Researches on malaria Nobel Lecture, December, 12, 1902
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R O N A L D R o s s Researches on malaria Nobel Lecture, December, 12, 1902* Contents
1. Preliminary p. 26
2 . The discovery of the parasite of malaria p. 27 3. The problem of the mode of infection p. 29
4. First researches in India; 1889-1894 p. 30
5. Return to England; 1894 p. 31
6. The theories of King, Laveran, Koch and Manson p. 32 7. Nature of proposed investigations p. 36
8. Preliminary observations at Secunderabad; 1895 p. 37 9. Secunderabad; 1895. The motile filaments in mosquitos p. 38
10. Difficulty of the task. The methods devised p. 39
11. Bangalore; 1895-1897. Progress of work p. 42
12. The Sigur Ghat; 1897 p. 49
13. Secunderabad; 1897. The fundamental discovery p. 53
14. Interruption; September 1897-February 1898 p. 62
15. Calcutta; February-April 1898. The theory proved p. 65
16. The Darjeeling Terai; April-June 1898. Efforts to obtain assistance p. 72
17. Calcutta; June-August 1898. The route of infection p. 76
18. Darjeeling District; August-September 1898. Kala-Dukh p. 82
19. Assam; September-November 1898. Kala-Azar p. 83
20 . Calcutta; November 1898-February 1899. The work conf irmed p. 85 21 . England; March-July 1899. Foundation of the Liverpool School of Tropical Medicine p. 89
22 . Sierra Leone; August-September 1899. The investigation completed p. 92 23. Confirmation and extensions p. 94
(1) The work of Koch p. 94
(2) The Italian writings p. 96 (3) The Commission of the Royal Society p. 103
References p. 105
Plates p. 110
* The lecture as given on this occasion was only an abstract of the present publication. 26 1 9 0 2 R .R OS S 1 . Preliminary. Malarial Fever, or, as it is often called, Paludism or Intermittent Fever, is perhaps the most important of all diseases which afflict humanity. Broadly speaking it is spread over almost the whole of the tropics, and also ex- tends into many countries which possess temperate climates - being found as far north as Sweden and Canada. Although, happily, it is not a very fatal dis- ease, yet it is generally so prevalent in the countries in which it exists that the sum of the illness which it causes is immense. To take for instance the great country of India with its enormous population of nearly three hundred mil- lions, we find from the sanitary returns of the government that the deaths from fever alone are given at 4,919,591 for the single year 1900; and average roughly about five million deaths yearly - a population nearly as large as that of Swe- den and Norway. Although it is not possible to state that all this fever is mala- rial fever, there are reasons for thinking that most of it must be such. From the more exact returns of the army and of the jail prisoners in India - returns at- tested by medical men - we find that in 1900, out of the total of 305,927 per- sons, no less than 102,640 were admitted into hospital for malarial fever during the year; and even this large figure is below the truth, because in India many slight cases of fever are not admitted into hospital at all. The following Table I taken from the returns of the British Troops in India for 1900 will enable us to compare the sickness due to malaria and to other diseases respectively. It should be noted that the death rate for malaria is here far below the truth; because, the disease being often very chronic, many of the worst cases are in- valided to Europe; while in others death is often recorded as being due to inter- R E S E A R C H E S O N M A L A R I A 27 current affections, such as pneumonia or dysentery, even though malaria may have been the original or principal cause of the fatal result. Similar statistics will be found in most of the tropical countries of the world where statistics are kept at all. Even in such a temperate climate as Italy, the annual number of cases amounts, according to Celli, to something like two millions, while the number of deaths may be fifteen thousand a year. For the great continent of Africa we have, of course, no figures; but we know from the important discovery of Koch, confirmed by many German and British workers, that between fifty and a hundred per cent of the negro children al- ways remain infected from which also we may assume that the terrible in- fantile mortality among negroes is largely due to this disease. But malarial fever is important, not only because of the misery which it in- flicts on mankind, but because of the serious opposition which it has always given to the march of civilization in the tropics. Unlike many diseases, it is essentially an endemic, a local, malady; and one which unfortunately haunts more especially the fertile, well-watered and luxuriant tracts - precisely those which are of the greatest value to man. There it strikes down, not only the indigenous barbaric population, but, with still greater certainty, the pioneers of civilization, the planter, the trader, the missionary, the soldier. It is there- fore the principal and gigantic ally of barbarism. No wild deserts, no savage races, no geographical difficulties have proved so inimical to civilization as this disease. We may almost say that it has withheld an entire continent from hu- manity - the immense and fertile tracts of Africa; what we call the dark con- tinent should be called the malarious continent; and for centuries the successive waves of civilization, which have flooded and fertilized Asia, Europe, and America, have broken themselves in vain upon its deadly shores.
