Henry Dale: a Wellcome man

Tilli Tansey (Professor of the History of Modern Medical Sciences, School of History, Queen Mary, University of London) looks at Sir Henry Dale, a founding Trustee and pioneering Chairman of the Trust.

Sir Henry Dale (1875-1968), one of the most eminent biomedical scientists of the 20th century, is the foremost figure in the early years of the Wellcome Trust. First Trustee, then Chairman, he guided the Trust through its difficult early years so that it could become established as an internationally renowned institution.

Dale also had a personal association with the Trust's founder: early in his career, he worked for Henry Wellcome, and the two men developed huge mutual respect, despite occasional disagreements. It was actually a suggestion from Wellcome himself, to investigate a fungus called ergot of rye, that sparked the research of Dale's that ultimately led to the theory of chemical neurotransmission. Dale won the Nobel Prize for Physiology or Medicine in 1936 for this work, which revolutionised the study and understanding of the nervous system and the way in which drugs were designed and developed.

In the same year, he was appointed under the terms of Sir Henry Wellcome's will as one of the first Trustees of the Wellcome Trust. In 1938 he became the Trust's Chairman, which he remained until 1960. He continued as an Adviser to the Wellcome Trust until his death in 1968 aged 93.

Working for Wellcome

In 1904, Dale was a young medical graduate who wanted to establish a career in physiological research. That he should accept an offer to work in the Wellcome Physiological Research Laboratories (WPRL) was a highly unusual step. Why so unusual? At the beginning of the 20th century there were few openings in Britain for aspiring medical researchers. The professional study of medical science was still a relatively recent phenomenon, and there was little in the way of dedicated research institutes and the grant-awarding bodies with which we are now familiar. A teaching post in one of the few medical schools was the principal way in which scientists could carve out a little dedicated time for research; otherwise, research was an occasional part-time activity for a medical practitioner.

Dale had trained in physiology at the University of Cambridge and University College London; among his teachers had been some of the most distinguished physiologists of the period, including Michael Foster, John Langley and Ernest Starling. Until 1904 he had financed his studies and research with support from his parents and a series of scholarships and rare studentships, sometimes two or more at a time to make ends meet. Yet in that year he faced a bleak career choice - either to take a post in medical practice and effectively renounce his desires to undertake full-time laboratory research, or accept a teaching post that involved a heavy teaching load with only a little time for research. It was Starling who suggested that he might consider a vacancy that Henry Wellcome had at the WPRL for an experimental physiologist.

These Laboratories had begun in 1894 as a facility to produce the then new therapy of diphtheria antitoxin that was subsequently marketed by the Burroughs Wellcome & Co. pharmaceutical firm. By 1900, Henry Wellcome was the sole proprietor of the company, his partner Silas Burroughs having died in 1895, and he wanted to expand the biological research carried out at the labs.

Realising that animal experimentation was essential for the advanced physiological and bacteriological work he hoped to encourage, he applied to the Home Office for the registration of his premises under the 1876 Cruelty to Animals Act. After much debate and discussion, reaching to some of the highest levels of government, Wellcome was eventually successful in 1901. Thus the WPRL became the first lab associated with a commercial manufacturer to achieve the registration status that had previously been awarded only to universities or medical establishments.

By 1904 Wellcome wanted to employ a physiologist to undertake experimental research at the labs and he asked Starling if he knew "a man who is capable of broad and deep thinking, who has fertility of mind, originality and alertness, and patient persistence; a man who will concentrate his whole mind and energies on this work. I want the work in these laboratories to be done on the highest scientific lines and with such a thoroughness and precision that it will stand the test of time and the keenest criticism". Starling recommended Dale.

The novelty of these research labs, and their association with commerce, led some of Dale's colleagues to caution him against accepting any such position. But Dale was mainly concerned about the permanence of labs, as they seemingly existed as the personal plaything of a rich man already in his 50s. Wellcome advised Dale that he had already put in place a trust to maintain his laboratories after his death. Thus reassured, Dale began what became an illustrious career in biomedical research. However, he had no burning research problem of his own to tackle, and readily agreed to follow Wellcome's suggestion of investigating the physiology and pharmacology of ergot of rye, then widely used in obstetrics.

Ergot - a treasure house of drugs

Wellcome's desire for an investigation of the actions and constituents of ergot was motivated by commercial, not scientific, interests. A rival US pharmaceutical company was successfully advertising and selling an ergot preparation as "scientifically standardised" and Wellcome wanted a product that was just as good, if not better. Dale started a series of experiments, and although he never discovered the obstetrically active ingredient (he did later advise the young obstetrician who finally discovered it in the 1930s), his work on ergot produced a number of major discoveries and determined the direction of his entire career.

Among the chemicals he isolated and identified for the first time were some that seemed to block the known physiological effects of adrenaline. Fifty years later, this discovery would be better understood and the terminology 'beta-blocker' would be applied to similar drugs used to treat angina and other cardiac conditions, which work by blocking unwanted effects of the sympathetic nervous system. This early work of Dale's brought him into direct conflict with Wellcome.

