Dale, Henry Hallett
DALE, HENRY HALLETT
(b. London, England, 9 June 1875; d. Cambridge, England, 23 July 1968)
physiology, pharmacology.
Son of a London businessman, Dale received his education at Tollington Park College, London; the Leys School, Cambridge; and Trinity College, Cambridge. He earned first-class honors in the natural sciences tripos in 1898, then succeeded Ernest Rutherford in the Coutts-Trotter studentship at Trinity. At Cambridge he came under the influence of the great physiologists of the “Cambridge School,” including Michal Foster, W. H. Gaskell, J. N. Langley, and H. K. Anderson. Dale began clinical training at St. Bartholomew’s Hospital in 1900, receiving his B. Chir. in 1903 and proceeding to the M.D. in 1909. He continued his physiological studies at London under Starling and Bayliss from 1902 to 1904, first as George Henry Lewes Student, then as Sharpey Student with the department of physiology of University College. He also studied for several months with Paul Ehrlich at Frankfurt.
Against the advice of his colleagues, Dale in 1904 accepted a position at the Wellcome Physiological Research Laboratories, a post that paid a salary adequate to allow him to marry Ellen Harriet Hallett; they had a son and two daughters. At the Wellcome he began, at Sir Henry Wellcome’s suggestion, his investigations into the physiological actions of ergot. This work eventually led him, through a series of fortuitous discoveries, to his two major research interests:
These two lines of enquiry have led, on the one hand, by way of studies which involved the specific actions of adrenaline and of acetylcholine, to a widening application of the conception of a chemical phase in the transmission of excitation from nerve-fibre endings to responsive cells; and, on the other hand, by way of studies of the actions of histamine and of its distribution in the animal body, to evidence for its contribution to local and general reactions, by which the organism as a whole and its separate tissues respond to various chemical, immunological, or physical assaults upon the integrity of their living cells (Adventures in Physiology, x).
Dale left the Wellcome Laboratories in 1914 to become a member of the scientific staff of the Medical Research Committee (or, as it was called after 1920. the Medical Research Council); from 1928 until 1942 he served as the first director of the organization into which the Medical Research Council evolved, the National Institute for Medical Research. From 1942 to 1946 Dale was resident director of the Royal Institution of Great Britain, acting as chairman of the Scientific Advisory Committee to the War Cabinet in 1942- 1947. He received virtually every honor England could bestow on a man of science. Elected a fellow of the Royal Society in 1914, he served as secretary from 1925 to 1935, received its Copley Medal in 1937, and was its president from 1940 to 1945. The Royal College of Physicians made him a fellow in 1922. He served as president of the British Association in 1947, of the Royal Society of Medicine 1948-1950, and of the British Council 1950- 1955. Dale was knighted with the Grand Cross Order of the British Empire in 1943, and in the next year the Order of Merit was bestowed on him. He shared the Nobel Prize for medicine or physiology in 1936 with his friend Otto Loewi. The Dale Medal was struck by the Society for Endocrinology in 1959, to be awarded annually; and the Royal Society established the Henry Dale professorship in 1961. The latter was endowed by the Wellcome Trust, which Dale had served as chairman from 1938 to 1960.
Dale never wrote a book; in his later life, however, two collections of his papers were published: An Autumn Gleaning (1954), a selection of his addresses and occasional papers; and Adventures in Physiology (1953), a collection of his scientific papers with a valuable retrospective comment by Dale. In the latter volume Dale frequently draws attention to the key role of serendipity in his work. His early researches into the physiological actions of ergot failed in their explicit goal of clarifying the pharmacologic and therapeutic properties of the drug. A set of fortunate circumstances, however, caused him to use a spinal animal, which had just been given several doses of a preparation of ergot, to measure the strength of a newly extracted batch of adrenaline. (A spinal animal is one in which the brain has been separated from the spinal cord.) He rejected the first set of data, which was exactly opposite to the expected results; but when the same sequence of events recurred the next week. Dale pursued the anomalous data, thereby discovering the important phenomenon of adrenaline reversal. The present-day use of phentolamine in the diagnosis of pheochromocytoma is based on Dale’s investigations. Two years later, in 1909, while using posterior pituitary extracts as a control for his ergot investigations, he first identified the oxytocic effects of the extracts when he incidentally noted their tonic actions on the pregnant cat uterus.
