The War of the Soups and the Sparks: The Discovery of Neurotransmitters and the Dispute Over How Nerves Communicate

More than anyone else, Henry Hallett Dale (1875–1968) is responsible for the discoveries that provided the foundation necessary for proving that nerves secrete humoral substances. However, this was not his intention at the time he was working, and it took the speculation of others to provoke him to look at the problem.

Dale was born in London in 1875, the third child of seven. He later said that despite a concerted effort by a relative to prove otherwise, no family members engaged in any kind of scientific work. His father managed the pottery branch of a large firm, as did his paternal grandfather. Dale’s maternal grandfather, Frederick Hallett, came from a family of farmers, but he became a skilled cabinetmaker and owned a small factory that made fine furniture.

Dale began his education at a neighborhood school in Crouch Hill, North London, that was run by two ladies. At the age of eight, he was sent to a nearby private school. The vice principal of the school, a man named Edward Butler, was the author of several popular books for naturalists and was an authority on an order of insects. Dale attributed his early interest in natural science to Butler’s influence, particularly to his insistence that the way to prove that you really understood something was to explain it to someone who knew nothing about the subject. He must have been a superb teacher, for Dale in later years related happy memories of being kept after school for half an hour or more while Butler prodded him to improve an explanation he had written. Butler would say: “Now my boy, you are going to stay with me till you have written that, so that I, as the most stupid person imaginable, cannot possibly misunderstand it.” Dale apparently enjoyed the challenge of rewriting an explanation again and again, until finally he elicited a smile and a pat on the back from Butler with a “Now you’ve got it; I can’t misunderstand it and I can’t improve it. Off you go.” Dale later reported that he would walk home, late for tea but brimming over with the happiness of achievement. Later, he attributed to this training the reason why his work submitted to the Journal of Physiology was often accepted without corrections from the editor, John Langley, who was widely known for his “savage” criticism of manuscripts.²

Dale was an excellent student. At the age of fifteen he won second prize, and the following year, first prize honors, in the examination of general proficiency given by the College of Preceptors. Despite this show of talent, it was understood within his family that he would leave school and enter his father’s office. However, during his last year at the Tollington School he did so well on an examination that he was offered an additional tuition-free school year. During that year, Dale took an examination in twenty-one different subjects given by the London chamber of commerce and won a prize of 20 pounds, not an insignificant amount of money at the time. He was nevertheless still expected to leave school, until a fortunate circumstance arose. It seems that his father, while on a trip north, boasted about his son’s achievement to the headmaster of the Leys School in Cambridge. This led to Dale being offered the opportunity to take a competitive examination late and to be judged against those who had already taken the exam. Dale was awarded one of the three scholarships offered and entered the Leys School in September 1891, remaining there until 1894.

At the Leys School, Dale’s teachers recognized his inclination toward natural science, and they had him concentrate in that area with the goal of obtaining a scholarship in science at Cambridge. This encouragement gave Dale, for the first time, the ambition to do something besides “occupying a stool in some city office.” Although Dale later regretted that he might have specialized too early, he was definitely not a “specialist drudge.” He edited the Leys Fortnightly, the school magazine, and was awarded a prize for an article he wrote for the magazine and another prize for translating a passage from Virgil into English prose.

After passing an examination in the science courses at the age of seventeen, Dale was permitted to substitute physiology, a more experimental field, for biology. He was fortunate in being guided in physiology by the science master Alfred Hutchinson, who had his students work through Michael Foster’s definitive four-volume Textbook in Physiology, published in 1891. Some supplementary readings of more recent work were also assigned. Dale was thus exposed at a young age to what was new in physiology, such as Minkowski’s research on the relation of the pancreas to diabetes and the thyroid gland to myxoedema, work not yet included in Foster’s textbook. Dale was receiving excellent preparation to impress his future mentors at Cambridge.

In the fall of 1894, Dale entered Trinity College, Cambridge, with a small scholarship and some additional support in natural science, which included physiology, chemistry, and physics. He impressed his instructors and won a Major Foundation Scholarship in the spring of 1896. The freedom at Trinity College was enormously attractive to Dale, and he later counted the six years spent there as being among the happiest of his life. The scholarship students at Trinity formed a small, congenial group of friends, twelve of whom formed the University Natural Science Club. The group met in members’ rooms, with the host responsible for providing refreshments—sardines on toast was a common fare—and for reading a paper or leading a discussion on some current topic of scientific interest. At one such meeting they discussed the newly discovered X-rays, and at another meeting there was a demonstration of these rays with a Crooke’s tube borrowed from the Cavendish Laboratory.³ At still another meeting, one of the members set up what must have been one of the earliest demonstrations of “electromagnetic (wireless) transmission,” wherein a bell was rung by a remote signal sent from the Cavendish Laboratory at the exact moment prearranged.

