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ALMROTH EDWARD WRIGHT

1861-1947

A lmroth W right’s life did not conform to the conventional pattern. As a boy he did not go to any school but was taught chiefly by tutors. As a graduate in medicine he did not follow any of the usual paths to a medical career; and when in due course he did embark on that career his road was never that of other men. His intellectual life too was remarkable in that it ran always in two separate streams—that of medical science on the one hand, and in broader philosophical speculations on the other.

He was born on 10 August 1861 in Yorkshire, where his father, the Rev. Charles H. H. Wright, held a curacy. His mother was Ebba, daughter of Nils W. Almroth, Professor of Organic Chemistry in Stockholm and later Director of the Swedish Mint. Professor Almroth was also a Knight of the North Star and a friend of Berzelius. The Rev. Charles Wright held curacies in turn in Dresden, Boulogne and Belfast and in all these places the boy Almroth was taught by tutors and, no doubt, acquired the basis for that fluent command of German and French, which was to serve him so well in later life.

His university education was at Trinity College, Dublin, where he took First-Class Honours in modern literature, and then graduated in medicine (1883). The ordinary practice of medicine, however, did not appeal to him and for some years he seems to have been in doubt as to the best course to take. After working for a time in Germany under Cohnheim, Weigert and Ludwig at Leipzig, and also visiting Strasburg and Marburg, he returned to England and took a studentship at the Inns of Court, reading Jurisprudence and Inter­national Law with a view to the Bar. But his heart was in medical science and he soon abandoned law in order to help Wooldridge and Victor Horsley, who were both working (on the coagulation of blood and on the central nervous system respectively) at the Brown Institution in Wandsworth, one of the few laboratories at that time where medical research was being carried on. This was unpaid work, done in the early mornings and the evenings. A clerkship at the Admiralty during the day provided him with a slender livelihood. His association with Wooldridge led in due course to the offer of a Demonstratorship in the Department of Physiology at Cambridge, but he was not happy there. The atmosphere was too conventional and he had no great regard for Michael Foster; so he did not stay very long. During his vacations he again visited Germany to work on pathological anatomy under Recklinghausen, and on physiological chemistry under Professors Kulz and Hoppe Seyler. His next appointment was to a Demonstratorship in Physiology at Sydney, where he

carried out investigations on diabetes and acidosis, and on intravascular coagula­tion. But here too he did not find the field of work he was seeking, and he returned to England in 1891 and worked for a while in the laboratories of the College of Physicians and Surgeons at the chemistry of tissue fibrinogen. In 1892 he was offered, and gladly accepted, the Professorship of Pathology at the Army Medical School, then established at Netley Hospital on Southampton Water. There he found a group of young ‘Surgeons on Probation’ doing post-graduate training for the Indian Medical Service or the Research Department of the Government of India. George Birt, W. B. Leishman, George Lamb, David Semple, W. F. Harvey and Lyle Cummins were among those whose enthusiasms were stimu­lated by Wright’s active mind and leadership. This group of men was not concerned with passing examinations or making a living—their minds were ready to be fired by the vision of a new medicine not to be found in any text­book, a medicine in which scientific measurement and the experimental method played an ever-increasing part. Wright gave them that vision. Plis mind was busy at this time with problems in many widely different fields: the differential diagnosis of typhoid and malta fevers by the agglutination test; the influence of its carbon dioxide content on the coagulation of blood; the effect of citrating cow’s milk for infant feeding; the physiological element of the emotions; colour blindness and the occurrence of ‘colour shadows’ in nature; and on the optical principles involved in microscopy.

But his chief activity from 1895 onwards was the development of active immunization against typhoid fever, which was to have such immense practical results in the two world wars. In his first report on this work Wright made it clear that he was led to undertake it by the earlier work of Haffkine on cholera in India, and of Pfeiffer on the agglutination of typhoid bacilli by the serum of men inoculated with those bacilli; and, of course, by the earlier classical experi­ments of Pasteur on the protection of sheep against anthrax by inoculation. Wright’s great contribution was fourfold; he saw the need to break away from the Pasteurian practice of using attenuated, but still living, material for human inoculations, and he established that a killed vaccine would serve as well for inducing the formation of antibodies; he devised a procedure for counting the microbes in the vaccine so that he could accurately standardize dosage; he took great pains to find the optimal dose—using for that purpose an entirely novel quantitative technique; and finally, having convinced himself that the vaccine did render the inoculated man’s blood highly bactericidal to the typhoid microbe, he saw that this change would inevitably give protection against infection by that microbe. In that belief he strongly urged the adoption of this procedure for all our armies serving overseas, but his faith was not shared by some of those who were responsible for army policy at the time, and Wright’s proposal was at first rejected by the War Office. This decision seemed to Wright such a serious mistake that he resigned the post in which he had been so happy and so fruitful at Netley, but the younger men he had influenced there, under Leishman, carried on the work and finally obtained overwhelming statistical proof of the efficacy of Wright’s method. A Royal Commission reversed the

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earlier War Office decision, and anti-typhoid inoculation was adopted as a standard procedure in the British Army. As a result England was the only country to enter upon the First World War with most of her troops so protected. The Germans were quick to follow our example when typhoid threatened their armies in Flanders.

Statistical evidence of the success achieved by preventive inoculation against the enteric group of infections during the 1914-1918 War is shown in the follow­ing table taken from the Medical History of the War (Section of Pathology,p. 211).

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South African War

Annual incidence per 1,000 strength

Annual death rate per 1,000 strength

Totalcases

Totaldeaths

Meanstrength

1899-1902 105 00 . 14-6 57,684 9,022 208,226

1914-1918 War 2-35 0139 20,139 1,191 2,000,000(approx.)

It has been estimated that if the South African rates of incidence and deaths had prevailed in the 1914-1918 War (as they might well have done, considering the conditions of trench warfare) there would have been 927,500 cases of enteric fever instead of 20,139—and nearly 129,000 deaths instead of 1,191.

In recognition of this work Wright received a Knighthood in 1906.Before he left Netley, Wright was seconded for a time to serve on the Indian

Plague Commission which was appointed to inquire into the mysterious spread of that disease, and to report upon the method of preventive inoculation which Haffkine had introduced to deal with it.

