Sir Edward Sharpey-Schafer, Adrenaline and the Hormone Concept

The Hunt for Internal Secretions

The intellectual foundation for everything that follows was laid by the French physiologist Claude Bernard (1813–1878), who in the 1850s developed the concept of "internal secretion" — the idea that organs could release substances directly into the bloodstream rather than through a duct. Bernard demonstrated the glycogenic function of the liver, showing it released glucose into the blood, and coined the notion of the "milieu intérieur," the internal environment the body works to keep stable. His term "internal secretion" did not yet carry its precise modern meaning, but it reframed physiology around the idea that the blood itself could be a channel of chemical communication between organs.

Several further strands converged in the second half of the nineteenth century to focus attention specifically on the adrenal glands. Thomas Addison, in 1855, described the fatal wasting disease now named after him, caused by destruction of the adrenal (suprarenal) glands, proving that these small, paired organs were essential to life — though nobody yet knew why, or what substance they might make. Charles-Édouard Brown-Séquard, having shown in 1856 that surgically removing the adrenals killed animals, caused a public sensation in June 1889 when, aged 72, he told the Société de Biologie in Paris that self-injection of extracts prepared from animal testicles had rejuvenated him. His claims were never substantiated, and modern re-creation of his extract has found testosterone concentrations four orders of magnitude below any plausible biological threshold — the effect, insofar as there was one, is now understood as a placebo response. But the announcement launched a public and scientific craze for "organotherapy," the treatment of disease with extracts of animal organs, and it sharply raised scientific interest in exactly what such extracts might contain and do.

By 1893–1894, then, the state of knowledge was tantalisingly incomplete: it was firmly established that the adrenal glands were essential to life, and there was a fashionable, if scientifically undisciplined, enthusiasm for organ extracts of every kind. But nobody had yet shown, with rigorous experimental method, what the adrenal gland actually did, nor had anyone yet distinguished clearly between its outer cortex and inner medulla, structures with entirely different embryological origins and functions. The question of what the adrenal gland secreted, and what that secretion did to the body, hung open, waiting for a decisive experiment.

The 1894 Discovery

George Oliver (1841–1915) was a physician in the Yorkshire spa town of Harrogate. Born at Middleton-in-Teesdale, County Durham, the son of a surgeon, he trained at UCL — where he too had come under William Sharpey's influence — and ran a busy general practice from 1876. The seasonal nature of a spa-town practice gave him unusually long winter leisure, and he devoted it, year after year, to physiological experiment, building his own precise instruments for measuring blood pressure and circulation. He later endowed the Oliver-Sharpey Lectureship in honour of his old master, a fitting gesture from an amateur scientist whose greatest work grew directly out of that mentorship.

The story of how Oliver and Schäfer came together is one of the most vivid in the history of medicine, told repeatedly by Sir Henry Dale, who witnessed its aftermath as a young student. Oliver, experimenting at home, prepared a glycerine extract of adrenal gland obtained from the local butcher, injected it into his own young son, and used an instrument of his own devising to measure the effect on the boy's radial artery, observing contraction. Dale later remarked, half in jest, that the boy "deserved a memorial." It is worth flagging, in the interest of accuracy, that this anecdote rests substantially on Dale's retelling years afterward, and some modern historians treat its more colourful details — the precise method, the boy's exact reaction — with mild caution, even while accepting the broad outline as well-attested.

Convinced he was onto something important, Oliver travelled to London to see Schäfer at UCL — the two men shared a bond as former pupils of Sharpey. Schäfer's own later account records the encounter: "In the autumn of 1893 there called upon me in my laboratory at University College a gentleman who was personally unknown to me, but with whom I had a common bond of interest — seeing that we had both been pupils of Sharpey." Schäfer, according to the traditional telling, was in the middle of an unrelated experiment, recording a dog's blood pressure, and was reportedly sceptical and somewhat impatient with his unannounced visitor. Oliver waited, then produced his adrenal extract from his pocket and asked Schäfer simply to inject it and watch. Schäfer did — and saw the mercury column of his arterial manometer shoot upward until the recording float very nearly lifted clear out of its tube.

