Early research

Black's early work on intestinal absorption raised many fundamental questions for the young experimenter, the most important of which was whether and how local blood flow could be a rate limiting factor in metabolism. This was a pointer to much of his subsequent research. Black never studied for a PhD and he was to describe himself as 'one untrained in experimental science who picked it up along the way' (British Journal of Clinical Pharmacology, 440).

Beset by financial problems and without clear academic prospects, the young Blacks moved in 1947 to Singapore, where Jim Black became a lecturer in physiology at the University of Malaya for three years. As well as teaching medical students he made some progress in his research, although he was later to reflect that the lesson from this stage of his career was that 'experimenting in physiology was too difficult if the inspiration was no more than wishful thinking' (autobiography, nobelprize.org).

Black returned from Singapore in 1950, free of debt but without a job. A chance meeting with his old chief, Professor Garry, led directly to an offer to establish a new department of physiology in the University of Glasgow Veterinary Medicine School. He was to remain in Glasgow for eight years and there he created a research laboratory which incorporated the most advanced cardiovascular technology available, and which attracted a multi-talented team to work with him.

Propranolol and cimetidine

Two of the research programmes which Black established in Glasgow were to form the basis of his major work in subsequent years. The first was a search for pharmacological means of increasing the oxygen supply to the heart when compromised by impaired blood supply. The second research project was investigation of the effects of various autocoids such as 5-hydroxytryptamine and histamine on gastric secretion.

Anti-adrenaline drugs were already well known in the late 1950s. Raymond Ahlqvist, an American physiologist, had proposed that the effects of adrenaline, one of the transmitters in the sympathetic nervous system, were mediated by two distinct types of receptor, which he termed alpha and beta. Black immediately realized the implications of Ahlqvist's ideas and set out to find a beta-receptor antagonist which would block the effects of adrenaline on the heart. In 1958 he approached ICI Pharmaceuticals Division for financial help, but instead the pharmaceutical company recruited Black to its laboratories in Alderley Park, Cheshire, where he was to spend the next six years working on ways of improving blood flow to the compromised heart. The basis of this work was that as the heart is deprived of blood and therefore oxygen, the body responds by releasing hormones which instruct the heart to beat faster; if the circulation cannot sustain this a vicious cycle develops, in that it becomes deprived of oxygen and angina results. Black was already familiar with this clinical picture as at the age of fourteen he had seen his father, who suffered from angina pectoris, die from a myocardial infarction. His hypothesis was that antagonizing the effects of adrenaline on the heart would break the cycle and prevent the increase in heart rate and therefore the angina.

Just as he had done in Glasgow, Black recruited a small group of scientists of different backgrounds to work with him at ICI—John Stephenson, a synthetic chemist, Ben Crowther, a medicinal chemist, and Bill Duncan, a biochemist, with Black himself as the pharmacologist. A sample of a substance, dichloroisoprenaline (DCI), which was known to block the effects of adrenaline on the heart and blood vessels, was obtained from the pharmaceutical company Eli Lilly. This had other unwanted effects on the heart so an analogue, the beta-receptor antagonist pronethalol, was invented by his team. This, however, was shown to cause thymic tumours in mice and was withdrawn soon after marketing. Its successor, propranolol, was equally effective and revolutionized the treatment of ischaemic heart disease by relieving angina pectoris and prolonging the life of many cardiac patients. More fortuitous was the realization by another collaborator, Brian Prichard, a clinical pharmacologist from London, that propranolol also lowered blood pressure and could be clinically valuable in treating hypertension. Propranolol thus became one of the most important drugs in cardiovascular medicine and a considerable commercial success for ICI Pharmaceuticals.

Black remained intrigued by his second Glasgow project, how drugs could alter gastric secretion. An opportunity arose to pursue this work at the pharmaceutical company Smith, Kline and French in Welwyn Garden City, where he moved in 1964, accompanied by his ICI collaborator Bill Duncan. The lessons they had learned at Alderley Park while working on the sympathetic nervous system were transferable to the new programme on gastric secretion because many of the basic principles were similar. Another team of physiologists, pharmacologists, chemists, biochemists, and clinicians was created, of whom Robin Ganellin, a medicinal chemist, was one of the most important members. This was not a smooth path, and only after four fruitless years of scientific and commercial battles were they able to show that N-guanyl histamine had a modest effect on gastric secretion. Nevertheless this was sufficient evidence to suggest the existence of histamine H2 receptors in the stomach, and this discovery allowed medicinal chemists to produce a series of histamine analogues which blocked these receptors. The first of these was burimamide which, when tested in healthy volunteers, was shown to decrease gastric acid secretion, but it had low potency and poor oral availability. Another early analogue, metiamide, decreased gastric acid secretion to a greater extent, but also caused adverse effects on the bone marrow and lowered the white blood cell count. Molecular manipulation obviated this effect and its successor, cimetidine, was both clinically and commercially successful (it was the first drug to achieve annual sales of more than $1 billion). Patients with peptic ulcers, for whom surgery had hitherto been the only available treatment, could now be successfully treated with a drug. So in the same way that propranolol had revolutionized the treatment of patients with angina pectoris, cimetidine was to change the natural history of peptic ulcer.

