THE WORM TURNED—ACTION AND REACTION*

I)ONALD L. AUGUSTINE

Harvard School of Public Health, Boston, Mass.

My reason for selecting a subject on worms “TheMuse's Looking Glass― takes cognizance for this address is that my professional career of the fact that, has been largely devoted to the study of para “Poorworms being trampled on turn tayle, sitic worms, and I have always found these As bidding battail to the feet of their opres creatures interesting and at times exciting. It is, sors.― therefore, another instance of “Doing What This observation was made in 1638. I do not Comes Naturally.― hold that it is exactly the precursor to the dis At what time man first attached any signif covery of dermal infection made 260 years later icance to the action of worms must be a matter by Professor Looss. of pure conjecture; it is quite unimportant. But Despite its great age, the phrase has never at one time, somewhere along our ancestral grown stale or hackneyed. I would remind you trail, someone possessing that rare quality, of its fresh appearance in Roger Lee's fascinating curiosity, stopped long enough to watch a autobiography, “TheHappy Life of a Doctor― crawling creature; he probably poked at it, and which was published just two years ago. also, probably to his astonishment, noted that “Theworm turned― was very much of an old the creature turned sharply against the poker. saw to me until one day it suddenly came to The observation provoked an idea: the proverb, mind and it carried new significance; in fact, it “Theworm turned.―Thus, a saying burst forth. had a very singular meaning. It occurred some It was pleasing, it spread, became commonplace time ago during one of our symposia on malaria. and, let us say with all due credit to Theodor The speaker, who was reviewing the history of Storm, the author of that delightful novelette, malaria, at the moment was dwelling on the “Immensee,―it sprouted, it dropped from a origin of Manson's mosquito-malaria theory. cloud, floated over land like gossamer and was The old saw burst upon me, for it was indeed the sung in a thousand places at the same time. It turning of a worm that prompted Manson's became a favorite epigram of poets and scribes. theory; it ushered in a new era in medicine, it You may well recall that Clifford, in Shakes was the beginning of modern tropical medicine. peare's “HenryIV,―cautions his gracious liege Reflecting for the moment, I ceased to follow that, “Thesmallest worm will turn, being trod the speaker. I sat there recalling some of the den on.― And, Cervantes, being more than a turnings of worms which had had direct and little vexed over the publication of a second “Don forceful influence on the development of tropical Quixote― while he was preparing his own second medicine and tropical public health. I assure you part for press, notes in his foreword, “Blessme, I had visions of actions and reactions. Reader, gentle or simple, or whatever you may Now, seemingly going somewhat astray, I be, how impatiently by this time must you am going to dwell briefly on a certain phase of expect this Preface, supposing it to be nothing physics, a phase of the subject which was of but revengeful Invectives against the Author of particular interest to all of us early in our scien the second Don Quixote. But I must beg your tific careers; in fact, much before we decided upon pardon—though it be universally said, that a scientific career, namely, Newton's third law even a Worm when trod upon, will turn again, of motion; “Toevery action there is an equal yet I'm resolv'd for once to cross the Proverb.― and opposite reaction.― Objects which turn are And again, Thomas Randolph in his entertaining objects in action. Although the action and the reaction are always equal, the action may be * Presidential address before the American readily perceived but the reaction may not be Society of Tropical Medicine and Hygiene at its annual meeting, November 7th, 1958 at Miami noticeable. For example, when a person pushes Beach, Florida. his stalled automobile along the street, the force 93 94 DONALD L. AUGUSTINE he applies against the automobile is equal to concerned, that bit of added equipment permit that applied against the pavement. The action ting accurate observation of action and reaction is perceptible, but the reaction is not. Let the was introduced, namely Leeuwenhoek's simple pusher put on roller skates and the reaction lens of small size and with considerable curva becomes immediately and decidedly apparent. ture for close focus. The study of intestinal In other words, the roller skates were added worms became the vocation and avocation of equipment which made visual perception of the the naturalist. It became a specialty; the reac reaction possible. Similarly, the reaction to the tion became more apparent than the action and turning of a worm was not sensed until compar a new branch of zoology, helminthology, came able added equipment was applied. In the present into existence. presentation, reaction will refer to man's under The present long list of helminthologists could standing and appreciation of the worm's action, rightly begin with Marcus Bloch, Johann August rather than to a direct reaction; namely, any Goeze, and Peter Simon Pallas, whose years were pathologic physiology. from 1723 to 1811. Whether these gentlemen In all probability our parasitic worms in would have accepted such distinction is, I believe, ancient times did as much turning as they do a bit of a question for each is well known, if today; there was the same action on the part of not better known, for contributions in other the worm but the equipment for sensing any fields; two were