At the end of his third year at Trinity, Dale succeeded in getting a B.A. degree by passing both parts of the special physiology examination a year earlier than usual. He was anxious to do this because he wanted to keep up with the other members of the natural science group, most of whom were a year ahead of him and had started to eat at the Bachelors’ table. Dale was given a part-time job teaching biology three times a week to a small group preparing for an examination. His father was pleased with this, for he considered it a step toward Dale’s successful career as a schoolmaster, which would justify the expenses he had incurred in sending his son to Leys and Trinity. Dale, however, felt that he had no special talent to help him arouse interest in elementary science in boys who in most instances had no aptitude or inclination for the subject. He did, however, have one boy in his class, Peter Laidlaw, who later became a valued collaborator and a Fellow of the Royal Society.

As teaching undergraduates did not appeal to Dale, he never applied for or held a university appointment. He later wrote that he recognized that many regard teaching as not only personally rewarding but as a way of generating ideas that may facilitate one’s own research, but he added:

When he completed his examinations at Cambridge, his teachers took it for granted that Dale would stay on and become a candidate for a college fellowship. However, the annual support of 100 pounds was not sufficient to live on, and he felt that he could not ask his father for any more help. Financial support had been a continuous concern for Dale throughout his course of study. He had hoped to receive the Coutts-Trotter studentship at Trinity because it brought with it a living stipend, but it was awarded to Ernest Rutherford. The competition between the two must have been fierce, as both were clearly qualified. Rutherford received the Nobel Prize in chemistry in 1908, although he is generally thought of today as a physicist because of his work on electromagnetic fields and the nucleus of the atom. Dale went on to supplement his inadequate stipend with whatever “demonstratorship” and private tutoring he could obtain. Rutherford was appointed professor at McGill University the following year, and Dale then shared the Coutts-Trotter studentship with another student. John Langley had wanted Dale to receive it alone, but another professor had nominated the Honorable R. J. Strutt (the future 4th Lord Raleigh), necessitating a compromise. Dale was allowed to keep his modest college stipend and this made it possible for him to subsist.

At Cambridge Dale had been instructed by both John Langley and Walter Gaskell. Langley, while brilliant, was exacting, hypercritical, and reluctant to speculate or theorize, while Gaskell was a teacher who described experimentation to test hypotheses as an exciting adventure. Dale later wrote

Dale left Cambridge in 1900 to complete the requirements for his medical degree at St. Bartholomew’s Hospital in London. He was awarded another fellowship, the Schuster Scholarship in anatomy and physiology, which supported him during the two years spent at “Old Bart’s.” Dale neither enjoyed nor felt comfortable in the clinical environment. He thought that the medicine he was exposed to had little scientific basis and was frustrated by staff members who tended to back up their statements by simply referring to their experience or else “made obviously foolish pretensions to giving it a basis of experimental science.” Dale could not help contrasting the “oracular authority” of the clinical staff with the give-and-take exchanges with his teachers at Cambridge where even “the very great W. H. Gaskell, seemed to be ready for discussion on an assumed basis of equality with the humblest of us, and eager to encourage us in frank and critical enquiry. “⁵

After completing his clinical training, Dale, who still needed to be concerned about support, was given an opportunity to apply for the George Henry Lewes Studentship. This fellowship, which was for Cambridge men only, had been established by the novelist George Elliot. Being awarded the fellowship helped Dale make the career choice between clinical medicine and research. He chose research even though the level of support was modest and then only guaranteed for a few years.

In 1902 Dale was given the use of a research room in Professor Ernest Starling’s laboratory at University College, London. Starling and his brother-in-law, William Bayliss, had just discovered secretin, and Dale was given the task of studying whether this hormone affected the production of insulin. Dale studied the histological changes in the pancreas produced by prolonged stimulation with secretin. He made some interesting observations that seemed to indicate that some pancreatic cells might be converted to the insulin-secreting islets of Langerhans cells, but the validity and true meaning of this observation was never established.

More important for Dale’s scientific career than his preliminary studies of secretin and insulin was the fact that working in Starling’s laboratory provided him the opportunity to meet Otto Loewi, who was working in pharmacology in Marburg, Germany. Loewi, who was close to the same age as Dale, was spending a brief time in England in order to gain some firsthand experience with pharmacological research in Great Britain. This meeting of Dale and Loewi, which is described in the next chapter, formed the beginning of a close friendship and a sharing of scientific interests, which ended only with Loewi’s death in 1961. In 1936 they would share the Nobel Prize in Physiology or Medicine.

