Epinephrine and Crystalline Insulin: John Jacob Abel's Hunt for Pure Hormones

Twice in his working life John Jacob Abel (1857–1938) set out to take a powerful but mysterious animal extract and pull from it a single, pure chemical substance. The first time, in the 1890s, the extract came from the adrenal glands, and the substance was the hormone we now call epinephrine, or adrenaline. The second time, in the mid-1920s, the extract came from the pancreas, and the substance was insulin. In the first case Abel came agonisingly close and was overtaken; in the second he became the first to see insulin as crystals in a test tube.

This page tells those two stories as a single story of method: how a chemist in the early days of pharmacology tried to turn a gland extract into a pure compound, why that mattered, and how the priority questions around epinephrine are told today by historians and by Abel himself. Abel’s life, the biology of the glands and animals he drew on, and his artificial kidney and journals each have their own page in this wing, linked in the Connections section below.

Table of Contents

  1. A Pressure-Raising Extract, 1894–1895
  2. Abel and Crawford’s Benzoyl Derivative, 1897
  3. Epinephrin: A Name and a Formula
  4. Takamine’s Visit and the Ammonia Step
  5. Crystals in 1901: Takamine, Uenaka and Aldrich
  6. Epinephrine or Adrenaline? How the Priority Story Is Told
  7. An Invitation to Pasadena, 1924
  8. Is Insulin a Sulphur Compound?
  9. Crystalline Insulin, 1926
  10. From Crystal to Standard: What Purity Changed
  11. Key Research Papers
  12. Connections

1. A Pressure-Raising Extract, 1894–1895

The epinephrine story begins not in Baltimore but in London. In 1894 and 1895 the physician George Oliver and the physiologist Edward Schäfer showed that an extract of the adrenal glands — then usually called the suprarenal capsules, the small caps of tissue that sit on top of each kidney — had a dramatic effect when injected into an animal: the blood pressure rose sharply. They published their findings in 1895 in the Journal of Physiology under the title “The Physiological Effects of Extracts of the Suprarenal Capsules.” Medical historians still treat this as the discovery of the cardiovascular action of the adrenal gland.

The result raised an obvious question. Somewhere in that crude tissue extract was a substance strong enough to raise blood pressure in tiny amounts. What was it? An extract is a soup of proteins, salts, fats and dozens of other compounds. To know what the active agent was — to give it a formula, to measure a dose of it, to compare one preparation with another — a chemist had to isolate it: separate it from everything else and obtain it pure.

Why purity was the whole problem

For a pharmacologist of the 1890s, an extract had real limits. Two batches made from different glands might differ several-fold in strength. A substance that cannot be weighed out pure cannot be studied precisely, and its chemical structure cannot be worked out. Abel had been trained in Germany in the chemical tradition of pharmacology associated with Oswald Schmiedeberg, whom his biographer credits with first arousing Abel’s interest in the chemical side of pharmacological research. The adrenal extract was exactly the kind of problem that tradition was built for, and Abel took it up almost at once.

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2. Abel and Crawford’s Benzoyl Derivative, 1897

According to his National Academy of Sciences biographer, the pharmacologist William deB. MacNider, Abel worked on the adrenal-medulla hormone “for over a period of ten years,” and it was this work that first gave him an international reputation. His first paper on the subject, written with his assistant Albert C. Crawford, appeared in 1897 in the Bulletin of the Johns Hopkins Hospital (volume 8, pages 151–157).

Abel and Crawford’s approach was a classic one for organic chemists of the time. A substance that refuses to separate cleanly from its surroundings can sometimes be captured by attaching a chemical “handle” to it, converting it into a derivative that is easier to precipitate and purify. They treated the active principle of the adrenal extract with benzoyl groups — a chemical fragment derived from benzoic acid — and obtained a benzoyl derivative of it.

The method gave Abel something he could work with and study, but it also carried a cost that would only become clear later. The material he held was not the free hormone itself; it was the hormone bound to an added chemical group. Removing that group again without destroying the delicate molecule underneath proved to be the step that defeated him. In his own later words, quoted in section 4, years of effort ended with the hormone “not in the form of the free base but in that of its monobenzoyl derivative.”

A method of small steps

Isolation work of this kind was slow. Each step — extraction, precipitation, washing, testing the product on an animal’s blood pressure to see whether the activity had followed it or been lost — might take days, and a single mistake could destroy a batch of glands. The physiological test was the chemist’s compass: a fraction that still raised blood pressure still held the hormone; a fraction that did not, did not. This interplay of chemistry and biological testing was the core of the new experimental pharmacology Abel was bringing to America.

