Richard Hankins Ph.D. Adis International Ltd.
Previous Page Malaria Therapy American Research Network 1918-1945 Norman Stoll William Taliaferro Sir Alfred Lewis Jones Laboratory-Liverpool
Whilst many authors have traced the origins of immunology back to the late nineteenth century they have concentrated on issues of immunity to microbiological pathogens or studies of autoimmunity. Few have considered the political relations of immunological studies of parasitism. This paper examines these relations in the inter-war period across a number of countries and locates a vastly differing social and economic relations.
Early in the inter-war period the development of malaria therapy for the treatment of general paralysis of the insane provided new opportunities in human experimentation. Immunological approaches were applied and as a result debates surrounding racial immunities to malaria resurfaced. Following an account of the relationship between malaria therapy and immunological studies this article seeks to provide a comparative history of the development of parasite immunology in the U.K. and U.S.A.
In America the inter-war period is characterised by the development of an identifiable parasite immunology research network. The members of this group communicated and shared technologies. These developments were associated with the institutionalisation of parasite immunology studies within high status institutions such as the University of Chicago, Johns Hopkins University and the Rockefeller Institute. Certain actors can be seen as being central to the developing field. William W. Cort's School of Hygiene at Johns Hopkins supplied the developing network with many new students who continued to work on host parasite interactions. Norman Stoll at the Rockefeller Institute did not train students, but the research group he created (predominantly Cort trained) introduced important technical and intellectual stimulants to a decreasingly fragmented field. William Taliaferro collected the information being generated into a single volume, trained a number of students and published extensively over several decades.
By the outbreak of World War II, American parasitologists - and even parasite immunologists - were a sufficiently defined group to be mobilised within the `total war' effort. By comparison, with the exception of malaria therapy associated work, British involvement in parasite immunology was almost completely absent. An exception was a research programme into the immune response towards the tumbu fly which was carried out by the staff of the Liverpool School of Tropical Medicine in Sierra Leone. The social, economic and political history of this episode is examined, and the factors that encouraged the staff of a tropical medicine laboratory to work on an essentially agricultural problem are articulated.
Contrasting continuity and discontinuity is evident throughout. The disparateness of British developments is similar to the pre-war era. By contrast, the increasing institutional and political role of American actors is radically different from the situation earlier in the century. Such differences can be explained in a number of ways. The tradition of British tropical medicine as essentially a field science may have discouraged laboratory based studies in the UK. Such a strong tradition did not exist in the United States and the field developed variously in schools of Hygiene, zoology departments and research institutes. Further, in America considerable amounts of Rockefeller money was available for parasite immunology work, with Stoll, Cort and Taliaferro all receiving patronage. The availability of such money was clearly a major stimulant in the States. Whatever factors prevailed, by the end of World War II America had yielded a considerable literature on metazoan and protozoan immunology including two reviews in the form of books. By comparison, literature from the UK remained disparate and fragmented.
This article uses a variety of sources.
Scientific publications and secondary literature provide an insight into malaria
therapy in the UK. The Rockefeller archives have yielded considerable amounts
of previously unexplored material regarding Norman Stoll, Theobald Smith and
William Taliaferro. Much biographical information has been gleaned from the
University of Nebraska State Museum's `Parasitologists of the World' archive.
The records of the Sir Alfred Lewis Jones Laboratory and related correspondance
form an important and thorough archival resource. Using such a breadth of sources
it has been possible to address relevant biographical, scientific, institutional
and economic factors in this period.
Malaria Therapy and Immunological Research
The practice of treating general paralysis of the insane (G.P.I), a debilitating neurological outcome of uncontrolled syphilis, through deliberate infection with malaria was developed in continental Europe shortly before World War One. As Magda Whitrow has shown, the curative effect of fever on neurological disease had been noted as early as Hippocrates and Galen. Similarly, Sydenham and Boerhaave were aware of the advantages of feverish complications.
The experimentation that led to the development of malaria therapy was inspired by chance observation. Shortly after a newly trained Austrian psychiatrist, Julius Wagner von Jauregg, began work at the Asylum of Lower Austria in Vienna, he observed the recovery from a severe mental illness of a woman following an infection of erysipelas. Wagner von Jauregg searched the literature for similar cases and in 1887 wrote a review article on the subject. Between this date and 1917 he experimented with injections of streptococcal material, tuberculin and Bacillus pyocyaneus in attempts to induce therapeutic fevers. These experiments produced some limited successes but did not become accepted techniques. In June of that year however, a soldier was admitted to Wagner von Jauregg's hospital, who subsequently developed malarial symptoms. Wagner von Jauregg used the blood of this patient to inoculate a number of sufferers of G.P.I., and from them transferred the infection to a number of other patients. In total nine were inoculated, of whom one died, two showed little improvement and soon entered an asylum, and six showed considerable improvement. Some of the patients who most benefited were able to return to work although four eventually suffered relapses.
The introduction of the new technique into the UK was delayed by the death of three of Wagner von Jauregg's patients following accidental inoculation with the virulent and uncontrollable Malaria tropica, and the outbreak of World War One. It was not until July 1922 that Warrington Yorke, Professor of Parasitology at the Liverpool School of Tropical Medicine, and John W.S. Macfie, Director of Medical Research for the Gold Coast, deliberately induced malaria in a syphilitic patient for the first time in the UK. Yorke presented their results verbally to a meeting of the Royal Society of Tropical Medicine and Hygiene. Of 84 paretics who had been treated and observed 23 were considered `provisionally cured' and a further seventeen showed distinct mental and physical improvement. Whilst the treatment had met with successes fourteen patients had died around the time of malaria treatment and it was `impossible to affirm that in none of them was death accelerated by the malaria'. One patient had been infected with malignant tertian malaria with a fatal outcome.
This earliest work established a link between malaria therapy and immunology. Yorke and Macfie argued that quinine therapy in itself never destroyed all the malaria parasites. This they contested was heavily supported by the fact that relapses occasionally occurred amongst patients who had been infected with the same strains of malaria and subsequently treated similarly. Such curative failures they postulated was the result of inconsistencies in the individual's response rather that the action of quinine:
In the treatment of malaria, the train of events is in our opinion as follows:-Quinine given to a patient whose blood contains numerous malaria parasites invariably destroys directly, or more probably indirectly, large numbers, but not all, of the parasites, thus setting free a considerable quantity of soluble antigen. The antigen provokes by stimulation of the host's tissues the formation of immune-body. The immune-body, if present in sufficient amount, destroys the remaining parasites, thus resulting in sterilisation of the infection and in the cure of the patient. For a cure to be obtained, this hypothesis demands firstly, the setting free of a considerable quantity of antigen by the destruction of a large number of parasites, and, secondly, a capacity on the part of the host to respond to the antigen by the formation of a sufficient quantity of immune-body. If, for any reason, either of these two requirements is not satisfied, the infection is not completely sterilised and a relapse occurs.
Yorke and Macfie claimed that there could be `little doubt' that `the human host exhibits a certain degree of natural immunity to malarial infection and that this is capable of being increased in response to the proper stimulus.' They went on to quote four points of evidence in detail. These included the variance in incubation periods between individuals, failures to inoculate successfully, spontaneous cure in nature and sub-clinical infections in endemic areas.
The immunological basis proposed by Yorke and Macfie to explain the effectivness of quinine was not readily accepted by the audience. Colonel S.P. James, Adviser on Tropical Diseases to the Department of Health, suggested that `"susceptibility," "immunity," "tolerance to the effects of parasite invasion," and "individual resistance"' were all debatable and the issues too complex to address in a paper of this nature. Further, he postulated that the failure of the parasites to develop in certain individuals was the product of their undernourishment or generally feeble health. If such was true, he argued, then Macfie and Yorke would be required to modify completely their argument. C.M. Wenyon similarly disputed the immunological basis suggesting that it would take a longer time for immune bodies to be produced.
Despite these attacks on their immunological theory of quinine response Yorke and Macfie remained resilient. Yorke answered in response to Wenyon's comments that he had misunderstood the time period, it was not three days that was relevant for the prevention of a relapse but three weeks. In his closing remarks he announced that despite the criticisms levelled he saw no reason to abandon the theory as stated:
Dr Macfie and I have given our theory prolonged and careful consideration, and believe that it affords the explanation of the various facts which have emerged in connection with quinine treatment of malaria; and I think I can say that, in the most interesting discussion which has taken place to-night, we have not heard anything which would give us cause to abandon or even to modify the theory.
The public health and safety aspects of malaria therapy caused some concern. Fearing transmission of the disease Wagner von Jauregg himself had tasked a more able patient to search the grounds of the hospital for anopheles following his first deliberate infection. In 1923 Dr P. Mühlens of the Institut fur Schiffs- und Tropenkranheiten, Hamburg, wrote a letter to the Klinische Wochenschrift. This was subsequently translated and published in the Journal of Mental Science under the title `The Dangers of the Fever Treatment of Paralysis'. Mühlens believed that `indiscriminate and free use [of malaria therapy] in private practice' was `generally dangerous'. In his subsequent recommendations he made it clear that the technique presented dangers not only for the patient, but for the population of the institution and its surroundings. Consequently, he held that the technique should be limited to `well-conducted institutions free from anopheles and vermin' which were also to have the facilities for `daily expert blood tests'.
