newly "nationalised" University of Glasgow Veterinary School. He gave me the opportunity to start a new Physiology Department, and during the next eight years I built a state-of-the-art physiology teaching laboratory based on my enduring belief that our brains work best when doing focuses our thinking. We had a daughter, Stephanie, born in 1951; I built a workshop-coupled research laboratory providing the most advanced cardiovascular technology I knew; and persuaded George Smith and Adam Smith, academic surgeons, to join me.

As I slowly learned, like a primitive painter, how to be an effective experimenter, ideas began to ferment. Work with Adam Smith on the effects of 5-hydroxytryptamine on gastric acid secretion was to surface again later on in my interest in the pharmacology of histamine-stimulated acid secretion. Work with George Smith, concerned with finding ways of increasing the supply of oxygen to the heart in patients with narrowed coronary arteries, led me to propose that reducing myocardial demand for oxygen by annulling cardiac sympathetic drive might be equally effective. By 1956, I had clearly formulated the aim, based on Ahlqvist's dual adrenoceptor hypothesis, of finding a specific adrenaline receptor antagonist. Egged on by their local representative, I successfully approached I.C.I. Pharmaceuticals Division for help and ended up being employed by them at their exciting new laboratories at Alderley Park, Cheshire. During my six years with them Dr Garnet Davey (subsequently Research Director) constantly supported me and, I have no doubt, fought many battles on my behalf to keep the initially controversial programme going. All I ever promised was that I was sure I could develop a new pharmacological agent which might answer a physiological question. Any utility would be implicit in that answer.

My years at I.C.I., between 1958-1964, were some of the most exciting of my life. I was assigned a brilliant chemist, John Stephenson. He taught me about modern deductive organic chemistry; how to be more than merely curious about a molecule with an interesting biological effect: how to ask questions about it. He converted me to pharmacology. Indeed, my whole experience at I.C.I. was an educational tour de force. I had to learn how to collaborate across disciplines, how to change gears when changing from research to development, how to make industry work - in short, how to be both effective and productive.

Among the numerous people who were involved in bringing the first beta-receptor antagonist to the marketplace, three played crucial roles. Bert Crowther masterminded the medicinal chemistry development. Genial, enthusiastic and highly experienced he was a splendid colleague. Bill Duncan, biochemist, brilliantly controlled the linchpin between research and development. He illuminated the black box between drug delivery and effect, developing analytical methods for estimating the levels and tissue distribution of a drug and its metabolites which allowed us to monitor and control toxicity tests, human pharmacology and clinical trials. Duncan brings brio and bravura to everything he does; and he is reliably my severest critic. Without him I would have made many more mistakes than I did. Brian Pritchard, clinical pharmacologist at University College, London, spearheaded the clinical development of the beta-adrenoceptor antagonists and crusaded on their behalf - as well as revolutionising their use by his discovery of their antihypertensive effect.

By 1963, I faced opposing pressures. I saw that the success of the beta-receptor antagonist programme would suck me more and more into the role of giving the young propranolol technical support and promotion - just as I was itching to start a new programme. I was convinced that the histamine antagonists of the day were analogous to the alpha-receptor antagonists and that the equivalent of a beta-receptor antagonist was needed to block, for example, histamine-stimulated acid secretion. Then Edward Paget, Head of Pathology at I.C.I., who had accepted the Research Directorship at Smith, Kline & French Laboratories asked my advice about finding a pharmacologist to run the biological research there. Half-jokingly, I asked what was wrong with me. So we made a deal: I would run his biological research provided I had a free hand to run my new project. Bill Duncan joined me to run the Biochemistry Department, so maintaining a tremendously successful partnership which lasted 15 years.

The histamine project, modelled by analogy with the beta-adrenoceptor project, was also somewhat controversial at the beginning. It succeeded because of the faith of my managers and the scientific skill and devotion of my colleagues. When I was struggling at the front, Bill Duncan was defending the rear. Mike Parsons adopted the new pharmacology with rare enthusiasm and commitment and became one of the doughtiest colleagues I have ever had. I think we made a good team. Graham Durant made the initial breakthrough with a partial agonist, and Robin Ganellin exploited that lead by brilliant, deductive, medicinal chemistry. The years I spent working with Ganellin were the most sustained, intellectually exciting and productive period of medicinal chemistry I have ever experienced. John Wyllie, surgeon from University College London, contributed the last critical piece in a sucessful mission.

By 1972, the H₂-receptor antagonist programme was launched, cimetidine was in development and I was looking for a new project. I was now totally committed to arranging marriages between bioassay and medicinal chemistry. Obvious candidates existed, such as 5-hydroxytryptamine, but other shadowy ideas were lurking about in my imagination.

The potential freedom from commercial constraints in academia was looking more and more attractive. Yet, when I was eventually offered the Chair in Pharmacology at University College, London, I was apprehensive about my ability to achieve my new goals. I had developed two ambitions. In research, I wanted to establish the medicinal chemistry/bioassay conjugation as an academic pursuit, as exciting to the imagination as astrophysics or molecular biology. In teaching, I wanted to offer a general pharmacology course based on chemical principles, biochemical classification and mathematical modelling. In the event I achieved neither of my ambitions. I failed to raise support for my medicinal chemistry project - by academic peerreview standards my proposals were altogether too wispy and expensive. My ideas about teaching based on a catechismal approach to drugs in general, rather than cataloguing drugs in particular, turned out to have too many curricular difficulties. I did help to set up an undergraduate course in medicinal chemistry and made progress in modelling and analysing pharmacological activity at the tissue level, my new passion. But after four years, I was suffering from withdrawal symptoms from lack of a chemical collaboration. Thus, I eagerly accepted John Vane's invitation to join the Wellcome Foundation.

My years at the Foundation (from 1977 to 1984) were an emotional roller-coaster. I wanted to make use of ideas I had been chiselling out, over the years, about the differences between successful and failed industrial projects. The division I took over at Wellcome, however, was remarkable for its traditional, conservative, ways and feudal structures. Entrenched attitudes can absorb reformist efforts like a punch bag. Yet despite disappointment in my managerial role, I made great progress in my own research. Working with brilliant young investigators such as Paul Leff, I began to see analytical pharmacology as a viable discipline. I had found myself a new mission - and once more my recurring dilemma between corporate commercial needs and personal scientific ambitions was solved unexpectedly. The Wellcome Foundation offered me the chance to establish a small academic research unit, modestly funded, but with total independence. The real opportunity, however, came from King's College, London. The College and Medical School between them have not only solved problems and smoothed diffficulties they have positively welcomed and supported my small unit. In intellectual terms the last five years at King's have been the most productive in my life. Surrounded by talented researchers and PhD students, I feel I have found my niche at last.

From Les Prix Nobel. The Nobel Prizes 1988, Editor Tore Frängsmyr, [Nobel Foundation], Stockholm, 1989

This autobiography/biography was written at the time of the award and later published in the book series Les Prix Nobel/Nobel Lectures. The information is sometimes updated with an addendum submitted by the Laureate. To cite this document, always state the source as shown above.

 

Copyright © The Nobel Foundation 1988