Glands, Toads, Leeches and Mushrooms: The Natural Sources of John Jacob Abel's Chemistry

Table of Contents

1. Chemistry of the Living Body: Abel’s Aim
2. The Adrenal Medulla and What Epinephrine Does
3. Epinephrine, Noradrenaline and the Nerves
4. The Pancreas, Insulin and Zinc
5. The Pituitary Gland and Its Puzzling Extracts
6. Histamine Hidden in Tissue Extracts
7. The Cane Toad: Epinephrine and Bufagin
8. The Death Cap: Poisons of Amanita phalloides
9. The Medicinal Leech and Hirudin
10. Why Natural Sources Mattered Before Synthesis
11. Key Research Papers
12. Connections

1. Chemistry of the Living Body: Abel’s Aim

Abel learned his trade in the German laboratories of the 1880s, and it was Oswald Schmiedeberg in Strassburg who, in the words of his biographer William MacNider, first aroused his interest in pharmacological research “particularly in its chemical aspects.” From then on Abel’s working life had a single thread running through it: to take a tissue that clearly did something powerful to the body and isolate, in pure form, the one substance responsible.

That was a harder problem than it sounds. A gland extract is a soup of thousands of compounds — proteins, salts, fats, breakdown products — and the active hormone may be present at a few parts per million. Many of these substances are fragile: they oxidise in air, break down in acid or alkali, or stick to other molecules so tightly that they travel with them through every purification step. And the only way to tell whether a fraction still held the active principle was to test it on a living animal, watching for a rise in blood pressure, a fall in blood sugar or a contraction of smooth muscle.

Abel himself, in his 1927 Willard Gibbs Lecture to the American Chemical Society, framed his career as chemistry in the service of biology and medicine, with insulin and the other hormones as his chief examples. The sections below follow his raw materials one by one, starting with the gland that occupied him for more than a decade.

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2. The Adrenal Medulla and What Epinephrine Does

The adrenal glands are two small caps of tissue sitting on top of the kidneys. Each has two quite different parts. The outer layer, the cortex, makes steroid hormones such as cortisol and aldosterone. The inner core, the medulla, is really a piece of the nervous system: its cells (called chromaffin cells, because they stain brown with chromium salts) develop from the same embryonic tissue as nerve cells and are wired directly to nerves from the spinal cord. When those nerves fire, the medulla releases its hormone straight into the bloodstream.

That hormone is epinephrine, known in Britain and Europe as adrenaline. The two names mean the same thing — “on the kidney,” one from Greek and one from Latin. Abel chose “epinephrin” in 1899, taking up the anatomist Joseph Hyrtl’s suggestion that “epinephris” was the fittest name for the gland; American usage kept his word, while Europe adopted “adrenaline.”

The discovery that set the problem

In 1894–1895 the English physician George Oliver and the physiologist Edward Schäfer showed that a small injection of extract from the “suprarenal capsules” (the old name for the adrenals) sent an animal’s blood pressure soaring. Their 1895 paper in the Journal of Physiology described the effect in detail, and later historians have treated it as the founding observation of adrenal endocrinology. The extract clearly contained something extraordinarily potent; the question Abel set himself was what, exactly, it was.

What epinephrine does in the body

Epinephrine is the chemical messenger of the body’s emergency response — what the American physiologist Walter Cannon called “fight or flight.” Released into the blood, it reaches almost every organ within seconds and acts on receptors (the adrenergic receptors) on the surface of cells. The best-described effects include:

• a faster, more forceful heartbeat and a rise in blood pressure;
• narrowing of blood vessels in the skin and gut and widening of those in skeletal muscle, steering blood to where it is needed for action;
• relaxation of the smooth muscle of the airways, opening the bronchi;
• release of glucose from stored glycogen in the liver and of fatty acids from fat tissue, providing fuel;
• widening of the pupils and a general heightening of alertness.

Those same actions are why epinephrine became, in the twentieth century, the first-line drug in anaphylaxis: it tightens leaking blood vessels, raises a collapsing blood pressure and opens swollen airways all at once. The site’s anaphylaxis pages, linked below, describe that modern use. A later generation of scientists, including Earl Sutherland, went on to show how epinephrine’s signal is passed on inside the cell through a “second messenger,” cyclic AMP.