From the first then, the study of this potent foe of mankind has given a great occupation to science. It is not within my province at this moment to detail the early steps by which science grad- ually penetrated the mystery-steps, however, which are not the less interest- ing to follow. Though it was well known to the ancients, the disease was not clearly differentiated from other fevers until much later. Towards the middle of the seventeenth century, however, physicians recognized that in cinchona bark we possess a drug which is a specific for a certain class of fevers, namely the intermittent fevers. As Kelsch and Kiener remark, this discovery was not only an immense therapeutical benefit, but also led to a notable pathological advance, because it enabled Morton and Torti to prescribe the exact limits of 28
1 9 0 2 R . R O S S the disease curable by the medicine, namely malarial fever; and the works of these writers, especially Torti, who without possessing thermometer or mi- croscope accurately described the intricate course of the disease, are among the most admirable works of medical science. At the end of the seventeenth and the beginning of the eighteenth century Morton and Lancisi elaborated an- other important conception, that the disease is produced by some poison which enters the body from without; and the latter especially clearly under- stood what may be called the great law of malarial fever that it is connected with stagnant water on the ground. The next great advance was made in the middle of last century by Meckel, Virchow, Planer, Arnstein, Frerichs, and others, who discovered that the disease is characterized by the presence in the blood and some tissues of a peculiar black granular substance, the malarial pigment or melanin; and this observation led directly to the great discovery of Laveran in 1880, that the melanin is produced within multitudes of minute amoeboid parasites which live within the blood corpuscles of the patient - a discovery which not only illuminated the whole subject of malaria, but, by opening a new department of parasitic pathology, has put the name of Lave- ran in the place of honour beside those of Pasteur, Lister, and Koch. The work of Laveran and of those who followed him affords one of the most beautiful and useful chapters in the whole book of science; and I wish that it were possible to deal with it here at length. We owe to Danilewsky, Theobald Smith and others the discovery of similar parasites in the blood of many vertebrates, and to Laveran and Golgi the determination of several im- portant laws concerning the whole group of these organisms. Marchiafava, Celli, Mannaberg, Metchnikoff, Canalis, Antolisei and many others added important details; Kelsch and Bignami made minute clinical and pathological studies; Romanowsky discovered the best method of staining the parasites; Gerhardt and others produced infection by inoculating the blood of patients into healthy persons; and Richard, Councilman, Vandyke Carter, Osler, Plehn and numerous other skilled observers confirmed those results in many parts of the world. The principal conclusions reached by this mass of investiga- tions are as follows : (1) That Laveran’s parasite is the cause of malarial fever. (2) That it is a sporozoon belonging to a group probably allied to the Coc- cidiidae, of which other members are found in birds; and that somewhat sim- ilar but more distantly related haemocytozoa are found in other vertebrates. (3) That the organisms propagate in the blood by spore formation. (4) That there are probably at least three varieties of the human parasites, R E S E A R C H E S O N M A L A R I A 29 which cause respectively the quartan, the tertian, and the irregular (pernicious or aestivo-autumnal) fevers. (5) That the paroxysm of fever commences with the release of the spores. (6) That with all varieties of the parasites, there are certain forms which do not produce spores, but which, shortly after blood containing them is drawn from the host, emit certain singular motile filaments; and that the nature and functions of these forms still required further investigation. 