It was not only in Germany that concerns were raised regarding the safety of the procedure. In England and Wales the Board of Control had been involved in limited trials and consultation with the Ministry of Health. Informed by these activities in February 1924 O.E. Dickinson, the Secretary of the Board wrote to the senior officers of each hospital and licensed house. He reported that the inquiry had found methodological inconsistencies in the procedure not only between Austria and the UK but also between individual hospitals in England and Wales. The high number of fatalities and the risk to the general population which had been emphasised by experiments that had shown the common British mosquito, Anopheles maculipennis, to be a capable malaria vector, required that some degree of regulation was enforced. Consequently, six rules were `recommended for adoption':
(1) The hospital should be
adequately equipped with laboratory facilities for systematic blood
examinations, which, as regards all inoculated patients, should be made daily
from the date of onset of the first febrile attack.
(2) The medical officer or laboratory assistant, who makes the microscopic blood examinations should be well qualified in this branch of laboratory work.
(3) The patients undergoing the course of treatment should be in charge of a medical officer who is familiar with malaria in all its aspects. During the period of the course the patients should be nursed and nourished with special care, and the progress of the infection should be modified or controlled from day to day, in accordance with the laboratory findings and clinical signs.
(4) From the 1st April until the 30th October, patients undergoing the course of treatment should be kept in a mosquito-proof ward or under satisfactory mosquito curtains during the period when parasites are present in their blood.
(5) Treatment by induced malaria should be confined to hospitals in which all the above rules are complied with.
(6) Notification of cases of inoculated malaria to the local medical officer of health under the Public Health (pneumonia, malaria, dysentery, etc.) Regulations, 1919, will not be required until the patient is discharged from the hospital, when his name and home address with an intimation that he has undergone a course of inoculated malaria should be notified to the medical officer of health of the district in which he will reside.
Following increased interest in malaria therapy a specialist centre was founded by the ministry of health, board of control and London County Council at Epsom, Surrey in 1925. The Horton Malaria Laboratory was intended to provide facilities for clinical practice as well as research into malaria therapy and malaria. According to the laboratories one time Director, Sir Gordon Covell, the association of research with malaria therapy `rendered possible for the first time a detailed study of the clinical as well as of the parasitological aspects of all forms of human malaria in non-immune subjects throughout the entire course of the disease.' These opportunities were to radically alter contemporary knowledge of malarial infection. Not only did research on syphilitic subjects lead to the recognition of the pre-erythrocytic stage of malaria but they also allowed more closely controlled observations than had previously been possible. The outcomes were numerous. The existence of a profound immunity to the Madagascar strain upon reinfection was demonstrated by Shortt and Garnham in a patient who had undergone malaria therapy two years previously. Further, the laboratories first Director, S.P. James, was able to demonstrate that acquired tolerance was strain specific. The very highly controlled environment at Horton and the access to patients who had almost certainly not previously been exposed allowed the development of resistance to be studied in detail. Consequently, it was shown that whilst a single infection of Plasmodium falciparum often failed to induce complete resistance to that strain, subsequent exposure may eventually do so.
The immunological researches at Horton were clearly important and the discovery of the liver stage in P. vivax was a seminal event in the history of malariology. However, it was in the United States that related research caused the greatest controversy. The highly multiracial American population facilitated studies of immunity in whites and negroes - the result was the resurgence of racial immunology. In 1933 Mark F. Boyd M.D. (Rockefeller funded Director of the Station for Field Studies of Malaria, Tallahassee, Florida) and his medically trained assistant Warren K. Stratman-Thomas, published a paper announcing that negroes were refractory to infection with vivax malaria. Boyd's interest in racial aspects of tropical disease wasn't new. As early as 1927 Boyd was studying malaria in negro school children by measuring their spleen indices. In the spring of 1928 whilst on a study trip to Jamaica he had annoyed a local doctor so much by his questions on the racial incidence of Blackwater fever that the Doctor reportedly `went off on an anti American tirade'. Boyd's reaction to this was somewhat harsh: `Evidently he has an anti American complex, or feels the color line'.
Boyd's attitudes should be interpreted within the context of the 1930s segregated Southern States of America. However, it is worthy of note that his attitudes were at times unsympathetic towards negroes. In 1928 he complained bitterly to his sponsors, the Rockefeller Foundation, that the ship he travelled on from Jamaica not only possessed a `negro crew' but there were also `several negroes and colored people among the passengers.' Symptomatic of these attitudes was the tendency of Boyd to refer to negro subjects on whom mosquitoes had been caught simply as `bait'.
In 1931 Boyd was moved from the
Station for Field Studies of Malaria, Edenton, N.C. to the Station for Field
Studies of Malaria, Tallahassee, Florida. Once in his new location Boyd and his
new assistant Stratman-Thomas, forged links with local hospitals and began
experimentation on syphilitics almost immediately. Their work initially
concentrated on homologous immunity in malarial infection, but by the second
quarter of 1932 they were beginning the seventh series of cases to be used in
the demonstration of negro tolerance. Their work was a little delayed after
Stratman-Thomas developed malaria following a bite from one of the experimental
mosquitoes. Also, a Mr S, one of the experimental subjects died although Boyd
was sure this was the result of paresis rather than malarial infection.
Despite these hindrances by August 17th Boyd was preparing to experiment on Ms I.L.J, a five year old negro child with hereditary syphilis.
In the resultant paper Boyd and Stratman-Thomas described the case histories of six male negro syphilitics. All had been fed upon by mosquitoes that infected white controls prior to and post feeding on the negro patient. Of the six negroes three failed to show any signs of infection whilst the other three suffered only mild malaria. All the white controls suffered fevers and so the authors concluded that there was `a very evident refractoriness of negroes to Plasmodium vivax inoculation.' It was not clear however, whether the immunity was `natural or acquired'. The opportunity of experimenting on a child therefore, presented the possibility of demonstrating the heritability or not of the refractory state. The reported failure of the child to develop malaria when fed upon by mosquitoes that successfully infected white controls, allowed the authors to reach a broad conclusion:
It would appear from these observations that negroes usually exhibit a high degree of tolerance to P. vivax inoculations. In most individuals this resistance seems to be absolute, but occasionally it is found to be only relatively high in comparison with that shown by whites. The high degree of tolerance exhibited by a negro child whose blood examinations over a period of weeks after inoculation were consistently negative, suggests that this tolerance or resistance is a racial rather than acquired characteristic.
Once Boyd and Stratman-Thomas had eliminated the possibility of the use of vivax malaria for GPI treatment in negroes through their demonstration of immunity, they found the opportunity to begin research upon a new parasite. On the third of February 1933 they began inoculating syphilitic patients with the more virulent and dangerous Plasmodium falciparum. Whilst Boyd's personal papers show that these experiments included infecting at least one white patient the subsequent publication reported the details of experiments on negroes only. The obvious acceptability of experimentation on negroes in the Southern States of America in the thirties, probably contrasted greatly with the politics of subjecting whites to a potentially fatal disease. Subsequently, Boyd and his colleagues published only work solely on negroes. The potential danger of this experimental procedure was recognised by Boyd who as a safeguard arranged for Stratman-Thomas to live at the hospital whilst the patients were in `the acute phase.'
Boyd, Stratman-Thomas and S.F. Kitchen published the results of their researches in the American Journal of Tropical Medicine. Despite their claim that the experimentation was solely on negroes they made general arguments in their conclusion without recourse to race. This is anomalous in that their previous works had highlighted racial differences. Through their experiments they claimed to have demonstrated an acquired homologous immunity to P. falciparum. This immunity could exist in the presence of a latent infection for up to four months and was believed to be effected against the trophozoite stages.
In 1942 Boyd acknowledged that many whites possessed a refractoriness to vivax infection. Data gathered at the Florida State Hospital over a ten year period revealed that `white patients infected with vivax malaria show great variation in the character and duration of the subsequent infection they experience.' In fact in some sixty-nine white patients exposure to vivax infected mosquitoes failed to induce an infection at all. Boyd concluded that whilst many whites possessed a `pristine susceptibility, others exhibited evidence of previous autochthonous infection'. Whereas in the Negro Boyd had carried out experimentation on a child to determine the supposed hereditary nature of the condition, he did not try to repeat this experimentation in whites. Instead, he was happy to conclude with very limited evidence that the immune state in the white was an acquired condition.
Boyd's findings regarding vivax immunity in the negro and acquired immunity in residents of the Southeastern States were verified by a US military study with which he collaborated. Becker, Kaplan and Read of the Medical Corp, Army of the United States, had recorded their experiences of treating 300 soldiers (225 white and 75 negro) with malaria therapy. Whites were usually treated with P. vivax unless there was evidence of previous exposure. Negroes received initially P. malariĉ but in individuals where the resultant infection was inadequate a further inoculation was made with falciparum malaria. Using data gathered from daily parasite counts and hourly temperature records the authors proposed that four states of immunity or susceptibility to malaria be recognised: `hyperimmune', `immune', `partially immune' and `hypersusceptible'. The hyperimmune individual was a rarity one would not expect to encounter in the clinical situation. Such a person showed neither a parasitemia nor a rise in temperature following infection with 50 to 100 million trophozoites. The cause of this profound resistance it was believed was a homologous immunity due to the individual `presumably having had previous experience with the same strain of malaria.' The immune patient suffered a slight parasitemia and rise in temperature to less than 100°F. This state was most commonly seen in negroes in whom it apparently represented the innate immunity described by Boyd in 1933. Its occurrence in whites, however, was to be `taken as evidence that they have had previous experience with a homologous strain of malaria.' The partially immune group could be split further into two subdivisions: `(a) those experiencing five or less paroxysms of fever to 103°F., and (b) those experiencing 6 to 10 such episodes.' This partial immunity it was believed was the product of heterologous immunity through prior exposure to a similar (although different) malarial parasite.
