Substance X

Alumnus Philip Showalter Hench's Path to the Discovery of Cortisone, and the Nobel Prize
Cortisone crystals (Image: Merck & Company)
Packed shoulder-to-shoulder beneath the chandeliers of the Waldorf-Astoria ballroom, hundreds of physicians fell silent as Philip Showalter Hench (MD ’20) was about to speak. He had avoided this moment until he was sure his research findings were solid. Rumors were stirring. Someone heard Hench had discovered the cure for rheumatoid arthritis. It was time to set the record straight.
Philip Hench
It was 1949, a year before he would share the Nobel prize, when the University of Pittsburgh School of Medicine alumnus turned to his audience to introduce a drug that functioned in a way they had never imagined. It didn’t kill germs, like penicillin, nor did it replace hormone deficiency, like insulin. It actually changed a patient’s body, enhancing its ability to resist inflammation and repair injured tissue. Hench’s story spanned more than 20 years but came to a head only one year before, in 1948, when a patient refused to leave his office. 
Jean Olsen (not her real name) came to Hench when she couldn’t take it anymore. She’d been an outpatient at the Mayo Clinic, where Hench directed the rheumatology section. Olsen’s joints were deteriorating. Her right hip splintered after her 25th birthday, and at 29 she could not trust either leg for support. She came for relief, she told Hench, and wasn’t leaving until she got it. She demanded to be hospitalized. Though Hench resisted, Olsen’s insistence came at an opportune time. He was onto something. He and a colleague, Edward C. Kendall, were doing some research, and Hench thought they might have found a treatment for rheumatoid arthritis. This treatment, a substance they called compound E, was an adrenocortical hormone so precious it took three thousand pounds of beef adrenal glands to make one gram. No one had ever given it to a patient with rheumatoid arthritis. But with Olsen waiting in a nearby hospital bed, Hench was determined to try. So he wrote a letter to Merck & Company, Inc., the one laboratory that had managed to manufacture it, and asked for several grams of compound E. 
Olsen was at the point where she could not hold a cup, lift a spoon, or comb her hair. When she awoke the morning of her first compound E injection, she couldn’t get out of bed. The next day, still no change. But within a few days, she rolled over painlessly, jumped out of bed, and felt like, well, shopping. Olsen was a new woman with a new body—she wanted to dress it up. 
The drug’s real name was 17-hydroxy-11-dehydrocorticosterone, but Hench resisted calling it that. “Can you blame me?” he asked, “I can hardly pronounce it.” Hench had a cleft palate he fought to overcome, but its effects lingered. Sometimes he couldn’t say complex words, and his speech came out muffled. So Hench and Kendall dubbed the drug “cortisone.” After seeing its effects on Olsen, Hench gave it to four more patients, with the help of colleagues Charles Slocumb and Howard Polley.
“I got sick of having to wash my face with a dripping cloth,” one patient said. “You see, I couldn’t wring it out.” She opened doors with her elbows and used her teeth to pull blankets over her body. Hench began compound E injections and everything changed. “I just threw off the covers and jumped out of bed,” she said. “I felt so good that I walked across the room on tiptoes—the first time I’d been able to do that in years.” She washed her face, wrung the cloth, and a few days later climbed hills behind the hospital, “just for fun.” 
Thanks to cortisone, the inflammation in these patients’ joints decreased; and with it went their pain. The results were liberating— at first. But the excitement didn’t last. There wasn’t enough compound E for Hench’s five patients, let alone millions, but that wasn’t the real problem. There were side effects. 
Olsen’s reaction to the drug came quickly. Her face grew pale and swelled like the moon. Her periods stopped. Some days she gained four, maybe seven pounds. But Olsen wasn’t the only one whose body went haywire. Some of his trial patients were overtaken by euphoria, others by psychosis. They became dizzy and disoriented. Their blood pressure fluctuated as rapidly as Olsen’s weight. Hench lowered their doses and the pain flooded back, yet he was confident he had found a tool for understanding rheumatoid arthritis. 
