Tuesday, April 16, 2013

Brian B. Hoffman, MD Blog: My Journey With Adrenaline

Adrenaline has garnered considerable attention as an agent of excitement and thrills, as well as stress and abject terror.

A Google search of 'adrenaline' generates more than 50 million hits. Newspaper and magazine articles employ adrenaline in adding emphasis to the dangerous fun of mountain climbing, in explaining remarkable feats of strength in frightening emergencies, and as a cause of intense emotions.

Many of these concepts stem from the work of Walter Cannon at Harvard Medical School in the early 20th century. He proposed that adrenaline integrates 'fight or flight' responses, increasing our capacity to survive in hostile environments.

These days, scientifically sound ideas about adrenaline are often unknowingly intermixed with some fanciful and sensational capacities. I have recently written a biography of adrenaline to tell the full story of this intriguing molecule.

After completing my education in clinical medicine, I encountered firsthand the joys of biomedical investigation in the laboratories of Robert Lefkowitz, whose research focuses on the fundamental biology of adrenaline.

I learned about how adrenaline activates specific receptors in cells, much like keys that fit into specific locks.

Most of my research involved the multifaceted effects of adrenaline in cells and in people. While scientists pay most attention to publications involving the latest results, I gradually became more acquainted with research published in the earliest days after the discovery of adrenaline 100 years ago.

As I dug deeper, I began to realize that many key insights involving the effects of major drugs and hormones had their origins in research on adrenaline.

Consequently, an understanding of adrenaline paid wide dividends across a broad swatch of modern pharmacology and biology.

Moreover, I became aware of the range of fascinating characters -- in addition to Lefkowitz -- involved in adrenaline's story.

Adrenaline's life story includes not only a slew of Nobel Prize-winning scientists who made remarkable discoveries, but also early entrepreneurs and bold physicians who transformed biomedical science throughout the 20th century up to the present day.

George Oliver, a physician in rural England, started experiments in 1893 with extracts made from adrenal glands that led to the discovery of adrenaline. He practiced medicine in a tourist town and devoted his free time in the winter months to rigorous intellectual pursuits. Some of Oliver's experiments were stimulated by the intellectual ferment suggesting that glands had previously unknown special powers: extracts of sheep thyroid glands had just been found to cure life-threatening failure of the human thyroid; and the famous elderly French neurologist Charles-Edward Brown-Séquard had announced that he had rejuvenated himself with extracts of animal testicles.

Even though injections of adrenal extracts had been shown to kill rabbits, Oliver boldly moved forward with human experiments, including possibly using his only son as a subject. Oliver's discovery, in partnership with his collaborator Professor Schafer in London, of a substance in the adrenal glands that caused unprecedented increases in blood pressure, ignited a furious competition in Europe and North America to isolate this mysterious substance.

John Jacob Abel, a professor at John Hopkins and formidable builder of American academic pharmacology, worked hard on this problem for several years, and described that he had purified the unknown substance. However, with great disappointment, he later realized that he had only come very close.

Seemingly out of the blue, Jokichi Takamine announced that he had isolated adrenaline from adrenal extracts in his private laboratory in New York City. Takamine, a very early innovative Japanese biotechnologist, had moved to the United States a decade earlier to implement a potentially cheaper method for fermenting alcohol that he had developed from traditional methods used to prepare sake.

After this project failed, Takamine survived financially when a byproduct of the method proved useful in treating indigestion. A decade later, using profits generated from his patent on adrenaline, Takamine arranged for a gift of cherry trees from Japan that still grace Washington, D. C. more than a century afterward.

Many of the stories surrounding developments with adrenaline illustrate the twist and turns that characterize research on challenging biomedical problems.

In 1901, Ferdinand Blum found that injections of adrenaline led to the spilling of glucose into the urine. With this clue, other investigators demonstrated that adrenaline stimulates the release of glucose from the liver.

Remarkably, research aimed at teasing out how this worked led to multiple Noble prize-winning discoveries.

The first Nobel Prize in this series (1947) went to Carl and Gerty Cori who discovered that adrenaline activates the enzyme in liver cells that cleaves glucose free from its storage in glycogen.

Earl Sutherland (1971) made the unexpected discovery that a previously unknown substance called cAMP transmits these effects of adrenaline into cells.

Edwin Krebs and Edmund Fischer (1992) identified a novel enzyme that is activated by cAMP, which in turn stimulates the enzyme that releases glucose from glycogen.

Alfred G. Gilman and Martin Rodbell (1994) discovered novel proteins that play an essential role in the capacity of adrenaline to stimulate the production of cAMP.

Most recently, Robert Lefkowitz and Brian Kobilka (2012) shared a Nobel Prize for their discoveries involving the receptors that are activated by adrenaline.

Together, these discoveries have had broad implications for understanding the actions of many drugs and hormones. Adrenaline is aimed at anyone interested in the history of medicine or scientific ideas.

Book Review

Adrenaline by Brian B. Hoffman 

The most complete and detailed book ever written on Adrenaline. Hoffman presents a fascinating account of the history-from the earliest days of its discovery to its most recent clinical and therapeutic developments. (Edmond H. Fischer, Winner Of The 1992 Nobel Prize In Physiology Or Medicine )

Adrenaline has long captured the attention of all flavors of physicians, biologists, and storytellers. Now, happily, Brian Hoffman has captured the complete 'biography of adrenaline' in substantial detail. The story and science are delivered with just enough--but not too much--technical detail, and numerous vignettes make it a very human read. (Alfred G. Gilman, Winner Of The 1994 Nobel Prize In Physiology Or Medicine )

Hoffman has done a beautiful job of integrating the story of scientific discovery with commercial application, demonstrating the ways in which this is truly a circular process with both discovery and application happening in both industry and academia, rather than the way it is often viewed as a simple matter of companies 'scaling up' discoveries in university laboratories. (Carla C. Keirns, M.D., Ph.D., Stony Brook University, Author Of measured Breath: A Short History Of Asthma )

Famous as the catalyst of the fight or flight response, adrenaline has also received forensic attention as a perfect, untraceable poison—and rumors persist of its power to revive the dead. True to the spirit of its topic, Adrenaline is a stimulating journey that reveals the truth behind adrenaline’s scientific importance and popular appeal.

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