3. The problem of the mode of infection. But even after all these fine discoveries, there still remained for solution a problem of the greatest difficulty and of the greatest importance. We had discovered the pathogenetic organisms of ma- larial fever, and had studied them and their effect with the greatest care. This was much, but not all; it sufficed for the treatment of individual cases; but not for the prevention or extirpation of the disease on a large scale. For this we were obliged to seek a wider knowledge: the parasites occur in the human blood - but how do they arrive there? On this scientific question turned the whole prophylaxis of malaria - a subject the importance of which in connec- tion with the future development of many of the richest portions of the world’s surface I need not enlarge upon. Ignorant of the route of entry, we could rest our prophylaxis only upon an unsatisfactory empirical basis; cog- nizant of it, we might hope to stamp out the plague even in its most redoubt- able haunts. It is my privilege in this lecture to describe particularly the steps by which this great problem has at length received its full solution. In what manner precisely does the malarial infection reach the human blood? From early times certain cardinal facts regarding the disease have been known to us and have limited the area of investigation regarding this question. It has been recognized, first that malarial fever is essentially an endemic disease - that is, that it does not easily spread from man to man independently of local- ity, as do for instance, small-pox or plague; secondly that it adheres especially to warm localities where there is much stagnant water, such as marshes. Upon these facts, themselves perfectly true, numerous hypotheses have been con- structed; notably the one, dating from the times of Lancisi and Morton, that the disease is due to miasmata exhaled from the stagnant water whence in- deed the word malaria has originated; and later the allied theory of the telluric miasm, according to which the soil possesses a poisonous effluent so powerful at certain spots that it can there produce fever in man. It was even thought that when the surface of the ground is disturbed, this effluent escapes like a gas, infecting all those who live in the vicinity. These speculations afford an in-
30 1 9 0 2 R . R O S S teresting example of the manner in which the human mind is apt to embroider fact with hypothesis. It is a fact that malarial fever is connected with stagnant water; but that the connection is due to an aerial emanation from the stagnant water was only an hypothesis which has never received experimental verifica- tion. Nevertheless, it was almost universally accepted until the true explana- tion of the connection referred to was given in the manner which I shall pres- ently describe. The discovery of the pathogenetic organism by Laveran produced but little change in our ideas on this point. It was simply thought that the parasites must be capable of saprophytic life in stagnant water, and may enter the body by the inhalation of watery vapour or by infected drinking water; and, in- deed, efforts to obtain experimental proof of these conceptions were quickly made, especially by Calandruccio, Marina 8 , Agenore 7 , and Celli and Mar- chiafava 4 , who endeavoured to infect healthy persons by means of water brought from notoriously unhealthy sources. The experiments proved, how- ever, entirely negative - somewhat to the surprise of those who were acquaint- ed with them. At the same time parallel enquiries were commenced to ascer- tain the saprophytic stage of the parasites; and Grassi and Feletti found an amoeba (Amoeba guttula) which they thought might be the parasites in their free condition 10 . Their work recalls that of Crudeli and Klebs who, before Laveran’s discovery, claimed to have found the cause of malaria in the form of a bacillus which they asserted abounds in the water and soil of malarious localities, especially in the lowest stratum of the air, and gives typical inter- mittent fever to rabbits and other animals. All these observations are now proved to have been unsound.
