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The Quest for Cortisone

The Quest for Cortisone

by Thom Rooke

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In 1948, when “Mrs. G.,” hospitalized with debilitating rheumatoid arthritis, became the first person to receive a mysterious new compound—cortisone—her physicians were awestruck by her transformation from enervated to energized. After eighteen years of biochemical research, the most intensively hunted biological agent of all time had


In 1948, when “Mrs. G.,” hospitalized with debilitating rheumatoid arthritis, became the first person to receive a mysterious new compound—cortisone—her physicians were awestruck by her transformation from enervated to energized. After eighteen years of biochemical research, the most intensively hunted biological agent of all time had finally been isolated, identified, synthesized, and put to the test. And it worked. But the discovery of a long-sought “magic bullet” came at an unanticipated cost in the form of strange side effects. This fascinating history recounts the discovery of cortisone and pulls the curtain back on the peculiar cast of characters responsible for its advent, including two enigmatic scientists, Edward Kendall and Philip Hench, who went on to receive the Nobel Prize. The book also explores the key role the Mayo Clinic played in fostering cortisone’s development, and looks at drugs that owe their heritage to the so-called “King of Steroids.”

Editorial Reviews

From the Publisher

A must-read for anyone interested in the history of modern medicine, Rooke masterfully weaves together the life stories of characters as disparate as John F. Kennedy, Ernest Hemingway, Thomas Addison, and Nobel laureates in physics and medicine to tell the compelling story of how scientific progress is truly made, with a particular focus on the development of cortisone and related steroid therapeutics. Far from the “neat and tidy,” inexorable, and logical process most readers may assume underlie scientific breakthroughs, the reader will learn of the protagonists’ flashes of brilliance, but also of their mistakes, losses, and many disappointments overcome through bull-headed perseverance, hard work, and team work. I couldn’t put it down.
—David M. Harlan, Chief of Diabetes Division and Co-Director of the Diabetes Center of Excellence, UMass Memorial Health Care; William and Doris Krupp Professor of Medicine, University of Massachusetts Medical School

Rooke has accomplished the almost impossible: he has produced a scholarly account of the discovery of cortisone that reads like a novel. It is packed with fascinating people, who are connected by their passion for science, medicine, and the race for more than one Nobel Prize. This book is a fascinating blend of authoritative medical history and exciting story telling.

—Harvey Sparks, University Distinguished Professor of Physiology, Michigan State University

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Michigan State University Press
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By Thom Rooke

Michigan State University Press

Copyright © 2012 Mayo Foundation for Medical Education and Research
All right reserved.

ISBN: 978-1-61186-033-7

Chapter One

Addison and his Disease

It is of the highest importance in the art of detection to be able to recognize out of a number of facts which are incidental and which vital. Otherwise your energy and attention must be dissipated instead of being concentrated. —SHERLOCK HOLMES, "THE ADVENTURE OF THE REIGATE SQUIRE"

At two o'clock the afternoon dinner bell rang. Dr. Thomas Addison was ambling through the well-manicured garden outside his home, accompanied as always by two watchful "companions." Unfortunately, the thought of English cuisine again was more than his fragile psyche could handle today; he suddenly broke away from his attendants and hurled himself over a dwarf-wall, diving headfirst onto the stone pavement nine feet below. The impact shattered his forehead, driving jagged fragments of skull deep into the underlying gray matter. The brain damage was massive and irreparable. Dr. Addison never regained consciousness and, according to the Brighton Herald, died at 1:00 a.m. on June 29, 1860. His body was returned to his family home in Cumberland, and he was buried in the priory churchyard in Lancaster Abbey on July 5.

Why would a man who had grown up eating haggis kill himself rather than face another home-cooked meal? Two reasons.