Whilst the discoveries of Boyd, Stratman-Thomas and colleagues had important medical ramifications in the treatment of G.P.I., they were also potentially important for military strategists. A limited amount of data on the racial epidemiology of natural malaria infections in Southern school children had been gathered. This information suggested that negro children were over five times more likely than white school children to carry a parasitaemia at any one time. However, vivax accounted for a smaller proportion of these infections (18.6%) in the negro than in the white (57.2%). The meanings of these findings were unclear as access to antimalarials was not equal between the two groups. With the outbreak of World War Two and the involvement of American forces in the highly malarious South Pacific region it was recognised that `the availability of troops possessing actual resistance to vivax, partial or complete, would naturally be a military asset of importance'. The vivax malaria prevalent in this area possessed a prolonged course `and was productive of great loss in time and efficiency on advance combat bases' . To examine the racial variation in the frequency of malarial infection and relapse in this region, Commander Fred Butler and Captain James Sapero of the U.S. Navy, collected statistics on a mixed group of troops stationed on a malarious island for eleven months. The group consisted of several thousand troops of whom 28% were negroes largely from Georgia and the Carolinas.
The difference that conventional wisdom had accepted for over a decade was not demonstrated when natural transmission was studied on a large scale. In fact:
`Incubation period, clinical severity, response to antimalarial drugs, frequency of recurrences and man days lost were, as nearly as could be determined under routine military conditions, virtually identical among the two races'.
Butler and Sapero concluded that negro immunity did not exist. With these findings any intended policy of favouring the deployment of negro troops into malarious districts lacked scientific legitimation. Butler and Sapero's convincing refutation of negro immunity marked the closure of debates on racial immunity to malaria. With the increasing availability of antibiotics in the post war years the incidence of G.P.I. declined sharply and the associated practice of malaria therapy soon became redundant. Consequently, the significance and influence of works on immunity in therapeutic malaria was curtailed. The issue of racial immunity which had been so current at the turn of the century and had regained prominence through the development of malaria therapy did not become prominent again.
The Development of an American Research Network 1918 -1945.
The founding of the American Society of Parasitology early in the century was symptomatic of the advanced nature and increasing interest in parasitology in America. This was often linked to the interests of the Rockefeller Foundation, especially with regards to hookworm and malaria. Agriculturally-based works continued to be of considerable significance however. In this period the links between agricultural and medical parasitology were very close, with some scientists working on both human and animal infections. This intimate relationship led to one of the most important discoveries in the developing field of parasite immunology. In the inter-war period American parasitology developed a new level of cohesion. The disparate developments of the earlier years matured into the activities of a recognisable network of scientists. The attached diagram which is based only on a limited review of conference attendances, joint publications and surviving letters demonstrates the complexity of the network and the centrality of actors such as Norman R. Stoll, William H. Taliaferro and William W. Cort. The limited nature of the material reviewed suggests that communication between parasite immunologists at this time was in reality far more complex than shown, with many peripheral workers omitted from the survey.
Certain loci were central to inter-war developments in parasite immunology. W.W. Cort's group at the Johns Hopkins School of Hygiene was possibly the most influential due to its large number of postgraduate students. Norman Stoll's group at the Rockefeller Institute was staffed largely by former students of Cort. Whilst Stoll's group did not train students it influenced the emerging field through important conceptual developments. The other notable group was that headed by William Taliaferro. Taliaferro had worked with Cort as a member of faculty at Johns Hopkins and was assisted by his wife, Lucy Taliaferro, who had studied for her Sc.D. as a member of the Johns Hopkins school.
Around Johns Hopkins and the helminthologist W.W. Cort a group formed that possesed many of the characteristics outlined by Jack Morrell in his 1972 description of a research school. William Cort's school was built around the reputation of its Director. This reputation attracted many students who subsequently worked on a shared field of study, i.e. host-parasite interactions. Facilities for publication appear to have been readily available and Cort was able to place many of his students in high status positions upon their graduation. Cort was not however, the only important parasitologist at Hopkins. Other faculty included such eminent scientists as R.W. Hegner and W.H. Taliaferro, both of whom had interests in the immunology of parasitic infections. Students of the school included many of the first generation of laboratory trained parasite immunologists including J.H. Sandground, Lucy Taliaferro, H.W. Brown, G.F. Otto, M.P Sarles, J.E. Stumberg, A.O. Foster and E.H. Sadun. Cort himself was of considerable academic pedigree having studied under Leuckhart's student, Henry B. Ward. Initially based at the University of Lincoln, Nebraska, Ward had moved to the University of Illinois in order to found a research and training laboratory based on a German model. Whilst at Illinois Ward founded the Journal of Parasitology and subsequently became the first president of the American Society of Parasitologists.
Cort's primary helminthological interest was in the study of hookworm infections of man. According to Stoll, this was an unusual topic to choose at this time. He claimed it was believed that the hookworm problem was fully understood and anyway with the Rockefeller Foundation's interventions promising eradication in the near future the laboratory study of these parasites was unattractive. Despite this Cort secured funding from the International Health Board of the Rockefeller Foundation and organised a number of expeditions to the Caribbean and Central America (Trinidad 1921, Puerto Rico 1922, Panama 1926). In 1923 -1924 Cort was exchange Professor at the Peking Union Medical College where he used his change of location to facilitate a broad study of the distribution and epidemiology of hookworm in that country. Throughout these studies Cort was accompanied by graduate students and recent doctoral graduates. The first expedition to Trinidad was attended by Donald Augustine and Florence Payne in this role. The second expedition ventured to Puerto Rico with Norman R. Stoll as the attending graduate student. The final expedition visited Panama with Stoll now in the role of postdoctoral fellow and Harold W. Brown fulfilling the role of graduate student. In future years Brown would take the chair in parasitology at Columbia, Augustine would take the chair of tropical public health at Harvard and Stoll would eventually become Member and Professor at the Rockefeller University.
Norman Stoll and the Development of Parasite Immunology
Of these early notable parasite immunologists it was Norman Stoll that was to have greatest impact on the development of the subject. Stoll entered parasitology via a circuitous route. After attending one year at Syracuse University he was forced to leave due to financial difficulties. Subsequently, he worked for a trade newspaper in the construction industry before, the generosity of a relative afforded him the opportunity to complete his undergraduate studies at Mount Union College, Alliance, Ohio. On completion of his degree Stoll went back to journalism working as a reporter on the Alliance Review before accepting a post as a biology teacher. Having studied almost no biology in his degree it was during this year (in which he studied hard to accumulate the appropriate knowledge) that Norman developed an interest in biology that was to shape his professional life. To increase his knowledge Stoll registered for a part time Masters degree in zoology at the University of Michigan, Ann Arbor. His lack of formal training impeded his progress however, as he was required to take a number of courses to qualify as a full graduate student. Despite conscription and the death of his father, Stoll completed his genetics-based masters in 1918 and on release from his war work accepted the post of head of science at Detroit Central High School. In this post Stoll continued to develop his interests in biology by spending his summers at the University of Michigan Biologic Station. Pragmatic considerations led Stoll to conclude that genetics was an inappropriate subject to study for a part time doctorate. As he had only the summers available for research he required a subject area in which the experimentation would be less laborious. Consequently, he began to develop his interests in limnology which he felt provided the opportunity for a more manageable research project. It was through these summers at the Biologic Station that he became acquainted with Professor W.W. Cort who had recently been appointed to the Johns Hopkins School of Hygiene and Public Health. Cort too was in the process of changing his research interests. Recent contact with field officers in the Rockefeller hookworm campaigns had enlightened him as to the scale of the anchylostomiasis problem. As a result he chose to investigate human helminthiasis in preference to his intended trematode researches. A friendship developed between the two men and in February 1921 Cort wrote to Stoll inviting him to fill the vacant place in the project subject to a scholarship becoming available. Seeing this as an opportunity to gain his doctorate more rapidly Stoll accepted the offer and in 1922 after moving to Baltimore became a member of the Puerto Rico expedition.
The expedition concentrated predominantly on epidemiological studies and included studies of infection levels in sugar and coffee estates, a small village and a mountainous region. In 1923 Stoll accompanied Cort as a member of the China Hookworm Commission which revealed for the first time the levels of infection in the Orient. Subsequently, Stoll was a member of the 1926 Panama expedition which again concentrated on epidemiological and life history studies.
Following completion of his Sc.D., in 1926 whilst associate in parasitology at Johns Hopkins, Stoll was offered a Chair at the University of Puerto Rico. This post would have afforded him the opportunity to expand his interests in human helminthiasis. However, Cort had expressed his enthusiasm regarding Stoll's potential to the eminent pathologist Theobold Smith, who was then Director of the Department of Animal Pathology at the Rockefeller Institute. In response Smith wrote to the Director of the Rockefeller Institute, Simon Flexner, describing the post that Stoll had been offered in Puerto Rico and asking Flexner to find out more about him. Subsequently, Flexner and Stoll met in the second week of March 1926 and discussed the opportunities available at Smith's Princeton laboratory. On the fifteenth of March Stoll submitted an application for work at the Rockefeller Institute. According to his application he intended to carry out studies on `the general experimental problem of the host-parasite relation with special reference to the effects on both parasite and host and methods of measuring and evaluating the same'. Aware that Stoll was already considering one offer Flexner replied with a full job offer just four days later. The post of associate member at the Rockefeller Institute was arguably of lower status than the full chair at Puerto Rico and provided significantly less income. However, for Stoll the opportunity to work with Theobold Smith `the outstanding experimental pathologist of his era' was very attractive and so he joined the Rockefeller laboratory in New Jersey.