From Netley, Wright went to St Mary’s Hospital as Professor of Pathology, and gradually built up there the ‘Inoculation Department’ of which he remained the Director for forty-five years. At first he taught morbid anatomy and histology as well as bacteriology, but he soon became absorbed in further work on im­munization and teaching was relegated to others. His work on typhoid fever had planted in his mind the conception that recovery from all infective diseases must be largely determined by the development of ‘antibodies’ in the patient’s blood and that this process could be probably stimulated by inoculation of the appropriate vaccine. ‘The Physician of the Future’, he wrote, ‘will be an Immunizator.’ Pasteur had shown by his anti-rabies inoculations that it was possible to induce immunity in the interval after the patient had become infected but before the symptoms of disease had developed. Wright’s vision went further: he saw that whenever a patient with an infective disease was not reacting successfully to that infection it might be possible to assist his recovery by appropriate doses of vaccine—‘to exploit’, as he put it, ‘the uninfected tissues in favour of the infected’. To that aim he devoted the next forty years of his life.

First he had to collect round him a team of young men with ‘fire in the belly’ to pursue his idea. Stewart Douglas, who had worked with him in India, joined

him almost at once, and John Freeman and J. H. Wells a little later. Leonard Noon, Alexander Fleming, John Matthews, Carmalt Jones and the present writer were added to the team within a few years. Laboratories, clinic rooms, and, later, wards had to be found as the Department grew. What was more difficult was to find a procedure for guiding the inoculations of vaccine. Measure­ment of the bactericidal power of the serum, which had served him so well in the anti-typhoid work, would not do for studying the immunity of patients suffering from many of the more common infections, e.g. by Staphylococcus and Streptococcus, because there was little or no production of bactericidal antibody in response to these infections. The mechanism of recovery was evidently quite different in the different diseases. But the recent work of Metchnikoff on phago­cytosis by leucocytes had given the clue to an alternative immunity process— and in this Wright saw his opportunity. His colleague Leishman at Netley had already begun to develop a laboratory method for the study of phagocytosis by human blood, and when Wright joined him in the investigation they quickly made an important advance. Phagocytosis by leucocytes, they found, was dependent on two factors, namely, the avidity of the cell for the microbe on the one hand, and the prior sensitization of the microbe—or as Wright called it the ‘opsonic’ action—by the serum on the other. At first Wright paid little attention to variations in the avidity of the leucocytes (early experiments seemed to show that this did not vary much) but the ‘opsonic’ activity of the patient’s sera was measurable, and was found to be often much below the normal level. By in­cubating a suspension of microbes with leucocytes obtained from the blood of a normal man, and with samples of serum obtained respectively from patients and normal people—and preparing stained films from these mixtures—it was possible to gauge the capacity of each patient to deal with his infection by phagocytosis. This technique of the ‘opsonic index’, and the system of inocula­tion based upon it, attracted attention all over the world during the ten years preceding the 1914-1918 War. To-day, with our attention diverted to chemo­therapy and the possibility it brings of conferring bactericidal power upon the patient’s blood, it is the fashion to regard phagocytosis and the opsonic property of serum as of secondary interest, but it is well to remember that, by and large, this mechanism still remains the first, and probably the most important, natural defence against the majority of common infections.

It is difficult to assess the results which were obtained by the campaign of immunization initiated by Wright and his team at St Mary’s Hospital. Many different bacterial infections were treated—notably those by ,(furunculosis and carbuncle, osteo-myelitis, sycosis); infections by Streptococcus (erysipelas, cellulitis and puerperal fever); by B. tuberculosis (pulmonai^gr glandular, lupus, as well as infections of bones and joints); infections of the respiratory and urinary tracts. Sometimes the dosage of vaccines was guided by blood examinations—more often it was not. Results were usually assessed by the ‘Experiential’ method rather than by statistical analysis, because in Wright’s view the latter must inevitably be so fallacious as to be of little value when it was applied to data derived from such heterogeneous material. To his

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critics it seemed that he overstated this point of view and did not make sufficient allowance for possible improvements in statistical technique.

The impressions based on unaided clinical observation have differed widely. In the present writer’s experience vaccine treatment was sometimes associated with unmistakable benefit to the patients; more often, although the clinical course was satisfactory and part of the improvement may well have been due to the immunization, one could not be quite certain of that. Wright himself, in later years, realized to the full the formidable difficulties in arriving at a correct estimate of the optimal dose of vaccine at different phases of the patient’s illness—and he has well summarized the conditions which make for success and failure in vaccine treatment {Lancet, 1919, 1).

What is certain is that this large-scale attempt to treat infective diseases in the light of a scientific conception, however imperfect, was a complete break­away from the loose-thinking empiricism and symptomatic treatment of medical practice prior to 1900. Also, as a by-product of this new departure, medical bacteriology was certainly ‘put on the map’. When Wright went to St Mary’s Hospital in 1902 very few hospitals had even the nucleus of a bacteriological laboratory and there was little or no chance for any young man to make a career in that field. By 1912 all that was changed and British bacteriologists had made many important contributions to medical science. That would have happened inevitably in due course, but there can be no doubt that Wright’s influence did more than anything else to bring it about.

Towards the end of the ‘opsonic era’ (1902-1914) Wright was invited by the Witwatersrand Native Labour Association to go to South Africa to investigate the problem of pneumonia among the native mine workers. The mortality among these men when they went underground was becoming so serious that the South African Government threatened to stop their recruitment. Wright, with Parry Morgan and Dodgson and the present writer, went and established a laboratory in the Johannesburg General Hospital. Preventive inoculation was initiated on a considerable scale, but assessment of its effects proved very difficult. There was an undoubted reduction in the incidence of pneumonia, but this reduction was accompanied by a parallel fall in the incidence of other diseases. Many believed that both results were due to synchronous changes in the living conditions of the natives but Wright himself was disposed to attribute the decline in the incidence of other diseases to a non-specific effect of the inoculations—a possibility which much of his later work, and also Haffkine’s anti-plague work in India, seemed to support.