physicians and the third was a reaction was lacking. Essentially there was theologian. But all had a common avocation; little or no reaction. It is true that the commoner, they were naturalists in the true sense of the cosmopolitan helminths, Ascaris lumbricoides, word and probably would have preferred to Enterobius vermicularis, and the larger tapeworms remain in this category. were known. Primitive man as well as the medi Even in the present day of specialization it evalite must have been well aware of these is difficult, if not hazardous, to place a scientist creatures. They did not know how they got in any definite category. He might disagree with into the body, but they were fully cognizant of your classification. For example, some years ago the way they left the body. To some, they were at an evening seminar the then recent studies the obvious cause of their intestinal disorders, on bird malaria were to be presented. The speaker abdominal pain, while to others their presence was the late Dr. Samuel T. Darling. The chair was an indication of normal health and well man reviewed Dr. Darling's outstanding scien being. tific contributions and introduced him as a However, once it was assumed that these protozoologist. I was looking at Dr. Darling worms could cause pain, it was natural first to and noticed that he shuddered a bit; then he suspect, and later conclude, that worms caused rose to speak, beginning somewhat as follows, pain and illness elsewhere in the body, particu “Gentlemen, I have been introduced to you as larly the most violent pain, the toothache. a protozoologist. Urumph! This is indeed some The symptom was the disease, as a rule, but in thing new and strange to me. I always considered other cases the cause of the symptom was con myself a pathologist—and I hope I shall be sidered the disease. The patient had worms, remembered as such.― the worms were the disease. Thus, action was During the 18th and 19th centuries helinin observed, but the reaction was overlooked thology was in its heyday, and there were he! except by the physicians who prescribed remedies minthologists of that day: Kitchenmeister, against the worms or the disease. The naturalist, Herbst, Colbald, Steenstrup, van Beneden, and the zoologist of the day, speculated on the ques many others; and especially Leuckart, affection tion of the origin of worms. Further than this ately recognized at home as Altmeister der point, it mattered little if the worm turned, for Helminthologie and acknowledged as the great to them, it looked much the same on both sides. leader by students in all nations. The apparent This trend of thought remained unchanged force of the reaction equalled that of the action. until well into the 17th century. Thousands of animals were examined for their Then came an abrupt and glorious awakening, worm parasites and records were made. It a time of spiritual and intellectual uplift, an was discovered that a worm does not look the age of individual scientific endeavor and un same on both sides. Sex was revealed. The ex biased observations. As far as the worms were perimental method was successfully introduced THE WORM TURNED—ACTION AND REACTION 95 into research, life histories were discovered and rapidly put into action. Prior to this time the the widespread belief in the myths of necro prevalence of echinococcosis in Iceland was genesis and abigenesis became lost in oblivion. astonishingly high. Following the application I look upon the elucidation of the life-history of control measures there was a remarkable and of Triehinella spiralis as the first epochal con steady decline in the number of cases. Sanborn tribution of helminthology to the medical visited Iceland in the early 1920's. Later, in an sciences, particularly to the fields of epidem address before the Institut Pasteur, Paris, iology and public health. You will recall that Sanborn remarked, “Icelandhas long been known this worm was first described in 1835. Twenty as the classic land of hydatid disease, but nowa five years later it was demonstrated that T. days echinococcosis has diminished in frequency spiralis could cause fatal illness in man and as strikingly as yellow fever at Panama fol that, almost immediately following this dis lowing the application of preventive measures covery, the disease in Germany was recognized based on true and precise etiological knowledge.― in epidemic proportion with high mortality. In Today there appears to be no echinococcosis the meantime the parasite had been of keen in Iceland. These are examples, par excellence, interest to the helminthologists. Herbet demon of reactions to the “turningof a worm.― strated the transfer of the worm from one When Dubini, in 1838, discovered hookworms animid to another. Leuckart, Virchow, Kilchen in the intestines of an Italian peasant, his reac meister and others, by careful feeding experi tion appears to have been scarcely more than a ments with laboratory animals, had worked fleeting glanee. Fifty years later hookworms out its complete life cycle, and Leidy had dis were recognized as the cause of a violent epidemic covered trichinae in the flesh of swine. Studies of anemia, that of Saint Gotthard, and twenty of the great epidemics in Germany clearly five years after this epidemic, hookworm disease showed that the disease was of porcine origin was recognized as a major public health problem and government action for control was applied. on every continent. Hookworm control was a Epidemiology, due to the early influence of potent force in the introduction, development Sydenham, reached a high state of development and extension of public health services through during the 18th