Sir Walter Morley Fletcher (born 1873)

Sir Walter Morley Fletcher, KBE, FRS ^[1] (21 July 1873 – 7 June 1933)^[2] was a British physiologist and administrator. Fletcher graduated from Trinity College, Cambridge and was most significant in his administration of the Medical Research Council (MRC) during the interwar years. Under his guidance, the MRC focused its funding on basic scientific research at the expense of clinical research but he made Britain a leader in biomedical research in the period.

References[edit]

^ e., T. R. (1933). "Sir Walter Morley Fletcher. 1873-1933". Obituary Notices of Fellows of the Royal Society. 1 (2): 153–163. doi:10.1098/rsbm.1933.0015.

https://europepmc.org/article/med/16745236
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OBITUARY NOTICE. WALTER MORLEY FLETCHER. (1873-1933.)

source - Biochem. 1933 xxvii

OBITUARY NOTICE. WALTER MORLEY FLETCHER. (1873-1933.) THE death of Sir Walter Fletcher, Secretary of the Medical Research Council, on June 7th, in the sixtieth year of his age and the nineteenth of his tenure of an office he had made great, removed with tragic unexpectedness a public servant who by sheer merit had raised himself to be the trusted captain and apologist of a great host of workers striving in their many different ways and for the most part in the seclusion of the laboratory for the advancement of scientific medicine. These now mourn the loss of a friend. Medical research, as the late Sir Walter never ceased to emphasise in many a weighty and admirably drafted pronouncement, calls to its service the labour corps of many ancillary sciences and from none perhaps does it expect more help in the solution of its increasingly complicated problems than from Biochemistry. To the members of the Biochemical Society, therefore, of which Fletcher was an original member, his loss is a particularly severe one, in that his appreciation of the part that Biochemistry has to play in the general advancement of medical science came from his own discipline and distinguished performance in physiological chemistry throughout a period of nearly twenty years. Undoubtedly Fletcher would have called himself a physiologist first and foremost, but, so far as concerned the particular problem to which his laboratory life was dedicated, he had the clearest vision of its further illumination when helped on its way by modern biophysics and modern biochemistry-a vision that has more than materialised. The many appreciations of the late Sir Walter which have already appeared and their varied sources are eloquent testimony to the numerous links he had forged between the laboratory worker and the outside world of affairs. His task may be said, indeed, to have been to explain the day's work-the 'pya Kat 5,utEpat-of the laboratory to a non-scientific and not always too appreciative public, a public, however, which paid the piper and might even, if unwisely guided, call the tune. Fletcher was the conductor in fact of a great orchestra of many and strange instruments, and it was his business to harmonise and co-ordinate the tunes of each to the greater glory of medical progress. "Instruments," I venture to think, would have pleased him. It was a favourite notion of his that disciplines should be divided not according to their matter but according to their methods and that the latter alone had in them the seeds of universal value. What then were Sir Walter's antecedents and how was it that he, a devoted man of science yet not unfamiliar with affairs, resigned his place in the orchestra to become its conductor when the call came to him just before the outbreak of the great war? Fletcher began his academic career in 1891 when he entered Trinity College Cambridge. Three years later he graduated with first class honours in the Natural Science Tripos, and from that date for nearly twenty years the Cambridge School of Physiology was his workroom and Trinity College, of which he was elected