There were two interesting side issues of this work in Johannesburg. In addition to his preventive inoculations Wright had to meet the challenge of a fulminating infection—pneumonia—as he saw it in the Rand hospitals. It was doubtful whether vaccine therapy could help in such circumstances. The patient might be so overwhelmed by the microbic products of his infection that he could not respond, and might even be harmed by the injection of more: or failing that, his response might be too tardy. Chemotherapy seemed to offer more hope if a suitable drug was available. Morgenroth and Levy in Germany

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had recently shown that mice experimentally infected with a fatal dose of virulent pneumococci could frequently be saved by the injection of a new sub­stance, ethyl hydrocuprein hydrochlorate (‘optochin’) which was known to be bactericidal to this microbe. Wright decided to try it on his pneumonia cases, but soon had to abandon it when news came from Germany that the drug occasionally gave rise to alarming disturbances of vision. It had apparently a selective action upon the optic nerve as well as upon the pneumococcus. In the course of this work, however, Wright showed, for the first time, that bactericidal power could be conferred upon a patient’s blood in the body—and in the body of the experimental animal also—by administration of a chemical substance. That was a landmark in the history of chemotherapy.

Apart from this observation, his experience of pneumonia set Wright’s mind at work upon the general question—how should one adjudicate upon the results of any form of treatment. His first reflexions on this fundamental issue were embodied in his report on the pneumonia work. They were to occupy his mind for many years subsequently and I doubt whether he ever arrived at an answer which satisfied him.

Soon after his return to England the First World War broke upon us, and Wright’s help was at once sought by Sir Alfred Keogh, Director-General of the Army Medical Service—first to mobilize the resources of the Inoculation Department at St Mary’s Hospital for the immediate production of anti-typhoid vaccine on an unprecedented scale; and, secondly, to investigate the appalling wound infections which modern warfare, with its reliance upon high explosives, had brought in its train. Wright went to .Boulogne with Alexander Fleming, and set up a research laboratory in the Casino, which was then a large hospital. That was his headquarters for the rest of the war and here he did some of his most outstanding work.

His approach to the problem was fundamentally different from that of the surgeons, who were one and all thinking in terms of an antiseptic which would sterilize the wounds. Wright saw at once that we could not hope for any such short-cut—the bactericidal properties of the antiseptic would inevitably be ‘quenched’ by the serum proteins and leucocytes and the fixed tissues of the wound. We must look below the surface: to find out what was happening in the wound to permit such enormous proliferation of the microbes; what were the physiological mechanisms of defence against such massive bacterial infections; and whether it was possible to assist those mechanisms. His unceasing labours by night and day brought a flood of light upon these questions: he showed that some of the microbes found in the wounds were able to multiply freely in fresh blood serum and in the exudate into fresh wounds before they became ‘septic’ (these microbes he called ‘serophytes’); whereas many others were only able to multiply freely after the exudates had become ‘corrupted in the wound (‘sero-saprophytes’); and he demonstrated one at least of the factors involved in this ‘corruption’ process. It resulted, to a large extent, from neutralization of an anti-proteolytic property (not previously recognized and still not fully understood) normally present in blood (and fresh wound exudates) which

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restrains the growth of many microbic species by interfering with their nutrition.

Wright claimed that this ‘corruption’ of the wound exudates could be prevented or delayed by promoting a free flow of fluid from the vascular bed in the wall of the wound by osmotic agents such as hypertonic salt solution. (It was later shown by Fleming that the hypochlorites so largely used in wounds as antiseptics had also a somewhat similar action.)

The leucocytes, as anti-bacterial agents, also came under intensive study. With Fleming, Wright devised a great number of highly ingenious methods for investigating the emigration of these cells out of blood clots, the conditions which enabled them to destroy microbes, and the inimical effect upon them of many substances commonly employed in the treatment of wounds.

From all this work, essentially physiological in its outlook, Wright deduced that the logical procedure was first to get rid of anything in the wounds which favoured the growth of microbes and the ‘corruption’ of the exudates (dead tissues, clothing and other foreign bodies, etc.) and then to close the wound as early as possible in order to give the leucocytes the most favourable conditions. He told the surgeons that they should close the wounds in order to sterilize them, instead of trying (unsuccessfully) to sterilize them in order to close. The leucocyte, he maintained, is our best antiseptic. Thanks in part to Wright’s advocacy, and in part because its advantages were amply confirmed by surgical experience, the early closure of wounds became standard practice towards the end of the war, and since that time has been adopted all over the world. That change, and the saving of life by anti-typhoid inoculation, were probably the outstanding gains of the war in the medical field.

One of the special problems arising in connexion with the war was that of gas gangrene, which was developing with such catastrophic suddenness in many of the wounded and was so frequently fatal in spite of mutilating amputations. It seemed to Wright as a physiologist that such an overwhelming process must be associated with some profound disturbance of one of the fundamental adjustments of the body; and that such a disturbance must be reflected in the circulating blood.

There were several reasons for suspecting that acid intoxication might be one such disturbance. (1) Recent experiments in the laboratory had shown that the Clostridia associated with gas gangrene, which could scarcely grow at all in normal blood, would multiply enormously when the same serum was slightly acidified (and also when its anti-proteolytic property was neutralized); (2) Fletcher’s findings on the production of lactic acid in injured muscle suggested that in the man with a high explosive wound there would often be a local focus of acidified muscle lymph which would prove an ideal culture medium for the initial growth of Clostridia’, (3) Cannon, too, had shown that acidosis was a feature of ‘shock’ in the wounded, and Wright conceived that such an acidosis would favour invasion of the blood stream by the Clostridia, and this in turn perhaps an overwhelming disintegration of liver cells, analogous to that which Welch had described in animals dying of clostridial infection.

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For the study of this problem Wright had first to devise a micro-titration method which would enable him to make repeated estimations of the alkalinity of the serum obtained from very small samples of blood (the patients were often very collapsed, and blood from the veins was difficult to obtain). He, with Fleming, ascertained that this micro method gave substantially comparable values to those obtained by a more conventional procedure (Marriott’s method), and was in some respects more suitable than the latter. Their tests on patients gave unmistakable evidence, in Wright’s view, of the existence of severe acidosis —or ‘acidaemia’ as he preferred to call it—in most of the gas gangrene cases; and infusions of sodium bicarbonate (to counteract this ‘acidaemia’) sometimes restored the patient’s clinical condition in a remarkable manner.

