TEM 1393 No. of Pages 3 Trends in Endocrinology & Metabolism Forum The First carried by the blood to the pancreatic activity in 1895 and its chemical purifica- gland cells. ‘The crucial experiment’ was tion in 1901 predated those of secretin in Hormone: Adrenaline performed on 16 January 1902, with all 1902 and 1961. fi Yi Rao1,* experiments nished by March 1902, pub- lished in a preliminary form as Bayliss and Purification of the Active Principle Starling (1902) [1] and in the full form in from Adrenal Glands the Journal of Physiology. In 1895, Schäfer asked two of his col- It is not often that three misconcep- leagues at UCL to study adrenal extracts Starling coined the term hormone in 1905 tions are associated with one mole- chemically. In 1897, Sigmund Fränkel and acknowledged that the first hormonal cule for more than a century. This is (1868–1939) of Germany extracted from activity was the increase of blood pressure the case with adrenaline. The aim the adrenal capsules what he called by the injection of suprarenal extracts ob- spygmogenin [4].From1897to1901, here is to clarify that adrenaline served by Oliver and Schäfer [2]. John Abel of Johns Hopkins University was the first hormone, with the dis- published a series of papers on what he The adrenal gland (or suprarenal capsule) covery of its activity and chemical called epinephrin from 1898 onwards fi is a small gland above the kidney. In puri cation being prior to secretin. [5–7]. The molecular formula of epineph- 1855, Dr Thomas Addison (1793–1860) Adrenaline is the correct name rine was C H NO [6].In1900,the of Guy’sHospitalinLondondiscovered 17 15 4 given by Jōkichi Takamine, epi- Austrian scientist Otto von Fürth what was later called Addison’s disease, (1867–1938), then working at Strasbourg nephrine being its inactive benzoyl caused by damage to the adrenal glands University, after pointing out that epineph- derivative. [3].Soonresearcherswereinterestedin rine was inactive, purified what he called finding what was in the glands. Removal suprarenin, with the molecular formula While adrenaline is a well-known molecule, of adrenal capsules from animals often re- C H NO [8].In1901,Abelofferedare- there have long been three misconcep- sulted in death. 5 9 2 tions. It has not been recognized as the buttal to von Fürth, claiming that his princi- first hormone, its discovery is obscure, George Oliver (1841–1915) was an En- ple was active, although it was not the and its names are confusing. This Forum glish doctor with a home laboratory who native principle, but might contain an aims to clarify the history of its discovery. may have even experimented with his extra benzoyl [7]. son, feeding him adrenal extracts. Edward Secretin versus Adrenaline Albert Schäfer (1850–1935) was then a The pharmaceutical company Parke- Most textbooks state that secretin was the professor of physiology at UCL, whose Davis in Detroit, MI suggested that first hormone, discovered in 1902 by the contributions included the proposal of the Takamine purify the active principle from British cousins William Bayliss (1860–1924) term ‘endocrine’ for ductless glands. In the adrenal gland. In 1900, Takamine and Ernest Starling (1866–1927), at 1893, Oliver went to Schäfer, suggesting and his assistant Keizo Uenaka fi University College London (UCL). that they collaborate on the physiological (1876–1960) had puri ed a highly active effects of adrenal extracts. Oliver and principle with the molecular formula In 1899, Bayliss and Starling followed up on Schäfer published two abstracts in 1894 C10H15NO3. In January 1901, Takamine fi one of Ivan Pavlov’sobservationspublished and a full paper in 1895, showing the ef- reported his ndings to the Society of in 1898 that different kinds of substances in fects of adrenal extracts, including that of Chemical Engineering in New York and food, after digestion into chyme and move- increasing the blood pressure and the published in the American Journal of ment into the duodenum, induced the pan- heart beat [2].Theydeterminedthatthe Pharmacy [9].InDecember1901, creas to secrete different kinds of juices. active principle was from the medulla, not Takamine reported adrenaline to the Pavlov and others performed experiments the cortex of the adrenal glands. British Physiological Society, and he and concluded that the effects of chyme published in the Journal of Physiology in on pancreatic secretion were due to nerves As detailed below, adrenaline was purified 1902 [10]. (the vagus, splanchnic, or local). in 1901 by Takamine (Box 1). Secretin was not purified until 1961 and determination By the summer of 1900, Thomas Aldrich Bayliss and Starling made the novel dis- of its primary structure would take another of the Department of Biology of the Scien- fi fi covery that this resulted from the chemical decade (1970). ti c Laboratory of Parke-Davis had puri ed substance they called secretin, which was adrenaline, and he published his results in made by the mucous membrane of the Thus, the first hormone was clearly adren- 