a Fellow in 1897 and to whose affairs he was devoted, his real home. His clinical training in medicine he took at Bart.'s and in 1900 he obtained his Cambridge M.B. Throughout his whole Cambridge career Fletcher's immediate scientific interests were centred almost exclusively in the problem of muscle respiration, an important field of enquiry in which, at the outset of his work, little or no certain knowledge was available. Between 1898 and 1914 he contributed to the Journal of Physiology a valuable series of papers on this subject, including two in collaboration, respectively, with Hopkins and G. M. Brown. These papers definitely established Fletcher's reputation as a physiologist of distinction. His first contribution in 1898 on the survival respiration of muscle was a substantial one. of nearly a hundred closely reasoned pages, and fully documented, the elaborate apparatus of which he made use for continuous estimations of CO2 being a modification of that devised by F. F. Blackman for research on gaseous exchange in plant leaves. The work was carried out during his tenure of the Coutts-Trotter Studentship and was communicated to the 4th International Physiological Congress which met in Cambridge in August of that year. The normal curve of CO2 discharge from excised frog muscle was fully worked out and the effect thereon of various poisons and temperature changes. Of fundamental importance was his observation that in an excised muscle which has been made to contract, there was no accompanying increase in the rate of CO2 discharge. Throughout this work Fletcher took pains to exclude from consideration late yields of CO2 arising from putrefactive changes in the muscle. In his second and third papers in 1902 another important stage was reached when, in investigating the influence of oxygen on the survival respiration of muscle, he showed that loss of irritability in a surviving muscle is greatly delayed by an abundant supply of oxygen. In 1904 he recorded the fact that exposure of a fatigued muscle to an atmosphere of oxygen restored to it, in a marked degree, the osmotic properties of resting muscle. In 1907, in collaboration with Hopkins, appeared a most important contribution to the biochemistry of muscle showing that contraction of excised muscle is regularly accompanied by an increase of lactic acid and that, if the fatigued muscle is placed in oxygen, the lactic acid already formed disappears. The paper contains also the technical details of a new colour reaction for lactic acid devised by Hopkins for this work. Later papers in 1911, 1913 and 1914 (the last in collaboration with G. M. Brown) continue the discussion of lactic acid production particularly in connection with its alleged formation during autolysis and its formation in mammalian muscle. Fletcher's work and that of his collaborator Hopkins laid the foundations on which was built the elaborate treatment on thermodynamic lines of muscular action by Hill and Meyerhof. An analysis of its main conclusions will be found in the Croonian Lecture before the Royal Society by Fletcher and Hopkins in 1915 (Proc. Roy. Soc. Lond. 1917, B 89, 444) while critical reviews by A. V. Hill of the relations existing between heat production in muscle and the underlying chemical processes will be found in the Ergeb. d. Phys. 1916, 15, 340 and in Phys. Rev. 1922, 2, 310. Writing in 1923 (Nature, July 14th, Suppl.), A. V. Hill ascribed nearly all the recent advances in muscle physiology to the study of the phenomena of fatigue in muscle. Recovery from fatigue occurred apparently only in the presence of oxygen, while the lactic acid, which was found by Fletcher and

Hopkins to increase by exercise, was diminished or abolished by recovery in the presence of oxygen. Further work on the problem demanded a new technique for correlating the heat produced with the observed chemical phenomena. This was supplied by the delicate thermoelectric apparatus devised by Hill, and by its aid it has been possible to build up what is a completely new chapter in muscle physiology-the thermodynamics of muscular work. The mysterious lactic acid is now known from estimation of the heat evolved in contraction to be derived from glycogen. In recovery the lactic acid is rebuilt into the glycogen from which it was derived except for about one-sixth of it which is oxidised to provide energy for the restoration. The essential point is that contraction and discharge of lactic acid are anaerobic processes and that oxidation is concerned only with the phenomena of recuperation. It has been said that Fletcher's soul was not fuliy and entirely satisfied by the strivings and triumphs of laboratory toil and that he sought a wider arena in which his intellectual versatility and his flair for managing might have full play. Possibly he felt that after 18 years' devotion to one single problem of high physiological importance, he could safely say that he had rounded it off quite satisfactorily according to his lights and that he might now pass on the burden of its further pursuit to workers of other disciplines, biophysics, molecular physics, enzyme chemistry and what not. The call came to him on July 1st, 1914, to take up the duties of Secretary of the Medical Research Committee founded in 1913 as part of the provisions of the National Insurance Act of 1911. From the wide scope of the Committee's reference, and its own views with regard to the extension of the term "Medical Research" as part of a national scheme, it was quite clear that, in the search for the ideal secretary, no ordinary person of narrow views and interests was likely to be successful in guiding its destiny. Fletcher proved himself no ordinary person. This is how the Committee outlined their conception of research. "The object of the research is the extension of new knowledge with the view of increasing our powers of preserving health and preventing or combating disease. But otherwise than that this is to be the guiding aim, the actual field of research is not limited and is to be wide enough to include, so far as may from time to time be found desirable, all researches bearing on health and disease whether or not such researches have any direct or immediate bearing on any particular disease or class of diseases provided that they are judged to be useful in promoting the attainment of the above object." How well Fletcher and his Committee of changing personnel succeeded in translating into administrative practice the wide conception of research contained in this carefully drafted statement and how deftly he defended, when necessity arose, the more subtle and perhaps not too readily appreciated implications of its later phrases, are matters of history. It is the history in fact of a highly fertile period of medical research in this country and the empire, which owes much of its success to Fletcher's gifts of co-ordination and the personal and friendly terms on which he invariably met the numerous workers and grantees in the vast organisation of which he held the threads. This is not the place to record in detail the landmarks of Fletcher's 18 years' secretaryship-the pooling of the forces he wielded, at the very outset of his career, to meet the medical emergencies of war, the happily engineered emergence of the Medical Research Committee as the Medical Research Council with a new Charter and holding office with greater freedom and responsibility under the Privy Council, the centralisation at the National Institute, Hampstead, of