Dale first witnessed the use of the horn of the cat uterus as an isolated experimental organ in 1907, when Ferdinand Kehrer employed it at a physiological congress in Heidelberg to demonstrate the immediate and quite powerful tonic effects on the uterus of an ergot extract, results that suggested to Dale the presence of an unidentified contaminant. In collaboration with George Barger, a colleague at the Wellcome Laboratories whose name is frequently associated with Dale’s early work, Dale in 1910 successfully identified the contaminant as histamine. In the same year Dankwart Ackermann at Würzburg produced histamine by decarboxylation of histidine. Over the next few years Dale, working first with Barger and then with P. P. Laidlaw, A. N. Richards, J. H. Burn, and others, subjected histamine to an intensive pharmacologic investigation. As early as 1911 Dale and Laidlaw pointed out the similarities between the effects of histamine poisoning and anaphylactic shock. Furthermore, in 1911 Dale and Barger showed that histamine is a naturally occurring substance by identifying it in the intestinal mucosa of the ox. They minimized the importance of their findings, however, for they could not exclude the presence of the histamine as secondary to bacterial decarboxylation of histidine. Consequently, the nexus between histamine and anaphylaxis was not established for another fifteen years.
In the meantime, in a series of classic experiments Dale attacked the problem on two fronts: his work with isolated guinea pig uteri (also begun through a chance observation) established that the anaphylactoid antibodies are attached to cells rather than circulating; and his research on the pharmacology of histamine yielded precise data on the mechanism of “histamine shock” as he called it. Through the simple expedient of carefully measuring the volume of a limb of an experimental animal into which histamine was being injected, correlated with serial hematocrit determinations. Dale showed that histamine causes the loss of plasma fluid into the tissues, to produce edema, along with vasodilation, resulting in marked hemoconcentration, stagnation of the blood in the dilated vessels, decreased blood return to the heart, decreased cardiac output, and shock. His work also demonstrated the importance of chemical and humoral factors in the control of the circulation, especially at the micro level. Two Croonian lectures delivered by Dale summarize his work during this period: “The Biological Significance of Anaphylaxis” before the Royal Society in 1919, and “Some Chemical Factors in the Control of the Circulation,” before the Royal College of Physicians in 1929: both are reprinted in Adventures in Physiology.
In 1927 Dale, collaborating with C. H. Best, H. W. Dudley, and W. V. Thorpe, conclusively proved that histamine is normally present in animal tissues, being particularly rich in the lung. In his 1929 Croonian lectures he summarized the overwhelming evidence in favor of histamine release as the primary cause of the physiological features of anaphylaxis. He also identified the “H-substance” of Sir Thomas Lewis —the chemical that produces the characteristic erythema, wheal, and flare of the Lewis “triple-response” when cells of the skin are injured-as probably histamine itself. Dale’s lectures stimulated an intense interest in the physiological properties of histamine, an interest unabated today.
Dale’s work with histamine not only clarified several poorly understood phenomena; it also served as a pivotal point for his other primary research interests: histamine, in common with adrenaline, vasopressin, and acetylcholine, is a vasoactive substance. It has already been mentioned that early in his career Dale had noted that some preparations of ergotoxin reverse the action of adrenaline, and had separated the oxytocic from the vasopressive qualities of pituitary extract. (The vasopressive property was discovered by Oliver and Schafer in 1895.) Acetylcholine is also vasoactive and, like histamine, first came to Dale’s attention as an active contaminant of ergot extracts. The intense depressor (vasodilatory) effect of acetylcholine was first reported by Reid Hunt in 1906. Dale published a comprehensive review of the physiological properties of the substance in 1914, noting its muscarinic action, paralyzed by atropine, and its nicotinic action, paralyzed by excess of nicotine. He called attention to the striking similarities between the actions of acetylcholine and those produced by stimulation of the parasympathetic nervous system.
Dale’s lifelong friend T. R. Elliott had shown in 1904 that many of the actions of the sympathetic branch of the autonomic nervous system could be duplicated by the injection of adrenaline; he had even suggested that the effects of the sympathetic system might be mediated by the release of adrenaline at the nerve endings. Elliott did not follow up his notion, although in 1907 W. E. Dixon extended Elliott’s concept by postulating that a muscarine-like substance is liberated when the vagus is stimulated. But the parallels between nerve stimulation and muscarine or adrenaline injection, although striking, were not exact; and there the matter rested until Dale reopened the door with his 1914 paper on acetylcholine. The main difficulty in accepting a physiological role for acetylcholine was that its natural occurrence in animal tissue had not been proved.