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3. Epinephrin: A Name and a Formula

In papers published in 1899, in the American Journal of Physiology and in the German journal Zeitschrift für physiologische Chemie (volume 28, pages 318–362), Abel gave the active principle a name: “epinephrin.” The word came from the anatomist Joseph Hyrtl’s suggestion that “epinephris” was the fittest name for the suprarenal gland — from the Greek epi, “upon,” and nephros, “kidney.” The gland sits upon the kidney, and the hormone took its name from the gland.

Abel also proposed a chemical formula for his substance: C17H15NO4. That formula described his benzoyl-containing material, not the true hormone. The correct formula for the free base — C9H13NO3, a much smaller molecule — would be worked out in 1901 by another chemist, as section 5 describes. The gap between the two formulas is a measure of how much of Abel’s product was the chemical handle he had attached, rather than the hormone itself.

Suprarenin in Vienna

Abel was not working alone in the world. At about the same time the Austrian chemist Otto von Fürth prepared an amorphous (non-crystalline) active compound from the adrenal gland, which he named “suprarenin.” Like Abel’s epinephrin, it was active but not yet a single, pure crystalline substance. Several laboratories on two continents were closing in on the same molecule, each from a slightly different direction, which helps explain why the naming and the credit later became tangled.

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4. Takamine’s Visit and the Ammonia Step

The turning point came from a visitor. Jokichi Takamine, a Japanese chemist then working in the United States, came to Abel’s laboratory in Baltimore. Abel told the story himself in 1927, in his Willard Gibbs lecture, later printed in Science as “Chemistry in relation to biology and medicine with especial reference to insulin and other hormones.” MacNider quotes the passage at length in his memoir, and it is Abel’s own account rather than a later retelling.

In Abel’s telling, Takamine examined his compounds and asked whether they could be prepared “by a simpler process.” Takamine then “simply added ammonia—the reagent that I had so long employed—to his concentrated extracts, whereupon he immediately obtained the native base in the form of burr-like clusters of minute prisms in place of my amorphous base.”

Abel’s explanation of the difference was chemical, not personal: “Takamine’s success was due to the employment of ammonia on very highly concentrated, though impure extracts.” The reagent was the same one Abel had used; what differed was the concentration of the starting material and the decision to go straight for the free base rather than a derivative. And he summed up his own result plainly: “The efforts of years on my part … eventuated, then, in the isolation of the hormone not in the form of the free base but in that of its monobenzoyl derivative.”

Abel’s disappointment

MacNider, who knew Abel, wrote that he felt great disappointment at not having obtained the crystals — a disappointment “at times almost of an incapacitating character.” It is a rare glimpse of the emotional cost of laboratory science. A decade of patient work had brought him to the edge of the answer, and a simpler step taken by someone else had carried it over the line.

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5. Crystals in 1901: Takamine, Uenaka and Aldrich

In 1901 Takamine reported crystalline adrenaline, in papers published that year in the American Journal of Pharmacy and the Journal of Physiology. Crystals mattered because a substance that forms well-shaped crystals is usually close to pure: crystallisation itself is a purification step, sorting identical molecules into an orderly lattice and leaving most impurities behind in the liquid.

Keizo Uenaka at the bench

Japanese anaesthesia historians have drawn attention to a figure the older English-language accounts often left out. Keizo Uenaka, Takamine’s assistant, carried out the practical purification work. His handwritten laboratory memorandum, covering July to December 1900, survives in a temple in Japan. A 2020 paper by Mieda and colleagues compared four documents describing the purification, and set out the work of three Japanese scientists — Uenaka, Nagai Nagayoshi and Takamine — in the story of adrenaline.

Thomas Aldrich and the true formula

In the same year, 1901, the chemist Thomas B. Aldrich determined the formula of the free hormone as C9H13NO3. MacNider names Aldrich among Abel’s students and associates, so the correct formula came from a chemist connected with the very school that had been working on the problem for years. Set beside Abel’s C17H15NO4, the formula showed clearly what the pure hormone was and what in Abel’s product had been the added benzoyl group.

A patent and a lawsuit

Takamine patented the substance. Whether a substance extracted from a natural source could be patented at all was later fought out in the courts, a case that historians of catecholamines still discuss in their accounts of how adrenaline reached medicine. The firm that sponsored Takamine’s work and employed Aldrich marketed the hormone under a trade name; this page uses only the generic names epinephrine and adrenaline.

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6. Epinephrine or Adrenaline? How the Priority Story Is Told

The two names for the same molecule are a living record of the two lines of work. “Adrenaline” comes from the Latin ad, “at,” and renes, “kidneys”; “epinephrine,” Abel’s word, comes from the Greek for the same idea. Both mean, in effect, “the substance from the gland on the kidney.” American medicine kept Abel’s name, epinephrine, as its official term; Europe and much of the rest of the world kept adrenaline.