The extract had caused massive vasoconstriction — a sudden, powerful squeezing of the small arteries. As the historian T. Yamashima records in his 2017 account "Adrenaline/Epinephrine Hunters," the injection "caused an enormous rise (from 2 to 4 times above normal) of blood pressure, although it entirely passed off after a few seconds." Schäfer immediately agreed to collaborate, and through the winter of 1893–1894 the two men systematically studied the effect: they tested the extract against known circulatory agents such as ergot and digitalis, and subjected it to heat, acids, alkalis and digestion to characterise its chemical nature. Crucially, they localised the active principle to the medulla — the inner part of the gland — rather than the outer cortex, a distinction that later proved fundamental to endocrinology.

They presented their findings to the Physiological Society on Saturday 10 March 1894. Among those present, as Yamashima notes, were an 18-year-old student named Henry Dale and a 37-year-old physiologist named Charles Scott Sherrington, both, by the historical record, greatly impressed by the demonstration. The full paper, "The Physiological Effects of Extracts of the Suprarenal Capsules," appeared in the Journal of Physiology in 1895 (volume 18, issue 3, pages 230–276), following a preliminary note published in volume 16 in 1894 — a discrepancy in dating that different sources resolve differently, some citing 1894 for the discovery and others 1895 for its formal publication. It is fair, and necessary for precision, to give both dates. The paper's conclusion was carefully stated: "the suprarenal capsules are to be regarded, although ductless, as strictly secreting glands." What Oliver and Schäfer did not do, and never claimed to do, was isolate or chemically identify the specific active substance responsible for the effect. That remained, for seven more years, a mystery.

From Extract to Pure Substance

The chain from Oliver and Schäfer's crude extract to a pure, identifiable chemical ran through several further hands, and it is important to state clearly who did what, because popular retellings often compress this into a single moment that never actually happened.

John Jacob Abel, at Johns Hopkins, purified an active constituent from adrenal extract and in 1899 named it "epinephrin." But, as the endocrinologist J. D. Wilson notes in a 2005 historical account in Clinical Endocrinology, "In 1897 Abel and Crawford at the Johns Hopkins Hospital used the Oliver/Schäfer bioassay to purify the active principle as a monobenzoyl derivative of epinephrine that was not very active physiologically" — in other words, a chemically modified compound, not the pure, fully active hormone itself. Abel's claim to priority in isolating adrenaline does not, on close examination, hold up.

The pure, stable, crystalline substance was isolated in 1901, and by two people working independently. Jokichi Takamine, a Japanese chemist working in New York with his associate Keizo Uenaka and backed by the pharmaceutical firm Parke, Davis & Co., isolated the pure substance and named it "Adrenalin" — a name he trademarked in the United States. Thomas Bell Aldrich, a chemist also at Parke, Davis & Co. who had earlier worked in Abel's own laboratory, independently isolated the same substance around the same time and, comparing his product against Takamine's, determined the correct empirical chemical formula, C9H13NO3, in 1901.

This dual, near-simultaneous isolation, together with Takamine's American trademark on "Adrenalin," produced the transatlantic naming split that persists to this day: "adrenaline" (the standard British and European usage, from the Latin ad, "near," and renes, "kidneys") versus "epinephrine" (American usage and the official United States Pharmacopoeia name, from the Greek epi, "upon," and nephros, "kidney") — both names describing, in different classical languages, the same anatomical fact of origin near or upon the kidney. The pharmacologist Henry Dale championed "adrenaline" for British and European usage, cementing the split.

Adrenaline was soon synthesised chemically as well as extracted biologically: Friedrich Stolz in Germany produced a related ketone form, adrenalone, in 1904, and adrenaline became the first hormone ever to be chemically synthesised. It moved into clinical use quickly thereafter — first used in asthma in 1903 — and became valued as a vasoconstrictor for controlling surgical bleeding and prolonging the action of local anaesthetics.

Naming the Endocrine Revolution

Oliver and Schäfer's 1894 demonstration was the essential experimental precursor to the birth of endocrinology as a discipline — but the word that came to define that discipline was not Schäfer's. The word "hormone" belongs, without ambiguity, to Ernest Henry Starling. In 1902, Starling and his brother-in-law William Bayliss discovered secretin, a substance released by the duodenum that travels through the blood to stimulate the pancreas — itself a landmark demonstration of chemical, as opposed to purely nervous, control within the body. In his Croonian Lectures to the Royal College of Physicians in 1905, titled "On the Chemical Correlation of the Functions of the Body," Starling introduced the term "hormone," from the Greek for "I arouse to activity," a word suggested to him by the Cambridge scientist W. B. Hardy. This is a point worth stating with complete plainness, because popular accounts of Schäfer sometimes credit him with the word: he did not coin it, and this article will not repeat that error.