All this work, which Wright reported in a series of lucid papers, seemed to him to explain, in part at least (he did not, of course, ignore the part probably played by bacterial toxins), much that had been mysterious in the explosive onset and the unfavourable clinical course of gas gangrene.

As in many other matters his approach to the problem and his methods were too unconventional to command immediate assent and the war came to an end before agreement had been reached. Since that time divergent views have been expressed by biochemists as to the adequacy and reliability of Wright’s titration method for the assessment of acidosis, and not much fresh evidence was obtained in the Second World War. The part played by acidosis is, therefore, still judice. There can, however, be little doubt about the great significance of Wright’s findings as to the growth of the Clostridia in acidified serum and their bearing on the pathology of gas gangrene.

During the war Wright had allowed himself no rest and he returned from it at the age of fifty-eight very exhausted—feeling that his working days were nearly done. In these circumstances he was disinclined to take up the Director­ship of the new bacteriological department of the Medical Research Committee to which he had been appointed shortly before the war, and he, therefore, went back to the Inoculation Department at St Mary’s Hospital to continue his researches on immunization so long as his health should allow. Happily his doubts on that score proved misplaced, and this final spell of work, at his laboratory bench and in his study, lasted no less than twenty-five years.

The general trend of his war-time work had been a continuation of that of the pre-war years: its underlying idea being to look beyond the foul discharges and the sloughing tissues to discover where the patient’s normal defence mechanism was inadequate and how it could be helped most effectively. In the course of this work he had learned the important part played by the anti- proteolytic power of the blood serum in restraining the growth of many species of microbes; and he had learned a great number of new facts about the anti­bacterial activities of the leucocytes. It had always been supposed that these cells could only destroy bacteria by phagocytosis, but that view now seemed to be mistaken; mistaken, too, was the pre-war assumption that the functional activity of leucocytes remained constant in sickness and in health: it had been

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shown by Shattock and Dudgeon (and their findings were confirmed by Wright) to vary considerably.

All this meant that Wright came back after the war to the problems of bacterial infection with an outlook very different from that of the pre-war period. He now saw that the opsonic test alone could not always give an adequate indication of the state of a patient’s immunity—it required to be supplemented by functional tests of his leucocytes—and perhaps also by an estimate of the bactericidal rather than of the phagocytic power of his blood. He conceived too that it was possible to determine a patient’s power of response to a bacterial infection by an in vitro test with a sample of his blood. His laboratory note­books and his published papers after 1918 contain records of a great number of such tests. For twenty years these ‘epiphylactic responses’ of the blood, as he oalled them, were uppermost in his mind, and even after the arrival of the sulphonamides and of penicillin he did not waver in his belief that the main stream of progress in anti-bacterial therapy would ultimately be along the road of scientifically guided immunization by vaccines.

During this post-war period (1919-1945) his work yielded three items of special interest. The first had to do with tuberculosis. For fifty years investiga­tions of that disease all over the world had been hampered by the slowness of growth of the tubercle bacillus on artificial culture media—a matter of several weeks. Wright, reflecting that the microbe could grow all too successfully in the human body (and remembering too his earlier work on ‘serophytic’ microbes during the war), realized that it would probably grow more quickly in human blood; and that demonstration of such growth might open up new lines of investigation. The method of ‘slide cells’ which Wright and his colleagues had devised, and had found so useful in the study of the bactericidal power of blood, proved to be admirably adapted to this purpose also. Tubercle bacilli grew readily in these cells and their growth could be detected after four or five days. The fate of these bacilli in the blood of tuberculous patients could be compared with that in normal blood, and also the effect of incorporating chemotherapeutic substances in the blood.

The second observation which merits particular attention concerned the mechanism of phagocytosis by leucocytes. This process had always been looked upon as a leisurely one, involving the sending out of pseudopodia to surround and engulf the bacteria—a process which, when observed on the warm stage of a microscope, occupied five to ten minutes. Wright showed that it could be accomplished much more quickly (in less than a minute) if the experimental method increased the opportunities for collision between the leucocytes and the bacteria. Simple centrifugalization conveniently supplied such increased opportunity. The surprisingly rapid phagocytosis thus obtained was found to be dependent, like that which had been studied earlier, upon previous ‘opsonization’ of the bacteria. This observation is likely to be of fundamental importance in arriving at an understanding of the mechanism of phagocytosis.

The third noteworthy item of this period was the diversion Wright made into the new science of chemotherapy. After his work in South Africa on ‘Optochin’

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he himself did little experimental work in this field but he had been profoundly interested in Ehrlich’s work which led up to the introduction of Salvarsan for the treatment of syphilis in 1911. Clearly this opened up an alternative road in therapeutics to that of immuno-therapy which he had himself elected to follow. Moreover Ehrlich had introduced, along with the new drug, a whole battery of new technical terms to convey his ideas about the scientific treatment of infections by chemical agents. To Wright, always himself convinced of the importance of new words as the missionaries of new ideas, some of those employed by Ehrlich seemed happily chosen, and valuable—others not so happy. At any rate they set Wright thinking about the whole programme of chemotherapy and he spent many weeks trying to get it into sharp focus in his mind. The result took the form of a ‘Discourse on Ehrlich’s chemotherapy’ ( Lancet, 1927, 2, 1327) in which he discussed at some length the conditions which make for success and failure in this form of treatment—and also the terminology appropriate to it. While he freely acknowledged the great service Ehrlich had rendered to medicine Wright argued that his conception of chemo­therapy was at fault in one important respect—it took no account of the fact that in many parts of the body, and in various circumstances, the infecting microbes are not readily accessible to an anti-bacterial agent circulating the blood stream. In addition to the choice of an effective and non-toxic drug there is, therefore, also the problem of its transport within the body to be considered. To cover the whole range of these transport problems Wright proposed the term ‘Kataphylaxis’. There can be little doubt that the penetrating analysis contained in this paper will be read for many years to come by those who are seriously concerned with the intellectual basis of chemotherapy.