a permanent nucleus of experts in many fields of medical enquiry, and, as the years passed, the numerous opportunities seized by Fletcher to promote his one great ambition, to see the health of man and beast cared for and studied not only as a national and imperial charge but as the natural and fitting obligation of every right-thinking individual. One may fittingly refer here, however, to his many efforts in the cause of biochemical research and pay tribute to his many successful interventions in securing financial help for what are now active centres of research not only in biochemistry but also in nutritional studies. These centres have greatly enriched the resources at the Empire's disposal for attacking effectively the many problems that concern the health of its human and animal populations. Nutrition studies and all that these imply were very dear to Fletcher. Possibly the last reasoned article from his facile pen was a contribution to the new journal, Nutrition Abstracts and Reviews (1932), on the urgency of nutritional studies. There, in commending the new journal to its readers, he referred to the range and variety of interests served by advances in nutritional science and to the fact that no visible limits can be set to them. A perusal of the table of contents of any number of this new journal is indeed sufficient to indicate the far-reaching character of nutrition problems and goes far to establish a real truth underlying the adage "Der Mensch ist was er isst." Fletcher in his role of the complete advocate would have added "and beast too." By his very position Fletcher could feel the pulse of medical progress at many, points and generally with much acumen. So far as biochemical and nutritional science is concerned, its devotees owe him much for the sympathetic and always helpful interest he invariably took in their special problems. Lastly, a glimpse of Fletcher in the midst of his daily office routine, interviewing friends and strangers, arranging committees and often presiding over them, translating draft reports, resolutions and preambles into the excellent English on which he justly prided himself and through it all, striving to secure action and effective action. It has amazed me to watch him preside, it might be, over a conference on poliomyelitis and to see him display his wonderful flair for ordered discussion and his real understanding of the subject in hand. His versatility was not that of the briefed barrister. Truly Fletcher's scientific discipline stood him well. Eighteen annual reports of his Council will inform the medical historian of the future what Fletcher did and what he strove to do to further the work and influence of an organisation which has abundantly justified its national character, but, without their aid, his memory will long remain green in the hearts of those who knew and loved and admired him. J. C. G. L.

influenza-virus-discovery-mrc-nimr

2013-07-08-the-guardian-80-yrs-ago-mrc-researchers-discover-viral-case-of-flu

80 years ago today: MRC researchers discover viral cause of flu

Forget bird flu and swine flu, it was ferret flu and The Field magazine that helped MRC scientists discover the influenza virus, after eleven years of dedicated research.

Long term programmes and dedicated researchers: Mr Dennis Busby was one of the youngest recruits to the flu research programme, starting as a lab technician for the NIMR in 1934, aged just 15. Pictured here in 1969, and in 2013 at the MRC’s centenary celebrations. Picture courtesy of the Archives of the NIMR at Mill Hill (c) 2013 and Mr Busby.

Michael Bresalier

Mon 8 Jul 2013 02.30 EDT

In the spring of 1933 a team of Medical Research Council (MRC) staff gathered nasal fluids and throat garglings from a sick researcher, filtered them, and dripped them into ferrets. Within forty-eight hours the ferrets would start sneezing and displaying signs of an influenza-like disease. This research formed the basis of an extraordinarily important Lancet paper by Wilson Smith, Christopher H Andrewes and Patrick Laidlaw, published on 8 July 1933, identifying a 'virus' as the primary causative agent for influenza. This was no serendipitous finding, but the result of a sustained campaign of funding and research.

The 1918-9 influenza pandemic and virus research

The 1918-19 influenza pandemic challenged ideas about influenza, as at the time most microbiologists believed that influenza was caused by a bacteria. But during the pandemic, pathologists failed to consistently find the bacillus. This undermined claims about its primary role and jeopardised the prospect of producing a vaccine.

Walter Morley Fletcher, Secretary of the MRC, suggested to the War Office and Army Medical Services that attention should be turned to the possible role of a so-called 'filter-passing virus', and in November 1918 the search for the virus began. The first British investigations into the role of a virus in influenza were carried out by two teams in France and within weeks both claimed they had identified a filterable agent from sick servicemen.

These findings were controversial - there was no test for a virus, so its presence had to be inferred: it could not be seen with light microscopes, retained by bacterial filters or studied using culture methods. Only the presence of symptoms, and traces in serological tests suggested any 'thing' was present in infected people (and animals).

In the summer of 1922 Laidlaw was recruited to the MRC's National Institute of Medical Research (NIMR) to develop a project on "diseases probably caused by filter-passing organisms." Although such organisms had been identified as the probable causes of many infectious diseases they had eluded standard laboratory techniques, so new methods had to be developed using 'model' diseases in animals. Canine distemper was selected as the model for influenza, and for over a decade Laidlaw and the resident veterinary pathologist, G. W. Dunkin, used distemper to build virus research at the Institute.