Imbued with the host- parasite inter-relational interests of the Cort group, Stoll arrived in Princeton with the intention of studying the host parasite relations with special reference to reinfection rates of Halig Maselamiros in the rat. Stoll considered this gut nematode a good model of human hookworm infection. However, a system that matched more closely the interests of the Department of Animal pathology was to be found at the Princeton laboratories. Smith had developed a line of almost parasite-free sheep during his studies of diarrhoea in livestock. This had been achieved by removing sheep from their mother at birth and rearing them on cows' milk in a clean environment. With this material available Stoll decided to use the economically important Haemonchus contortus infection in his experiments. Stoll cultured Haemonchus and infected one of the parasite-free lambs. This lamb was then put to pasture with an uninfected parasite free lamb in an enclosure. Infection levels were monitored using an adaption of an egg counting technique that Stoll had been so influential in developing some years earlier whilst studying hookworm.
Based on contemporary assumptions
the experiment was designed to test what length of time and what level of
parasitic assault was necessary to bring about a fatality. The relationship was,
however, shown to be more complex than a simple positive correlation between
intensity of infection and death rate. Instead of an increasing infection
leading eventually to the animal's death Stoll observed susceptibility to the
infection followed by a sudden and unpredictable cure. Subsequent exposure to
infective larvae failed to produce infection. In his initial report on the
matter to the Helminthological Society of Washington he suggested that the
observations may be the product of the `special conditions' appertaining. At a
meeting of the Society in 1929 however, Stoll was able to report that the most
likely experimental consideration - the use of a less pathogenic strain of
Haemonchus in the experiments - was not the cause of the phenomena observed.
This had been shown by the occurrence of a single fatality amongst sheep used in
a replication of the earlier experiment.
Despite his own evidence Stoll did not have the conviction to challenge directly the orthodoxy. Both himself and his respected adviser, Theobald Smith, held so strongly to the contemporary belief `that worm parasites were not able to produce an effective immunity' that he chose to develop his own terminology that would be independent of the language of the immunological tradition. Consequently, he used the terms `self-cure', `resistance' and `protection' to describe his observations. These apprehensions were enduring, with Theobald Smith using the word immune in quotation marks as late as 1931.
Resistance to gut helminths became a long term research area for Stoll. A couple of years after his demonstration of the phenomena in sheep, he reported similar observations in the goat. Stoll continued Haemonchus experiments in sheep for fifteen years. During this period he was able to examine the significance of many factors including the strains of sheep used, diet and concurrent infections with more than one gut helminth. Stoll also began to examine the diagnostic and prophylactic implications of the demonstrated immune response. In collaboration with Dr J.B. Nelson also of the Rockefeller Institute he was able to demonstrate that sheep produced little precipitin when horse serum and dried Haemonchus were used as antigens. Intradermal tests for Haemonchus were also attempted in sheep, goats, rabbits and guinea pigs. These researches suggested that sheep showed an `immediate hypersensitiveness' to intradermal injection of worm antigen. This was found to be a non-specific reaction, however, with sheep reacting not only to Haemonchus and Ascaris lumbricoides from which they regularly suffered but also eliciting responses to Macracanthorhynchus hirudinaceus which is unknown in sheep. The lack of specificity of these findings limited their potential use. Rather cynically Smith concluded in his annual report that `perhaps the contribution of most significance is that we can definitely exclude previous infection with worms as being necessary to the production of a positive skin reaction'.
The demonstration of a curative immune or self-cure response soon led Stoll to draw analogies between parasitic and bacterial immunology. Consequently, he was quick to try to emulate the successes in vaccination that had been demonstrated by bacteriologists. Stoll's prophylactic investigations began with attempts to induce resistance through the parenteral injection of dried Haemonchus suspended in saline. Preliminary results were extremely positive encouraging Stoll to conclude that `saline worm extracts given subcutaneously have both curative and protective effects against worm infestations'. A year later, however, the results of further investigations led Stoll to play down the protective effects of the administration of dried Haemonchus.
An experiment in progress, with both sheep and goats, indicates that parenteral injection of dried triturated Haemonchus in saline produces some protection against a heavy test dose of live worms, but less protection than infective Haemonchus larvae parenterally injected. A good quality of resistance appears to have been produced in a sheep by the latter method.
Attempts to develop an axenic culture of Haemonchus for use in injection took up many of the following years of Stoll's work often in collaboration with his colleague Dr R.W. Glazer. Whilst Glazer had earlier been successful in the axenic cultivation of protozoa and also a nematode parasite of the Japanese beetle Haemonchus was to prove a stumbling block. It was not until twelve years later in 1943 that Stoll was finally able to experiment with injections of axenic cultures of Haemonchus. The loss of many of these experimental animals through `poor feeding' coupled with Stoll's wartime commission into the American Navy finally terminated his involvement in this line of research. Entry into the Navy was not a matter of regret for Stoll. He had actively sought the commission to become involved in `project x'. At the time he justified this move in terms of operational significance and opportunities for professional development:
`The opportunity to bring my training and field experience into play directly in the war effort, as contemplated, naturally commands a strong professional interest'.
Many years later, however, he described how unhappy he had been at the Princeton laboratories in the years preceding the war when he had achieved little of academic value. Retrospectively he described his war service working on human helminthological problems as Lieutenant commander at the Naval Medical Research Unit number 2 on Guam as `a sort of release' from the `long lean years'. Stoll's attempts to develop a method of prophylaxis produced little of value despite the years of work he had invested. It has been claimed, however, that these experiments should be considered as forerunners to the works of Jarrett et al which would later lead to the development of an irradiated vaccine against Dictyocaulus viviparus in cattle. Regardless, it is difficult considering the differences in the approaches of the two groups to frame Stoll's work as a precursor of the development of `Dictol'.
Following Stoll's earliest and highest profile investigations in the sheep further workers were brought in to investigate the immunological basis of the `self cure' reaction. In 1930 Dr Merritt P. Sarles a young helminthologist began working under Stoll on the host-parasite relations of Trichostrongylus in the rabbit. This host-parasite system was chosen partly because Stoll was keen to demonstrate the generality of his discoveries. Pragmatic considerations were also important in the choice of model. As was noted in the annual report rabbits were smaller, easier to handle and cheaper than sheep. Stoll's research group was completed briefly by the arrival of John E. Stumberg who was a graduate of Cort's Hopkins school. Through this research group Stoll was further able to influence contemporary developments in parasite immunology. Sarles demonstrated resistance to Trichostrongylus calcaratus in the rabbit and went on to show that injections of the nematode could induce acquired resistance. Sarles also showed resistance to Ascaris infections in the cat. John Stumberg's membership of the group began well, rapidly producing two publications on the detection of parasitic proteins in sera of infected animals. However, his tragic death in a road accident on January 20 1933 ended prematurely a promising career.
The `high and meaningful adventure of spirit' as Stoll described his early years under Theobald Smith at the Rockefeller Institute clearly produced findings that were to become the cornerstone of a newly developing laboratory-based parasitic immunology. Why such an evident phenomena as `self cure' to nematodes had not been observed earlier is unclear. The diseases studied by Stoll and his group were not obscure. They were economically important, of interest to veteranary practitioners and scientists as well as biologists and had medically important related conditions. Smith associated the timing of the observation with the development of new technologies:
This [timing of the observation of self cure] does not seem difficult to explain in that worm infections have usually been studied for the purpose of securing adult worms in the host, rather than with the thought of studying the reaction of the host under conditions of continual reinfection. Moreover, the study of such an effect (except through the slaughter of numerous animals, all infected and handled alike, at successive stages of the infection) has waited upon the development of the technic of egg counting. It would appear that the information discoverable by such means of measuring the parasitic burden may profoundly modify our notion of the typical course of helminthic parasitism under conditions of continual reinfection.
Through the development of experimental technology Stoll had further influenced the field of helminthology. The egg count technique commonly known as the `Stoll dilution egg counting method' had been largely developed by Stoll during his doctoral studies at Johns Hopkins. The methodology was developed to facilitate the quantitative study of factors influencing the development of hookworm larvae in soil. Upon beginning this work he had found that `no such procedure was in general use'. Attempts had been made over the previous half-century to create a quantitative method. Stoll found the technique suggested by Lutz (1885) which involved counting eggs in a dilution of one part faeces to three parts water produced a solution that was too concentrated for accurate sampling. The method of Leichtenstern (1886) was reported to be of more use although the lack of uniformity in the size of the faecal sample and the volume of dilutant used introduced inaccuracies. The floatation method of Darling (1922) whilst producing uniform results appeared to produce inaccurately low readings. Finally, the smear techniques advocated by Smillie (1921) and Cort (1922) introduced variables in the volumes of water, faeces and the microscopic techniques used.