First, Addison was depressed. In the mid-1800s clinical depression was poorly understood, largely untreatable, and frequently lethal. Mental illnesses were enigmas (Sigmund Freud, the father of psychoanalysis, was only four years old at the time of Addison's death). The modern discipline of "psychiatry" didn't exist yet. Those around him merely accepted that Addison had for many years suffered from a form of insanity called melancholia, which they believed was caused by overwork of the brain. During the winter of 1859–60 his condition worsened, forcing him to retire from clinical and teaching responsibilities at Guy's hospital in London. Addison retreated from his London home in Berkley square and relocated to Brighton, where his family hoped the seashore would restore his faculties. unfortunately, his depression worsened. After a couple of halfhearted attempts at suicide, his wife and stepson hired two bodyguards, Abraham Quilter and John J. Medcraft, to prevent any further attempts. It wasn't money well spent, as these were the very attendants Addison eluded on his way to fatal humpty-dumptification.

The second reason for choosing death over dinner may have been physical illness. For months Addison had been experiencing abdominal pain, weight loss, and bouts of jaundice—ailments that have led to speculation that he was suffering from gallstones or even cancer of the pancreas. His aversion to food—a symptom commonly seen in conjunction with certain malignancies of the digestive system—might have reflected something more sinister than the body's natural response to English cuisine.

Thomas Addison was born in October 1795 in Long Benton, a rural village of Northumberland near the Scotland border. His parents, Sarah and Joseph Addison, ran a grocery and flour business. As a youth he attended various schools in Newcastle-upon-Tyne. His father wanted him to become a lawyer, but Addison decided to become a physician. In 1812 he entered the University of Edinburgh Medical school. He was proficient at Latin, having mastered it in grammar school, and he prided himself on his ability to take lecture notes in that language. In 1815 he completed a doctoral thesis provocatively entitled "Concerning syphilis and Mercury" and subsequently received his MD degree.

Medical and surgical therapeutics in nineteenth-century Scotland were embarrassingly primitive, yet in certain areas of biological science—particularly the discipline known as physiology—rapid advancements were being made. Many long-standing mysteries concerning bodily functions were suddenly yielding to the investigations of medical detectives like Addison.

Addison left Edinburgh and moved to Skinner Street in the Snow Hill region of London, becoming a "house surgeon" at Lock Hospital and beginning a short affiliation with St. George's Hospital. After dabbling as a practicing physician, first at the Carey Street Dispensary and later at the Royal Infirmary for Women and Children, he entered Guy's hospital as a "physician pupil" on December 13, 1817, at which time he paid 22 pounds for the privilege of becoming a "perpetual student." His performance must have been satisfactory; in 1824 he was invited to become an assistant physician, and in 1837 he was promoted to full physician. Together with Richard Bright and Thomas Hodgkin, he would become known as one of the so-called three giants of Guy's Hospital. But Addison's steady rise through the ranks of the prestigious facility reflected his genius, insight, and teaching ability more than his political savvy—indeed, most sources suggest that Addison was, put bluntly, socially challenged.

It's not easy to understand the mind and personality of Addison. His contemporaries described him as withdrawn and unapproachable, traits that hint at the underlying depression that later destroyed him. Some attributed these characteristics to "excessive shyness and sensibility," but that explanation is surely too kind. Withdrawn? Unapproachable? Shy? Hardly. Addison surely intimidated many of those who worked with him; comments abound regarding his "severe, pompous manner," the way in which he chose his words with irritating precision, and a physical appearance that was alleged to strike terror into his students. He may have been hailed by his supporters as a "natural leader," but his detractors portrayed him as a man who could skewer his confronters with a penetrating glance. Given the conflicting descriptions of Addison, one must question whether episodes of subclinical mania may have intervened between bouts of depression—in other words, did he suffer from bipolar disease?

Addison paid a steep price for his eccentric personality. His fame, which was considerable at the height of his career, should have provided him with significant perks, including a large clinical practice of rich patients, scientific recognition, and the other kudos normally awarded to the top medical men of London society. But it didn't. Addison's medical practice was small, and those rewards that trickled down to him—membership in the royal College of Physicians, invitations to lecture the royal society, appointment as court physician, titles, and honoraria—all came later, in many cases decades later, than one would have expected for a physician of his prominence.

