Adrenaline and Cherry Trees

October 23, 2018

 

 

Jokichi Takamine, a pioneer of American biotechnology, isolated the hormone a century ago.

 

Jokichi Takamine
NATIONAL LIBRARY OF MEDICINE

The isolation of adrenalin (also: adrenaline)—the first hormone to be obtained in pure form and called “the blood-pressure-raising principle of the suprarenal glands”—was first reported in 1901. The work was done in a small independent laboratory run by Jokichi Takamine, a Japanese chemist who spent most of his adult life in the United States. His success in isolating adrenalin was a surprise to the scientific community, especially because his competition included such better known figures as John Jacob Abel of Johns Hopkins University and Otto von Furth of Strasburg, Germany (now France).

 

Jokichi Takamine was born on November 3, 1854, in a small town on the west coast of Japan, shortly after Commodore Matthew Perry’s black gunships arrived in Tokyo Bay and opened Japan to the West. At the age of 12, he began to study “foreign science” in Nagasaki; by 24, he was selected by the government to study technology at the University of Glasgow. While Takamine was in the British Isles, he polished his English and took a particular interest in the manufacture of fertilizers. When he completed his education, he returned home to work in the newly established Japanese Department of Agriculture and Commerce on the application of Western technology to Japanese problems. Shortly thereafter, he was sent to represent Japan as commissioner at the 1884 Cotton Exposition in New Orleans, and he stayed on in that city. Takamine lived in a French Quarter apartment that he rented from a retired Union officer, Colonel Ebenezer Hitch. He continued his research into fertilizer powders and, in his free time, courted and married his landlord’s daughter, Caroline Field Hitch.

For their honeymoon, Takamine took his bride to South Carolina, where they visited fertilizer plants; to Washington, DC, where he studied U.S. patent law; and then west to California, where they embarked on the long sea voyage to Japan. Takamine had secured government support to establish the Tokyo Artificial Fertilizer Company, the first superphosphate works to supply fertilizer to rice farmers, and the young couple settled near the new fertilizer factory. They had two sons, Jokichi Jr. and Eben. In Japan, Caroline was a blue-eyed, blond-haired geijin (outsider) with a mother-in-law who disapproved of her independent American ways.

To save his marriage, Takamine sought new business opportunities back in the United States, but he knew that he could not compete in the already well-established American fertilizer industry. Eventually, he hit upon a concept that would make him a pioneer of industrial enzymology: He decided to adapt the methods of Japanese sake (rice wine) manufacture to the brewing industry.

Yeast can ferment sugar, but not starch, into alcohol. Prior to alcoholic fermentation, the starch in grains must be treated with diastatic (i.e., starch-degrading) enzymes. In Western brewing, the diastatic enzyme is obtained from malt made from germinating barley. In Japan and some other Asian cultures, the enzyme is derived from a filamentous fungus grown on rice; the resulting “koji” is comparable to the malt enzymebut far more active and less expensive to prepare. Believing that the mold enzyme could revolutionize the distillery industry, Takamine and his young family returned to the United States in 1890 with the financial assistance of Colonel and Mrs. Hitch. Takamine worked first in Chicago and then in Peoria, IL, commercializing the Japanese process for the beer and whiskey business by substituting the fungal starch-splitting enzyme for the malt. The Peoria distillery where he worked manufactured an affordable new whiskey that he named Bonzai.

In 1894, Takamine applied for, and was granted, a patent titled “Process of Making Diastatic Enzyme” (U.S. Patent 525,823)—the first patent on a microbial enzyme in the United States. He licensed his preparation to Parke, Davis & Company of Detroit under the brand name Taka-diastase. The company aggressively marketed the diastase as a digestive aid for the treatment of dyspepsia, which was said to be due to the incomplete digestion of starch. The product was enormously successful, and Takamine became a consultant to the pharmaceutical company.

With Parke, Davis as his patron, Takamine moved his family to New York and established an independent laboratory on East 103rd Street around 1898. It was there that the famous work on adrenalin was conducted. Using his profits from Taka-diastase, Takamine hired a young chemist from Japan, Keizo Uenaka (sometimes transcribed as Keizo Wooyenaka), to assist him. For the next two years, their main attentions were focused not on enzymes but on another class of biological compounds that were active in minute amounts, namely, the “internal secretions” associated with glands.

In 1895, George Oliver and Edward Schäferhad discovered that when the secretions of adrenal glands were extracted and injected into an experimental animal, they could raise blood pressure. The purification of this principle became a matter of interest, and in 1897, John Jacob Abel and Albert C. Crawford thought that they had succeeded when they purified a crystalline principle they named epinephrine. (It was later shown that they had isolated a benzoyl derivative rather than the pure hormone.)