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3. Epinephrine, Noradrenaline and the Nerves

The adrenal medulla does not make only one substance. It also releases noradrenaline (norepinephrine in American usage), a close chemical cousin that differs from epinephrine by lacking one small methyl group. The two belong to a family called the catecholamines, together with dopamine, from which the body builds both of them. The pathway runs from the amino acid tyrosine to L-DOPA, then dopamine, then noradrenaline, and — mainly in the adrenal medulla — on to epinephrine.

Neither Abel nor his rivals could know this at the time. David Goldstein’s review of catecholamine science notes that Abel’s years of effort ended, in Abel’s own words, in the isolation of the hormone “not in the form of the free base but in that of its monobenzoyl derivative” — a chemically altered form. A Spanish historical account of Abel’s life reports that the first “pure” adrenal preparations of the period were later found to contain noradrenaline as well.

From hormone to nerve transmitter

The deeper surprise was that the nervous system uses the same chemistry. In 1904 the Cambridge physiologist Thomas Elliott noticed that adrenal extract mimicked the effects of stimulating the sympathetic nerves and proposed that those nerves might work by releasing an adrenaline-like substance at their endings. Max Bennett’s centenary history of adrenaline traces the idea from Abel’s and Takamine’s isolations (1899 and 1901) through Elliott to the Swedish physiologist Ulf von Euler, who showed in 1946 that the real transmitter of the sympathetic nerves is noradrenaline, not epinephrine. Von Euler later shared the 1970 Nobel Prize for this line of work; the site’s page on Katz, von Euler and Axelrod tells that story.

So the substance Abel spent a decade chasing turned out to stand at the crossroads of two body systems: a hormone carried in the blood and, in its noradrenaline form, a chemical messenger passed from nerve to muscle and from nerve to nerve. Otto Loewi and Henry Dale’s work on acetylcholine, the other great transmitter of the era, is covered on its own page.

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4. The Pancreas, Insulin and Zinc

The pancreas is a long gland tucked behind the stomach that does two jobs. Most of it makes digestive enzymes that drain into the intestine. Scattered through it, like islands, are small clusters of cells — the islets of Langerhans — that release hormones directly into the blood. The beta cells of the islets make insulin, the hormone that lets muscle, fat and liver cells take up glucose after a meal and store it. Without insulin, blood sugar climbs and the body turns to burning fat, the state that made type 1 diabetes fatal before 1922.

Insulin itself was first extracted from animal pancreas by Frederick Banting, Charles Best and their Toronto colleagues in 1921–1922. When Abel took up the problem at Pasadena in 1924, the insulin he worked with was still a crude powder from animal glands, its strength measured by how much it lowered the blood sugar of rabbits. In 1926 he announced, in a short paper in the Proceedings of the National Academy of Sciences, that he had obtained insulin as crystals. That chemistry, and the long argument over whether the crystals were the hormone itself, are told on the wing’s epinephrine-and-insulin page; John Murnaghan and Paul Talalay’s 1967 history covers it in depth.

The zinc in the crystals

One natural clue was hidden in the pancreas all along. At the Connaught Laboratories in Toronto, the chemist David Scott found that pancreas tissue contains zinc, and that adding small amounts of zinc to a buffered insulin solution made crystals form readily. His observations date from about 1930 and were published in full in the Biochemical Journal in 1934, where he built directly on Abel’s 1926 report.

Later protein chemistry explained why. Inside the beta cell, insulin molecules pack into groups of six (hexamers) arranged around zinc ions, and in that form they are stored in tiny granules until they are released. Zinc is a trace mineral the body needs for hundreds of enzymes, and the insulin granule is one of the places in the body where it is most concentrated. Scott’s finding had a practical sequel too: by the autumn of 1936 protamine zinc insulin, a slower-acting preparation built on the same chemistry, was in wide use.

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5. The Pituitary Gland and Its Puzzling Extracts

The pituitary is a pea-sized gland hanging from the underside of the brain. Like the adrenal it has two distinct parts. The front part, the anterior lobe, makes hormones that control growth, the thyroid, the adrenal cortex and the reproductive glands. The back part, the posterior lobe, is an extension of the brain itself: nerve cells in the hypothalamus make two small hormones and send them down their own fibres to be stored and released there.