The method devised by Stoll offered the advantage of a much tighter standardisation coupled with a manageable concentration of eggs in the dilution produced. Further, Stoll's approach required no equipment that would not ordinarily be found in a rudimentary laboratory. The technique involved the suspension of three grams of faeces in 45cc of Sodium hydroxide. The recommended procedure to ensure an equal suspension involved inserting ten glass beads of three millimetres diameter into a tube containing the faeces and Sodium hydroxide, inserting a rubber stopper, and shaking for one minute. When dealing with very compact faeces `the tube was given a preliminary shaking and temporarily set aside. Reshaking then quickly produced an even suspension.' Once an even suspension was achieved 0.15cc of the solution was drawn from the vertically held tube. The entirety of this sample was then inserted under a number two cover slip and the total number of eggs counted. The number of eggs per gram of faeces could be calculated simply by multiplying the total number of eggs in the sample by 100.
It was perhaps the simplicity of Stoll's methodology that ensured its endurance. Over half a century later, the technique was still in use and had been adapted for many experimental and domestic animals. The impact of the technique on experimental studies was great. For the first time this tool facilitated non invasive observation of gut parasites in situ. Described by the helminthologist Bailey K. Ashford as `Stoll's scouting plane' the procedure made it possible to observe helminthic activity over long periods of time in vivo without destroying either host or parasite. Not only did Stoll's technique open the formerly closed gastro-intestinal tract of the live animal for observation, it also introduced quantitative assessment on a theoretically sound footing. One colleague went as far as to say of Stoll that `he has been the driving force behind the whole development of quantitative aspects of helminthic infections'.
As well as his role in the development of quantitative technique and the initial recognition of helminthic immunity, Stoll took on other important roles in the development of parasite immunology in the States. He was an influential member of the American Society of Parasitologists where he held a number of posts including secretary-treasurer, 1930-32; Council member 1933-1941 & 1952-1957; Editorial Board (Journal of Parasitology) 1944-1955; Chairman of the Editorial Committee, 1938-1943 and President, 1946. Such institutional positions place him centrally within the network of parasitologists that developed in America during the inter-war years. Stoll also had a role in publicising the helminthological problems of the world. In his presidential address in 1946 he attempted to present a quantitative assessment of the current human helminthological situation. The resultant paper which was based on considerable research was published in the Journal of Parasitology. `This Wormy World' as the presentation was titled had a considerable impact. According to Stoll the paper was reputedly `the most widely read and quoted publication in helminthological parasitology since the war'. Certainly it provoked considerable public interest with both Time and Newsweek carrying reviews. The helminthologist Meir Yoeli paid tribute to Stoll's `Wormy World' shortly before his death:
By underlining the tremendous global significance of endemic parasitic infections upon the health and economy of the world at large, he performed a most valuable pioneer task, the echo of which is still strong and clear - many, many years after his lines were uttered. The strength of his statement was in the element of its truth, substantiated by years of painstaking observations and data.
It can be seen therefore, that Stoll played a multifaceted role in the development of immunological studies of helminthic infections in the States.
William Taliaferro and the Development of Parasite Immunology
The themes and problems central to inter-war parasite immunology are best accessed through William Taliaferro's monographic publication The Immunology of Parasitic Infections, 1929. This book was one of Taliaferro's earlier inputs into the field and according to his student Bernard Jarslow, this `landmark' served `to orient and direct research in this broad field for at least twenty five years'. As with Stoll, W.H. Taliaferro's entry into parasite immunology was prior to the establishment of a distinct training route for parasite immunologists and was therefore somewhat circuitous. As an undergraduate at the University of Virginia he was heavily influenced by the zoologist W.A. Kepner, with whom he published his first work, a paper on the ciliated pits of Microstoma caudatum. Subsequently, Taliaferro and Kepner collaborated on works on the reactions of Amoeba to food and on the sensory organs in Prorhynchus applanatus.
During his undergraduate studies Taliaferro was impressed greatly by Herbert S. Jennings' Behaviour of the Lower Organisms. Consequently, upon graduating B.S. in 1915 he moved to Johns Hopkins to study zoology under Jennings. Upon arrival in Baltimore however, he found that Jennings had changed his research interests to genetics. Consequently, he studied for his Sc.D on the structure and behaviour of the lower invertebrates under Samuel Mast. Despite enlistment in the army in 1917 during which time Taliaferro worked on respiratory gasses in dogs at Yale, he completed his Sc.D. in 1918. On leaving the army in 1919 Taliaferro was awarded a Johnston fellowship with which to return to Hopkins. It had been his intention to continue his studies on the sense organs of lower invertebrates, but after some persuasion he chose instead to join R.W. Hegner in the Department of Protozoology and Medical Entomology at the School of Hygiene and Public Health. This was an unlikely but fortuitous move for someone with no parasitological training. In the same year William Taliaferro married Lucy Graves Sc.D. (Johns Hopkins). Lucy became not only William's partner but also a voluntary assistant in his laboratory and an influential collaborator, colleague and autonomous parasite immunologist.
Shortly after their arrival at the School of Hygiene and Public Health Lucy and William Taliaferro began to work on the immunology of parasitic infections. In 1922 they published their first paper on resistance to trypanosome infections. This work demonstrated that trypanosomes initially reproduced rapidly within the rat but soon ceased reproduction after which large numbers existed in the blood. Eventually, after a number of weeks or months, the infection was shed by the rat leaving the host immune to further infection. In his 1924 paper on the subject William Taliaferro set out to demonstrate the existence of `a reaction product' with the specific action of inhibiting trypanosome reproduction. The inhibition of reproduction was demonstrated using the technique that Lucy and William had outlined in their first paper on the subject. This method worked on the basis that a reproducing population would include juvenile and intermediate forms of the parasite of different sizes to adult trypanosomes. The amount of reproduction was therefore correlated by the coefficient of variation of the total length of the parasites. William Taliaferro demonstrated that this coefficient varied from 30% in the earlier stages of an infection to a plateau of 3% (the normal variation among adult forms) during the latter phase of the infection. He concluded that a reproduction inhibiting substance was active in resistance to trypanosomiasis:
The first manifestation of resistance, viz. the retardation and final inhibition of reproduction, is the result of the formation of a reaction product in infected rats which inhibits reproduction of the trypanosomes but does not kill them.
In 1932 Taliaferro published a more in depth study of the reproduction inhibiting component active in Trypanosoma lewisi infections in rats. This large work was partly funded by the Rockefeller Foundation - the major patron of American inter-war parasite immunology and the funder of W. Taliaferro's immunological researches well into the next decade. This influential paper introduced the factor for the first time as an antibody, for which Taliaferro proposed the name `ablastin' from the Greek ablastos meaning not budding, barren etc. He was able to show that ablastin precipitated with the globulin fraction and could be separated from trypanocidal antibody by absorption with T. lewisi. Whilst production of this antibody could easily be stimulated in rats by immunization with killed trypanosomes, rabbits produced only trypanocidal antibodies when challenged. In 1974 Bernard Jarslow claimed that the demonstration of ablastin `led to worldwide scientific discussion that has stimulated research to the present time'. Of particular interest was the inability to absorb ablastin specifically from immunoglobulin mixtures in the serum.
The discovery of ablastin, however, related specifically to a number of trypanosomal infections in rodents. Consequently, the discovery was far from central to immunological understandings of disease. Even in J.T. Culbertson's Immunity Against Animal Parasites, the only inter-war specialised publication post Taliaferro's ablastin work, the subject received only limited attention. The impact of this work on immunology generally was even more limited. Ablastin did not warrant a mention in William C. Boyd's 1943 edition of Fundamentals of Immunology although by the 1956 edition its existence was noted. Similarly, ablastin received no attention in the second edition of W.W.C. Topley and G.S. Wilson's vast and popular The Principles of Bacteriology and Immunity which was published in 1936. Whilst the ablastin work may not have been hugely influential the publication of one of the associated papers in the Journal of Immunology demonstrates that it was at least considered respectable immunological work.
The Taliaferro's research on protozoal immunity continued unabated until the close of the 1940s. During this time they published both jointly and solo dozens of articles in journals and books. Whilst the primary focus of their work was the cellular immunology of malaria in birds and monkeys, a number of other topics were covered. William Taliaferro ventured occasionally into metazoan immunology collaborating with Merritt Sarles of Norman Stoll's Rockefeller Institute group to write a number of works on helminthic immunity, and produced solo reviews of metazoan immunity. Frustrated by the difficulties involved in the quantification of antibodies to living systems the Taliaferros moved away from parasitological studies around the end of the 1940s. As a new subject area they selected the production of haemolysins against non-living antigens: an approach that allowed quantitative study using the emerging techniques of colourimetry.
This change of research activity was partly instituted by the outbreak of World War II. During this conflict parasitologists in America were a highly mobilized group. For some 20% of the membership of the American Society of Parasitologists this meant entry into the military. Another 69 members of the Society were involved in work for governmental civilian organisations often in research related positions. For those 185 members resident in university positions wartime involvement varied by degree. For William Taliaferro the pressure to adapt his research profile began in April 1941. Dr Mark F. Boyd who had accepted a position in the military wrote to him explaining that he believed that Chicago was an ideal institution to develop a programme in malarial chemotherapy due to the nature of its chemistry, pharmacology and parasitology departments. For Taliaferro, however, such a research area was unattractive. He feared that entry into chemotherapeutic research would cause his facilities to be turned into a `purely testing laboratory'.
