Sir James Black, Nobel laureate who invented beta blockers, dead at 85

James Black, the Nobel Laureate who followed up his invention of propranolol, the first beta blocker, with key contributions to the discovery of cimetidine, the first effective anti-ulcer drug, has died at the age of 85.

A Scotsman, Black was educated at St Andrews University. He won the Nobel Prize in 1988. According to Wikipedia, Black was employed by ICI Pharmaceuticals (1958-1964), Smith, Kline and French (1964-1973) and the Wellcome Foundation (1978-1984) and was appointed professor of pharmacology at University College London (1973-1978) and King’s College London (1984-1992).

Black was an outspoken critic of the state of research at big pharmaceutical companies. Last year, in an interview in the Financial Times, he talked about the Pfizer-Wyeth merger:“Will they never learn? They will completely exhaust each others’ energies for two years.”

Sixteen years ago, in 1994, Black delivered a lecture at the American College of Cardiology meeting, which by coincidence was also held in Atlanta that year. I covered that talk for one of the trade publications at the time. Here, with no changes, is that article:

Chaos and the Heart

Chaos and the heart. Cardiologists for the most part avoid extensive theorizing and stick close to the solid data derived from clinical trials to inform their very untheoretical practice of medicine. But when Sir James Black — the Scottish nobel laureate who practically invented beta blockers and the antiulcer H2 blockers — delivers the opening plenary lecture at the American College of Cardiology and argues that future advances in our understanding of the heart will depend on our understanding of that organ as a complex, that is, chaotic system, then everybody, clinicians, researchers, and medical journalists alike, should probably start to take notice.

Rather than looking at the heart as if it were a simple pump, Sir James suggests we look at it as something infinitely complex, like a river. “A river,” he said, “is a chaotic nonlinear dynamical system that nevertheless regularly, reliably, and adaptably fulfills its function of gathering water up off mountains and dumping it into the sea.”

Sir James began his talk by decrying the current state of cardiac pharmacology. He observed that the field has been overtaken by “combinatorial chemistry” to produce legions of new compounds that are then tested by “robotic chemical assays,” thus removing “from the first most crucial stage of drug research,” the most important “human qualities of intelligence, imagination, and intuition.” Even worse, said Sir James, this new biotechnology has an “excessive and risky dependence on wishful thinking,” which he characterized as stemming from a simplistic “view of life” in which “each gene and its expressed product must fulfill a unique and vital function and that there is no redundancy in the system.” In this linear, highly rational perspective, the effect of a molecule, whether produced by the body or by a biotechnology company, should be highly predictable.

As an alternative, Sir James proposed an entirely different perspective, in which the body is viewed as a nonlinear dynamical system, a system which, though it evolves through time in a deterministic fashion, is yet totally unpredictable, because, as in all highly complex systems, there is a sensitive dependence on initial conditions. That is, the smallest differences in the initial parameters or details can have an enormous, and unpredictable, effect on outcome. This can be thought of as the “butterfly effect,” because, in the famous example, the action of the wings of a butterfly in Tokyo could conceivably initiate a cascade of events that might lead to storm over New York City a week later.

Sir James then presented some highly technical data from his own laboratory exploring the effect of adenosine and a number of other antagonistic and agonistic compounds on the PR interval in the AV node. Unfortunately, Sir James may have lost a good portion of his audience (and at least one medical journalist) at this point in his talk, but the overall point still remained clear. The effects of adenosine and other agents, he said, are typical of the effects of agents in any highly complex system. When two regulatory chemicals converge on a complex system like a cell, they can cause nonlinear potentiation, in which “ineffective concentrations of either alone can, when they arrive at the same time at a cell surface, interact to produce a switch-like effect.” As a model to help understand the effect of these regulators, Sir James said they “operate in the advise and consent mode rather than the command and control mode.”

Furthermore, said Sir James, cells may be influenced by a whole host of regulatory molecules. Every day, he said, new interleukins, neurotransmitters, growth factors and other important regulatory molecules are being discovered. As to the sheer number of such molecules, it is impossible not to agree with Sir James when he said “the mind boggles.” He cited one recent study in which the effects of four different interleukins together could not be predicted from their individual activities. “The information richness of a regulatory process will go up as some power of the number of converging molecules involved.”

But what is the practical effect to the cardiologist of this level of complexity? To begin with, said Sir James, it means older models of cardiac pharmacology will need to be enhanced. In order to alter a complex physiologic process, he said, “a highly selective antagonist of a single regulatory molecule might be ineffective.”

Perhaps this explains some of the mysterious findings of recent years. The negative results of the CAST study, the failure of a whole host of drugs for congestive heart failure, the recalcitrance of the restenosis problem, all suggest the need for more complex models of the physiology and pathophysiology of the heart. Consider the relatively simple example of thrombolysis in the treatment of acute myocardial infarction. At first it was thought that all one needed to do was dissolve the clot with a thrombolytic agent. Then it became clear that the act of dissolving a clot was itself thrombogenic. Both clot formation and clot dissolution turned out to be related and highly dynamic processes. For years now physicians have been using heparin and aspirin to help combat the thrombogenic stimulus of plasminogen activators, but it is now clear that newer and far more potent agents, such as the leech anticoagulant protein hirudin, will be required to put the lid back on the thrombogenic system. And then, undoubtedly, some other problem will present itself.

Rather than looking at the heart as if it were a simple pump, Sir James suggests we look at it as something infinitely complex, like a river. “A river,” he said, “is a chaotic nonlinear dynamical system that nevertheless regularly, reliably, and adaptably fulfills its function of gathering water up off mountains and dumping it into the sea.”

Comments

  1. A great tribute to a great man of powerful intellect and insight. The addition of the material from 16 years ago is as crisp and relevant as when it was delivered over a decade and a half ago. Given that the half-life of information in cardiology is estimated to be about 3 years, that his ideas brought forward over 5 half-lives “old” and found to be fresh and arresting is quite startling and the ultimate eulogy. Thanks Larry!

  2. Great article Larry!

  3. Thanks, John. I was a bit afraid at first to read the article from so many years ago, but then I was amazed at how relevant his remarks still are.

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