History of Medicine

CHERRY TREES AND ADRENALIN

     Washington’s gorgeous cherry trees were in full bloom recently, a beautiful welcome to spring in our capital city.

Cherry trees, Washington (National Park Service photo)

     Ever wonder where the trees came from? The answer has a lot to do with adrenalin and progress in endocrinology and pharmacology.

     In the winter of 1893-4 George Oliver and Edward Schäfer in London showed that extracts of adrenal medulla tissue injected into dogs produced sudden hypertension and arterial

Edward Schafer (left) and George Oliver (right)
(from Wikipedia)

constriction. A few years later Bayliss and Starling demonstrated secretin, a substance from the intestine that stimulated secretion of pancreatic enzymes. And something in thyroid tissue produced metabolic effects.  Starling, in 1905, introduced the word “hormone”, Greek for “I excite”, as a label for these secretions.

     What was the blood-pressure-active adrenal hormone? The search was on in several laboratories, but only two “benchmen” will be highlighted here. The first is John J. Abel.

     Born near Cleveland in 1857, Abel studied mainly chemistry and physiology at the University of Michigan and Johns Hopkins.

John J Abel (Wikipedia)

Then he made the pilgrimage to Europe, where he studied under the physiologist Karl Ludwig (who trained a legion of Americans, including William Welch, a founder of Johns Hopkins), and Oswald Schmiedeberg. Schmiedeberg was a founding father of a new discipline, experimental pharmacology, whose students eventually occupied chairs of some forty different pharmacology departments. While in Europe Abel obtained an MD degree and accepted the chair of a new pharmacology department at the University of Michigan Medical School, where he built a laboratory and introduced hands-on German teaching methods. It was the first such department in the U.S. (as distinct from old, didactic departments of “Materia Medica”). Two years later, in 1893 William Osler enticed him to Johns Hopkins to head their new department.

     At Hopkins, after considerable hard work Abel obtained crystals of a substance from adrenals that was physiologically active. He named it “epinephrine” in a publication in 1897, believing it to be the natural compound. Unfortunately, though he was close he had actually isolated a benzoyl derivative. And he had lost an eye in a laboratory explosion, a loss he never complained about.

     Abel made many contributions, including isolation of poisons from Amanita Phalloides mushrooms, and, most famously, the crystallization of pure insulin. He helped found three journals. He invented a dialysis procedure to remove toxins from the blood of animals and developed a plasmapheresis process. Both ideas, ahead of their time, gained clinical use later. He did not believe in patenting his discoveries.

     The second protagonist is Jokichi Takamine, born in Japan in 1857 to a physician father. Jokichi started in medical school but switched to chemistry, in which he excelled. He worked for the

Jokichi Takamine (Wikipedia)

Japanese government on industrial projects, and was sent in 1884 to represent Japan at the New Orleans World Exposition. There he met, and later married, his landlord’s daughter and eventually took up residence in the U.S. Before long Jokichi patented the first digestive enzyme for human use (an amylase), and Parke-Davis marketed it under the name Taka-Diastase. Since Jokichi had set up his own lab Parke-Davis soon asked him to try to purify the active substance in adrenals. He visited Abel’s lab and, using a different chemical approach, proceeded to isolate the pure compound. He named it “adrenalin” in 1902 – after taking out a patent. Careful review indicates that he did not “steal” any ideas from Abel, nor did Abel accuse him of it.

     Adrenalin was a “blockbuster drug” in today’s parlance, used topically for all sorts of bleeding or inflammatory lesions, asthma, hay fever, and systemically for anaphylaxis. Quacks peddled it for cancer, etc. Royalties from sales of Adrenalin (the trade name) and enzymes made Takamine a rich man. He was one of the first “biotech entrepreneurs”. 

     Takamine’s wealth and business accomplishments helped him establish important social and political contacts and he became a sort of unofficial Japanese ambassador. In 1909, hearing that President Taft’s wife was interested in planting cherry trees in Washington, Takamine secured her acceptance of 2,000 trees as a gift from the mayor of Tokyo, though Takamine quietly paid for them. Unfortunately they were diseased and had to be destroyed, but Takamine financed, behind the scenes, a second lot of 3020 carefully grown trees. They have persisted, been added to, and are in bloom today.

    The contrast between Abel, a dedicated academic researcher and teacher who refused to patent ideas, and Takamine, an equally brilliant laboratory man who used his wealth from patents to foster cross-cultural amity, is striking.

Addenda:

     1. The name “epinephrine” is the approved one in the U.S. in recognition of Abel. “Adrenaline” is approved in the U.K., and in Japan a change was made in 2006 from “epinephrine” to “adrenaline” in honor of Takamine.

     2. The H K Mulford drug company marketed its own adrenalin, arguing that since it was a natural substance it was not subject to patent. Parke-Davis sued them. The Parke-Davis v Mulford case ended in a decision by Learned Hand in 1911 holding that the isolation/purification of a natural substance rendered it patentable. The decision was cited often in the recent Myriad Genetics case about the patentability of naturally occurring genes.

     3. The study of adrenalin effects opened the way to the discovery of chemical neurotransmitters.

SOURCES CONSULTED:

Hoffman, B. B. Adrenaline. 2013. Harvard Univ Press.

Kawakami, K. K. Jokichi Takamine: A Record of his American  

    Achievements. 1928. W E Rudge, NY.

Parascandola, J. The Development of American Pharmacology:  

   John J Abel and theShaping of a Discipline. 1992. Johns Hopkins  

   Press.

Voegtlin, C. “John Jacob Abel”. 1939. Journal of Pharmacology 

    and Experimental Therapeutics. 67: 373-406.

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