As an alternative he had originally thought of suggesting the development of `an integrated programme on the mode of action of plasmodicidal drugs in the body'. However, the loss of `a number of our men' to other `defence programmes' had ended his interest in this approach. Through consultation with other colleagues Taliaferro had become `convinced...that it might be much better for us to continue along the lines of immunology and life-history work, especially as related to sporozoites and exoerythrocitic stages'. His stance was supported by the Rockefeller Foundation based parasite immunologist L.T. Coggeshall. Not only did he believe that the Chicago immunology work was important but also warned that the field of chemotherapeutics was far from coherent:
I think you are quite correct in maintaining a research programme that involves the fundamentals rather than undertaking any new investigations on straight chemotherapy. It seems to me the whole idea of co-operative studies in chemotherapy and all its relationships are very good on paper but in actuality they are in a very confused state.
Despite his unenthusiastic response to the initial approach regarding war work William Taliaferro became a member of a secretive American `Malaria conference'. This group included John Maier, E.K. Marshall, A.P. Richardson and J.A. Shannon. Whilst wartime contingencies did lead both William and Lucy to embark upon malarial chemotherapy research, their work was far from the routine testing William had feared. Using Plasmodium lophurae and P. gallinaceum infections in the chicken as models the Taliaferros studied the mechanism of quinine chemotherapy. They also began to study the effects of x- irradiation on malarial immunity. This was the beginning of a long-term research interest in radiation and immunity that would last two decades and culminate in a monograph.
The outbreak of war combined with intellectual considerations therefore changed the Taliaferro's research programme away from the host-parasite studies of the previous twenty years. Although they continued to publish into the 1960s their research interests never returned fully to the immunological study of parasitism.
British Developments 1918-1945: The
Development of a Veterinary/Medical Research Programme in a Colonial
The history of parasitology in Britain in the inter-war period has been little addressed. Significant histories of the London and Liverpool schools of tropical medicine are not yet available whilst the Molteno Institute at Cambridge has escaped attention. Further, the twentieth-century history of veterinary medicine in the UK remains unwritten. Those works that have been published on the history of tropical medicine in the UK have striven largely to set the major institutional developments within their social, economic and political context rather than to analyse the scientific activities of those involved. Whilst the authors of these works have been very successful in exploring the contingencies that were significant in the development of this medical and scientific discipline, they have provided little insight into the laboratory activities that occurred in these institutions.
Michael Worboys has suggested that the nature of tropical medicine changed during the inter-war period. He has claimed that the study of tropical diseases was a `leading part' of biomedicine before 1914. However, between the Wars issues of recession and rearmament dominated Northern concerns. Subsequently, `the whole discipline [of tropical medicine] moved from a heavy research orientation to routine, the health problems of the tropics lost their political urgency, researchers were dispersed rather than clustered, and they began to lose touch with other medical and biological subjects'.
The role of immunology in British tropical medicine in the inter- war period was very limited. No dedicated department existed at the Liverpool School of Tropical Medicine. At the London School of Hygiene and Tropical Medicine W.W.C Topley, formerly Professor of Bacteriology at the University of Manchester, was appointed to a new Chair in Bacteriology and Immunology in 1927. As such he took over the Directorship of the Division of Bacteriology and Immunology. The appointment of Topley, however, precluded a parasitological focus for the immunological work of the department. Essentially an epidemiologist Topley's work focused predominantly on the epidemiology of bacterial epidemics until his premature death in 1944.
At the Liverpool School of Tropical Medicine inter-war parasite immunology was predominantly marginalised within the school's Sierra Leone based extension laboratory. The laboratory opened in 1922 having been built using £10 000 bequested by the schools founder and former chairman, Sir Alfred Lewis Jones. The locating of the laboratory in West Africa marked a continuity of interest in this region for members of the Liverpool School. The School's first expedition had travelled to Sierra Leone in 1899. Alfred Jones, who had influenced the school so greatly during his life, had had a `passionate interest in the economic development of West Africa and a firm belief in the need for the application of scientific methods and discoveries to promote that development'. The School itself was in fact largely a manifestation of the concerns of Liverpool's traders who were very dependent upon their West African links. The strength of the relationship is illustrated through the structure of the early management committees. In 1899, Alfred Jones, whose wealth was from the proceeds of the Elder Dempster Shipping Company, was in the chair. The committee consisted of representatives of the senate and council of university college, merchants, steamship owners, sailing ship owners, and members of the chamber of commerce.
The limitations of the funding with which the laboratory was established was a significant factor in shaping its research/work profile throughout its eighteen year history. The intended role of the laboratory was poorly defined and consequently its relationship with the Sierra Leone government was permanently in flux.
Parasite Immunology and the Sir Alfred Lewis Jones Laboratory
The Liverpool School of Tropical Medicine was a laboratory based institution from its founding in 1898. Initially it was split between the Thompson Ward of the Royal Southern Hospital and a number of rooms in the Thompson-Yates Laboratory. Later it was moved into the Johnston Laboratory at University College, Liverpool before finally entering purpose built premises with numerous laboratories around 1921. The Sir Alfred Lewis Jones Laboratory was the third extension laboratory associated with Liverpool School. The first external laboratory was opened in 1904 at Runcorn in Cheshire `for the purpose of maintaining strains of trypanosomes and spirochaetes'. With the outbreak of World War One the Runcorn laboratory was closed due to staff shortages. The second extension laboratory was founded by the School's fifteenth expedition which left for the Amazon on 19 April 1905. Based in Manaos, this laboratory had a small private hospital attached for use by `foreign firms' and combined a research function with routine pathological work.
The opening of the Sir Alfred Lewis Jones laboratory was delayed by many years due to the disruption of World War One. However, on the 10 January 1922 the two storey laboratory with accommodation for two persons finally opened. Initially, the laboratory boasted a compliment of three scientific staff and was headed by D.B. Blacklock, M.D. Edin., D.P.H., D.T.M., Professor of the Tropical Diseases of Africa at the Liverpool School. His assistants were Dr Saul Adler, who later as Professor of Parasitology at the Hebrew University of Jerusalem became an influential parasite immunologist and Dr E.J. Clark who was soon forced to leave due to ill health. Within a few years following numerous staff changes the compliment of staff was reduced to two due to financial stringencies.
The finances of the Sir Alfred
Lewis Jones Laboratory remained precarious throughout its existence. The initial
£10 000 provided insufficient funds to run the laboratory on a long-term basis. As a result as early as 1922 the issue of the laboratory carrying out routine pathological work for the colony in return for funding was being raised by Blacklock with the Governor. The reply of the Governor that the Laboratory would be most useful if it concentrated solely on research was greeted with enthusiasm by Blacklock but only if `at the same time [we] can get financial support from the government'. Research at the laboratory, however, never received financial support from the government of Sierra Leone.
By 1923 the Director was impelled to appeal to the Rockefeller Foundation for funds, pointing out the deficiency of equipment, periodicals, buildings and technical staff at the Laboratory. Later in 1923 funding of £800 p.a. was agreed by the Sierra Leone Government in return for which the staff of the laboratory were required to carry out a considerable amount of service laboratory work. This agreement signalled a new era for the laboratory during which routine pathological work and environmental surveys became a significant part of the work, and at times dominated the Laboratory's activities.
The surviving records and correspondence of the Sir Alfred Lewis Jones Laboratory provide an outstanding insight into the social and economic factors that led to the development of a ground breaking parasite immunology research programme. In the rest of this article I will examine the internal and external relations that shaped the scientific activities of the laboratory and led to one of the earliest laboratory based parasite immunology research programmes.
Scientific Activity at the Sir
Alfred Lewis Jones Laboratory
The laboratory appears to have opened without a pre-defined research programme. The earliest work was based on the chance observation that a chimpanzee was carrying an unidentified Plasmodium parasite. When the chimpanzee died the cause of death was found to be a Strongyloides infection of the lungs and so Strongyloid infections became a research focus. The research activities of the laboratory's staff continued along these haphazard lines for some time. As it was not possible to examine child cadavers strongyloid infections were studied in dogs and cats. The work on the blood parasite of chimpanzees was continued and once again the death of an experimental animal - this time from acute ascending paralysis - became the focus of research activity.
Within the first year of operation the laboratory began to carry out ad hoc tasks for the government. Through such an activity Blacklock spent the Summer of 1922 on the Cape Light House Peninsula studying the Glossina palpalis population. He concluded that with continued scrub clearance the land could be used for cattle farming. Other government work included studies of rat populations in Freetown and Beriberi in the local jail. These projects were continued into 1923. At the same time a number of non-governmental research activities were under way. This included the study of three locally collected ectoparasites. Life cycle studies were made of the congo floor maggot as well as Bombax Sp. a previously unidentified plant feeding bug with a tendency to bite humans and the Tumbu Fly (Cordylobia anthropophaga). Unsurprisingly, for a laboratory associated with a school of tropical medicine, the staff of the Laboratory drew links between their research activities and medical issues. These however, were often tenuous. Consequently, the work on Bombax was justified because the species was found to carry flagellates similar to those that formed a stage in the life cycle of the parasite that causes Kala azar. Work on the Tumbu fly was justified both because the larvae was known to cause boils on the skin of people and because it caused a large amount of damage to the hides of cattle.
In 1923 the Director attempted to increase the Laboratory's involvement in clinical research. However, his request for the control of ten beds in the newly constructed Freetown Hospital was denied and the unstructured laboratory research programme continued. During this year the governmental work increased considerably. In the early months of the year Saul Adler collected neoplasms from native cadavers and studied filarial chemotherapy whilst Dr Maplestone worked on the development of hookworms in soil types. The appointment of the Director of the Laboratory as pathological consultant to the colony led to a further massive increase in the routine work of the staff and guaranteed only a modest income of £800. Consequently, with the staff reduced to two (Maplestone and Blacklock) following the departure of Adler, the period November 1923 to April 1924 saw a total cessation of research activities.