Sharpey-Schafer's own contributions to the vocabulary and the conceptual apparatus of the new science were nonetheless real and foundational in their own right. He coined the term "endocrine" for the secretions of the ductless glands — a word that has since given its name to the entire discipline of endocrinology — and he also introduced "autacoid" and "chalone." He argued that the term "hormone" should properly be reserved for stimulatory chemical messengers, proposing "autacoid" as a broader category for substances that could either stimulate or inhibit; this particular terminological campaign did not ultimately prevail in general usage, but it reflects how actively he was thinking about the underlying concepts, not merely describing isolated facts. He proclaimed what he called a "New Physiology" of chemical regulation succeeding the "Old Physiology" of purely nervous control, writing that "the Old Physiology was based… on nervous regulation; the New Physiology is based on chemical regulation" — a genuinely important reframing of how the body's internal communication was understood, even if the specific word "hormone" for that chemical communication belongs to someone else.

The Insulin Prediction

Sharpey-Schafer's most prophetic single contribution concerns insulin, and it deserves to be told with its genuine complexity intact rather than smoothed into a simple story of solitary foresight.

As early as 1894, Schäfer had suggested, on morphological grounds, that the islets of Langerhans — small clusters of cells scattered through the pancreas, structurally distinct from the pancreas's main digestive tissue — might act as an organ of internal secretion controlling blood sugar. In his Lane Medical Lectures at Stanford University in 1913, published as "The Endocrine Organs: An Introduction to the Study of Internal Secretion" (Longmans, Green and Co., London, 1916), he proposed the name "insuline" — from the Latin insula, "island" — for the still entirely hypothetical pancreatic substance. He went further than simply naming it: he predicted, in terms that later proved remarkably close to correct, how such a substance would work, and he even suggested that it might exist first as an inactive precursor, which he called "pro-insuline" — anticipating, by roughly half a century, the actual discovery of proinsulin.

He was not, however, the first to use the name. The Belgian physician Jean de Meyer had already used "insuline" in 1909, apparently entirely unknown to Schäfer, writing in a paper titled "Action de la sécrétion interne du pancréas" (Archives de Physiologie, 1909) that the internal secretion of the pancreas, "if derived, as we believe, from the islets of Langerhans, could be called insulin." This article states that priority fact clearly and without hedging: Sharpey-Schafer's proposal was independent of de Meyer's, and it was influential and prophetic, but it was not primary.

The name nonetheless stuck, and it stuck to the actual, isolated substance rather than remaining a historical footnote. When Frederick Banting, Charles Best, James Collip and J. J. R. Macleod finally isolated the real hormone in Toronto in 1921–1922, they adopted the name "insulin." In his Nobel Lecture, Macleod acknowledged the debt directly: "This name had previously been suggested by Sir E. Sharpey Schafer (1916), who had been one of the first to support the hypothesis of the insular derivation of the antidiabetic hormone."

That acknowledgment creates a genuinely remarkable link within Scottish science, and it is one this article is glad to make explicit rather than merely gesture at: Sharpey-Schafer, Edinburgh's professor of physiology, named insulin years before anyone had isolated it, and the Scottish-born J. J. R. Macleod — who shared the 1923 Nobel Prize in Physiology or Medicine for the Toronto team's work — oversaw the very research programme that finally isolated the substance Sharpey-Schafer had named.

The Schafer Method

In 1903, by then Professor of Physiology at Edinburgh and chairman of the fourth committee of the Royal Medical and Chirurgical Society examining methods of resuscitation, Sharpey-Schafer described his "prone pressure method" of artificial respiration. The patient is laid face down; the operator kneels astride or beside the body, places both hands on the lower ribs, and rhythmically swings his weight forward to compress the chest for about three seconds, then releases for about two — roughly twelve times a minute — mechanically forcing air out of, and then allowing it back into, the lungs.