and 19th centuries, in the hands out the world, particularly influencing their of British epidemiologists. The epidemiological development in rural areas. inquiries of the time were, however, mainly From the very beginning, public health serv directed toward establishing the distribution ices were designed primarily for the improve of the epidemic in time and space, the historical ment of the health and comfort of the city and inductive methods of epidemiological re dweller and to protect the city from epidemic search. The cause was unknown and the methods disease. Even the later developments following for control lacked scientific support. The inves the advent of bacteriology, food sanitation, tigation of the epidemic was often not begun methods for tracing epidemics, laboratory diag until after its termination. Thus, the early nosis, the preparation of vaccines and vaccine studies on Trichineila spiralis ushered in a new prophylaxis, were to a large extent developments method of epidemiological research, the para of bacteriological laboratories within the city and sitologicai method, for here is the first epidemic for urban populations. The countryside, from disease for which both cause and transmission ancient times, was considered a healthy environ were fully known and for which sound control ment and a refuge in times of pestilence. measures were available at the time of the epi Very late in the year 1899 Bailey K. Asiiford demic. saw a worm turn; in fact he saw thousands of Likewise, the first endemic disease of which these particular worms turn. All were parasites the agent, host, and environment were known recovered from rural Puerto Rican patients; was of helminth origin, namely echinococcosis. the peasants, the jibaro, sick and so utterly This knowledge was gained through the applica miserable that, according to Ashford, they could tion of the parasitological method of research not be more so. Ashford proved the parasites and it led to astonishingly effective means of were hookworms and a cause of the malady control. Prophylactic measures against the which was rampant throughout the rural areas disease were proposed in 1863 to the Icelandic of the island. Ministry of Health and these measures were Ashford's reaction was explosive; it was 96 DONALD L. AUGUSTINE epochal. Following the formal announcement of testing on experimental animals. Such critical his discovery, Ashford made a strong appeal testing of anthelmintics was first approximated that government action be taken to combat the in 1884 by Grassi and Calondruccio. The method existent conditions. I will not relate the steps was overlooked, or at least unused, until it was in the development and extension of hookworm reintroduced in 1902 by Stiles, and later de control to rural areas throughout the world. veloped in the United States Bureau of Animal These are well known by all present. I will note Industry under Ransom. Hall did not limit only that wider health services to rural com his studies on anthelmintics to animal experi munities followed the hookworm campaign mentation. To gain information on the safety as their benefits were realized. It can be rightly and subjective effects of tetrachlorethylene, said that the foundation of rural public health Hall ingested the drug one day shortly after was laid when it was realized that hookworm breakfast, which included liver and bacon, disease was a reality and that it constituted a both probably contraindicated, drank milk serious menace to rural health and prosperity. later which is also contraindicated and indulged This discovery marked the awakening of health in smoking throughout the day. As I recall, consciousness of rural areas; a definite reaction Dr. Hall was a fairly heavy smoker. He reported to the “Turningof a worm.― that the only apparent effect of this self-medica There were many ‘sidereactions', or should I tion was a complete relaxation of the muscles say ‘chainreactions' to the turning of the hook on retiring that night leading to an unusual worm. Of these, I shall briefly mention only dream of levitation. It seems very likely that two which I hold to be of particular interest and Hall's report never reached the masses; no addic significance. These were the development of tion to tetrachiorethylene has been noted among anthelmintic medication and the introduction the thousands who have tasted this little-known of parasitology into the curricula of our medical euphoriant. schools. Prior to the turn of the present century, Late in the 19th century, when ancylosto parasitology was primarily a field for academic miasis was recognized as the cause of the Saint graduate study. It seems to have been given Gotthard epidemic, the known vermifuges proved very little, if any, attention in the medical schools. to be worthless. An eager and competitive search In 1891, Charles Wardell Stiles returned to the began immediately for an effective drug. Boz United States after a period of study in Europe, zolo, in 1879, found thymol to be highly effective. to enter government service in the U. S. Bureau Its value was confirmed by others, and it became of Animal Industry. He had received the Ph.D. almost a universal remedy and the drug of degree from the University of Leipzig where choice for nearly thirty five years. The search he studied under the renowned and immortal for better anthelmintics was, and is, continuous. helminthologist, Rudolf Leuckart. The following In 1921, Hall discovered carbon tetrachloride year Stiles was lecturing in parasitology before to be remarkably effective against hookworm the medical students of Georgetown University, infection and, in 1925, he announced the