Not long after Dale and Loewi met, Dale was given the opportunity to spend several months (October 1903 to February 1904) in Paul Ehrlich’s laboratory in Frankfurt-am-Main. On the way to Frankfurt, Dale stopped to visit Loewi in Marburg, and the two of them traveled together to Frankfurt. Ehrlich, a bacteriologist and immunologist, was at the time the director of the Royal Institute of Experimental Therapy (Königliches Institut für Experimentelle Therapie) in Frankfurt, had theorized that many physiological processes result from the interaction of a chemical substance with a preformed receptor. Ehrlich applied this theory to the field of immunology, where he argued that antibody formation results from the binding of antigens to specific chemical configurations on cell surfaces, which he called “side chains.” According to Ehrlich’s theory, this binding, or recognition of the antigen by side chains, resulted in the release of antibodies into the bloodstream. Ehrlich’s ideas had evolved from earlier research on staining techniques in which he had developed a similar concept of a specific affinity between the stain and the target tissue.⁶ Later, when Ehrlich began to concentrate on chemotherapy, he emphasized that the chemical constitution of therapeutic drugs have a special affinity for the cells of the pathogenic organisms against which they must act. This was the origin of the concept of the “magic bullet,” the name given to the arsenic drug that Ehrlich later developed for treating syphilis.

This idea of specific binding was closely related to Langley’s concept of “receptor substances,” and Ehrlich and Langley were well aware of each other’s work. Ehrlich eventually adopted Langley’s terminology and began to use the term “receptor substance” rather than “side chains.” Dale, having been a student of Langley, was familiar with this history and was pleased when Starling helped arrange for him to spend some time with Ehrlich.⁷ Starling also had an interest in the concept of receptor substances because it had obvious implications for the affinity that exists between a hormone and its targets. Dale later described his first contact with Ehrlich:

Dale did not spend enough time with Ehrlich to enable him to accomplish much, and he later wrote that: “I had no results of my own worthy to record, but I have been glad to have had contact with Ehrlich’s stimulating mind and personality.”

In 1904, after Dale had returned to London, he accepted a position as a pharmacologist at the Wellcome Physiological Research Laboratories, located at Herne Hill, a suburb of London. Ernest Starling had recommended him for the position when Henry Wellcome asked him to suggest some candidates. Dale’s friends tried to persuade him not to take the position, arguing that working for a pharmaceutical company would be a “dead end,” amounting to “selling his scientific birthright for commercial pottage.” At the time, most pharmaceutical companies did research only directly related to developing drugs and little, if any, basic research. However, Henry Wellcome was quite persuasive in reassuring Dale that he would be free to follow his own scientific interests and that he himself had established the laboratory in order to make contributions of “permanent scientific value.”

Dale carefully weighed all the factors. He felt that his academic prospects were not promising, because he had not done anything especially noteworthy. The Wellcome position would provide him with his own laboratory and the opportunity, as he put it, “to make my own mistakes.” Dale later admitted that he was also attracted by the offer of a “marrying income.” For many years, he had lived on a bare subsistence level with income from various fellowships. Having a “marrying income” must have been on his mind, for in November 1904, shortly after accepting the position, Dale married his first cousin “Nellie” (Ellen Harriet Hallett). It turned out to be a most fortunate move, as within two years Dale was appointed director of the Wellcome Laboratories and at the end of the ten years (1904–1914) spent there, he was recognized as a major figure in pharmacology and physiology.

Henry Solomon Wellcome (1853–1936)

It is impossible to know what Dale would have accomplished had it not been for the support and opportunities that Henry Wellcome provided. Wellcome was a remarkable man and while not a scientist himself, his enormous importance in nurturing scientific work, preserving medical history, and supporting exploration in various fields was later recognized when he was elected a Fellow of the Royal Society.

Although Henry Wellcome headed the Burroughs Wellcome and Company, a British pharmaceutical firm, he was born in the United States and was an American citizen. He later acquired British citizenship. Wellcome was born in a log cabin 125 miles from Milwaukee. His father was an itinerant missionary who traveled in a covered wagon through Wisconsin and Minnesota. When Henry was eight years old the family moved to a small settlement in the Blue Earth County of Minnesota. When the settlement was attacked by a Sioux tribe, Henry helped to hold off the Indians by casting rifle bullets and assisting in caring for the wounded. Nevertheless, he had a lifelong sympathy for the plight of the Indians and later contributed a considerable amount of money to support an Alaskan Indian tribe. Henry Wellcome later wrote a book about these people, The Story of Metlakatla, which was published in 1887.

Henry Wellcome’s early education was achieved in a log house frontier school. He developed an interest in chemistry and pharmacy, and at the age of fifteen he started a three-year period as a drug clerk in Rochester, Minnesota. There he was befriended by Dr. William Mayo, the father of the Mayo brothers, who later founded the now famous Mayo Clinic. William Mayo, who was a friend of Henry Wellcome’s uncle, advised the young Henry to pursue his interest in chemistry and pharmacy by getting additional schooling. Henry took the advice and started at the Chicago School of Pharmacy, later switching to the Philadelphia School of Pharmacy and Chemistry. After graduation, he worked as a pharmacist for various New York firms, traveling around the United States and South America. In Peru, he learned about cinchona cultivation and the method of producing quinine from the bark of that tree, and this gave birth to a life-long interest in plants that had medicinal properties.

