James Black (1924–2010) Pharmacologist Who Changed the Face of Medicine

NEWS & VIEWS NATURE|Vol 464|29 April 2010

OBITUARY James Black (1924–2010) Pharmacologist who changed the face of medicine.

James Black, Jim to his many friends gastric-acid secretion could be blocked, he IMES T and colleagues, shared the Nobel Prize postulated, then the corresponding reduction E Th in Physiology or Medicine in 1988 for in acidity would allow patients’ peptic ulcers / N pioneering research that led to two new to heal. But at this stage, it wasn’t clear o

classes of drug. Adrenergic β-blockers and whether histamine was even involved as a ARKES

histamine H2-receptor antagonists have natural stimulant. M S. benefited millions of patients and often In the early 1960s, gastroenterologists saved lives. By his example, Black made a were convinced that gastrin was the direct massive contribution to the concept that driver of gastric-acid secretion, and the pharmacological receptors offer fertile pharmaceutical industry, including ICI, were ground for drug discovery. His work opened set on finding a gastrin antagonist. Black had up research on biogenic amines — chemical other ideas. He could see a strong analogy messengers that have subsequently provided between histamine and adrenaline, and had the foundation for establishing new types of no doubt that a histamine antagonist that drug action. blocked secretion could be found. In 1964, he This is all the more impressive because accepted an invitation to join Smith Kline & Black never received formal research French Laboratories to pursue this project. training. Indeed, as a physiologist, he had to As before, Black started collaborating teach himself what he has termed ‘analytical with medicinal chemists. After nearly four pharmacology’. years of failure, he decided to reinvestigate Black, who died on 22 March, graduated in a particular class of compound using a medicine from the University of St Andrews, refined assay design. The sixth compound UK, in 1946, but decided against a career as synthesized, N α-guanylhistamine, on a medical practitioner. He found that “the Without an antagonist as a chemical lead, he retesting, was found to have a slight way patients were treated was unacceptably had to start cold, using the selective ‘agonist’ inhibitory effect on gastric-acid secretion. insensitive”, and instead chose a career in isoprenaline. This activates the β-receptors, Here at last was a lead for the medicinal physiology. In 1950, he created a physiology triggering a response that mimics the chemists. Refined into burimamide, the department at the University of Glasgow natural one induced by adrenaline. None of prototype drug proved the existence of Veterinary School, and over the next eight Black’s isoprenaline analogues blocked the histamine H2 receptors and was verified as a years built a research laboratory that housed β-receptors. Then, in 1958, a publication histamine blocker in human volunteers. The advanced cardiovascular technology. appeared describing dichloroisoprenaline chemists ultimately designed the anti-ulcer At Glasgow, Black became interested in the (DCI) as lowering heart rate. drug cimetidine, which very quickly became clinical problem of angina pectoris, severe Strangely, in Black’s bioassays DCI was the world’s first drug to make sales of more chest pain caused by a shortage of oxygen to as powerful a stimulant as isoprenaline. than US$1 billion a year. the heart. The heart responds to the body’s He set up other assays and was astonished Black identified his own criteria for demand for blood circulation, and when to find that, depending on the tissue successful drug research: well-recognized oxygen levels are low, hormones instruct it preparation, DCI could be a full agonist, clinical problems that could be related to to beat faster. If the circulation is unable to activating the β-receptors, or an antagonist physiological processes; a defined chemical keep up, the heart can become starved of that bound to the receptors but failed to starting point; and an easy way of proving oxygen and produces pain. Black argued activate them. As Black stated later, “as that the drug would work in humans. Black’s that reducing the effects of the hormones analytical pharmacologists, what we see of genius was to analyse pathways without adrenaline and noradrenaline on the heart the properties of a new molecule is totally resorting to wishful thinking. would break the cycle by preventing the dependent on the bioassay we use”. Jim Black was a formidable teacher. All increase in heart rate. A simple analogue of DCI soon led to the who worked with him benefited from his Anti-adrenaline drugs were a well- first β-blocker, pronethalol. This proved to enquiring mind and ability to make you recognized group in the late 1950s, and be only a prototype drug, and Black and his question what you were trying to achieve. Raymond Ahlquist had already proposed in team mounted a chemistry programme to No scientist from a pharmaceutical-industry 1948 that the widespread effects of adrenaline yield the drug propranolol in 1964. Today, background has been so widely recognized. were mediated by two classes of receptor, propranolol and related drugs are widely His achievements were acknowledged by his α and β. Black wanted to find a β-receptor used to control blood pressure. Yet the Nobel prize, his election to the Royal Society antagonist to block the effects of adrenaline. considerable effort required to develop such and membership of the Order of Merit. He He approached ICI Pharmaceuticals Division a compound and bring it to market was not was truly a giant. for a grant and they persuaded him to join intellectually challenging enough for Black, Robin Ganellin and William Duncan them in 1958. However, Black was careful not and by 1963 he was thinking about other Robin Ganellin is in the Department of to guarantee a new drug: “All I ever promised physiological problems. Chemistry, University College London, was that I was sure that I could develop a new Black had worked on gastric-acid secretion London WC1H 0AJ, UK. pharmacological agent which might answer a at Glasgow and now there was a fresh puzzle William Duncan, now retired, worked with Black physiological question. Any utility would be to solve — namely, the role of the hormone at ICI and at Smith Kline & French Laboratories. implicit in that answer.” gastrin and histamine in stimulating gastric- e-mails: [email protected]; At ICI, Black was introduced to chemistry. acid production. If the stimulants driving [email protected]