In this sketch of his contribution to medical science I have scarcely touched upon one of the most important. Sir Charles Martin, writing of Lord Lister, has said that ‘in the early days of a science the great discoveries are those of method’. Almost every year of his working life saw another such discovery made at Wright’s laboratory bench, and perhaps in the long run these will be held to be his greatest achievement. In the early days came the ‘Wright capsule’ and the method of obtaining samples of capillary blood; then the many devices for studying the coagulation of blood; and for estimating its bactericidal power after anti-typhoid inoculation; the ‘standard automatic pipette’ and the other calibrated pipettes, which paved the way for many micro determinations; the opsonic technique and, later, methods for investigating the migratory and bactericidal activities of leucocytes; and the anti-tryptic power of the serum.

None of these had an easy birth, for Wright was not, I think, a great technician —in the sense of being ‘good with his hands’. In the preface of his remarkable book On the Technique of the Teat and the Capillary Glass Tube he describes the raison d'etre of technique as being ‘to eke out the inadequate , skill of our hands by the contributory work of our brain’—and that was certainly his way in devising new methods. Some of his colleagues, notably Stewart Douglas and Alexander Fleming, had more flair for craftsmanship and often helped him

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considerably, but the fundamental ideas were always Wright’s—and he had, moreover, an infinite capacity for taking trouble.

Some who saw parts of his technique demonstrated at meetings, but did not share his continual urge to see below the surface of things and supplement his unaided senses, dismissed it as mere ‘laboratory tricks’ played with bits of glass and plasticene and sealing-wax; others, schooled in the traditional methods of the chemical and physiological laboratory, were frankly sceptical of micro­methods based on home-made apparatus; and were perhaps not wholly satisfied even when Fleming demonstrated that the accuracy of these methods, intelli­gently used, was at least as great as that of the more conventional procedures ( British Journal of Experimental Pathology, 1924, 5, 148). Wright himself was persuaded that it was often better to make many observations with an imperfect method than a very few with a more elaborate and perfect one. And, of course, to those who worked with Wright, it was always apparent that his highly-trained mind was much too alert to be easily misled by experimental error.

In relation to this question of technique and the experimental method, mention may appropriately be made of one project which occupied his mind at intervals for a number of years. Although he spoke and wrote somewhere of ‘science flooding into medicine’ he often deplored the fact that that flood was advancing much more slowly than it need. This he attributed in large part to the inadequate training of those recruited into medical research. They came into it for the most part as raw graduates having little acquaintance with many techniques which might be useful to them; and usually no appreciation of the fact that it is all too easy to go astray in planning and carrying out a scientific investigation. Wright did not by any means share the view that every research student knows how to do an experiment; or that his Chief is necessarily qualified to teach him.

Wright believed that the remedy for this state of affairs would be the establishment of something more or less analogous to the Army’s Staff College —a training school where those embarking on medical research could be taught many things they would not have acquired in their University course and might take years to pick up by haphazard contacts in the laboratory. In such a school they should also get practical experience of the more fundamental techniques such as glass-blowing, the making of simple apparatus, the calibra­tion of pipettes and perhaps photography. The recording of scientific experi­ments and the general principles of statistical technique would also be taught. To such a school those engaged in medical research could return from time to time to get acquainted with new developments, or for courses devoted to special subjects.

Wright’s career in medical research science virtually came to an end in 1941 (although he remained Principal of the Institute at St Mary s for another five years) when he delivered a remarkable lecture at the Royal Society of Medicine ‘On the need for abandoning much in immunology which has been regarded as assured’. He was then eighty years of age but he spoke for over an hour

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without a note. Reminding his audience of Goethe’s dictum ‘errors always matter but how very much they matter becomes clear to a man only at the end of his way’, he proceeded to look back over the history of immunization to see how many of the beliefs of the past were still tenable. In the light of new knowledge won during the 1914-1918 War, and since, by himself and others, he did not hesitate to jettison many of the beliefs he had held in earlier days about the specificity of immune reactions, about phagocytosis, and the part it plays in the destruction of bacteria.

To some who heard him but had not personal experience of the chain of events which had led Wright to abandon so much, it seemed that he had gone too far: others regretted that the range of his survey did not include more of the findings of workers outside his own school: but to all the lecture must have seemed a singular achievement—and few will read the story of it in print ( Proceedings of the Royal Society of Medicine, 1942, 36, 161) without some profit and stimulus. At the end of the lecture Wright admitted that he was too far ‘declined into the vale of years’ to pursue his investigations further—and he handed on the torch to younger men. But even then he had not quite finished his intellectual efforts.

At the beginning of this story of Wright’s life work I mentioned that his intellectual activity ran always in two main streams. ‘Pain in the mind’, which he experienced ‘when he was appealed to and was powerless to help’, was the spur which drove him all his life to seek new roads in medicine; and because ‘emotional tension is intolerant of an intellectual impasse’, his mind was also constantly trying to understand and to clarify ‘the Big Issues’. Everyday life to him was full of such intellectual impasses: the problem of distinguishing the false from the true; the problems of property and poverty; the problems of justice; of marriage and the guidance of children; and that of religious beliefs. There was for him no easy way to intellectual morality and truth: the writings of philosophers all through the ages had left too many questions unresolved. Major Greenwood wrote of him that ‘he had far more faith in dialectics and the possibility of reaching truth by mere force of reasoning than most men of science’. That was profoundly true.

I am not qualified to report upon this side of his life-^-much less to attempt any assessment of his contributions to thought—I can only put on record a few pointers to the way he took. In 1895 he published in Brain a paper ‘On the nature of the physiological element in emotion’. Following this he was concerned for some years in unravelling the processes by which we arrive at our beliefs—and in particular the part played by physiological events. In illustration of what he had in mind he used to quote the belief of certain Australian aborigines that white women had white babies because they ate white bread. The manuscript for a book on this subject was almost ready to go to the publishers as long ago as 1904—but it did not go. Wright’s mind was travelling on to new viewpoints, and his thinking was to some extent directed by world events. Thus, during the 1914-1918 War the pressing need for more enlightened treatment of the wounded impelled him to think about the application of logic to medicine;

308 Obituary Notices

;he paths by which we should arrive at generalizations; and the proper way to ldjudicate between rival systems of treatment.