“Cortisone,” Hench said, “is the fireman who puts out the fire, it is not the carpenter who rebuilds the damaged house.” It wasn’t the cure, but by studying how cortisone worked, he hoped to find something that was. He believed it existed; because he thought he’d seen it in action. 
April Fools’ Day in 1929, 20 years before his presentation at the Waldorf-Astoria, Hench walked into a Mayo exam room expecting to see yet another patient with rheumatoid arthritis. What he found instead, a limber man with skin the color of dried lemon, was unlike anything he’d ever seen. This, he thought, had to be a joke. 
“Where is this rheumatoid arthritis?” Hench asked. 
“I had it last week,” the man replied, “but when the jaundice came on it disappeared.”
Impossible. Rheumatoid arthritis was irreversible, everyone knew that. 
As the patient told his story in that exam room on April Fools’ Day, Hench absorbed every detail. The man hadn’t lifted his arms above his head in years. He couldn’t. And when he could walk at all, the effort was just shy of unbearable. Then his skin turned yellow. The next day, the pain and swelling in his joints disappeared—he threw his hands over his head and for the first time in years, nothing hurt. 
Jaundice occasionally was a problem for patients with rheumatoid arthritis; it was a potentially fatal side effect of cinchophen, an antirheumatic. Many of cinchophen’s jaundiced victims felt relief from arthritic pain, and most assumed this was cinchophen’s doing. But Hench’s yellowed patient never took cinchophen, or any other drug; still his pain vanished. Perhaps, Hench thought, it’s jaundice that relieves pain, not cinchophen. For rheumatoid arthritis, a disease with no known cause, any hunch was worthy of pursuit. 
Some called it compulsion, others called it passion, but Hench was driven by a desire to collect anything from which he could learn. Hench began “collecting” jaundiced patients with arthritis in 1929. All but two had taken cinchophen, and most were dying from the jaundice it induced. 
Each patient came to Hench with a similar story: Their joints had deformed. For some, it was so bad their fingers and toes curled, and they couldn’t dress or use a toilet alone. Then suddenly, thanks to their failing livers, they felt alive for the first time in years. Those who survived their jaundice eventually returned to their arthritic state. Though many colleagues thought he was running blind, Hench couldn’t shake the feeling he was onto something. It was clear, liver disease stimulated the body to produce a therapeutic substance, one he called “substance x.” He just had to find it. 
Hench started infusing human bile into the stomachs of volunteer patients with rheumatic disease. He had a hunch. If he could induce jaundice, he could study how it relieved pain. He infused these volunteers with jaundiced blood, gave them ox bile in olive oil, and though some became jaundiced, in the end, the experiments relieved no pain. 
After these experiments failed, he started a second “collection.” In 1931, Hench saw a pregnant patient with rheumatoid arthritis whose story echoed that of jaundiced patients. He sought others, and found many with similar histories: Deteriorated joints left them unable to manage their housework or care for their children, unless they were pregnant. After poring over patients’ stories, Hench realized substance x wasn’t a liver by-product at all. It was something stimulated by physical stress. The goal, as Hench saw it, was to find a common chemical denominator—something that explained how two otherwise unrelated conditions, jaundice and pregnancy, lead to a common outcome, the relief of rheumatic pain. To Hench, the most likely explanation was hormonal. It made sense that jaundice and pregnancy, with the stress they put on the body, could tweak some gland into producing extra—or different—hormones.
But he had no idea which hormone. He needed a chemist. 
Edward Kendall (in sweater) and Philip Hench (far right) with colleagues Charles Slocumb (left) and Howard Polley in Kendall’s laboratory at the Mayo Clinic
Edward Kendall, a soft-spoken biochemist at the Mayo Clinic, had worked on the same campus as Hench for years; but the two hadn’t talked much. Back in 1929, the year Hench started collecting jaundiced patients with rheumatoid arthritis, Kendall began studying the adrenal gland. By 1938 when Hench approached him, Kendall had identified six adrenal hormones. He named them compounds A through F. 
