How beta-blockers came to be

Ian Popple | Love them or hate them, there can be little doubt that pharmaceutical companies have made a significant contribution to the well-being of mankind. Sir James Black — Nobel Prize laureate for medicine in 1988 — highlighted many of these contributions, including his own award-winning research, in a Mini Beatty Lecture at McGill last month. Black invented beta-blockers, an adrenaline receptor–blocking drug that save the lives of countless heart disease patients around the world. No doubt Sir James wished he had a pack of his famous drug handy as he addressed a packed auditorium in the Stewart Biology Building for the first of two lectures.

"Art is a passion pursued with discipline; science is a discipline pursued with passion," Black once stated. It's clear that Sir James, whose career has been evenly split between both universities and industry, has a passion for pharmacology. "Drug design is a slow and dogged pursuit," he admitted. "But it's incredibly addictive."

According to Black, the story behind the creation of beta-blockers — considered one of the most important contributions to 20th-century pharmacology — began long before his illustrious career. In recounting the details of his research, Black felt obliged to summarize the accomplishments of numerous predecessors, many dating back over a century: Paul Ehlich, considered the father of modern chemistry; Gerhard Domagh, Nobel Prize–winner for medicine; Paul Jansson, founder of the pharmaceutical giant Johnson & Johnson; and many others. The research of each played a crucial role in the development of beta-blockers, Black said.

This research first coalesced in Black's Glasgow Veterinary School laboratory during the '50's. "Heart disease had become a serious epidemic," recalled Black. "Patients were suffering from angina pectoris (severe chest pains) and many were dying from heart attack." According to the World Health Organization, finding a way to control these conditions was the utmost priority.

Scientists had already established that heart disease was characterized by clogged arteries that restrict blood flow. But angina and heart attacks were often triggered by stress and exercise, no matter how mild. It soon became clear that adrenaline — secreted during moments of anger, fear, stress and exercise — was responsible for these complications.

Adrenaline — the body's wonder hormone — is part of our hardwired "fight-or-flight" machinery, providing an increased chance of escape from, or survival in, dangerous encounters. Adrenaline triggers the release of energy-rich glucose reserves into the blood; it binds to receptors on the membrane of heart cells causing the organ to beat faster; it also constricts arteries to increase the rate at which blood is pumped around the body. Unfortunately for those with a weak heart, adrenaline is more likely to initiate a "collapse-and-elapse" response.

American scientist Dr. Claude Beck — regarded as one of the world's leading heart surgeons of the day — had discovered that only a small oxygen increase in the blood was necessary to ease the pressure on the heart. "Beck was working on a way to increase blood flow to the heart from non-cardiac sources," said Black. "But I took a different approach." Instead of trying to increase the amount of oxygen that reached the heart, Black attempted to decrease the heart's need for oxygen. "I could see I needed to develop a drug that would block the effect of adrenaline on the heart," he said.

It took Black another decade before he created propranolol, a drug that successfully blocked the heart's adrenaline-responsive beta-receptors — hence the commonly used "beta-blocker" pseudonym. If you include the work of the numerous scientists whose research contributed to Black's invention, the development of the drug was close to a century in the making. "Science is a gradual progression that requires building on the hard work of others," he said.

According to Black, the drug industry has doubled expenditure on research and development over the years, but productivity (as judged by new drugs) has fallen by one-fifth. "The slow rhythm of science cannot be expedited by simply throwing money at it," said Black. "Progress is not limited by knowledge, but by ideas." According to Black, everything he needed for his beta-blocker invention was already at hand; all that was needed was some out-of-the-box thought and a liberal sprinkling of passion — the driving force of discovery. The genius of a few undoubtedly builds on the accomplishments of many.