Takamine was encouraged by Parke, Davisto follow up on the epinephrine work, and sometime in 1900, he visited Abel’s laboratory at Johns Hopkins, where he was welcomed and shown full scientific courtesy. Then, working with Uenaka, Takamine followed Abel’s methods for removing fat and protein, partitioning his concentrated extract with acidified water, and then precipitating the active principle with ammonia. It was Uenaka, working alone one night, who first obtained a crystalline product, but it was Takamine who filed a patent application on November 5, 1900, titled “Glandular Extractive Product” on a blood-pressure-raising principle he called adrenalin. Within a few months, Takamine presented two papers, one before the Society of Chemical Industry and another before the New York State Medical Society. That same year (1901), he published two single-author papersin the scientific literature and applied for and was awarded the right to use the word Adrenalin as a trademark. Simultaneously, a colleague at Parke, Davis, Thomas Aldrich, published the correct chemical structure, and the company began marketing the product under the trade name Adrenalin.

The discovery of adrenalin was a medical and popular sensation. Physicians carried it in their bags, and it is said that Gene Tunney, the champion boxer, always kept some on hand when he went into the ring. The drug transformed surgery, where it was used to control hemorrhage. Adrenalin also found uses in cardiology, obstetrics, and the treatment of asthma and other allergies. It was widely prescribed for several conditions for which it was useless, including goiter, deafness, and Addison’s disease.

 

 

The emperor of Japan acknowledged Takamine’s feat by conferring the Order of the Rising Sun, Fourth Class. He also sent 15 imperial cherry trees to Parke, Davis, where they were planted in front of the administrative offices.

John Jacob Abel, who had not spent his honeymoon studying patent law, felt scooped and duped. Although he accepted the fact that that Takamine had isolated a crystalline product, he persisted in the belief that the product was not pure and that the chemical formula proposed by Aldrich and Takamine was not correct. Horace Davenport, Beaumont Professor of Physiology at the University of Michigan, later wrote, “A faint air of scandal seemed to hang over adrenalin.” Gradually, the term “adrenalin” fell out of the scientific literature and was replaced with “epinephrine”. But adrenalin was the word adopted in ordinary language. People commonly talked about having “an adrenalin rush” or “getting their adrenalin up”.

Although Abel was wrong about the chemical structure of epinephrine, his assertion that Takamine’s adrenalin was impure was shown to be correct in a way that he did not anticipate, nor could he have demonstrated, given the chemistry of the time. The contaminant was norepinephrine. The early 20th-century product sold by Parke, Davis under the trade name Adrenalin was actually a mixture of epinephrine and norepinephrine.

Although Takamine’s patent was originally filed on November 5, 1900, the application was subsequently divided and refiled. Eventually, on June 2, 1903, five separate U.S. patents were granted to Takamine on adrenalin. He also obtained British and Japanese patent rights on the drug. Later, a rival company of Parke, Davis, H. K. Mulford, attacked the adrenalin patents with the argument that the hormone existed in nature and that Takamine’s work had been anticipated by Abel and von Furth.

Federal Judge Learned Hand listened to days of technical testimony and immersed himself in the chemical literature surrounding the rival claims. His cogent and chemically accurate summation contains one of the most famous lines in biotechnology patent history: “I cannot stop without calling attention to the extraordinary condition of the law which makes it possible for a man without a knowledge of even the rudiments of chemistry to pass upon such questions as these” (Circuit Court, S.D. New York, April 28, 1911, Federal Reporter189:115). Judge Hand ruled in favor of Takamine; Mulford was ordered to cease infringing.

Takamine used the royalties from Adrenalin and the continuing royalties from Taka-diastase to expand his business operations in enzymes and pharmaceuticals. He founded three major companies: Sankyo Pharmaceutical Company of Tokyo, the International Takamine Ferment Company of New York, and the Takamine Laboratory of Clifton, NJ.

As Takamine became wealthier, he left his laboratory work behind and turned his energies toward improving the position of the Japanese in the United States. He helped found the Nippon Club and the Japan Society to foster better relations between Americans and the Japanese. When Takamine learned in 1909 that First Lady Helen Herron Taft was working to beautify the Tidal Basin area around the Potomac River in Washington, DC, he funded a gift of 2000 cherry trees from the mayor of Tokyo to the city of Washington. This symbol of Japanese–American friendship has become a clichéd tourist attraction, but almost no one remembers the man who was instrumental in making it happen.

Jokichi Takamine died on July 22, 1922, of a liver ailment that had plagued him most of his life. In his obituaries, he was called the Japanese Thomas Edison and the Japanese Pasteur. For his pioneering patents and entrepreneurial spirit, he could also be considered the forgotten father of American biotechnology.

Acknowledgments

I thank Akira Arimura, Barbara Beckman, Douglas Plymale, Yutaka Yamamoto, and the late Agnes de Mille for help in locating certain materials. Special thanks to Mamora Arai of Sankyo Corporation.

Further reading

  • Davenport, H. W. Epinephrin(e). The Physiologist 1982, 25, 76–82

  • Kawakami, K. K. Jokichi Takamine: A Record of his American Achievements; William Edwin Rudge: New York, 1928.

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