In 1880, at the age of twenty-seven, Wellcome decided to settle in England, where his ancestors had come from. He was soon devoting his enormous energy to developing Burroughs Wellcome and Company, started with his partner Silas Burroughs. The company manufactured fine chemicals, alkaloids, and medicinal products. Following Burroughs’ untimely death, the entire enterprise was placed completely in Henry Wellcome’s hands. The firm was a success almost from the outset, and the company’s reputation grew after the company was the first to market drugs in a compressed form under the proprietary name “Tabloids.” These pharmaceutical pills were a great financial success, and Wellcome then had more time to travel and pursue his many scientific and intellectual interests.

Around 1895, Wellcome began to develop the research side of the company, and he established several laboratories for that purpose. One laboratory was devoted to pursuing his interest in the active ingredients in plants that had medicinal properties. There was also a research laboratory that studied serum therapy. Although these laboratories were clearly pursuing research that potentially could advance the commercial interests of the company, at the time Wellcome was unusual in giving researchers a relatively free hand to work on problems that had little or no immediate promise of producing marketable drugs. The investigators were also free to publish the results of their investigations, a policy that helped attract competent researchers.

Wellcome developed an interest in tropical diseases. He loved to travel to out-of-the-way places and was in Khartoum soon after General Kitchener had conquered the Sudan. At that time Khartoum was a hotbed of infectious diseases—malaria, dysentery, and other tropical illnesses. In 1903 he founded what would become the world-famous Wellcome Tropical Research Laboratories at Gordon Medical College in the Sudan, which played a major role in improving the health of people in that region.

Wellcome also had a strong interest in the history of medicine, and for a number of years he collected everything he could find about the practice of medicine from the earliest times to the present. In 1913 this collection became the core of the newly established Wellcome Historical Medical Museum in London. Wellcome’s traveling and his interest in archaeology, ethnology, and mythology provided the opportunity for him to visit relics and excavation sites in Ethiopia, Palestine, and other locations. He did some independent investigations himself and funded the archeological expeditions of others. Some of the findings from these expeditions were brought back to England and eventually placed in different museums in that country.

Wellcome visited Africa many times and also supported a number of explorations to the “dark continent.” He was an active member and officer of the Royal African Society and established the Wellcome Gold Medal given by that organization. He also funded a number of other medals and prizes, including several in the United States and England for work on the history of medical subjects. In 1905 he established a hospital dispensary in Mengo in Uganda. He also supported missionary projects and had a long friendship with the explorer Henry M. Stanley, who found the (never really lost) Scottish missionary, David Livingstone. Stanley later described his travels in his highly successful two volumes, In Darkest Africa, published in 1890. In 1931 Wellcome established the Lady Stanley Memorial Hospital in Makona, Uganda.

His interest in tropical medicine brought Wellcome into contact with General William Gorgas, who helped establish the role of the mosquito in spreading malaria and yellow fever among workers building the Panama Canal. Wellcome established the Gorgas Memorial Laboratories in Panama.

Toward the end of his life, Wellcome arranged for the many museums and laboratories he had established to continuously draw support from the profits of Burroughs Wellcome and Company. Wellcome lived simply, mainly in hotels, and spent little of his money on personal luxuries. He was a retiring man who lived a somewhat lonely life. He could exhibit a stubborn self-confidence in his own judgment, which often proved better than the “best advice” he was given. He had one son from a marriage that was subsequently dissolved, but in his will he left almost all of his wealth to science and medicine. He established the Wellcome Trust Fund, which continues to this day to provide major support for medical research in Great Britain as well as funds for fellowships and education.

Henry Dale, who headed the Wellcome Trust Fund for a number of years after he retired from active research, wrote in a letter to the Times (August 1, 1936), after Wellcome’s death, that Henry Wellcome told him that “he chose to spend his wealth in supporting research as another man might chose to spend his on a racing-stable.” Dale continued by noting that “the whole of his power of supporting research, which was the real aim of his ambition, came to him from the continued and increasing success of his business…. He knew, of course, that every public association of his name with what was scientifically worthy of regard might indirectly enhance the reputation and prosperity of his business: but that would give him added power to support research, much of it in fields which had no obvious relation to his business interests.”