The beautifully simple experiments of Otto Loewi, working with vagal and sympathetic stimulation of the isolated frog heart in 1921 and the succeeding years, made chemical mediation of nerve impulses seem highly probable. In 1929 Dale and H. W. Dudley —while assaying for histamine—unexpectedly found high concentrations of acetylcholine in the spleen of the ox and horse, thus proving its natural occurrence. Over the next seven years Dale and his colleagues at the National Institute for Medical Research, including W. Feldberg, J. H. Gaddum, M. Vogt, and G. L. Brown, greatly extended the concept of chemical transmission. They showed that acetylcholine is liberated not only at parasympathetic postganglionic endings but also at some sympathetic postganglionic and all preganglionic endings. They also experimentally proved that acetylcholine is released at nerve endings in voluntary muscles. In 1933 Dale introduced the useful terms “cholinergic” and “adrenergic” to refer to fibers releasing acetylcholine and an adrenaline-like compound (later shown to be noradrenaline) at their endings.
Dale and Otto Loewi shared the 1936 Nobel Prize for medicine or physiology for “their discoveries relating to the chemical transmission of nerve impulses.” It served as a fitting climax to Dale’s outstanding career as an investigator; after 1936 other obligations commanded a larger portion of his time. He continued as director of the National Institute for Medical Research until 1942, devoting much energy to the planning of the new facilities at Mill Hill, a project largely interrupted by the war and consequently erected under the direction of Dale’s successor, Sir Charles Harington.
In his later years Dale became a spokesman for British men of science, a role for which he was qualified not only by the force of his character but also by virtue of the active concern he had shown for the social consequences of science and medicine. Dale and Thorvald Madsen of Copenhagen were largely responsible for the adoption of an international scheme of standardizing drugs and antitoxins. At the 1925 conference of the Health Organization of the League of Nations, meeting in Geneva. Dale prevailed upon his colleagues to accept international standards for insulin and pituitary extract; and other drugs soon were agreed upon. He was also instrumental in the passage of the Therapeutic Substances Act in England. His concern for preserving the apolitical nature of science and for the peaceful use of nuclear energy was noteworthy.
BIBLIOGRAPHY
I. Original Works. Adventures in Physiology (London. 1953; repr. 1965) contains thirty of Dale’s major scientific papers, with comment on each paper by Dale. An Autumn Gleaning (London, 1954) reprints an additional fourteen of his occasional lectures and addresses. The two volumes together give an extraordinary picture of Dale, both as a man and as a scientist. Adventures in Physiology contains a bibliography of Dale’s published writings through 1953. Of his subsequent papers the most important are “Autobiographical Sketch.” in Perspectives in Biology and Medicine,1 (1957- 1958), 125-137; “Sir Michael Foster K.C.B., F.R.S., a Secretary of the Royal Society,” in Notes and Records. Royal Society of London, 19 (1964), 10-32; and the intros. to Collected Papers of Paul Ehrlich, edited by F. Himmelweit, with the assistance of Martha Marquardt, 3 vols. (London-New York, 1956-1960). Dale wrote the obituary notices in Biographical Memoirs of Fellows of the Royal Society of T. R. Elliott (1961) and Otto Loewi (1962), which are also of interest.
II. Secondary Literuature.Several short assessments of Dale’s work appeared during his lifetime. See British Medical Journal (1955), 1. 1355-1361. 1378-1379, for articles by several authors. Also see James F. Riley. “Histamine and Sir Henry Dale,” ibid. (1965), 1, 1488-1490. The most perceptive obituaries are those of W. Feldberg, in British Journal of Pharmacology and Chemotherapy, 35 (1969). 1-9; and in Biographical Memoirs of Fellows of the Royal Society, 16 (1970), 77-173. Dale’s work is put into perspective in Charles Singer and E. Ashworth Underwood, A Short History of Medicine, 2nd ed. (Oxford. 1962), 555-577. There is also sound historical treatment in L. S. Goodman and A. Gilman, eds., The Pharmacological Basis of Therapeutics, 3rd ed. (New York, 1965). esp. chs. 21. 23, and 29.
William F. Bynum