He published the technique as "Description of a Simple and Efficient Method of Performing Artificial Respiration in the Human Subject" (Medico-Chirurgical Transactions, 1904), having first reported it to the Royal Society of Edinburgh in 1903. Before this, there was no simple, standardised, effective manual method for reviving people who had drowned or been asphyxiated. According to A. H. Sykes's historical account "Edward Schafer (1850–1935) and artificial respiration," Schafer "described his own prone-pressure method which, on the basis of recorded respiratory minute-volumes, was superior to other methods and subsequently was employed worldwide for nearly 50 years." J. P. Marsh and colleagues, writing in Resuscitation in 2004, confirm that "Schäfer's eponymous method, first described in 1903, was recommended in successive editions of the American Red Cross First Aid Textbook until 1959, when the whispers of its detractors rose to a clamour for its abandonment and replacement by mouth-to-mouth respiration." It was ultimately superseded when mouth-to-mouth resuscitation, championed by Peter Safar in the late 1950s, was shown in controlled studies to move a greater volume of air more reliably.

The Schafer method is easy to overlook in an account focused on hormones, but it is worth dwelling on for a moment, because it is the one achievement here that is entirely and uncomplicatedly his: no rival claim, no priority dispute, no earlier partial version by someone else. For roughly half a century it was, quite simply, how the drowned and the asphyxiated were saved.

Edinburgh Career and Legacy

For 34 years — 1899 to 1933 — Sharpey-Schafer was Professor of Physiology at the University of Edinburgh, by his own reckoning and by any external measure the longest and most productive stretch of his life. He was one of the nineteen founder members of the Physiological Society in 1876, and founded and edited the Quarterly Journal of Experimental Physiology from 1908 to 1933. His textbooks reached an extraordinary readership: his "Essentials of Histology" ran to 16 editions between 1885 and 1954; he edited a major multi-author "Text-Book of Physiology" (1898–1900); he wrote "The Endocrine Organs" (1916), the book in which "insuline" reached print; and he composed a "History of the Physiological Society During Its First Fifty Years, 1876–1926" (1927).

His honours, accumulated substantially during his Edinburgh years, were extensive. He was President of the British Association for the Advancement of Science and President of the British Medical Association, both in 1912. He was elected a Fellow of the Royal Society of Edinburgh in 1900, served as its Vice-President from 1913 to 1917 and its President from 1929 to 1934, and won its Neill Prize. He received a Royal Medal from the Royal Society in 1902 and the Copley Medal, the Society's oldest and most prestigious award, in 1924, along with the Cameron Prize for Therapeutics from the University of Edinburgh. He was knighted, as already noted, as a Knight Bachelor in 1913. In 1902 he commissioned the distinguished Scottish architect Sir Robert Lorimer to design his Arts and Crafts villa, Marly Knowe, in North Berwick — a physical, domestic commitment to a Scottish life that outlasted his active career and became, in the end, the place where he died.

His mentor William Sharpey — born in Arbroath and buried in Arbroath Abbey — was thoroughly Scottish, so the 1918 name change made this English-born scientist's name unexpectedly and permanently Scottish, a small but telling detail that captures the whole shape of his relationship to Scotland: not a matter of origin, but a matter of loyalty, mentorship and the place where a career's real substance was built.

Modern Significance

Adrenaline is today one of the most important emergency drugs in the world. It is the first-line treatment for anaphylaxis, delivered through EpiPens and similar autoinjectors, in which it constricts blood vessels, raises blood pressure and opens the airways. It is a core drug in cardiac-arrest resuscitation, where its alpha-adrenergic effects help restore circulation. It is added to local anaesthetics to prolong their action and reduce bleeding at the injection site, and it remains a treatment for asthma and severe allergic reactions.

The understanding of how adrenaline actually works — through distinct alpha and beta adrenergic receptors, distinguished by the pharmacologist Raymond Ahlquist in 1948 — led directly to one of Scottish medicine's greatest later achievements: Sir James Black's development of beta-blockers at ICI in the early 1960s, drugs that selectively block adrenaline's effect on the heart to treat angina, hypertension and heart disease, work for which Black won the 1988 Nobel Prize in Physiology or Medicine. The scientific line runs, without a serious break, from Oliver and Schäfer's dog on a London laboratory bench in 1894 to the beta-blockers found in millions of medicine cabinets today.

Endocrinology — the discipline Sharpey-Schafer helped found and, in significant part, helped name — now encompasses diabetes, thyroid disease, reproductive medicine, adrenal disorders and a great deal more of modern medicine. And every EpiPen ever manufactured is filled with the very substance whose dramatic physiological effect Oliver and Schäfer first demonstrated in that London laboratory in 1894, more than a century before either device or drug reached its present, life-saving form.