Soon after Dale started his new position, Henry Wellcome mentioned to him “that when he could find the time without interfering with plans of his own, it would give him a special satisfaction if he could clear up the problem of ergot as the pharmacy, pharmacology, and therapeutics of that drug being then in a state of confusion.” This was not a completely disinterested suggestion, for several pharmaceutical companies at the time were exploring the feasibility of using an extract from the ergot fungus in obstetrics. Ergot had been used by midwives for centuries but was not commercially available in a standardized dose. Wellcome had recently learned that Parke Davis, a rival firm, had used a bioassay to standardize an ergot preparation they were planning to market. It was difficult for Dale, who was just starting out in a new position, to ignore Wellcome’s suggestion, no matter how mildly it was proposed, and he soon became involved in testing the properties of various compounds that were extracted from the ergot fungus.

History of the Ergot Fungus

Ergot, which is a fungus that grows on some grains, especially on rye, has a long history in folk medicine. An Assyrian tablet from 600 B.C. refers to a “noxious pustule in the ear of grain,” and one of the sacred Pharsee books refers to “noxious grasses that cause pregnant women to drop the womb and die in childbed.” Both of these references are thought to be to the ergot fungus.

The Greeks and Romans did not usually eat rye, and there are no written references to ergot in their literature. Although there do not seem to be any written accounts of the use of ergot for medicinal purposes during the Middle Ages in Europe, there is other evidence that some of its properties were known earlier. Ergot poisoning was recognized, and there are reports of seizures caused by consuming ergot. Epidemics caused by ergot poisoning were described, and these were characterized by gangrene of the feet or hands so severe that a limb might become dry and black as charcoal, sometimes falling off without any blood loss. The burning sensation from the limbs was called St. Anthony’s Fire, because of the belief that the shrine of that saint could provide relief from the excruciating burning sensation and even a cure. An epidemic in 1670 left the first recorded evidence that ergot poisoning was recognized as the cause of St. Anthony’s Fire. More recent reported outbreaks of St. Anthony’s Fire include one in Russia in 1926, another in Ireland in 1929, and still another in France in 1953.

It is now known that ergot spores are either deposited by insects or carried by the wind onto grain, usually rye, where they germinate and gradually consume the grain. These spores eventually harden into a purple curved body, called the sclerotium, that is the commercial source of ergot.

Ergot was being used as an herb in obstetrics before it was identified as the cause of St. Anthony’s Fire. Midwives had been aware of it for centuries before any physicians adopted it. Ergot produces uterine contractions, and there are clear records of its being used as early as 1600 to induce labor in pregnant women. There are also several later reports of the use of ergot by physicians. A letter in a New York medical journal in 1818 described a physician’s experience with ergot, which was called pulvis parturiens: “It expedites lingering parturition and saves to the accoucheur a considerable portion of time, without producing any bad effects on the patient…. Previous to its exhibition it is of the utmost consequence to ascertain the presentation [i.e., to determine the orientation of the child in the uterus] … as the violent and almost incessant action which it induces in the uterus precludes the possibility of turning…. If the dose is large it will produce nausea and vomiting. In most cases you will be surprised with the suddenness of the operation; it is, therefore, necessary to be completely ready before you give the medicine…. Since I have adopted the use of this powder I have seldom found a case that detained me more than three hours.”⁹

In the United States the use in obstetrics of some form of ergot preparation had been increasing. When in 1824 the incidence of stillborn infants was noted to be on the rise in some eastern cities, the Medical Society of New York called for an inquiry. A report issued in 1824 found ergot responsible and commented sarcastically that ergot should be called pulvis ad morte rather than pulvis ad partum. The report recommended strongly that ergot be used only to control postpartum hemorrhage, not to hasten parturition. However, even when Henry Dale started to do research on ergot, the accoucheurs were using a manufactured product called “Liquid Extract of Ergot,” a watery preparation given to induce labor.

As it turned out, the ergot fungus proved to be a treasure trove of active pharmacological substances, and their investigation set the direction of most of Dale’s research. George Barger, a Wellcome chemist whom Dale had previously known at Cambridge, had extracted several substances from ergot, presumably also with the prompting of Henry Wellcome. These extracts needed to be tested for their biological action. Among the substances Barger had extracted were histamine (not yet identified by this name), acetylcholine, tyramine, and other amines that mimicked many of the effects of adrenaline and sympathetic nervous system stimulation. Histamine, tyramine, and acetylcholine are not normally found in fresh ergot, but rather are products of putrefaction. Tyramine, for example, is also found in spoiled meat, and the acetylcholine present in ergot was due to bacterial contamination caused by Bacillus acetylcholini, the same bacillus responsible for fermenting sauerkraut. The acetylcholine found in ergot is relatively stable, as ergot does not contain any cholinesterase, the enzyme that rapidly degrades or inactivates acetylcholine in the body. Although at the time none of these extracts were known to be natural constituents in animals, they were being studied because of their physiological effects. In a number of respects the history of histamine and acetylcholine study closely parallel each other in ways other than their derivation from ergot. They both were synthesized earlier and were later found to have similar effects in stimulating the uterus. Neither histamine or acetylcholine were known to be present in mammals until the 1920s.