In the same year as their adrenal paper, Oliver and Schäfer published a brief communication showing that extracts of the pituitary body, too, raised blood pressure. Over the following two decades physiologists found that posterior-lobe extract did at least three different things: it raised blood pressure (a pressor effect), it made the muscle of the womb contract (an oxytocic effect) and it reduced the flow of urine (an antidiuretic effect). Whether those effects came from one hormone or several was one of the great open questions of endocrinology.

Abel’s pituitary years, 1917–1930

Abel spent much of the last part of his career on this question. In 1917, with the physician Maurice Pincoffs, he reported in the Proceedings of the National Academy of Sciences on the presence of albumoses — partly broken-down proteins — in extracts of the posterior lobe. Over the next years he worked to separate the active material from those proteins and from histamine (next section), concentrating what MacNider’s memoir calls the oxytocic-pressor-diuretic principle. In 1923 he published a preliminary therapeutic study of the extract in four people with diabetes insipidus, the condition in which the body loses enormous volumes of dilute urine because the antidiuretic hormone is missing.

Abel leaned toward the view that a single substance was responsible for all three effects, and argued the case for a unitary hormone as late as 1930. Others held that two separate hormones were involved. Later work settled it the other way: the posterior lobe releases two distinct hormones, oxytocin (which acts on the womb and on milk let-down) and vasopressin (the antidiuretic hormone, which also raises blood pressure at high levels). Vincent du Vigneaud, who had spent time in Abel’s laboratory, worked out their structures and synthesised oxytocin in 1953, the first peptide hormone made in the laboratory, and received the 1955 Nobel Prize in Chemistry.

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6. Histamine Hidden in Tissue Extracts

One reason gland extracts were so confusing was that many of them contained histamine. Histamine is a small molecule made from the amino acid histidine. In the body it is stored in mast cells and released during allergic reactions, where it widens small blood vessels and makes them leak, causes itching and swelling, and contracts the smooth muscle of the airways. In the stomach it drives acid secretion.

Henry Dale and Patrick Laidlaw had described histamine’s dramatic effects on animals in 1910, and it soon became clear that histamine turned up in extracts of many tissues. That mattered for anyone testing an extract on a strip of muscle or a blood-pressure tracing: some of the “activity” might be histamine rather than the hormone being sought.

Abel’s laboratory was among those that confronted this directly. MacNider’s memoir lists histamine in pituitary extracts among the topics of his pituitary period, and separating histamine from the oxytocic-pressor-diuretic principle was part of the work of concentrating it. The episode shows the hazard of the extract era in miniature: a crude preparation could produce a real effect for the wrong reason. Histamine and the allergic response it drives are also the background to the epinephrine story above, since the two act in almost opposite directions on blood vessels and airways.

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7. The Cane Toad: Epinephrine and Bufagin

Abel’s most unusual source of epinephrine came not from a mammal but from an amphibian. In 1912, working with David Macht, he examined the milky secretion of the large glands behind the eyes (the parotoid glands) of the tropical toad then called Bufo agua — the giant toad of Central and South America, known today as the cane toad and now classified as Rhinella marina. From that secretion they obtained epinephrine in pure form, and a second crystalline substance that they named bufagin.

A heart poison that resembles foxglove

Bufagin had a digitalis-like action on the heart — it behaved like the active principles of foxglove, the plant that William Withering had introduced into medicine in 1785. Later chemistry showed why. The toad poisons belong to a family of steroids called bufadienolides, and the foxglove glycosides (digitoxin and digoxin) belong to the closely related cardenolides. Both families act on the same target: the sodium–potassium pump in the membrane of heart-muscle cells. By partly blocking that pump they raise the calcium available inside the cell, which strengthens each heartbeat — and, at higher amounts, disturbs the heart’s rhythm.

That a toad and a garden flower arrived at nearly the same chemical weapon is one of the neat convergences of natural pharmacology. For the toad, the mixture of epinephrine-like amines and heart-active steroids in its skin is a defence: a predator that bites it receives a dose of both.