A limited research function was redeveloped towards the end of 1924 although the government work varying from pathological tests to the study of bacteria in soda water continued to dominate the staff's time. At this time Blacklock began to take an increased interest in native health becoming a member of the newly constituted Infant Mortality Committee. Other members of this group included Major W.A. Peacock of the West African Medical Service (WAMS), Dr E.J. Wright (WAMS) and boasted the newly arrived Assistant Director of the Sir Alfred Lewis Jones Laboratory, Dr R.M. Gordon, as a co-opted member. Research in the area of infant mortality was soon produced results with a 46% malarial infection rate demonstrated in locally collected placenta. Further native oriented research included the study of the effects on anchylostome infection on the mental and physical condition of natives and the assessment of a new urine test for malaria.
The interest in native health was not long lived. By May 1926, studies of the Warble Fly (Cordylobia anthropophaga) had begun to dominate research at the Laboratory. This small fly was known to damage cattle hides and cause small boil like lesions in people by laying it larvae - a metazoan parasite - under the skin. It had previously been studied in Sierra Leone by members of the Royal Army Medical Corps Laboratory in 1908. Considering the frequency of fatal and debilitating diseases in Africa in this period the choice of the tumbu fly as a focus for research in a tropical medicine laboratory could be considered to be inappropriate. The basis for this interest is explained best through social, economic and political factors rather than medical considerations. In the inter-war period there was increasing interest in the economic potential of the colonial empire. The funding potential associated with these political developments had already been demonstrated by the provision of an Empire Marketing Board Grant to the Committee on Civil Research to study dietetics in East Africa. In this period therefore, the study of `warble flies and other flies which so seriously injure cattle hides' was saleable and therefore attractive to a laboratory where funding limitations had led to the loss of staff and had severely limited facilities.
Studies at the Laboratory in 1923 had shown that the majority of the damage caused by the flies was known to be in cattle of one to two years old, with an immunity recognised in both older cattle and people. Preliminary work in 1926 had shown that this immunity was `of a peculiarly interesting and remarkable kind'. Consequently, studies of the fly were immunologically based as this approach was both scientifically interesting and through rhetorical association with immunisation was linked to preventive/curative theories.
By 30 April 1927, D.B. Blacklock was planning the organisation of the metazoan parasite research should a grant be obtained. In the event, he was concerned that he should be allowed to carry out a survey of the diseases of the Protectorate, and wished therefore not to be tied to laboratory based immunity work. Such a survey he believed would be profitable and would be beneficial to the School's profile in Africa:
I would only emphasise the point that such a survey can hardly fail to produce good results and that it should, if properly carried out, not only increase the volume of the research produced by the laboratory, but also materially add to the prestige of the school in Africa generally.
Whilst promoting the predominantly veterinary tumbu fly work Blacklock was also attempting to further involve the laboratory in veterinary/agricultural concerns. The development and promotion of West African Agriculture was a matter gaining increased consideration. Consequently, the Governor of Sierra Leone, Sir Joseph Byrne, appointed a committee to consider the potential of developing the Cape Peninsula as a Cattle Breeding Station. Represented on this committee were the Acting Commissioner of Lands and Forests, the Director of Medical and Sanitary Services and D.B. Blacklock.
The report of the committee
strongly supportedthe proposal to build a cattle breeding station. The aims of
such a project were multiple:
(a) To prove that cattle farming can be profitably carried out in Sierra Leone.
(b) The improvement of the native herd.
(c) The supply of suitable breeding stock to the chiefs and natives for that purpose.
(d) To establish dairying on modern lines.
(e) To breed suitable oxen for agricultural purposes, cart and pack transport, ploughing etc.
(f) To encourage cattle farming in the colony and protectorate and the production of all the cattle required for the dairying, transport and agricultural purposes, as well as for consumption.
Most significantly, the report suggested that the Sir Alfred Lewis Jones Laboratory should be strongly associated with such a venture. Not only would the staff of the Laboratory assist the cattle breeding station in relation to diseases, they could also become involved in the breeding experiments. Conversely, the facilities of the cattle breeding station could be used by members of the Laboratory to assist in their metazoan immunity studies. The committee were forced to conclude however, that `the cost of the scheme is for the present beyond the resources of the Sierra Leone government'. Despite a proposed application to the Empire Marketing Board the breeding station was not built during the lifetime of the Sir Alfred Lewis Jones Laboratory.
Despite the failure of the cattle breeding station the re-orientation of the laboratory towards veterinary parasite immunology was confirmed by the award of a £3 500 p.a. grant from the Empire Marketing Board for the continuation of work on metazoan immunity. As a result of this massive swing in the fortunes of the Laboratory both Gordon and Blacklock returned to Liverpool to consult with the School's committee on how best to arrange the research. The conditions of the grant were far from ideal for the School. For every pound invested by the board the School was to invest a further pound. Consequently, some creative accounting was required with almost all expenditure on Sierra Leone considered funding for metazoan immunity research:
I take it the broad position is that practically everything we spend on Sierra Leone at the present moment is for metazoan immunity research. In other words, apart from the survey, the, for practical purposes, only research going on at Sierra Leone is metazoan immunity. If this be so, we should have to calculate what Sierra Leone is costing us, and what we are spending on metazoan immunity will be this total amount less some at present unknown amount for the survey.
The award of the Empire Marketing Board grant was a notable event in Sierra Leone. Not only was the award and the work of the Laboratory described by the Governor, Brigadier General Sir Joseph Byrne at the opening of the 1927-1928 session of the legislative council of Sierra Leone. The Laboratory was also visited by the Prince of Wales who viewed a number of the flies exhibited in glass cases.
Upon their return to Sierra Leone Blacklock, Gordon and G. MacDonald, a research assistant, set about changing the physical environment of the Laboratory to suit the new research direction. The previously minimal library was refurbished with book shelves that were stocked with greatly enhanced immunological collections. The veterinary work required extensive in vivo research and subsequently a new animal house was erected with cages imported specially from England. To further extend the experimental facilities of the station large amounts of furniture and apparatus were purchased.
Whilst the Laboratory retained its pathology function throughout the period of the Empire Marketing Board grant the great majority of the work at the Laboratory between 1927 and 1930 was metazoan immunity based. The improved facilities were complemented by an increased staff. Drs R. Aiden and J. Fine arrived on 5 May 1928. Dr Aiden's stay was however, short and controversial. His replacement was the only female member of scientific staff to serve at the Laboratory. Dr Marion Watson had recently been studying bacteriology under W.W.C. Topley at the London School of Hygiene and Tropical Medicine. Despite being inexperienced in parasitology, Watson was appointed and arrived in Sierra Leone on 30 November 1928. Natives were appointed to the roles of junior and senior laboratory attendants.
The initial approach to the immunology research was unsophisticated. Attempts were made to immunise animals using injections of large doses of crude extracts of Cordylobia anthropophaga larvae. Whilst initial results suggested that such injections could lead to a partial immunity in some animals, the large amount of extract required made this technique of no commercial value. Consequently, the scientists turned their attention to the various enzymes they had demonstrated in the larvae. They believed that if any one of these provoked a sufficient immune response it might act as a vaccine:
The relationship of these enzymes to the immunity is now being investigated. If a relationship can be shown to exist it may be found possible to produce an artificial immunity by the injection of "commercial" enzymes of a similar type.
As the staff became more experienced at immunological experimentation the research programme became increasingly heterogeneous. Marion Watson studied the `bacterial fauna' of the larvae. Work continued on the isolation, assay, and immune response to enzymes extracted from the larvae and also experiments were made observing the effects of intra dermal injection of large amounts of ground up first instar. Despite the success of producing occasional immunity the findings were apparently of only academic interest:
It must be emphasised...that the labour of breeding out sufficient flies to produce large amounts of this antigen renders it improbable that such a method, however interesting it may be from a scientific point of view will be of commercial value.
Metazoan immunity was not only being studied in Sierra Leone, and the threat of competition was a matter of some concern to Blacklock. In the report for the period 11 November 1928 to 30 April 1929 he noted particularly the works of Professor Besredka at the Pasteur Institute, Paris, Professor Fulleborn of Hamburg University and J.H. Sandground in the United States. In response to the threat posed by this competition Blacklock proposed that the work of the Sierra Leone Laboratory should be published rapidly and brought to the attention of the Empire Marketing Board:
It is therefore considered opportune to publish a short account of the results hitherto obtained and it it is proposed to forward to the school in the immediate transmission to the EMPIRE MARKETING BOARD a report that will be of the nature of a progress report, and which it is hoped will be published.
This work was subsequently published in the Liverpool School's Annals of Tropical Medicine and Parasitology in a 61 page report titled `Metazoan Immunity; A Report on Recent Investigations'. The paper outlined eleven findings made by the Laboratory's staff. The issue of this paper marked the pinnacle of the Laboratory's parasite immunology successes. In October of 1930, D.B. Blacklock, Director of the Sir Alfred Lewis Jones Laboratory since its founding, left Sierra Leone to take the Chair of Parasitology back in Liverpool. The former holder of this chair, Warrington Yorke, had succeeded J.W.W. Stephens in the Alfred Jones Chair of Tropical Medicine and Head of the School.