Two additional extracts from ergot, ergotamine and ergotoxine, proved enormously valuable for testing the presence of adrenaline, for they were found to block the effects of adrenaline and sympathetic nerve stimulation on blood pressure. Dale later described, with some humor and modesty, how this property of ergotamine was discovered. When he had just begun working at the Wellcome Laboratories he was asked to perform some perfunctory tests on one of the ergot extracts supplied by George Barger. He felt unprepared for the task and later wrote, “Pharmacological research was for me a complete novelty, and I was, frankly, not at all attracted by the prospect of making my first excursion into it on the ergot morass.”¹⁰

Dale began by testing ergotoxine, a substance closely related to ergotamine, on the arterial pressure of a cat. This test, he later wrote, was one of the few “within reach of my limited competence.” As he was finishing this work, a sample of dried adrenal gland extract was sent up to him to test. He used the same cat to make the test and found that the adrenal extract did not produce the expected increase in blood pressure. At first Dale thought this odd result must have been due to his incompetence, but when he once again tested some adrenal extract on cats previously injected with ergotoxine he got the same result. It turned out that ergotoxine not only blocked but also reversed the effects of adrenaline and sympathetic nerve stimulation. Dale had inadvertently found the first adrenaline blocking agent, and this later became a basic pharmacological tool for testing for the presence of adrenaline.

Ultimately Dale did find a crude extract that caused the uterus to contract, but the substance was not identified and characterized until the early 1930s, when three different laboratories reported obtaining a purified ergot extract that when taken by mouth caused vigorous uterine contractions.¹¹ However, by this time Dale was no longer at the Wellcome Laboratories, and his interests had turned to other matters.

Henry Wellcome soon recognized Dale’s keen judgment and administrative ability, and within eighteen months he made him director of the Wellcome Laboratories. This enabled Dale to obtain the help of several chemists, in addition to his friend George Barger, and he could call on a number of people to assist in studying the properties of the various ergot extracts. With the collaboration of Peter Laidlaw, the undergraduate student Dale had taught at Cambridge, Dale demonstrated that the extract, which was later identified as histamine, produced a marked decrease in blood pressure. At first this was a puzzle, for they had observed that this substance constricted blood vessels in the uterus. Vasoconstriction should have produced an increase, not a decrease, in blood pressure. The explanation came when Dale found that the extract produced a marked vasodilation and an increase in permeability of the capillaries of the uterus.¹² Dale concluded that even though the substance caused vasoconstriction in some blood vessels, the vasodilation of the capillaries had the greater effect and was therefore responsible for the overall lowering of blood pressure.

This early work on histamine prepared Dale to appreciate later the possibility that the lowering of blood pressure that occurred during shock might be due to the dilation of the capillaries and leakage of blood through the capillary walls. During the First World War, Dale did research on a histamine animal model of “secondary wound shock,” a sometimes fatal drop in blood pressure experienced by soldiers with battle wounds. At that time, however, it was not known that histamine was a natural constituent in the body. Reflecting much later on how close he had come to discovering the role of histamine in shock, Dale wrote: “I have been quite shocked on reading anew one passage of our discussion to discover how we seemed to have gone almost out of our way even to preclude this possibility from consideration.”¹³

Dale’s research on histamine was a significant contribution in the eventual discovery of the importance of this substance in allergic reactions and shock, but it is his research on the pharmacology of other substances that is most relevant to the present story. Dale found several amine substances, such as tyramine, that could reproduce at least some of the effects of adrenaline and sympathetic nerve stimulation. With the help of George Barger, Dale found noradrenaline to be the most potent substance in mimicking sympathetic responses. Today noradrenaline (more commonly called norepinephrine) is recognized as the neurotransmitter secreted by most sympathetic nerves, but at the time it too was not known to be a natural substance in the body and Dale thought of it as only an interesting synthetic compound.¹⁴ Reflecting back to this time, Dale acknowledged his general hesitancy to speculate when he commented: “I failed to jump to the truth, and I can hardly claim credit for having crawled so near and then stopped short of it.”¹⁵

Dale was sent another ergot extract for routine testing around the year 1910. The substance was found to produce a profound inhibition of heart rate. In fact, the first time Dale used it, he thought he had killed the cat he was using as a subject, because he could not detect any heart rate or blood pressure. Although the substance was like muscarine in many of its effects, it was more potent and, unlike muscarine, which is quite stable, it was a labile ester that rapidly became inactive. Dale recalled that Reid Hunt and his assistant René Taveau had produced acetylcholine from choline and had reported in 1906 that its effect on circulation “is the most powerful substance known.”¹⁶ With the help of Arthur Ewins, a chemist in the laboratory, Dale was able to prove that this ergot extract was acetylcholine, and they found that it not only slowed heart rate, but also reproduced many other parasympathetic effects, such as increasing salivation and causing the esophagus, stomach, intestines, and bladder to contract.

