The Quest For Cortisone Thom Rooke MD Krehbiel Professor of Medicine
Mayo Clinic AACE, Las Vegas, 2014
The “Discovery of Cortisone” is an “Entrepreneurial Tale” • Mayo Clinic
• 1950 Nobel Prize • Kendall the Chemist • Hench the Doctor - Polar opposites - Brilliant / Quirky
The two least likely people to ever win the Nobel Prize ?
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Goals Describe the Entrepreneurial process that led to the development of Cortisone
(Cortin, Substance E) Discuss the Entrepreneurs who undertook this challenge Highlight the unique never-to-be-duplicated “entrepreneurial” role played (or not played?) by the Mayo Clinic
Born 1886 – Connecticut
Edward “Nick” Kendall
Ph.D. Chemistry 1910
“I must have been a poor mixer …”
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Nobel Prize for Kendall? T. Kocher (1909, Swiss) – “Studies on the thyroid gland” … Kendall’s efforts to study thyroxine from this point
failed miserably. He spent the next ten years attempting to make the hormone, but was unsuccessful … (had the formula wrong) forward
1926 – C.R. Harrington (London) – successful synthesis of Thyroxine Kendall – stopped work on thyroid
“… he
did not fully appreciate the extent of biological variability. He was also given to making premature announcements of laboratory results.” “Dr. Kendall was a man of scholarly demeanor, but
he
was not a scholar.” … “Kendall’s knowledge of physiology was shallow: he did not appreciate cause-andeffect relationships”… Kendall “was not then, nor was he to become a great chemist.”
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1929 – What next? Albert Szent-Györgyi had written to Kendall earlier asking if he could temporarily join the Mayo staff … as a visiting scientist while he was in the United States. He had recently isolated … an interesting material called hexuronic acid from the adrenal glands of cows. He hoped to … obtain large quantities of adrenal glands from the meatpacking houses in the area (particularly those in St. Paul) …
Kendall agreed to host the Hungarian
• Szent-Györgyi leaves Rochester after nine months - He left samples of his hexuronic acid with Kendall and offered to do joint studies on its function and possible use.
1929
“No thanks” • Hexuronic acid turns out to be Vitamin C • Nobel Prize! (1937)
Kendall inherits Szent-Györgyi set-up for adrenal extraction Decision made to search for “Cortin”
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1944- Compound E – now available in very limited 1947 quantities for clinical studies (Mayo / Merck) Tested in humans with adrenal failure – works !!
We’ve found “the” cortin i … and we know how to make it ! Unfortunately …
$13 million
1) Adrenal gland failure is rare (no $$$ to be made) 2) When given to normal subjects – no effect
Compound E – “A treatment in search of a disease”
Philip Hench Born Pittsburgh – 1896 Lafayette College – 1916 U of Pitt (M.D.) – 1920 6’ 4”, 220 pounds
Meticulous Thorough
Handsome Popular Speech impediment
Detail-oriented
Obsessive-compulsive?
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Employing Holmes-like logic, Hench … reasoned that some chemical produced in the body (FACTOR X) must exist. Because patients got better when their liver failed (jaundice), he deduced that … …”Factor X” must be something
broken down by the liver? If we can figure out what “Factor X” is, we can use it to treat Rheumatoid Arthritis
1948 – Introducing Mrs. G
• 27 years old • Severe RA • Delightful / likable • “Professional patient”
July, 1948 – comes to Rochester for lactophenin treatment. Not leaving until cured …
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Her body changed. She developed a bloated, “moon” face, …(fat on her neck)… and streak-like lesions on her body (called stria).
Recognized today as common sideeffects of cortisone
Mrs. G.’s compound E dosage was slowly adjusted … and she was eventually able to leave Saint Marys Hospital. It surprised no one when Mrs. G. discontinued using compound E and refused to ever take it again. Over the ensuing years Mrs. G.’s arthritic condition worsened, leaving her once again completely debilitated. Hench was extremely sensitive to criticism regarding the side effects and saw them as “personal attacks”
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1949
Merck insists on additional (non-Mayo) trials
Hench quietly arranges for five prominent rheumatologists to come to Rochester, see firsthand what is happening, and then take drug samples with them to test in their own practices.
The doctors return to their cities (Los Angeles, Tucson, Chicago, Boston, New York.) They test “E” on their patients.
It Works !!!
… rumors that the Mayo Clinic had made a breakthrough in arthritis were beginning to circulate nationally…
Time to go public … … it was decided that the regularly scheduled staff meeting of April 20, 1949, would be the appropriate time and the place for (an) initial presentation (to the Mayo Clinic staff).
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Nobody was surprised when Merck suddenly faced a huge demand for compound E. The new drug was an instant international sensation …
Time to ramp up production. But … “Five separate entities held patents related to the production of cortisone; these included Merck & Company, Ciba, Organon, Schering, and Kendall himself. Kendall … appeared to hold the key patents.”
(Kendall) …“It was necessary to make some working arrangement, and this had to be done without delay.”
“Patents were granted to me and other members of the laboratory as each new step in the preparation of (compound E) was devised. The Mayo Clinic did not
propose to exploit these patents for financial gain. … As
soon as the agreement had been prepared, I assigned all my interest in the patents to the Mayo Clinic, which in turn gave them unconditionally to the Research Corporation …”
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“… no physician engaged in the practice of medicine should profit from the exploitation of any drug, vaccine, or appliance used in the practice of medicine. This is a time honored statement; it has been the policy of the Mayo Clinic from its beginning.”
At 1:30 p.m. on October 26, 1950, an … announcement was made … Edward C. Kendall, Philip S. Hench, and Tadeus Reichstein were the recipients of the Nobel Prize in Physiology or Medicine for their “investigations of the hormones of the adrenal cortex.”
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