Even marital bliss came late to Addison. In September 1847, at the very ripe old age of fifty-two, he married Elizabeth Catherine Hauxwell in the same Lancaster church where he would later be buried. They never had children of their own, although she came with two from a previous marriage. Addison was the most brilliant diagnostician of the time. As the standard-bearer for the science of medical detection, he meticulously correlated his clinical findings with those noted at autopsy—all the more remarkable considering that autopsy was a rarely performed procedure in the 1800s. In the professionally competitive environment of Guy's hospital, Addison sought every advantage he could to maintain his mighty reputation as a master of diagnostic annihilation; he readily embraced new diagnostic tools (for example, while others were scoffing at Laennec's recently introduced stethoscope, Addison was championing its use). Like some Hippocratic version of Sherlock Holmes, Addison tackled medical mysteries by rigidly adhering to the code of the sleuth, the first rule of which is to recognize which facts are vital to the diagnosis and which are incidental. Addison believed that the physician's most important duty was to discover the correct diagnosis; therapeutics were an unfortunate annoyance that, as Sherlock Holmes might have put it, caused "energy and attention ... to ... be dissipated instead of being concentrated."

Not surprisingly, Addison's patients felt differently: they expected treatment for their ailments. Yet Addison seemed congenitally incapable of devoting as much energy to the cure of his patients as he did to the search for the cause of their disease. As he put it, "Once ... I have worked out the disease; if it be remediable, nature, with fair play, will remedy it. I do not clearly see my way to the direct agency of special medicaments, but I must prescribe something for the patient, at least, to satisfy his or her friends."

If Addison's temperament terrified his students, he compensated for it with exceptional teaching abilities. He was truly devoted to his pupils, and they to him. As he prepared to leave Guy's hospital on the way to his tragic ending in Brighton, he wrote a heartfelt letter to the students he was leaving behind, informing them of his ongoing breakdown and thanking them for the devotion they had shown not only to their teacher but to their medical studies as well.

Some of the Addison's "firsts" were major medical milestones. Addison first described pernicious anemia (a form of anemia later shown to be caused by vitamin B-12 and folic acid deficiency); appendicitis; and the various skin conditions caused by diabetes, scleroderma, or high cholesterol. He also was the first to demonstrate that pneumonia was caused by the deposition of fluids and other materials into the alveoli (air cells) of the lungs. He wrote one of the first textbooks of modern medicine (Elements of the Practice of Medicine, 1839). These accomplishments, however, are not the ones for which he is best known; it was Addison's work on the suprarenal glands that firmly established his place in history.

While investigating patients with pernicious anemia, Addison fortuitously noted that a few of them had the same unusual constellation of findings. Along with the characteristic anemia and general decline in health shared by all with the pernicious variety, there was also a small subgroup with atypical features that included absent appetite, weak pulse, abdominal pain, emaciation, vomiting, and—most strikingly—an unusual discoloration of the skin. It was the skin finding, a seemingly trivial detail and something only a dermatology expert like Addison was apt to notice, that ultimately convinced him he was dealing with a unique disease entity. The skin typically developed an odd discoloration, which the patients themselves usually noticed. It was described as being dingy or smoky in quality, with tints and shades of deep amber or chestnut brown; in some cases the pigment, which was most prominent on the face, neck, upper arms, axilla, and nether regions, was so dark that the affected patient "might have been mistaken for a mulatto." Addison recognized that a patient with these symptoms gradually weakens and dies. The autopsies he subsequently performed on them revealed something fascinating. And totally unexpected.

The suprarenal glands (later called "adrenal" glands), two small almond-size masses sitting atop the kidneys, had been known to exist since Eustachio described them in the 1500s, but their purpose, if any, was a mystery. Having no discernible function, most medical and anatomical textbooks ignored their existence entirely. By combining careful antemortem clinical evaluation with meticulous dissection at autopsy, Addison ascertained that many patients with the combination of constitutional symptoms and skin discoloration had suprarenal glands that were highly abnormal. Instead of being small and soft, they were "the size of a hen's egg" and as "hard as stones." In the 1800s these changes were most often the result of infection with tuberculosis, an epidemic illness across much of Europe caused by slow-growing bacterial rods with a propensity to attack the suprarenal glands. Based upon his eloquent description of this condition, the syndrome associated with destruction of the adrenal glands was soon referred to as "Addison's disease."