Hazards recorded in the literature

The toxicity is well documented. Case reports describe serious and sometimes fatal poisoning in people who have eaten toads or toad eggs or swallowed preparations made from toad secretions, with a picture resembling digitalis overdose: vomiting, a slow or irregular heartbeat and high blood potassium. Veterinary reports describe the same poisoning in dogs that mouth cane toads, and the toad’s spread as an introduced species in Australia has been linked to declines in native predators that eat it. Abel and Macht’s interest was purely in the chemistry of the secretion.

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8. The Death Cap: Poisons of Amanita phalloides

In 1907–1908 Abel worked with William W. Ford on the poisons of the death cap mushroom, Amanita phalloides, publishing in the Journal of Biological Chemistry in 1907. The death cap is a pale greenish-capped mushroom native to Europe that has spread to North America and other continents, often growing with oak and other trees. It is responsible for the great majority of fatal mushroom poisonings worldwide.

The death cap was a puzzle for early toxicologists because it contains more than one poison. Abel and Ford were among the researchers who tried to separate them, at a time when the only tools were extraction, precipitation and animal testing. The individual toxins were not isolated in pure form until decades later, when Feodor Lynen and Ulrich Wieland crystallised phalloidin in 1937 and Heinrich Wieland’s group went on to characterise the amanitins.

What the poisons do

Two families of compounds are now recognised:

• Amatoxins, chiefly alpha-amanitin. These are small ring-shaped peptides that block RNA polymerase II, the enzyme cells use to copy genes into messenger RNA. Without it, cells cannot make new proteins and die. The liver, which takes up the toxin first and most heavily, suffers the worst damage, followed by the kidneys. Amatoxins are not destroyed by cooking or drying.
• Phallotoxins, chiefly phalloidin. These bind tightly to actin, part of the cell’s internal skeleton. They are very toxic when injected but are poorly absorbed from the gut, so the amatoxins are thought to cause most of the harm in human poisoning.

Clinical reports describe a characteristic course: a delay of six or more hours after the meal, then severe vomiting and diarrhoea, an apparent recovery, and then liver failure over the following days. Liver transplantation is sometimes required. Silibinin, a compound from milk thistle seed, has been used in hospital treatment of death-cap poisoning in some countries; the site’s milk-thistle history page describes that connection.

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9. The Medicinal Leech and Hirudin

The medicinal leech, Hirudo medicinalis, has been used in medicine since antiquity, and in the early nineteenth century bloodletting by leech was so popular in Europe that wild populations were badly depleted. For Abel the leech mattered for a different reason: its saliva holds one of the most powerful natural anticoagulants known.

William Fields’ history of leeching and hirudin records the milestones. In 1884 John Berry Haycraft noticed that leech extract stopped blood from clotting. In 1904 Friedrich Jacoby isolated the active substance and named it hirudin. Fritz Markwardt obtained it in crystalline form in 1957, and recombinant hirudin, made by engineered microorganisms rather than leeches, followed in 1986.

How hirudin works

Blood clotting ends with an enzyme called thrombin, which cuts the soluble blood protein fibrinogen into strands of fibrin that knit into a clot. Hirudin is a small protein that binds thrombin directly and very tightly, blocking it. A leech needs this to feed: it can take in several times its own weight in blood over a long meal without the blood clotting inside it. Leech saliva also contains substances that widen blood vessels and numb the bite.

Hirudin was the anticoagulant that made Abel’s 1913 “vividiffusion” apparatus possible. Garabed Eknoyan’s history of the device lists its three essential materials as collodion, hirudin and glass: blood leaving an animal’s artery was treated with hirudin so that it would not clot in the tubes. The apparatus itself, and why it was eventually abandoned, are described on the wing’s artificial-kidney page. Later, heparin replaced hirudin in dialysis, and modern drugs modelled on hirudin’s action are used as anticoagulants.

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10. Why Natural Sources Mattered Before Synthesis

Looking back, Abel’s raw materials can seem like a cabinet of curiosities: adrenal glands, pancreas, pituitary, toad venom, poisonous mushrooms, leeches. But they shared one thing. In the decades before chemists could synthesise complex molecules routinely, living things were the only factories that made them. A pharmacologist who wanted a hormone, a heart poison or an anticoagulant had to find the organism that produced it and learn to extract it.