However, Dale did not do any “wild theorizing” and did not even hypothesize, at least in any publication, that acetylcholine might be secreted by parasympathetic nerves. He also ruled out the possibility that it would have any application as a therapeutic drug: “Acetylcholine occurs occasionally in ergot, but its instability renders it improbable that its occurrence has any therapeutic significance.”¹⁸

In regard to any possible physiological significance of acetylcholine, Dale wrote:

Although Dale had observed that the effectiveness of acetylcholine in reproducing parasympathetic responses surpasses adrenaline’s ability to mimic sympathetic responses, he noted an important difference, that adrenaline is found in the body while acetylcholine is just a drug, although one with most interesting properties: “There is no known depot of choline derivatives, corresponding to the adrenine [adrenaline] depot in the adrenal medulla, nor indeed, any evidence that a substance resembling acetylcholine exists in the body at all.”

Dale found that acetylcholine and muscarine had the same effect at a number of sites. There were other sites, however, where muscarine was not effective in mimicking acetylcholine, although at these sites low doses of nicotine did mimic acetylcholine.²⁰ When it was found that atropine blocked transmission at the muscarinic sites, but not at the nicotinic sites, Dale designated acetylcholine active sites as either “muscarinic” or “nicotinic,” a terminology still used today.²¹

Dale also introduced other terminology that was widely adopted and is still in use. He had found that many ergot extracts could mimic either sympathetic or parasympathetic nerve stimulation, and he and George Barber introduced the terminology “sympathomimetic” and “parasympathomimetic” to describe any drug that mimicked the effects of these two divisions of the autonomic nervous system:

A similar argument was advanced to justify use of the term “parasympathomimetic.”

Dale here describes acetylcholine’s action as “immediate” and “intense” but also “extraordinarily evanescent.” He suggested that the short duration of acetylcholine’s action and suggested that this was due to an enzyme, an esterase, in the body that rapidly broke it down into acetic acid and an inactive choline. Dale wrote:

Apparently, Dale did consider at this point that there might be some natural substance in the body that resembles acetylcholine, but because it is broken down so rapidly he knew of no way to recover any of it. Dale would have to wait two decades before Wilhelm Feldberg would bring the leech muscle technique to his laboratory, which would make it possible to detect the small amounts of acetylcholine secreted by nerves. This advance is described in chapter 6, along with the events that led to the awarding of the Nobel Prize for his proving the existence of neurohumoral secretions at different peripheral synapses.

From the perspective of what we now know, it seems remarkable that Dale did not speculate further about the possibility that parasympathetic nerves secrete acetylcholine. Several factors explain why Dale did not make this connection. As Dale later wrote, they had at the time “no evidence at all that acetylcholine was a constituent of any part of the animal body.”²⁵ Much later, when he was reflecting on his failure in 1914 to make the theoretical leap, he wrote that “by this time, both Elliott and I seem to have become shy of any allusion to the ‘chemical transmission’ theory, which had originated ten years earlier.”²⁶ It does not, however, seem to have been a question of “shyness,” but rather that Dale was simply not thinking at the time about the possibility that autonomic nerves secreted chemical substances.

Dale was by temperament reluctant to speculate much beyond what the evidence in hand could firmly support. He was cautious and perhaps prone to give too much weight to exceptions that might make any generalization risky. Dale was later described by Lord (Edgar) Adrian as more likely “to apply the brake than to be the first in the gold rush, but the gold he has found will keep its value.”²⁷

In 1914 Dale was elected to the Royal Society in recognition of his many contributions to pharmacology and physiology, and he was also appointed to the National Research Committee (now National Research Council). Dale was only twenty-nine when he started working at the Wellcome Laboratories, and the support he received for his research was unusual for a person of that age. He was able to take good advantage of this support and was enormously productive. There were, however, aspects of the position at the Wellcome Laboratories that became a source of irritation for him.

Dale had come to expect that from time to time he would be asked to assess the biological properties of some new compounds even though they were not relevant to his own interests, but such requests were becoming more frequent and burdensome. The director of Burroughs Wellcome’s Chemical Research Laboratories had been sending over large numbers of compounds for routine screening. Determining whether a compound had any interesting physiological properties could be quite time-consuming, but when Dale objected, the director informed Henry Wellcome that his work was being held back by Dale’s failure to cooperate. Although Dale was able to use the conflict to gain additional staff, the incident was an unpleasant reminder that despite Henry Wellcome’s assurances that he would be completely free to pursue his own scientific interests, his time and laboratory resources were increasingly being drawn upon to support the commercial interests of the company.