There was just one catch. Addison wasn't the first person to describe "Addison's disease."

Sir Zachary Cope, one of the most eminent surgeons and medical historians of the twentieth century, knew as much about abdominal problems as any doctor before him, with the possible exception of Addison himself. Cope's 1922 monograph, Early Diagnosis of the Acute Abdomen, written over 100 years after Addison entered Guy's Hospital as a student, remains among the most influential surgical texts of all time. Right up until his death in 1964 at the age of ninety-three, Cope was solving riddles involving abdominal and gastrointestinal distress. His last "patient" was a woman who had been dead for nearly 150 years when he claimed to have finally diagnosed her problem.

She was Jane Austen, the legendary author. Like many female authors of the time, her novels were published anonymously; despite this, the books written "By a Lady" made Austen one of the most influential novelists of the early 1800s. Her works, which include Pride and Prejudice, Sense and Sensibility, Emma, and many others, remain top sellers today. She died on July 18, 1817, at the age of forty-one—a full thirty-eight years before Addison published his description of the condition that carries his name. The cause of her demise has been a topic of interest to medical historians ever since, including sir Zachary Cope, who, at the time of his own death, believed he had solved the mystery of hers.

There have been many accounts of the afflictions Austen suffered during the last months of her life, but perhaps the best are those that she provided herself through correspondence with her sister, Cassandra, and others.

It is unclear exactly when Austen's illness began, but in July 1816 she began to describe fatigue and back pain. By December of that year her weakness was severe enough to interfere with routine activities. At one point she declined a dinner invitation, citing "the walk is beyond my strength." her condition waxed and waned. Over the course of the winter her pain and weakness improved, but gastrointestinal symptoms developed. Specifically, she began to experience abdominal pain, nausea, and vomiting. Apparently evoking the ancient Greek humoral explanation for disease, she wrote of her condition that bile was the cause of her suffering.

As spring approached she began to experience new symptoms. Diffuse joint pain developed, becoming especially severe in one of her knees. Her skin also began to change; regarding her complexion, she wrote that it had "been bad enough, black and white and every wrong color." Over the course of the spring her constitutional symptoms worsened, and she began to experience fever and weakness. In the weeks before her death, symptoms such as "faintness and oppression," pain, pallor, and "sufferings" intensified. On her final day she experienced fainting fits that left her too weak to move. Jane Austen died in the arms of Cassandra following an episode of unconsciousness from which she did not awaken.

The detective in sir Zachary was struck by the similarities between Jane Austen's illness and the disease later described by Dr. Addison. Intermittent but progressive weakness, abdominal pain, nausea, vomiting, weight loss, and, perhaps most important, the discoloration of the skin are all seen with Addison's disease of the suprarenal glands. Although some aspects of Austen's illness seem inconsistent with this diagnosis (for example, her intermittent fevers), these could be explained by the concomitant existence of tuberculosis, which was not only extremely common in her day but, as noted previously, accounted for most cases of adrenal gland destruction. As Cope concluded, "if our surmise be correct, Jane Austen did something more than write excellent novels—she also described the first recorded case of Addison's Disease of the adrenal bodies."

Addison's publication in 1855 of his observations on disease involving the suprarenal glands was the first suggestion that these small, seemingly obscure bits of tissue could have any clinical relevancy. Their importance was confirmed a year later when Charles Brown-Séquard demonstrated that surgical removal of the adrenal glands from animals produced a condition similar to the disease described by Addison—one that inevitably ended in the animal's death. But why? What did these seemingly trivial pieces of spongy meat do that made them so indispensable? What magical substance did they make? What controlled their activity? These questions would not be answered for almost a century.


Excerpted from THE QUEST FOR CORTISONE by Thom Rooke Copyright © 2012 by Mayo Foundation for Medical Education and Research. Excerpted by permission of Michigan State University Press. All rights reserved. No part of this excerpt may be reproduced or reprinted without permission in writing from the publisher.
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Meet the Author

Thom Rooke is the Krehbiel Professor of Vascular Medicine at the Mayo Clinic in Rochester, Minnesota.

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