As the war receded into the background his mind became increasingly occupied with morals—the problems of conscience, of voluptuary pleasures, of property, of our relations with our fellows. He argued that the science of morals, ike that of medicine, is in a very elementary state at present, and the way of progress should be by experimentation.

For many years too he pondered over the need for a revised system of logic. Aristotelian logic he maintained dealt only with certainties, and we needed one which was applicable to the many issues which were not certain. None of those who followed Aristotle had considered the kind of problems we are faced with in the modern world of science. As Wright saw it we needed now a logic with two main branches—the one ‘constructional’ which would have to do with build­ing up a body of knowledge—and the other concerned with the application of that knowledge.

All this—and much more—he wrote about as the years went by, and hoped to publish if he lived long enough. In his own view this writing was more important than his contributions to medical science. Various titles were assigned to his projected volume— The Physiology of Belief, A Dictionary of Principles, A System of Hedonistic Ethics, Morals in the Melting Pot (Shaw) and Alethetropic Logic. But the book was never quite finished. In 1941 he published (Heinemann) a small first instalment of it under the title Prolegomena to the Logic which Searches for the Truth, which contains a preface, an introductory chapter and a table of contents of the larger volume to follow. Happily much of this larger volume was left at his death in a condition which will allow of publication. The message of this book will be for the very few—as Wright fully realized. To the larger number his unconventional approach, and the liberal infusion of new words (not easily assimilated) will make it unacceptable. To some it will give offence— as he intended it should (for Wright could at times be almost savage in con­troversy). But if it serves in any measure to clarify some of the philosophical issues with which it deals Wright’s hopes of it will have been justified—and the great labour he spent on it. This labour continued till a few days before his death on 30 April 1947.

In this brief sketch I have tried to depict in broad outline Wright the scientific worker and thinker. To many who knew him he was much more than these a great human, outstanding in any company. We recall his quiet entry into the laboratory for the day’s work, and his greeting, ‘Well, friend, what have you won from our Mother Science to-day?’; we recall the simple austerity of his way of life; his great kindliness and generosity shown to many, known only to few; we see him wandering round his garden at the weekend, hoe in hand, the characteristic twinkle in his eye as he tells of some new discovery about the shortcomings of the female intellect—or of a new word he has coined; we remember, too, his wonderful gift for conversation, and the great store of poetry that enriched his mind throughout a long life.

L. Colebrook u*

Almroth Edward Wright 309

310 Obituary Notices

BIBLIOGRAPHY

Books

A Short Treatise on Antityphoid Inoculation. London: Constable.Principles of Microscopy. London: Constable.Studies on Immunization. London: Constable.The Technique of the Teat and Capillary Glass Tube. (Second edition, with L.

Colebrook, 1921.) London: Constable.The Unexpurgated Case against Woman Suffrage. London: Constable.On Pharmaco-therapy and preventive Inoculation applied to Pneumonia in the

African Native. London: Constable.Prolegomena to the Logic which searches for the Truth. London: Heinemann. Pathology and Treatment of War Wounds. London: Heinemann.Researches in Clinical Physiology. London: Heinemann.Studies on Immunization. First series. London: Heinemann.Studies on Immunization. Second series. London: Heinemann.

Papers

On Immunization; Preventive and Therapeutic Inoculation; and on Immunity to Bacterial Infections

Preventive Inoculation1891. On Wooldridge’s method of producing immunity against anthrax by the injection

of solutions of tissue-fibrinogen. Brit. Med. J. 2, 641.1893. (With D. Bruce.) On Haffkine’s method of vaccination against Asiatic cholera.

Brit. Med. J. 1, 227.1896. A note on the first two cases of typhoid inoculation in man. (See paper on serous

haemorrhages in ‘blood coagulation’ section below.) Lancet, 2, 807.1897. (With D. Semple.) On vaccination against typhoid fever. Brit. Med. 1, 256.1900. (With W. B. Leishman.) On the results which have been obtained by the anti­

typhoid inoculations, and on the methods which have been employed in the preparation of the vaccine. Brit. Med. J. 1, 122.

1900. On the results obtained by the anti-typhoid inoculations in the beleaguredgarrison in Ladysmith. Lancet, 2, 95.

1901. On the changes effected by anti-typhoid inoculation in the bactericidal powerof the blood, with remarks on the probable significance of these changes. Lancet, 2, 715.

1901. Note on the results obtained by anti-typhoid inoculation in the case of an epidemic of typhoid fever which occurred in the Richmond Asylum, Dublin. Brit. Med. J. 2, 1107.

1901. (With other members of the Indian Plague Commission.) On Haffkine’s anti­plague inoculation. Rep. Indian Plague Comm.

1902. On the results which have been obtained by anti-typhoid inoculation. Lancet,2, 651.

1903. On the bacteriolytic power of the blood, and on its relation to the problem ofanti-typhoid inoculation and the recent work of Dr Macfadyen. Brit. Med. J. 1, 786.

1903. On the protective effect achieved by anti-typhoid inoculation as exhibited in two new statistical reports. Brit. Med. J. 2, 906.

1914. (With W. P. M organ, L. Colebrook and R. W. D odgson.) Prophylactic inocula­tion against pneumococcus infections. Lancet, 1, 1 and 87.

1904.1906.1909.1912.

1913.1914.

1941.1942.1943.1943.1944.

Almroth Edward WrightTherapeutic Inoculation ,1902. Notes on the treatment of furunculosis, sycosis and acne by the inoculation of

a staphylococcus vaccine, and generally on the treatment of localized bacteriaL invasions by therapeutic inoculations of the corresponding bacterial vaccines.

Lancet, 1, 874.1903. On the therapeutic inoculation of bacterial vaccines and their practical exploitation

in the treatment of disease. Brit.Med. 1, 1069.1903. A note on the serum reaction of tubercle, with special reference to the intimate

nature of agglutination reactions generally, and to therapeutic inoculation of the new tuberculin. Lancet, 1, 1299.