in India (1889-1894). It is, I understand, the principal duty of those who are called to the high honour of presenting the lecture of the Nobel Medical Prize to give in it an account of their own researches ; and I shall there- fore begin my personal narrative at this point.* I had entered the medical serv- * More or less brief abstracts of these investigations have already been published 54,68 , but
their brevity has only had the result of permitting the genesis of many errors regarding the real nature of the task. I have therefore thought it best to give in this publication a ful- ler, and indeed almost autobiographical, narrative of the successive events. It is scarcely possible, except by this means, to present a true picture of the difficulties in the way of re- solving this intricate problem. As so often happens in science, the most important part of the investigations really consisted of the initial failures; and I
have therefore described these negative results in as much detail as is given to the discovery of the pigmented cells and of the life history of Proteosoma which afterwards gave the fundamental solution of R E S E A R C H E S O N M A L A R I A 31 ice of the government of India in the year 1881; but, although many opportu- nities for studying the malarial problem had been given me, I was not special- ly attracted to it until the year 1889, when I first began to observe many facts at variance with the telluric hypothesis which had been instilled into me dur- ing my curriculum. I noted especially that the disease had a much more limited and localized prevalence than could be explained on any theory of aerial con- vection; I found that outbreaks often appeared to occur among troops merely as the result of chill or fatigue; and that in many instances the symptoms accorded ill with the classical descriptions. These observations provoked in me much dissatisfaction with accepted theories; and gradually led me to the task of reviewing the whole subject by close analysis. Unfortunately at that time it was extremely difficult to obtain in India any of the more recent liter- ature on the subject; and even the discovery of Laveran (1880) had scarcely penetrated there as yet - much less the work of Golgi, Danilewsky, Marchia- fava and Celli. I was therefore forced to rely almost solely on my own observa- tions and thoughts; and at first fell into the mistaken conception, parallel with that of Broussais, that the disease may be due to intestinal auto-intoxication; and I published some papers supporting this view 12-16
. In 1892, however, several writers began to ventilate Laveran’s work, but most unfortunately de- scribed, not the parasites of Laveran, but a number of artifacts.* The error was speedily detected and exposed 17,18,20,21 ; but naturally led me (and many others in India) to doubt the whole discovery. As happened with many others, although in pursuance of these studies I had made a laborious examination of malarial blood for some years, I had failed entirely to find the true parasite at all.** Up to the year 1894, therefore, my work, though it gave me an invalu- able training for what was to come, remained in itself quite ineffective.
In 1894 I obtained furlough to England; and im- mediately on arrival sought the advice of Professor Kanthack. He assured me that I
was mistaken in doubting the truth of Laveran’s discovery, and referred the problem. It should be added that my work was minutely recorded not so much in publications, as in a long series of letters to Manson, Laveran, and Nuttall, and that ex- tracts from these letters are now about to be published, together with reprints of some of my papers. * Vandyke Carter had accurately followed Laveran in Bombay in 1887; but I
did not see his work until 1894. * * As I found subsequently, one reason for this was that I had been working principally with old aestivo-autumnal infections in which the larger and more obvious parasites (crescents) were scarce. 32 1 9 0 2 R . R O S S me to Dr. Manson (now Sir Patrick Manson). Manson, to whom the parasite had been previously demonstrated in England, now in his turn showed it to me; and also made me acquainted with the invaluable and illuminating mon- ographs of Mannaberg, and of Marchiafava and Bignami. I now collected my studies in the form of an essay (unpublished) in which I discussed the position of the malarial problem at the time, and which was accorded the Parkes Me- morial Prize for 1895. In November 1894, Manson communicated to me his hypothesis, just formed by him, that the mosquito is the intermediary host of the malaria parasite, as he had proved it to be of Filaria nocturna. I was immediately and powerfully struck with this hypothesis, and at once deter- mined to give it close experimental examination on my return to India. At the same time I remembered that the same hypothesis had been mentioned by Laveran, and I told Manson of the fact. It was not until 1899, after the solution of the problem, that Nuttall informed me of the earlier theories of King and Koch enunciating the same view. Consequently, I have always thought it proper to state that my own work on that part of the malarial problem which flowed from the mosquito theory was based on the hypothesis of Manson and Laveran. But I do not wish by this admission to underrate those of King and Koch; and I shall now enter upon a short digression in order to examine all these very interesting hypotheses together. 6. The theories of King, Laveran, Koch, and Manson. As already mentioned, when the malaria parasite was discovered everyone who remembered the old tel- luric and miasmatic hypothesis thought that it must live a saprophytic exist- ence in marshes; and up to 1894 Grassi’s Amoeba guttula was looked upon as being possibly the free form of the organism in water. Another interpretation of the connection between malarial fever and stagnant water had, however, been noted as early as 1883 in a remarkable paper by King 2 . He advanced the view that the malarial poison is carried from the marsh to the human being by the bites of mosquitoes which breed in marshes; and he gave with great dexterity no less than 19
reasons in favour of this position - reasons based en- tirely on epidemiological considerations such as the frequency of infection in warm moist climates, in the evening, in the lower stories of houses, etc. He refers to a previous enunciation of this conjecture in papers by Crawford in 1807 and Nott in 1847, now apparently lost; and he quotes Manson’s filaria- mosquito work as a reinforcement of his views; but he is evidently ignorant Yüklə 2,27 Mb. Dostları ilə paylaş:
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