With their first conversation about adrenals, Kendall was wary. He didn’t know much about arthritis, and he didn’t want his work with Hench to interfere with his adrenal research. But he gave it a chance and grew intrigued by the project. Other Mayo researchers would soon become accustomed to seeing Kendall and Hench together, leaning back in wooden chairs, feet propped on a radiator, deep in thoughtful conversation. The two spent endless hours pondering Hench’s question: What the devil could this mysterious substance x be? Kendall and Hench pondered and hypothesized; but little did they know, a few yards away in his lab, Kendall was isolating substance x. He called it compound E. 
In 1941, Hench and Kendall agreed to try compound E on a patient with rheumatoid arthritis. The reasoning was fragile at best, but seemed somehow logical. Hench had noticed that reactions to typhoid vaccines gave rheumatic patients pain relief. These remissions were freak events, but Hench kept track of them. 
Kendall (left) and Hench talking.  One day, Kendall mentioned compound E. He had separated it in tiny amounts and discovered that it made some animals resistant to typhoid vaccine reactions. To Hench, this was as good a connection as they’d seen. The two men decided it was worth a try but had no idea it would be almost eight years before they would have enough compound E to follow through on their decision. 
With a chemical structure more complex than any molecule ever reproduced in a laboratory, compound E had Kendall stumped. He needed the help of a pharmaceutical company. But because of the compound’s complexity, and merely a hunch about its value, there was little motivation for production. Later that year, as the war in Europe escalated, there was talk that submarines left Germany empty and returned full of Argentinian beef adrenal glands. Rumor had it German scientists had found an adrenal hormone they injected into fighter pilots, making them more resistant to oxygen deprivation so they could fly at inhuman heights. Suddenly, adrenal hormones became interesting.
The U.S. government called a special conference on adrenal research, and adrenal hormones became a top national priority. 
Though the rumor of German hormones soon died, it began a heated race toward compound E. It was 1948 when Kendall and Merck produced the first dose. But Hench had none, and Jean Olsen was refusing to leave the hospital. Beyond Olsen, there were many like her who needed relief; he believed compound E could provide it. So Hench sat down and wrote the letter to Merck asking for a few grams of compound E. 
In 1950, one year after his presentation at the Waldorf-Astoria, Hench found himself in Sweden, sitting next to William Faulkner, staring in awe at trumpeters on marble stairs, as he, Kendall, and Tadeus Reichstein (a chemist who mastered some of the essential steps in cortisone’s synthesis) waited to accept their Nobel prize for the discovery of cortisone and its clinical applications. 
Cortisone is not a cure for rheumatoid arthritis. Medical science is still searching for that miracle. But cortisone is a therapeutic for rheumatoid flare-ups. When he accepted his Nobel prize, Hench urged everyone to be patient and not rush to prescribe cortisone before they understood its dangers, limitations, and uses. 
Later, investigators illustrated the tremendous capabilities of cortisone: It could save an asthmatic whose airways collapsed suddenly, correct fatal hormonal imbalances, cure the maddening burn and itch of skin diseases, and much more. 
Without Hench, cortisone would have been discovered, but its clinical value might have stayed hidden for years. 
Hench simply refused to abandon his belief that our bodies are capable of producing a mysterious antirheumatic. He praised his colleagues in academia and industry, for without them, Hench once noted, he “would have been like a Columbus, sitting on the seashore, yelling futilely that the world was round, and nothing would have happened.”
A Merck scientist explains the crucial experiment for the synthesis of cortisone.
Photos: The University of Pittsburgh archives, Archives of Philip Kahler Hench (MD '58), The Mayo Clinic, Merck & Company, Inc.