This is the same thread that runs through the whole early history of pharmacology: willow bark leading to aspirin, foxglove to digoxin, opium to morphine, cinchona bark to quinine. Abel extended that tradition from plants into animal tissues, and the problems he faced — tiny amounts of active material, fragile molecules, contaminants such as histamine that mimicked the real thing — were the problems that pushed the science toward purity, crystals and chemical structure.

Many of his natural products were later made by other routes. Epinephrine was synthesised within a few years of its isolation. Oxytocin and vasopressin were synthesised by du Vigneaud in the 1950s. Insulin, once taken entirely from animal pancreas, has been produced by engineered microorganisms since the early 1980s, and hirudin by the same technology since 1986. But each of those advances began with the natural source and the patient work of identifying what in it was active. That is the part of the story Abel made his own.

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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. Oliver G, Schäfer EA. On the Physiological Action of Extracts of Pituitary Body and certain other Glandular Organs: Preliminary Communication. J Physiol. 1895;18(3):277-9. PubMed PMID: 16992253
3. 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
4. Goldstein DS. Catecholamines 101. Clin Auton Res. 2010;20(6):331-52. PubMed PMID: 20623313
5. Bennett MR. One hundred years of adrenaline: the discovery of autoreceptors. Clin Auton Res. 1999;9(3):145-59. PubMed PMID: 10454061
6. Abel JJ. Crystalline Insulin. Proc Natl Acad Sci U S A. 1926;12(2):132-6. PubMed PMID: 16587069
7. Murnaghan JH, Talalay P. John Jacob Abel and the crystallization of insulin. Perspect Biol Med. 1967;10(3):334-80. PubMed PMID: 5340582
8. Scott DA. Crystalline insulin. Biochem J. 1934;28(4):1592-1602. PubMed PMID: 16745551
9. 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
10. Abel JJ, Pincoffs MC. On the Presence of Albumoses in Extracts of the Posterior Lobe of the Hypophysis Cerebri. Proc Natl Acad Sci U S A. 1917;3(8):507-17. PubMed PMID: 16576252
11. Fields WS. The history of leeching and hirudin. Haemostasis. 1991;21 Suppl 1:3-10. PubMed PMID: 1894194
12. Eknoyan G. The wonderful apparatus of John Jacob Abel called the “artificial kidney”. Semin Dial. 2009;22(3):287-96. PubMed PMID: 19573009

PubMed Topic Searches

1. PubMed: “John Jacob Abel”
2. PubMed: bufadienolides, toad venom and cardiac glycosides
3. PubMed: Amanita phalloides and amatoxin poisoning
4. PubMed: hirudin and the medicinal leech
5. PubMed: insulin, zinc and crystallisation

Further Reading

• MacNider WdeB. Biographical Memoir of John Jacob Abel, 1857–1938. National Academy of Sciences Biographical Memoirs, vol. 24. nasonline.org
• Fresquet Febrer JL. John Jacob Abel (1857–1938). historiadelamedicina.org, 2019 (in Spanish). historiadelamedicina.org
• Connaught Fund history, article 5: D. A. Scott and zinc insulin. University of Toronto, Connaught Fund history pages.

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Connections

• John Jacob Abel: Epinephrine, Crystalline Insulin and the Founding of American Pharmacology
• John Jacob Abel: Life and Career of the Father of American Pharmacology
• Epinephrine and Crystalline Insulin: John Jacob Abel’s Hunt for Pure Hormones
• The Artificial Kidney, the Journals and the Legacy of John Jacob Abel
• Pharmacology: Notable Doctors
• William Withering: Foxglove and the Birth of Digitalis
• Katz, von Euler and Axelrod: How Nerves Talk, and How Antidepressants Work
• Earl Sutherland: Cyclic AMP, and How a Hormone Talks to a Cell
• Frederick Banting: Insulin and the First Great Cure of Modern Medicine
• Zinc
• Diabetes Insipidus
• The Sodium–Potassium Pump
• Milk Thistle: History and Traditional Use
• Anaphylaxis & Epinephrine