The word 'adrenaline' was a registered trade name of a rival pharmaceutical company, and Wellcome ordered Dale to use either the word 'hemisine', which was the same chemical preparation but produced by his company, or the term 'epinephrine', used in the USA to circumvent the trade name problem of adrenaline. This Dale refused to do because, trade name or not, the word adrenaline was in common usage among British scientists, and the use of any other word in a scientific paper would be ridiculed and his own academic independence questioned. The two men became engaged in an extensive correspondence about the disagreement. Dale explained to Wellcome that if he truly wished the WPRL to be seen as an independent establishment pursuing high-quality accepted research, he had to abide by the current scientific standards, not those of the commercial world.

It was a particularly worrying time for Dale: his wife was about to have their second child, and his employment prospects looked bleak if he had to resign, an option he explicitly considered, telling Wellcome his position would be untenable: "this I should most sincerely deplore, but the result would be inevitable". Finally convinced, Wellcome agreed, and allowed Dale to publish the word adrenaline.

It was an important decision that showed the scientific independence of the WPRL from the pharmaceutical company, as well as Wellcome's ability to change his mind in the light of convincing evidence and his desire to commit his labs to the highest scientific principles. Wellcome certainly never held the episode against Dale, writing to a company manager at the time: "I consider him the best man in his work I have ever met - for a young man, and he is developing well & I want him to develop my ideals in this Physiological work".

While at the WPRL, Dale also discovered acetylcholine, histamine, and tyramine (all now known to be naturally occurring, biologically active constituents of the body), and indirectly he also discovered that the posterior pituitary gland produced a chemical that speeded up labour (now called oxytocin).

Additionally, in 1906, he became the Director of the WPRL, another indication of the regard that Wellcome had for him, and he assumed additional responsibilities of not only supervising all the routine production and standardisation of antitoxins but also managing the internal staff of the laboratories and maintaining and extending the the WPRL's relationship with Henry Wellcome and Burroughs Wellcome and Co. Dealing with these and other administrative problems, many of which were directly attributable to the novel awkwardness of working in laboratories associated with a pharmaceutical company, provided him with rare experiences that were to be invaluable in later phases of his career.

In 1914 Dale accepted an appointment with the newly created Medical Research Committee, later called the Medical Research Council (MRC), and left the WPRL. He had just achieved the great distinction of election as a Fellow of the Royal Society, the first person associated with the pharmaceutical industry to be so honoured and a clear vindication of the quality of work done in Wellcome's research laboratories. The correspondence between Dale and Wellcome at this time illustrates their mutual regard, Dale remarking on the "broad minded encouragement" he had received, and Wellcome commenting on "our long and pleasant association which has proved so mutually satisfactory…I feel well assured that you will still further distinguish yourself".

Further distinguishing himself

Having started his career working for one unusual establishment, the WPRL, Dale moved to another, which arose from the 1911 National Insurance Act. This reforming piece of legislation provided sickness and disability benefits for insured workers and made some provision for medical research, initially intended for tuberculosis research only. The body established to administer these funds, which amounted to approximately £56 000 per year, was the MRC.

An early plan was for the MRC to have its own Central Research Institute, and it was to join this body that Dale was invited in 1914. After the disruptions of World War I, this finally became a physical entity in Hampstead, north London, and was then named the National Institute of Medical Research (NIMR). It was here that Dale continued the range of experimental work he had started at the WPRL, elucidating in particular the physiological roles of histamine and acetylcholine, and isolating and identifying them as natural constituents of the animal body.

At the same time he accepted increasing administrative burdens: in 1928 he was appointed as the first Director of the NIMR, which he remained until retirement in 1942. He also served the Royal Society as Biological Secretary from 1925 until 1935, and as President from 1940 to 1945. He was knighted in January 1932, appearing on the same New Year's Honours List as Henry Wellcome, and in 1936 he accepted the role as one of the first of the Wellcome Trustees.

Portrait of Sir Henry Dale by Sir James Gunn. Credit: Wellcome Library

The Wellcome Trust

For Henry Dale, 1936 was a momentous year. At the end of October it was announced that, with Otto Loewi from Austria, he had been awarded the Nobel Prize in Physiology or Medicine for his discovery of acetylcholine and its physiological actions, work that had started in the WPRL over 30 years earlier. Sadly, his old boss, Henry Wellcome, didn't live to learn of that astonishing accolade - he had died on 25 July.

Wellcome's will, signed on 29 February 1932, established the Wellcome Trust, and expressed the wish that there should be five Trustees, with the proviso that at any time two of them should be qualified in medicine or an allied science, and two should be experienced in the legal and business worlds. Six names were listed, three of whom were medical: Walter Morley Fletcher, Henry Dale and Thomas Elliott. Fletcher had started his career as an experimental physiologist at Cambridge, leaving in 1914 to become the first Secretary of the MRC, but he predeceased Wellcome in 1933. Thus Dale and Elliott, another former Cambridge physiologist, who became Professor of Medicine at University College London in 1913, were the first medical Wellcome Trustees.