Around this time, another difficult incident took place, concerning the appropriate terminology to be used in referring to the adrenal gland extract. Dale generally called the substance adrenalin and sometime adrenaline, as did most pharmacologists and physiologists. But after Parke, Davis & Company in Detroit patented a purified crystal under the proprietary name “Adrenaline,” some executives at the head office told Dale, who was submitting a paper for publication, that he should not use a patented name belonging to a rival company. Dale resented the interference and clearly said so. He had always used the term and insisted on his right to continue using it. The executives were close to Henry Wellcome, and Dale was not sure how the dispute would be resolved. In the end, Wellcome supported Dale, but the experience was unpleasant, and Dale began to consider offers of other positions.

Several possibilities presented themselves, but he was most attracted by the offer of the directorship of the biochemistry department of the newly formed Institute of Medical Research. He did not want to leave the Wellcome Laboratories, however, until he clarified what support he could count on in the position, and he also wanted to know who would be appointed director of the new institute. Moreover, because Dale did not consider himself a biochemist, he wanted to be able to create a position for a chemist skilled in synthesizing new compounds. Dale’s strength was his ability to develop techniques for determining the physiological effects of various compounds on various organs and then draw inferences about the normal physiology of these organs. He did not have the chemist’s ability to extract and synthesize potentially interesting compounds. Dale, who always seemed to know what and whom he needed to move his research to the next level, insisted that George Barger be offered a position in his new laboratory. After that was settled, Dale accepted the position at the Institute for Medical Research in Hampstead, a region in north London.

World War I broke out one month after Dale started at the institute, and he, like most scientists in Great Britain, now devoted his time to the war effort. Dale was well prepared for the task by virtue of his early studies on what turned out to be histamine, and as already noted, he did research during the war on the causes and treatment of “secondary wound shock.” This work, which will be discussed more fully in chapter 7, brought him in contact with others working on shock, including the American physiologist Walter Cannon.

During the war Dale also served on a committee working on ways to standardize the packaging and labeling of drugs. Drug standardization had become an acute problem with the outbreak of the war, because Germany had been the largest supplier of the drugs used in Great Britain and this source was now cut off. He helped to establish international standardization of drugs by getting agreement on the tests for specifying the quality and potency of drugs produced in different countries. Later, in 1925, he chaired a conference on this subject in Geneva for the Health Organization of the League of Nations.

When the war ended in 1918, Dale, who was recognized as one of the leading pharmacologists in the world, began to be pursued by institutes in the United States. He was invited to give the Herter Lectures at Johns Hopkins in 1919. At the time this was considered to be the most prestigious lectureship in medical science in the United States. After his lecture, Dale was offered a university chair and a position as head of the renowned department of physiology at Johns Hopkins. During the same trip to the United States, Dale visited New York as a guest of Simon Flexner, director of the Rockefeller Institute. Flexner had started to court Dale in London, and he offered him a position as head of the projected department of pharmacology at the Rockefeller Institute. Dale declined this offer as well as the position at Johns Hopkins. The facilities and support at the Rockefeller Institute would have far surpassed anything that Dale had at the Institute of Medical Research in Hampstead, but he turned the position down because he felt, “that when my own country was just emerging from the strain and impoverishment, inflicted by the whole four years of the war, it was not time to leave untried the prospect and opportunity which I had accepted there, in favor of the one offered in the U.S.A.”²⁸

Dale’s laboratory at the Institute for Medical Research was always referred to as F4, being the fourth laboratory on the first floor of the Institute. It was a large communal laboratory with storage cabinets packed with equipment from floor to ceiling. On one end was the equipment for smoking the paper used to record responses on kymograph drums as well as vats of the varnish used to preserve the kymographic records worth saving.²⁹ Located close to a chemical balance was a note that read “Near enough is not good enough.” The note had been placed there by the head technician, who had been with Dale for many years and no doubt knew his commitment to precision.

Dale created a friendly, open laboratory where all felt free to question any one else’s ideas, and interactions produced collaboration, not competition. Everyone worked close to each another, so that if one’s experiment wasn’t working or there was a necessary waiting period, it was natural to pay attention to how your neighbor’s experiment was progressing. This physical arrangement facilitated collaborative research as did the lunch and tea rooms shared by all working in the institute.

By 1920, Dale had contributed enormously to our knowledge of the pharmacological and physiological properties of many different compounds that mimicked sympathetic or parasympathetic effects and the various drugs that enhanced or inhibited these effects. He was reluctant, however, to speculate, at least in print, on the possibility that any of these compounds were secreted by autonomic nerves. He had, however, laid the foundation for others, particularly for Otto Loewi, who was willing to speculate about the significance of the experiment that had first occurred to him in a dream.