1904. On the inoculation treatment of tuberculosis. Clin. J. 25, 54.1904. On the treatment of acne, furunculosis and sycosis by the therapeutic inoculation

of a staphylococcus vaccine. Brit. Med. J . 1, 1075.1905. (With S. R. D ouglas.) On the action exerted upon the staphylococcus pyogenes

by human blood, and on the elaboration of protective elements in the human organism in response to inoculations of a staphylococcus vaccine. Proc. Roy. Soc. 74, 147.

1905. (With S. R. D ouglas.) On the action exerted upon the tubercle bacillus by human blood-fluids and on the elaboration of protective elements in the human organism in response to inoculations of a tubercle vaccine. Proc. Roy. Soc. 74, 159.

1905. On the general principles of the therapeutic inoculation of bacterial vaccines as.applied to the treatment of tuberculous infection. Lancet, 2, 1598 and 1674.

1906. Contribution to discussion on serum therapy. Clin. J. 28, 71.1906. The opsonic theory. Canad. Practit. 31, 605.1907. (With S. R. D ouglas, J. Freeman, J. H. Wells and A. Fleming.) Studies in

connexion with therapeutic immunization. Lancet, 2, 1217.1907. On the principles of vaccine-therapy. Lancet, 2, 423 and 493.1908. On some points in connexion with vaccine-therapy and therapeutic immunization

generally. Practitioner, 80, 565.1910. Introductory address on vaccine-therapy: its administration, value and limitations.

Proc. Roy. Soc. Med. General Reports, p. 1.1920. An introduction to vaccine-therapy. Nelson's Loose Leaf Medicine, p. 63. New

York: Nelson.1923. New principles in therapeutic inoculation. Lancet, 1, 365, 417 and 473.1931. On vaccine therapy and immunization in vitro. Lancet, 2, 225, 277 and 333.1931. Traitement des infections bacteriennes. Ann. Vlnst. Pasteur, 46, 639.

Immunity to Bacterial Infections1895. The pneumococcus, with relation to immunity. (Contribution to discussion.)

Brit. Med. J. 1, 302.1899. (With G. L amb.) Observations bearing on the question of the influence which is

exerted by the agglutinins in the infected organism. Lancet, 2, 1727.1902. (With F. N . W indsor.) On the bactericidal effect exerted by human blood on

certain species of pathogenetic micro-organisms and on the anti-bactericidal effects obtained by the addition to the blood in vitro of dead cultures of the micro-organisms in question. J. Hyg. Camb. 2, 385.

1903. (With S. R. D ouglas.) An experimental investigation of the role of the blood-fluids in connexion with phagocytosis. Proc. Roy. Soc. 72, 357.

1904. (With S. R. D ouglas.) Further observations on the role of the blood-fluids inconnexion with phagocytosis. Proc. Roy. Soc. 73, 128.

1906. (With S. T. Ried.) On the possibility of determining the presence or absence of tubercular infection by the examination of the blood and tissue fluids. Proc. Roy. Soc. B, 77, 194

3 11

1906. (With S. T. Reid.) On spontaneous phagocytosis and on the phagocytosis which is obtained with the heated serum of patients who have responded to tubercular infection, or, as the case may be, to the inoculation of a tubercle vaccine. Proc. Roy. Soc. B, 77, 211.

1926. Immunity. Encyclopaedia Britannica.1942. On the need for abandoning much in immunology that has been regarded as

assured. Proc. Roy. Soc. Med. no. 3, 35, 161.

312 Obituary Notices

OnChemo- or Pharmaco-therapy

1912. (With W. P. M organ, L. Colebrook and R. W. D odgson.) On the pharmaco­therapy of pneumococcus infections. , 2, 1633 and 1701.

1927. A discourse on Ehrlich’s chemo-therapy—and on certain general principles which require to be brought into application in all treatment of bacterial diseases. Lancet, 2, 1327.

On the Infections of War Wounds

1915. An address on wound infections: and on some new methods for the study of the various factors which come into consideration in their treatment. Brit. Med. J. 1, 625, 665, 720 and 762.

1915. (With F. Burghard, W. B. Leishman and B. M oynihan.) Memorandum on the treatment of bacterial infections of projectile wounds. Brit. Med. J. 1, 735.

1915. On wound infections and their treatment. Brit. Med. J. 2, 629, 670 and 717.1916. On the treatment of infected wounds by physiological methods. Lancet, 1, 1203.1916. On the question as to how Septic war wounds should be treated. (Being a reply

to polemical criticism published by Sir Watson Cheyne in the British Journal of Surgery.) Lancet, 2, 503.

1917. On the treatment of war wounds, supplemented by additional matter relatingto antiseptics and the methods of Carrel. Lancet, 1, 939.

1918. (With A. Fleming and L. Colebrook.) The conditions under which the steriliza­tion of wounds by physiological agency can be obtained. Lancet, 1, 831.

1919. On the lessons of the war, and on some new prospects in the field of therapeuticimmunization. Lancet, 1, 489.

1923. The physiology of wounds. Medical History of the War (Pathology).

On Gas Gangrene and Acidosis1917. On the conditions which govern the growth of the bacillus of ‘gas gangrene’ in

artificial media, in the blood-fluids vitro and in the dead and living organism. Lancet, 1, 1.

1918. (With A. Fleming.) Further observations on acidaemia in gas gangrene and onthe conditions which favour the growth of its infective agent in the blood- fluids. Lancet, 1, 205.

1918. (With L. Colebrook.) On the acidosis of shock and suspended circulation. Lancet, 1, 763.

On Intertraction1921. On intertraction between albuminous substances and saline solutions. Proc.

Roy. Soc. B, 92, 118.1927. A further contribution to the study of the phenomena of intertraction. Proc. Roy.

Soc. A, 114, 576.1929. Furtheries studon intertraction. Proc. Roy. Soc. A, 125, 587.

Almroth Edward Wright 3T3

On Blood Coagulation; the Treatment of Thrombosis and Haemorrhage; and on Serous Effusions

1891. On the conditions which determine the distribution of the coagulation following the intravascular injection of a solution of Wooldridge’s tissue-fibrinogen. J. Physiol. 12, 184.

1891. Upon a new styptic and upon the possibility of increasing the coagulability of the blood in the vessels in cases of haemophilia and aneurism and internal haemorrhage. Brit. Med. J . 2, 1306.