By April 1930 R.M. Gordon M.D.(Dub)., D.P.H., D.T.M., Assistant Director of the Laboratory since 1924, and a member of the School's staff since 1919, had taken the Chair of the Tropical Diseases of Africa and Directorship of the Laboratory. Following Blacklock's departure, however, the metazoan immunity work ran in to a number of problems. In early 1930 the work was greatly hampered by a high death rate amongst experimental animals. Gordon initially explained this in terms of the failure of imported British Guinea Pigs to do well in Sierra Leone and the toxicity of the larval antigens to which they were exposed. Despite this inconvenience Marion Watson had been able to demonstrate the loss of immunity in exhausted and cold animals. By May 1930 the death rate amongst the experimental animals had escalated sufficiently to cause the abandonment of the metazoan immunity research. On the assumption that the cause of death was an infectious agent, extreme measures were introduced to try and eradicate the problem. The entire stock of experimental animals was killed, the animal houses were disinfected and after a period of time re-stocked. Despite these precautions, within a few weeks, the epidemic recurred with `renewed vigour'.
Unable to continue the metazoan immunity work due to the mortality rate amongst the animals the experimental work of the laboratory began to focus on the sick animals themselves. Marion Watson was able to identify a Diplococcus in the tissues of `nearly 90%' of all imported guinea pigs that had been in the Laboratory. This microorganism was also found in 30% of the local animals that were inspected. R.M. Gordon concluded that the imported stock was being infected by local animals and once again ordered the destruction of all stocks and the disinfection of the animal house. This time it was proposed to use only imported animals:
In view of these experimental results we propose to again destroy the existing stock of animals, repeat our disinfection of the animal house and then re-stock using only imported animals.
These technical problems extended beyond the expiry of the Empire Marketing Boards grant in 1931. Despite this, attempts were made to continue the metazoan immunity work. This was again hampered by deaths amongst experimental animals which were later found to come from infected stocks in Liverpool. Following an unsuccessful bid for funding from the Colonial Development Fund the Laboratory went into rapid decline. As in the earlier period the research function of the Laboratory soon came under threat:
It is sufficient to point out that if research is to be maintained at its previous level it will be necessary either to increase the staff or reduce the present, very considerable, amount of routine government examinations.
Gordon's fears were soon recognised, however, with the prevailing `financial stringency' leading to the loss of E.P. Hicks and M. Watson thus reducing the Laboratory staff to two. In subsequent years the fortunes of the Laboratory declined considerably. By December 1933 its closure was being seriously considered by the senior staff of the Liverpool School. Whilst the Sir Alfred Lewis Jones Laboratory lingered on until the outbreak of World War II it remained predominantly a service laboratory. A brief renaissance was enjoyed in its research profile through the presence of a Leverhulme Research Assistant and a Royal Society fellow. Never again, however, was the Laboratory a major centre for parasite immunology studies.
With the exception of the malaria
therapy work discussed in the previous section, in the years leading up to World
War II Britain seems to have lacked almost any research in parasite immunology.
A couple of papers were reported in the Transactions of the Royal Society of
Tropical Medicine and Hygiene. However, immunological input into the British
Journal of Tropical Medicine was dominated by abstracts of the works of American
actors such as J.H Sandground, W.H. Taliaferro, M.P. Sarles, and E.H. Hinman.
Other works appeared published by German workers and members of colonial
research institutes. At the outbreak of World War II, Britain essentially lacked
a parasite immunology research tradition.
Discussion: Inter-War Parasite Immunology.
The development of malaria therapy as a technique and its application across Europe and America provided unrivalled opportunities to Western scientists for the controlled study of malarial immunity in the human. In the UK these opportunities were grasped by tropical medics, malariologists and practitioners. In the US the technique was similarly studied by a diverse group. The social factors so prominent in discussions of immunity prior to the First World War were almost entirely lost in the inter-war period. This allowed the terms immune and immunity to be clarified. However, immunological studies devoid of social considerations may have facilitated the development of racial immunity theories. For example, the risk of increased exposure to malaria as a child, and differences in access to chemotherapy or prophylaxis, seems to have been little discussed in debates about negro immunity. The focus of this work in the Southern States of America - an historically racist region - may further have influenced conclusions.
This comparative study has illustrated that parasite immunology developed geographically at different rates during the inter-war period. From the disparate beginnings at the turn of the century, American parasite immunology developed into a recognisable research network. Scientists, who were often based in high status institutions, cooperated, collaborated and communicated. They shared not only information but also techniques, such as the Stoll dilution egg counting method. From an early stage the American Society of Parasitologists was an important forum for these interactions. The high status and honorary positions held by a number of the parasite immunologists within this society shows that the field was not marginalised in the USA - it was a central part of the discipline of parasitology. In the U.S. a number of loci were central to developments in the 1920s. Of these the Johns Hopkins School of Hygiene in Baltimore with its faculty including W.W. Cort, R.W. Hegner and W.H. Taliaferro was most notable. Whilst Cort's own input into the field was limited and Taliaferro soon left to join the faculty at Chicago, former students of the Hopkins department were central to developments in the 1920s. One of Cort's students, Elvio H. Sadun, who became an influential parasite immunologist, later articulated the intellectual influence Cort had on his students. According to Sadun during his time at Pisa as a medical student he was taught to think of parasites merely as discomforts of man. At Harvard in the Zoology Department he learned that parasites were `interesting individuals', then:
under the benign and firm guidance of Dr Cort, [he] began soon to learn looking at man and his parasites, not as competitors for the center of the Universe but as participants in an endless game of tug-of-war. I began watching with interest the dynamic balance between the two opposing forces under the name of host-parasite relationships. I began trying to help now one side and then the other under the name of `factors which influence natural and acquired resistance'. I began looking for signs of the struggle through openings such as serological tests, blood counts, tests for the presence of enzymes, and many others which acted as windows for the insatiable peeping Tom.
Such an approach marked a significant break from both the contemporary zoological focus on parasites, and the medical/veterinary treatment of parasites in terms of disease syndromes. Whilst not exclusive to this group, this approach is strongly characteristic of their work.
The contribution of Norman Stoll, himself a former student of W.W. Cort, was clearly dependent upon the technical developments for which he was largely responsible. The introduction of the Stoll dilution egg counting technique was seminal in the development of quantitative helminthological studies. This technique facilitated in vivo population studies of gut parasites for the first time. This facility to visualise gut activity rapidly led to the observation of `self cure' in nematode reactions. The timing of the recognition of self-cure was the product not only of technical considerations. The reticence shown by both Stoll and Smith to describe the phenomena in immunological terms is demonstrative of a resilient and pervasive assumption that gut parasites were not subject to immune mechanisms. Consequently, even when presented with considerable evidence of an immunological basis for the rapid decline in the parasite population both Smith and Stoll avoided directly challenging the status quo. They achieved this by creating a descriptive language that avoided exclusively immunological terminology. Such consensus beliefs can be considered to have had a significant negative influence on the development of parasite immunology studies and may have considerably delayed important observations.
Economic factors were significant in shaping the development of parasite immunology. The relatively early development of parasite immunology in America as compared with the UK was partly a product of the accessibility of Rockefeller funds. This body was a major patron of W.W. Cort and the Hopkins department. Norman Stoll resided at the Rockefeller Institute and William Taliaferro was dependent upon Rockefeller income for his research for many years. L.T. Coggeshall was based at the Rockefeller Foundation's laboratories and other important figures also enjoyed relationships with the foundation. Consequently, Rockefeller money was influential in training students and opening a career structure as well as facilitating many of the most influential studies of the inter-war period.
By the outbreak of World War II parasite immunologists in America were a sufficiently differentiated group to be mobilised in the `total war' effort. The military concern with malaria provided a new source of income for Lucy and William Taliaferro's research programme. The scientists, however, were cautious in their initial involvement - the practical concerns of the government were incongruent with the intellectual aspirations of William Taliaferro. The resultant research programme combined a rhetoric of practical application with intellectually interesting experimental work. The actual value of this work to the war effort is somewhat questionable.
In the UK, without the stimulus of Rockefeller funding the development of parasite immunology was considerably slower. The experimental approach adopted by tropical medics in the pre-war period was retrenched in the lean inter-war period. Consequently, tropical medicine can be considered at this time to have essentially taken the form of a `field science' with a reduced research base. As Mick Worboys has suggested the issue of disease amongst natives of the tropics lost its urgency during the inter-war recession. The colonial contingencies and funding difficulties of the 1930s were sufficiently severe to attract the Liverpool School's extension laboratory into veterinary work. Whilst the tumbu fly work was often justified for its medical relevance the lesions caused by the fly larvae would not have been a significant health concern. The motivation for this essentially veterinary work was the relative ease with which funds could be ascertained for such a project. It would appear that in the 1920s the health of agricultural animals and their valuable hides was more significant to the British metropolitan power than the health of natives. In such an environment the financially vulnerable Liverpool School re-oriented its research interests in line with contemporary concerns and subsequent funding priorities. Such was the importance of this income to the School and the Sir Alfred Lewis Jones Laboratory in particular, that associated considerations were sufficient to justify the abandonment of the discipline of tropical medicine almost completely.
Inter-war parasite immunology can
therefore be seen to have developed at very different rates. Stimulants for
the development of the discipline in the U.S. were very different to those active
in the U.K. Subsequently, in the inter war period the intellectual focus and
rates of development of the field in the two countries were very different.
Previous Page Malaria Therapy American Research Network 1918-1945 Norman Stoll William Taliaferro Sir Alfred Lewis Jones Laboratory-Liverpool
Richard Hankins Ph.D. Adis International Ltd.
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