1901. He recognized the priority of upper parts of the small intestine and aline, because both the discovery of its Takamine’sreporttotheSocietyof Trends in Endocrinology & Metabolism, Month 2019, Vol. xx, No. xx 1 Trends in Endocrinology & Metabolism Box 1. Jōkichi Takamine (1854–1922) Henry Dakin (1880–1952) also credited Jōkichi Takamine was born in Japan to parents who had hoped for him to study medicine, but he liked chem- Takamine and Aldrich for discovering istry and graduated from Tokyo University before studying for his PhD in Glasgow, UK. After returning to adrenaline [15].In1906,HenryDale,the Japan, he established the first fertilizer factory in Japan [16]. While attending the 1884 World Cotton Exposition in New Orleans, he fell in love with Caroline Field Hitch, a daughter of his landlord. He worked in Japan for a few British pharmacologist who would later years before returning to New Orleans to fulfill their engagement. After marriage, Takamine and his wife went to win a Nobel Prize in 1936, insisted that Japan, where he discovered an amylase, capable of degrading starch, which decreased both the time and the adrenaline was the correct name, with epi- cost for fermentation. His mother in law suggested that he go to Chicago and apply the enzyme to whiskey nephrine as the name of the inactive manufacturing. From then on, Takamine and his wife settled in the USA, first establishing the Takamine Fer- ment Company in Peoria, near Chicago. There they met local resistance, with the factory burnt down by arson principle. and dissolution of his company by stockholders. Then the situation got worse when he suffered from a severe liver disease requiring immediate hospitalization. During the months of hospitalization, he noticed that the main Because Takamine and Parke-Davis pat- meal was starch and two-thirds of patients had digestive problems (dyspepsia). He showed that his enzyme ented adrenalin, Henry Wellcome was effective in treating dyspepsia. He named the enzyme Taka-Diastase and sold his patent to Parke-Davis, (1853–1936), the US founder of the British with sales exceeding US$ 30 million. This was a major contribution to early biotechnology. pharmaceutical company Burroughs- With a handsome income from Taka-Diastase, Takamine was able to establish his own laboratory in New York Wellcome, was reluctant to use the name, in 1897. In 1900, he hired Keizo Uenaka (1876–1960) as his assistant. Uenaka had excellent training in chem- even trying to block Dale, who was working istry with Nagayoshi Nagai (1844–1929) at Tokyo University, who discovered ephedrine from the Chinese herb in the Wellcome research laboratories, from medicine Mahuang. Together, they purified adrenaline. using adrenaline. Dale pointed out that Brit- ish scientists believed that adrenaline was Chemical Engineering. He compared the Pharmacology and Experimental Thera- the active principle while the epinephrine of physical and chemical properties and con- peutics in 1908. His influence was far Abel was inactive, insisting on the use of cluded that he and Takamine had isolated greater than that of Takamine. adrenaline in his papers. Because Parke- the same molecule, with the same molec- Davis patented adrenalin, scientists use Thus, although historians had argued for ular formula: C9H13NO3 [11]. The correct adrenaline. After Abel passed away, Takamine, it remains that for a long time formula was closer to that deduced by Dale wrote an obituary for Abel, still politely American scientists believed more in Takamine than those by Abel and von noting that Abel’s epinephrine was ‘a Abel than in Takamine. For example, in Fürth. monobenzoyl-derivative of the active 1982 the American physiologist Horace principle’. Adrenaline versus Epinephrine Davenport believed that Abel discovered Adrenalin was the name on the patent of the principle, although he changed his Credit Long Overdue mind by 1991 to recognize the discovery Takamine and Parke-Davis. After a lawsuit Adrenaline was important for both basic of Takamine. Although there have been re- filed by Abel, Takamine won. Both the Brit- research and medical applications. In peated arguments for the usage of adrena- ish and the European Pharmacopoeia basic research, it was not only the first hor- line, epinephrine is still used in US textbooks used adrenaline but the US Pharmaco- mone, it also helped in the discovery of the and by US scientists. Most assume that poeia used epinephrine. neurotransmitter noradrenaline, which is there had been priority disputes between the precursor in the biological synthesis In 1927, 5 years after Takamine died (and US and European scientists, whereas the of adrenaline. In medicine, adrenaline was 25 years after losing the patent fight), truth was that both names were proposed used almost immediately and it is still in Abel claimed that Takamine visited him by scientists working in the USA, although use today, a record not matched by and modified his method to purify adrena- one was of Japanese origin and the other many molecules.