Subsequent career

Despite his successes, the constraints and caprices of the pharmaceutical industry were becoming less attractive to Black, and when the chance to re-enter academia in the form of a chair of pharmacology at University College, London, presented itself in 1973 he was ready to accept it. He re-entered academia with two specific aims, one educational—the creation of a new course in pharmacology based on chemical principles and emphasizing the importance of biochemical and mathematical modelling—and the other a research programme to bring together medicinal chemistry and bioassay. In both of these he was frustrated. The slow process of academic peer review and increasing university financial constraints made him realize that, by leaving industry and entering academia, he had exchanged one set of frustrations in industry (which he understood) for others in academia (which he understood less well and found more difficult to deal with). So when John Vane, then research director of the Wellcome Foundation, invited him in 1977 to join him at the Wellcome research laboratories in Beckenham, Black accepted. The foundation, however, was a very traditional establishment and the ideas that Black wished to introduce based on his previous industrial and academic experience were not universally welcomed. In his own words, 'Entrenched attitudes can absorb reformist ideas like a punch bag' (autobiography, nobelprize.org). But if he was frustrated in his managerial role, his research programme in analytical pharmacology prospered, and the acquisition of a group of young investigators, including Paul Lett, allowed him to develop the ideas which had underpinned his previous commercial and academic careers.

After seven years in Beckenham the Wellcome Foundation agreed in 1984 to fund Black in a small independent unit in King's College Hospital medical school, in the University of London, where he became professor of analytical pharmacology. In 1988 Johnson and Johnson provided him with long-term funding and he established the James Black Foundation with a team of twenty-five scientists studying receptor pharmacology. Inter alia the group investigated the relationship between gastrin secretion and pancreatic cancer, produced receptor blockers for cholecystokinin and histamine H3 receptors, and characterized adenosine receptors. These years were described by Black as the most productive of his scientific life. Working with young scientists and without the pressures of either industry or academia represented what he had been seeking during his whole career. Although made an emeritus professor in 1993 he never truly retired from his post at King's College, and even when old age and illness took their toll his scientific curiosity and dynamism never left him.

Anatomy of success

One of the most important factors in Black's success was his upbringing in a Baptist household where learning was highly valued and all six children proceeded to higher education in spite of the adverse financial circumstances brought about by their father's early death. As Black said, if he had not gained a scholarship to the University of St Andrews, he doubted if there would have been sufficient family resources to send him there. He also led a very happy family life. The death of his first wife, Hilary, was a severe blow from which he took many years to recover and in those times the companionship of his daughter, Stephanie, was an important factor in buoying his spirits. On 16 April 1994 he married Rona McLeod MacKie (b. 1940), emeritus professor of dermatology in the University of Glasgow, an expert on malignant melanoma, and daughter of the distinguished biochemist (James) Norman Davidson. Following this second marriage Black's old enthusiasms for life, and in particular music, were rekindled, and theirs was a very happy union.

A second important factor in Black's success was his personal learning of the scientific method. With no formal training in experimental medicine and no higher qualification other than his medical degree, his ability to discover drugs was based on several self-taught principles. First, many well-recognized clinical problems can be related to underlying physiological processes. Second, to be successful, the underlying biological processes and their regulatory pathways must be established and thoroughly understood. Third, there must be a chemical starting point to design the compounds which act on these pathways. Interestingly these same principles were later rediscovered and described as ‘rational drug design’.

A third factor in Black's success was his insatiable scientific curiosity, which was manifest at an early age, was nurtured as a student, and persisted until the end of his life. Days before he died an article that he co-wrote with colleagues at Yale was published online, and other papers which he co-wrote with Desmond Fitzgerald, a former colleague at ICI, were published posthumously. His enthusiasm was genuinely infectious and many scientists—both clinical and basic—owed him huge debts of gratitude for his advice and encouragement when the scientific way ahead in their work appeared unclear. He was ever keen to engage in argument and controversy, and his criticisms of what he considered sloppy science could be truly scathing, but his support for what he considered good science was unstinting.

Honours and awards

The honours which came Black's way were numerous. He was made a fellow of the Royal Society in 1976 and knighted in 1981. In 1986 he won the Lasker prize, which he shared with Raymond Ahlqvist. In 1988 he was awarded the Nobel prize in medicine or physiology together with two other giants of drug discovery from the pharmaceutical industry, Trudy Elion and George Hitchens. In 2000 he was invited to become a member of the élite group the Order of Merit. Academia also honoured him in many ways, and one of the posts which gave him most pleasure was the chancellorship of the University of Dundee, which he held from 1992 to 2006. He had spent the clinical part of his undergraduate career in Dundee when it was still part of the University of St Andrews.

It is frequently said in obituaries or assessments of an individual's life that the person was not impressed by honours and adulation. However true this may be, it was genuinely the case with Jim Black. The story was told—not by him—of an occasion when, after giving an invited prize lecture in an American university, he was approached by a scientist of high reputation with the request for a discussion. He was told, courteously, by Black that he would be pleased to do this if an appointment could be made. When a student approached him next, and in faltering tones asked for advice, Black put his arm round the student's shoulder and invited him to have lunch with him.

Black died at King's College Hospital, London, of complications of prostate cancer on 22 March 2010, and was survived by his second wife, Rona, the daughter of his first marriage, Stephanie, and two step-children from his second marriage, Alison and Douglas. His funeral was on 30 March, at St Columba's Church, Pont Street, London.

It is interesting that in 1924 two of the most illustrious drug discoverers that the UK has known were born ten miles apart in the mining community of West Fife. Jim Black was one; the other was Sir David Jack, who died in 2011 and who invented the beta-agonist drugs and inhaled steroids which became the basis of the treatment of asthma and changed the lives of many sufferers of lung disease, in the same way that Black changed the lives of patients with cardiovascular disease and peptic ulcers.