How historians divide the credit

The question of who “discovered” adrenaline has no single answer, because it depends on what counts as discovery. The physiologist Max Bennett, writing in 1999 on the centenary of the hormone’s isolation, put it as joint research: the active principle was isolated “by the joint research of John Abel in 1899 and Jokichi Takamine in 1901.” The historian John Parascandola devoted a 2010 paper in the Journal of Allergy and Clinical Immunology to Abel, Takamine and the isolation of epinephrine, and short histories of the drug continue to name both men.

The Nobel archives add another angle. Pohar and Hansson, who studied the seventeen Nobel nominations Abel received in two prize categories, report that when Einar Hammarsten reviewed Abel’s hormone work for the Chemistry committee, he judged it not prizeworthy, in part because others — Takamine and Aldrich, who isolated epinephrine in 1901 — had made more important discoveries in the same field. In the eyes of that reviewer, the free crystalline base outweighed the first identification of the active principle as a derivative.

Abel’s own framing

What stands out in Abel’s 1927 account is its tone. He described what Takamine did, explained why it worked, and stated plainly where his own method had fallen short. Read today, the story is less a contest between two men than a lesson in chemistry: the route a chemist chooses to purify a fragile molecule can decide whether the pure substance appears at all.

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7. An Invitation to Pasadena, 1924

A generation later, Abel faced a new extract. Insulin had been extracted from animal pancreas by Frederick Banting and Charles Best in Toronto in 1921–22, and within a few years it was keeping people with type 1 diabetes alive around the world. Yet insulin was still an extract. Nobody knew what kind of chemical it was, and its strength had to be measured by its effect on animals rather than by weighing out a known pure compound.

In the early autumn of 1924 Abel, by then in his late sixties and one of the senior figures of American pharmacology, was invited by the chemist Arthur A. Noyes, director of the Gates Chemical Laboratory at the California Institute of Technology in Pasadena, to come and investigate insulin there, with support from a Carnegie grant. Abel accepted, and the work that followed was carried out in Pasadena, with his Johns Hopkins affiliation kept alongside.

A team assembled

Abel’s first insulin paper from Pasadena lists three co-workers: E. M. K. Geiling, a pharmacologist who would stay with the insulin problem through its proof, and the chemists G. Alles and A. Raymond. The partnership of a seasoned pharmacologist with a modern chemistry laboratory was itself a sign of the times: the hunt for pure hormones had become work for chemists and biologists together.

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8. Is Insulin a Sulphur Compound?

The first report of the Pasadena work appeared in Science on 21 August 1925 under the title “Researches on insulin. I. Is insulin an unstable sulphur compound?” The team’s starting material was commercial insulin, a powder with a strength of about 8 rabbit units per milligram — a unit then defined by the effect of the preparation on the blood sugar of rabbits.

The question in the title shows how open the chemistry still was. In 1925 chemists did not know whether insulin was a protein, a small molecule carried on a protein, or something else altogether, and they did not know which of its chemical features were essential to its activity. Asking whether the activity was tied to sulphur was a way of probing what part of the material carried the hormone’s power. Modern chemistry has since shown that insulin is a small protein made of two chains held together by sulphur-containing disulphide bridges, so the element at the centre of the 1925 question does form part of the molecule’s structure.

Following the activity

As with epinephrine thirty years earlier, the method was to purify step by step and test each fraction on animals to see where the activity went. The difference was that by 1925 Abel was working in one of the best-equipped chemistry laboratories in the country, with younger colleagues trained in the newest methods, and with the lesson of epinephrine behind him: the goal was the native hormone itself, not a derivative of it.

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9. Crystalline Insulin, 1926

In 1926 Abel announced that he had obtained insulin in crystalline form. His short paper, titled simply “Crystalline Insulin,” appeared in the Proceedings of the National Academy of Sciences (volume 12, pages 132–136), under his name alone, with his affiliation given as the Gates Chemical Laboratory of the California Institute of Technology and the Johns Hopkins University.

The crystals were the answer to the problem he had failed to solve with epinephrine. A hormone that could be crystallised could be purified to a constant composition, weighed, and studied as a single chemical substance. For a man who had come within one step of crystalline epinephrine and watched someone else take it, the insulin crystals carried a particular weight.

Proof with Geiling, 1927

A crystal by itself did not settle every question. The obvious objection was that the hormone might simply be clinging to crystals of some other substance — adsorbed on their surface — rather than being the crystal itself. MacNider describes the fuller work with Geiling, published in 1927 in the Journal of Pharmacology and Experimental Therapeutics with Geiling, Rouiller, Bell and Wintersteiner (volume 31, pages 65–85), as “clean-cut,” and says it showed that the insulin effect belonged to the crystalline body itself and not to a hormone adsorbed onto the crystals. In short: announced in 1926, with fuller proof in 1927.

The historians John Murnaghan and Paul Talalay later wrote a long account of Abel and the crystallisation of insulin, published in 1967 in Perspectives in Biology and Medicine, which remains a standard history of the episode.