The Distemper Experience

The research attracted some powerful patrons. The Field, a country and field sports magazine, already had a Distemper fund to finance work on the disease, and in October 1922 The Field's editor, Sir Theodore Crooke, proposed to Fletcher that the fund should be devoted to supporting Laidlaw and Dunkin.

This money enabled the MRC to develop new laboratories on a forty-acre agricultural site at Mill Hill , which included space to breed and house dogs, as well as a laboratory and isolation/quarantine unit. Until 1924, Laidlaw and Dunkin used puppies bred at Mill Hill to experiment on distemper, but dogs were not ideal experimental animals. Dogs presented an awkwardly variable clinical picture, they were expensive and slow to breed, sometimes hard to handle, and attracted vociferous antivivisection protests. So in late 1924, they introduced the ferret as a new experimental animal, marking the start of a long scientific career.

Laidlaw and Dunkin attributed much of their success on distemper to their work with the ferret; they developed an experimental vaccine for ferret distemper in 1926, then modified for dogs in 1927. Burroughs-Wellcome started commercial production in 1928, and by 1931 the vaccine was protecting the nation's dogs. This scientific and commercial success legitimised the NIMR's approach to virus diseases. Its primary goal became virus identification and control through the production of serological assays, therapeutic sera, and vaccines.

New interest in applying this approach to influenza was sparked in 1931, when the American researcher, Richard E. Shope announced that a combination of a bacillus and a filterable virus produced a disease in pigs – 'hog flu' – analogous to human influenza.

Ferret Flu

In late 1932 the MRC decided to concentrate on influenza, placing the research under Laidlaw's control, with experienced virus researchers Smith and Andrewes. At the time, the main obstacle for virus researchers was that they lacked a viable experimental animal to study influenza. Solving this problem was the team's first task.

Through January 1933 they tested nasal and lung material taken from influenza patients on rats, mice, guinea pigs, monkeys, pigs and horses. These efforts failed. They then turned to the ferrets at Mill Hill. In early February 1933, Smith dripped ("instilled") filtered nasal and throat garglings taken from Andrewes, who had himself caught influenza, into the noses of two ferrets. Unfortunately, before Smith could isolate the virus a distemper out-break destroyed the experiment. By chance, Smith himself caught influenza on 4 March, and this time Andrewes used his throat garglings and his instillation method to infect some ferrets.

They quickly identified the infecting agent as a virus on the basis that it was filterable, invisible, and not cultivable, but still produced disease in the animal. They named it "W.S." and it became the NIMR's master strain. Through spring 1933, they traced "the full course of [the] illness" in 64 ferrets, noting the analogies of "ferret flu" to human influenza. They were now able to develop a serological test showing that recovered ferrets had antibodies which inhibited the disease, an important piece of evidence in establishing the identity and role of the virus. With this test it was possible to trace neutralising antibodies in sick and healthy Londoners, and thus determine the presence of the virus in the human population. At the same time, they compared their virus antibodies with those identified by Shope in hog flu, to show that their virus specifically produced human influenza.

Smith, Andrewes and Laidlaw made a cautious claim in their report to the Lancet that,

the evidence strongly suggests that there is a virus element in epidemic influenza, and we believe that the virus is of great importance in the aetiology of the human disease.

The report caused a minor media sensation. The Lancet editorialized that it "offered almost conclusive evidence that the primary cause of human influenza is a filterable virus."

Within the year, researchers in other parts of the world confirmed the research. In 1934 mice began to be used in research, followed in 1940 by the developing chick egg, but the ferret and the virus model have become integral to new ways of understanding and controlling influenza. Experimental vaccines were produced in 1936 by Smith, Andrewes and Charles Herbert Stuart-Harris, and in 1947 the NIMR was designated as the World Influenza Centre of the World Health Organization. Work on the 'flu virus also spawned unexpected findings, such as the discovery of Interferon – a protein associated with immune responses – by NIMR researchers Alick Isaacs and Jean Lindenmann in 1957.

The NIMR's success came so quickly only because so much had been put in place in the previous decade. The experience of the 1918-19 pandemic and the MRC's development of virus research created the conditions for the success of 1933. The story is a reminder of the crucial role of the MRC and government-supported research in spurring scientific innovation through sustained funding.

Michael Bresalier is a historian of medicine at Imperial College London. His forthcoming book, "Making Flu: British Medical Science and the Definition of a Virus Disease", will be published by Palgrave. You can read more about his work on influenza and viruses here

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