Sir Henry Hallett Dale
Sir Henry Hallett Dale
The English pharmacologist and neurophysiologist Sir Henry Hallett Dale (1875-1968) shared the Nobel Prize in Physiology or Medicine for discoveries relating to the chemical transmission of nerve impulses.
Henry Dale, son of C. J. Dale, a businessman, was born in London on June 9, 1875. He entered Trinity College, Cambridge, in 1894 with a scholarship, read physiology and zoology, and graduated bachelor of arts in 1898. During 2 years of postgraduate work at Cambridge he worked under W. H. Gaskell, J. N. Langley, and (Sir) F. Gowland Hopkins. In 1900 Dale started the clinical work at St. Bartholomew's Hospital, London, that was necessary for his Cambridge medical degree, which he took in 1903. After research at University College, London, and a period in Paul Ehrlich's research institute at Frankfurt am Main, Dale was invited by (Sir) Henry S. Wellcome in 1904 to accept the post of pharmacologist to the Wellcome Physiological Research Laboratories. Two years later he became director of the laboratories, a post which he held until 1914. He graduated as a doctor of medicine at Cambridge in 1909.
In 1914 Dale was appointed the first pharmacologist to the National Institute for Medical Research, newly established under the Medical Research Committee (later Council). He became its first director in 1928, a post from which he retired in 1942. Dale's work embraced important researches in four different subjects, all initiated while he was at the Wellcome Laboratories and continued at the National Institute.
Problem of Ergot
A liquid extract of the fungus ergot had been used for centuries in obstetrics to stimulate the contractions of the pregnant uterus. Several alkaloids had already been isolated from this extract, and one of these was claimed to be the active principle. But this alkaloid, ergotine, was not nearly so powerful as the liquid extract, and, on Dale's appointment to the Wellcome Laboratories, Wellcome asked him to try to clear up the problem. Just before that the chemist George Barger, who was also working in the laboratories, had prepared other substances from ergot, and in 1906 Dale carried out a detailed pharmacological investigation of their activity. In succeeding years Barger and others isolated several more supposed "active principles," but Dale could not satisfy himself that any of these was the substance that made the watery extract so potent. It was not until 1935 that the real active principle, ergometrine, was isolated by Dale's former coworker Harold Ward Dudley. But the work that Dale carried out for some years on ergot was to give him pointers to nearly all his future work.
Action of Pituitary Extracts
In 1909 Dale showed that an extract of the posterior lobe of the pituitary gland produced powerful contractions of the uterus of a pregnant cat. As a result, pituitary extract (pituitrin) was soon extensively used in obstetrics. He also showed that this effect was caused by an active principle of the extract different from that which produced a rise of blood pressure. In 1920-1921, with Dudley, he isolated and studied the active principle, oxytocin, that produced the powerful contractions.
Histamine and Its Effects
In 1910 Barger and Dale, working on an ergot extract, discovered that a substance in it, later called histamine, had a direct stimulant effect on plain (smooth) muscle, especially that of the uterus and bronchioles. (Histamine had previously been synthesized, but it was not known to occur naturally, in the animal body or elsewhere.) They also showed that it caused a general fall in blood pressure and that its injection produced most of the features of anaphylactic shock. In 1911 they were the first to show that it could be present in animal tissues, as they had isolated it from the wall of the intestine.
No further work was done on histamine until the later years of World War I, when the problem of "secondary" surgical and traumatic shock had become of great practical importance. In 1918 Dale, working with Alfred Newton Richards, showed that small doses of histamine caused constriction of the arteries along with a general dilatation of the capillaries. In 1919 Dale, working with (Sir) Patrick Playfair Laidlaw, showed that massive doses of histamine produced a general dilatation of the blood vessels and capillaries, together with an exudation of plasma from the capillaries, a fall in body temperature, and respiratory depression. These features were almost identical with those found in surgical shock, and in a subsequent study Dale found that the dose of histamine necessary to produce the condition was much smaller if there had been previous hemorrhage. These discoveries were of great practical importance in surgery. Theoretically, they indicated that, in the case of injury to the tissues, histamine was produced by the body cells. But in 1919 there was no evidence that histamine was produced by the body cells, and it was not until 1927 that Dale and his coworkers showed that histamine is normally present in significant amounts in the lung and in the liver.
Meanwhile Dale had carried out various researches that were to lead to another aspect of the histamine problem. In 1913 he noticed the extreme sensitivity of the isolated uterus of a particular guinea pig when treated with a normally quite innocuous dose of horse serum. He later discovered that this particular guinea pig had already been used for the assay of diphtheria antitoxin and was therefore already sensitized to horse serum. By following up this chance observation Dale was able to produce in guinea pig plain muscle all the essential features of anaphylaxis, thus greatly advancing knowledge of the cause of this condition. In 1922 Dale and Charles Halliley Kellaway showed that anaphylactic phenomena are probably due to the location of the antibody in the cell substance. Ten years later other workers showed that in anaphylaxis histamine is actually released by the injured cells. The modern use of antihistaminic drugs stems essentially from Dale's work on histamine.