1891. A study of the intravascular coagulation produced by the injection of Wooldridge’stissue fibrinogen. Proc. Roy. Irish Acad. no. 2 (not found).

1892. On tissue or cell-fibrinogen in its relation to the pathology of the blood. Lancet,I, 457 and 515.

1893. A note on the preparation and employment of physiological styptics. Lancet, 1,435.1893. A contribution to the study of the coagulation of the blood. J. Path. Bad. 1, 434.1894. On the methods of increasing and diminishing the coagulability of the blood.

Brit. Med. J. 2, 57.1894. On the influence of carbonic acid and oxygen upon the coagulability of the

blood in vivo. Proc. Roy. Soc. B, 55, 279.1896. On the treatment of the haemorrhages and urticarias which are associated with

deficient blood coagulability. Lancet, 1, 153.1896. On the association of serous haemorrhages with conditions of defective blood

coagulability. Lancet, 2, 807.1896. Notes on two cases of urticaria treated by the administration of calcium chloride.

Brit. J. Dermatol. 8, 82.1897. On the pathology and treatment of chilblains. Lancet, 1, 303.1902. On the effect exerted on the coagulability of the blood by an admixture of lymph.

J. Physiol. 28, 514.1902. (With H. H. G. Knapp.) On the causation and treatment of thrombosis occurring

in connexion with typhoid fever. Lancet, 2, 1531.1905. (With W. E. Paramore.) On certain points in connexion with the exaltation and

reduction of blood coagulability by therapeutic measures; and in particular on the effect produced upon the blood by the ingestion of calcium chloride, calcium lactate, magnesium carbonate, cows’ milk and other medicinal agents. Lancet, 2, 1096.

1909. Haemophilia. Allbutt and Rolleston’s System of Medicine, 5, 918. London: Macmillan.

On Clinical Physiology1891. (With E. K ulz.) Zur Kenntniss der Wirkungen des Phlorhizins resp. Phloretins.

Z. Biol. 27, 181.1891. On some points connected with the pathology and treatment of diabetes.

Med. J . 1, 787.1893. On the possible advantage of employing decalcified milk in the feeding of infants

and invalids. Lancet, 2, 194.1896. On certain grave defects in the system of artificial respiration as ordinarily carried

out. Brit. Med. J . 1, 203.1897. On the pathology and therapeutics of scurvy. Scientific Appendix to Rep. Army

Med. Dept, for the year 1895 (not available).1900. On the pathology and therapeutics of scurvy. Lancet, 2, 565.1904. Discussion on the aetiology of scurvy. Trans. Epidemiol. Soc. Lond. 23, 94 and 108.1905. (With G. W. Ross.) On the discrimination of ‘physiological’ albuminuria from

that caused by renal disease. Lancet, 2, 1164.1908. The causation and treatment of scurvy in particular of infantile scurvy. Discussion.

Lancet, 2, 725.

On Technical Methods for Medical Research

1897. On the technique of serum diagnosis of acute specific fevers. Brit. Med. J. 1,139.1897. A method of measuring the alkalinity of the blood. Lancet, 2, 719.1898. A further note on the technique of serum diagnosis. Brit. Med. J. 1, 355.1900. On a method of measuring the bactericidal power of the blood for clinical and

experimental purposes. Lancet, 2, 1556.1901. On a quantitative estimation of the bactericidal power of the blood. Lancet, 1, 609.1902. On the measurement of the bactericidal power of small samples of blood under

aerobic and anaerobic conditions and on the comparative bactericidal effect of human blood drawn off and tested under these contrasted conditions. Proc. Roy. Soc. B, 71, 54.

1902. On some new procedures for the examination of the blood and bacterial cultures. Lancet, 2, 11.

1904. On certain new methods of blood examination, with some indications of their clinical importance. Lancet, 1, 215.

1904. On the preparation of microscopic slides for blood-films. Lancet, 2, 73.1915. Memorandum on the employment of bandages for the irrigation of wound

surfaces with therapeutic solutions, and the draining of wounds. Brit. Med. J. 2, 564.

1916. (With H. H. T anner and R. C. M atson.) On a rose irrigator for supplying atherapeutic fluid continuously and at a standard temperature to the whole surface of the wound. Lancet, 2, 821.

1918. New methods for the study of emigration and of the bactericidal effects exerted in the wound by leucocytes. Lancet, 1, 129.

1921. On the value of apparatus and technique in medical research. Lancet, 2, 642.1924. New methods for the study of the pathology and treatment of tuberculous disease.

Lancet, 1, 218.1926. On new methods, devices and apparatus for the routine and the research laboratory.

Lancet, 1, 4.On Optical Matters

1892. A suggestion as to the possible cause of the corona observed in certain after­images. J. Anat. Physiol. 26, 192.

1892. Colour blindness: its pathology and a possible remedy. Nineteenth Century, p. 648.1895. Colour shadow’s. Nineteenth Century, p. 819.1897. A method of projecting a micrometric scale upon a microscopic specimen. J.

Roy. Micr. Soc. p. 245.1904. On certain new methods of measuring the magnifying power of the microscope

and of its separate elements. J. Roy. Micr. Soc. p. 279.

Various1891. A new method of blood transfusion. Brit. Med. J. 2, 1203.1893. (With D. Bruce.) A note on the staining reactions of leucocytes. Brit. Med. J.

1, 400.1893. On the leucocytes of peptone and other varieties of liquid extra-vascular blood.

Proc. Roy. Soc. B, 52, 564.1895. (With D. Semple.) On the presence of typhoid bacilli in the urine of patients

suffering from typhoid fever. Lancet, 2, 196.1895. On the nature of the physiological element in emotion. Brain, 18, 217.1897. (With F. Smith.) On the application of the serum test to the differential diagnosis

of typhoid and Malta fever. Lancet, 1, 656.1897. (With F. Smith.) On the occurrence of Malta fever in India. Brit. Med. J. 1, 911. 1908. The physiology of the emotions. S t M ary’s Hosp. Gaz. 14, 18.1943. On the terminology of statistical experimentation. Lancet, 2, 657.

314 Obituary Notices