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10. From Crystal to Standard: What Purity Changed

According to the medical historian José Luis Fresquet Febrer, Abel’s observation was soon confirmed by others, and crystallisation gave insulin something it had lacked: a definitive standard for assay. Before crystals, the strength of any batch of insulin could only be judged against other batches by testing on animals. After crystals, there was a pure reference substance against which preparations could be compared.

Zinc and the next step

The crystals also opened the way to further chemistry. In Toronto, D. A. Scott of the Connaught Laboratories found that the pancreas contains zinc and that adding small amounts of zinc to buffered insulin produced crystals; his observations dated from 1930 and were published in the Biochemical Journal in 1934, in a paper that cites Abel’s 1926 work. Zinc-containing insulin preparations, including protamine zinc insulin, were in wide use by the autumn of 1936. The biology of zinc and the pancreas belongs to this wing’s natural-sources page; here it is enough to note that it grew out of the crystallisation problem.

The thread that ties the two stories together

Seen together, epinephrine and insulin show the arc of a single scientific idea across Abel’s career: that the powerful substances made by the body’s glands are definite chemicals, and that the way to understand them is to isolate them pure. With epinephrine, the free base escaped him and crystals came from another laboratory. With insulin, nearly three decades later, the crystals were his. In both cases the pure substance did more than satisfy curiosity — it made exact dosing, exact comparison and, eventually, exact structure possible. Epinephrine is now a standard emergency drug for anaphylaxis, and purified insulin is a daily medicine for millions; both histories run back through the glass of a laboratory test tube.

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Key Research Papers

  1. Oliver G, Schäfer EA. The Physiological Effects of Extracts of the Suprarenal Capsules. J Physiol. 1895;18(3):230-76. PubMed PMID: 16992252
  2. Barcroft H, Talbot JF. Oliver and Schäfer’s discovery of the cardiovascular action of suprarenal extract. Postgrad Med J. 1968;44(507):6-8. PubMed PMID: 4867248
  3. Abel JJ. Chemistry in relation to biology and medicine with especial reference to insulin and other hormones. Science. 1927;66(1710):307-19. PubMed PMID: 17797869
  4. Abel JJ. Chemistry in relation to biology and medicine with especial reference to insulin and other hormones (continued). Science. 1927;66(1711):337-46. PubMed PMID: 17834012
  5. Parascandola J. Abel, Takamine, and the isolation of epinephrine. J Allergy Clin Immunol. 2010;125(2):514-7. PubMed PMID: 20196206
  6. Mieda R, Aso C, Hiroki T, Kanamoto M, Suto T, Tobe M, Saito S. Comparison of four documents describing adrenaline purification, and the work of three important scientists, Keizo Uenaka, Nagai Nagayoshi and Jokichi Takamine. J Anesth Hist. 2020;6(2):42-48. PubMed PMID: 32593376
  7. Bennett MR. One hundred years of adrenaline: the discovery of autoreceptors. Clin Auton Res. 1999;9(3):145-59. PubMed PMID: 10454061
  8. Goldstein DS. Catecholamines 101. Clin Auton Res. 2010;20(6):331-52. PubMed PMID: 20623313
  9. Arthur G. Epinephrine: a short history. Lancet Respir Med. 2015;3(5):350-1. PubMed PMID: 25969360
  10. Pohar M, Hansson N. Between two stools? Pharmacologists nominated for Nobel prizes in “physiology or medicine” and “chemistry” 1901-1950 with a focus on John Jacob Abel (1857-1938). Naunyn Schmiedebergs Arch Pharmacol. 2021;394(3):503-513. PubMed PMID: 33057776
  11. Abel JJ, Geiling EM, Alles G, Raymond A. Researches on insulin. Science. 1925;62(1599):169-71. PubMed PMID: 17839379
  12. Abel JJ. Crystalline Insulin. Proc Natl Acad Sci U S A. 1926;12(2):132-6. PubMed PMID: 16587069
  13. Murnaghan JH, Talalay P. John Jacob Abel and the crystallization of insulin. Perspect Biol Med. 1967;10(3):334-80. PubMed PMID: 5340582
  14. Scott DA. Crystalline insulin. Biochem J. 1934;28(4):1592-1602. PubMed PMID: 16745551

PubMed Topic Searches

  1. https://pubmed.ncbi.nlm.nih.gov/?term=%22John+Jacob+Abel%22
  2. https://pubmed.ncbi.nlm.nih.gov/?term=epinephrine+history+Takamine
  3. https://pubmed.ncbi.nlm.nih.gov/?term=crystalline+insulin+history
  4. https://pubmed.ncbi.nlm.nih.gov/?term=Abel+JJ%5Bau%5D+AND+1890%3A1938%5Bdp%5D

Further Reading

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Connections