Dale and Elliott had known each other professionally since their student days in Cambridge, and were personal friends. In 1904 they had actually worked together in what Dale later described as a "joyous collaboration" at the WPRL, trying to unravel the strange effect that ergot had in reversing or blocking the effects of adrenaline. They also collaborated later in life in successfully proposing Wellcome for election as a Fellow of the Royal Society for his services to science, both recognising that such an honour "would give him more pleasure than anything else the world could give". In accepting and facing the entirely new challenges they faced as Wellcome Trustees, each took strength from their close friendship.

The early days of the Trust were troubled, and at a later stage Dale wrote to Elliott of the difficulties they encountered: "I am wondering whether our experiences as Trustees will eventually be more suitable for record as a novel or play". Not the least of their problems was that the relationship between the Trust and the pharmaceutical company had not been clearly delineated in the will, and it took many years for these to be adequately resolved. Equally problematic were the financial demands of the Inland Revenue in assessing the duties payable on the large and complex estate that Wellcome left.

For Dale and Elliott there were additional problems. The terms of the will required the Trustees to commit not to support any rival undertaking to that of the Wellcome Foundation (the organisation Wellcome had created in 1924 to include his pharmaceutical company, laboratories and other interests). Neither Dale nor Elliott was prepared to make such a commitment, as it suggested to them a responsibility to the commercial company that might interfere with their larger obligations to medical science.

Eventually, recourse was made to the High Court to authorise a modified covenant that satisfied the concerns of the medical Trustees, who took up their duties in January 1937. Their appointments were greeted warmly by the medical profession, the 'British Medical Journal' commenting: "No more fitting choice could have been made than Sir Henry Dale...and Professor T R Elliott", while also prophesising that the Wellcome Trust was "a big undertaking, perhaps bigger in the next generation than it can be in this". In 1938, the first Chairman of the Wellcome Trust Hudson Lyall, who had been Wellcome's solicitor, died, and Dale was appointed Chairman, which he remained until 1960.

The Wellcome Trust: its first grant and early schemes

Dale's scientific standing and authority, his personal connection with the founder, and his wide experience of the practical and administrative sides of medical research, its prosecution, funding and promotion, meant that he exerted considerable influence at the Wellcome Trust. Indeed, the very first external grant awarded by the Trust was in 1938 to Dale's co-Nobel Laureate Otto Loewi.

Loewi, Professor of Pharmacology in Graz, Austria, was Jewish, and had been subjected to dismissal and imprisonment after the Anschluss by Nazi Germany in 1938. Dale had little difficulty in persuading his fellow Trustees to release a little money to offer to the Society for the Protection of Science and Learning, a British organisation of academics anxious to assist continental colleagues expelled from German-occupied lands, to help Loewi and his family leave Austria; Loewi work in London and Oxford before finally settling in the USA. It was not until after World War II that the Trust was able to offer further support to individual scientists.

In the first 20 years of the Trust's life, the Trustees authorised expenditure of a little over one million pounds, supporting research in medical science and the history of medicine, which had been a major interest of Wellcome's and specifically targeted for support in his will. The early Trustees developed three clear funding priorities: people, places and equipment. A major investment was in talented individuals, demonstrated by the creation of research chairs in the UK and the USA to liberate senior staff from routine teaching, administrative or clinical work, and personal and travel grants to support and stimulate research projects - in a way that had not been readily available to Dale at the start of his career.

Additionally, building projects had been approved at universities and research institutes across the UK to provide new facilities, and large items of equipment too were purchased for 'loan' to named scientists. Indeed, the Trust was responsible for providing some of the first electron microscopes in the country, at the Universities of Oxford and Cambridge and University College London.

The Trust's support was never confined to the UK, and in the mid-1950s Dale suggested that the furthering of Wellcome's intentions in the USA would be possible if Burroughs Wellcome Inc., the American branch of the pharmaceutical company, took advantage of generous tax exemptions on charitable giving to endow a separate trust. Thus was created the Burroughs Wellcome Fund, to promote medical science and the history of medicine within the USA.

Dale's firm hold on the Wellcome Trust extended beyond his formal retirement in 1960 (aged 85), and later Trustees and administrators were aware that the elderly Dale was then more likely to block innovations and changes than support them. Yet one of his final recommendations as a Trustee was the forward-looking proposal, implemented some years later, to introduce a series of expert committees to advise the Trustees on the distribution of grants, a process that had relied almost entirely on the scientific Trustees until that time. His wide knowledge and experience continued to make him a valuable adviser to the Trustees and their staff: the first Director of the Wellcome Trust, Dr Peter Williams, recalls visiting Dale every month to discuss Trust business, the final visit being just two days before Dale's death.

Dale's association with Henry Wellcome and with the Wellcome Trust was unique. Writing in the 'Times' after Wellcome's death, Dale recalled a conversation in which Wellcome had told him that "he chose to spend his wealth in supporting research as another man might choose to spend his on racing stables", a choice that was clearly perpetuated in the creation of the Trust and the choice of Henry Dale as one of his first Trustees.