Chemical Transmission of the Nerve Impulse
Even as late as the first 2 decades of the 19th century the manner in which an impulse, passing down a nerve to a muscle, causes the latter to contract was quite unknown. In 1904 Dale's friend Thomas Renton Elliott, then working in the same laboratory as Dale at Cambridge, suggested as a result of his research on adrenaline that sympathetic nerve fibers might act on plain muscle and glands by liberating this substance at their endings. But this suggestion was never actively followed up by anyone, though it profoundly influenced Dale's later research.
In 1914 Dale found unusual activities in a certain ergot extract, and the active principle responsible for these unusual effects was isolated by Dale's chemical coworker, Arthur James Ewins. It proved to be acetylcholine, the acetyl ester of choline. This work led to an important paper by Dale (1914), in which he showed that the action of acetylcholine on plain muscle and glands was very similar to the action of parasympathetic fibers, and that acetylcholine reproduces those effects of autonomic nerves that are absent from the action of adrenaline. These observations had no direct sequel at that time, because there was then no evidence that acetylcholine was normally present in the animal body. Nevertheless, this paper foreshadowed an understanding of the chemical transmission of the nerve impulse.
In 1921 one specialized form of chemical transmission was proved by Otto Loewi, who showed that the slowing of the frog's heart that occurred when the vagus nerve was stimulated was due to the liberation of a chemical substance. He suspected that this substance might be acetylcholine, but he cautiously called it the "vagus substance" because even then acetylcholine was not known to be present in the animal body. Indeed, it was not until 1933 that two of Dale's coworkers proved that Loewi's vagus substance was acetylcholine.
In 1929 Dale and Dudley found acetylcholine in the spleens of horses and oxen—the first occasion on which it had ever been found in the animal body—and the experiments of Dale and John Henry Gaddum (1930) strongly suggested that the effects produced by stimulation of para-sympathetic nerves were due to the liberation of acetylcholine. But about this time Dale became convinced that, in laboratory animals, if acetylcholine was present at all, it must either be in very much smaller quantities than was found in the spleens of oxen, or alternatively it must be destroyed very rapidly.
In 1933 and 1934 the mode of action of impulses in sympathetic nerves was cleared up by Dale and his coworkers, (Sir) George Lindor Brown, Wilhelm Siegmund Feldberg, Gaddum, and others. It was known that, when fibers leading to a sympathetic ganglion were stimulated, a minute amount of a substance suspected to be acetylcholine was produced in the ganglion, but this substance was immediately destroyed by an esterase. But the action of this esterase was inhibited by eserine, so that, by adding eserine to the fluid used to wash out the ganglion, sufficient of the substance was collected for it to be tested. The substance was thus shown to be acetylcholine. They then showed that even a single nerve impulse in a single nerve fiber passing to a sympathetic ganglion, released an incredibly minute amount of acetylcholine, and this amount was approximately measured (10−15 gram). It was shown that, having acted as a trigger at the synapse, the acetylcholine was immediately destroyed.
Dale and his coworkers then turned to the problem of a chemical transmitter in the case of voluntary muscle. This problem, which had eluded all others who had worked on it, was technically more difficult. But in 1936 they showed that the amount of acetylcholine liberated when a single impulse in one motor fiber reached the end plate of that fiber was also of the order of 10−15 gram. In 1936, also Dale, with Brown and Feldberg, showed that the direct injection—under certain conditions—of acetylcholine into the drained vessels in a muscle produced a contraction. The chemical transmission of the nerve impulse, in both para-sympathetic and motor nerves, was now conclusively proved and its mode of action elucidated. For these researches Dale shared the Nobel Prize with Loewi in 1936.
From 1940 to 1947 Dale was a member of the Scientific Advisory Committee to the War Cabinet, and he was its chairman from 1942. When he retired from the directorship of the National Institute in 1942, he became Fullerian Professor and director of the Davy-Faraday Laboratory at the Royal Institution. From this post he retired in 1946. He had been chairman of the Wellcome Trust since its establishment in 1936, and he now devoted more and more of his time to the work of this scientific trust, of which he remained chairman until 1960.
Dale received very many honors. He was elected a Fellow of the Royal Society in 1914. He was its Croonian Lecturer in 1919; he received its Royal Medal in 1924 and the Copley Medal—its highest honor—in 1937. He was its Secretary from 1925 to 1935 and its President from 1940 to 1945. In 1947 he was President of the British Association and from 1948 to 1950 President of the Royal Society of Medicine. In 1922 he was elected a Fellow of the Royal College of Physicians, and he gave its Croonian Lecture in 1929.
Dale was knighted in 1932 and created Knight Grand Cross of the Order of the British Empire in 1943. In 1944 he was appointed to the Order of Merit. He received honorary degrees from 25 universities, and he was an honorary or corresponding member of over 30 foreign learned societies. He died at Cambridge on July 23, 1968.
There is a short biography of Dale in Nobel Lectures, Physiology or Medicine, 1922-1941 (1965); it also contains his Nobel Lecture, which deals solely with his work on the chemical transmission of the nerve impulse. Dale's work as a whole is discussed in some detail in C. Singer and E. A. Underwood, A Short History of Medicine (1962). More important, but more difficult, is Dale's own Adventures in Physiology (1953), in which he reprinted 30 of his most important scientific papers, with his later comments on each paper. □