dis the Army Medical School and Johns Hopkins covery of tetrachlorethylene as a new anthel University. He later introduced the subject in mintic, believed to be safer and even more Medical Schools of North Carolina, Georgia, effective than carbon tetrachloride. It remains and Louisiana. Hookworm bionomics and hook today as the drug of choice against hookworm worm disease must have remained foremost infection. with him from his Leipzig days, for in his lec It was the results of crude experiments in tures to these students he emphatically stressed which hookworm larvae were subjected to various the possible existence of hookworm disease in chemicals which led to the use of thymol as an the United States and he cautioned his students anthelmintic. However, its value as an anthel that, if they found cases of anemia in man in mintic, as well as the value of other anthelmin the tropics or subtropics, the cause of which tics, was judged for many centuries mostly by was not clear, they consider the possibility of clinical improvement and the passage of worms. hookworm disease, make a microscopic examina Our knowledge of the value of carbon tetra tion of the feces and look for eggs of the parasite. chloride and tetrachiorethylene as anthelmintics It is of interest to note that Bailey K. Ashford came from carefully-planned studies with critical had attended Stiles' lectures both in the George THE WORM TURNED—ACTION AND REACTION 97 town Medical School and the Army Medical This is a very one-sided impression and it is School. due to the fact that, although our texts on biology It cannot be said, however, that ancylosto and parasitology expressly deal with the im miasis was of primary, or even secondary, influ portant parasites, the word ‘important'invari ence in bringing parasitology into the curricula ably means important to man and domesticated of all of our medical schools. Certainly it was animals and, particularly, ‘important' to man. not at the Harvard Medical School. In this The helminths parasitizing plants are either school such recognition was a sequel of Theobald ignored or are given the slightest attention. Yet Smith's course, “ComparativeEtiology of Infec these plant-inhabiting helminths are world-wide tious Diseases,―first offered during the second in distribution, they rank among the worst half year in 1898. The content of this course is agricultural pests and their significance as not described in the school catalogue of that limiting factors in crop production is unknown. year, but the catalogue of the following year I should like to give a specific example: Thirty states that the course was a fourth-year elective, years ago on the Island of Bangka which lies off and limited to men qualified to do original re the east coast of Sumatra, hundreds of acres search work. It consisted of lectures and demon were devoted to the growing of black pepper. strations on the comparative etiology of infec The economy of this island was based on this tious diseases, general principles underlying crop. Today, due to a particular burrowing infection, and on public health problems arising helminth, the pepper industry on this island from infectious diseases of animals. has been wiped out. This same worm parasitizes In 1900 three optional courses were added citrus; it has already affected 8,000 acres of to pathology, one of which was a course on the citrus in this, the State of Florida. pathology of certain parasitic diseases, given The plant-inhabiting helminths are all nema by Theobald Smith. Parasitic worm diseases todes and include both obligatory and facultative probably were included, but none is mentioned. parasites. Despite the fact that the first species In 1901 the content of this course is more clearly was discovered more than a hundred years defined: it was a course of lectures and labora before the discovery of Triehinella spiralis was tory exercises on animal parasites, particularly announced, and that its life-history stages and protozoa, and the infections produced by them. pathogenicity, i.e., gall formation, were known The annual examination in pathology for the almost a hundred years before trichiniasis was following year included for the first time a recognized as a disease, the plant nematodes question on parasitology, namely, “Givethe interested but few of the early helminthologists complete life-cycle of the blood-parasite of and remained neglected until fairly recent times. tropical malarial fever as now generally ac Among the pioneers I would mention Needham cepted.― Some questions on parasitism in the of England, Kithn and Steinbuck of Germany annual examinations in pathology for the next and Dovaine and Chatin of France. few years were comprehensive and would re In 1907 a most remarkable man joined the quire answers mentioning hookworms. But no United States Department of Agriculture as direct, specific, question on ancylostomiasis ‘AgricultureTechnologist'. He was enthusiastic, appears until 1907 when the student was asked visionary, mathematical, and possessed of keen to give the biology and pathological action of and rare sense of humor. It is rightly said of Uncinaria. Therefore, it seems quite clear that this man that he embodied all that is meant by the introduction of parasitology at the Harvard a “scientist.―He was Nathan Augustus Cobb; Medical School was not a reaction to a worm's Nay Cobb to his close associates. Cobb's early action, but rather to that of a protozoan which fields of interest were in standardization of was, I suspect, Babesia bige@nina Smith and cotton types and free-living and plant nema Kilborne, 1893. todes. Under him the study of plant nematodes From the foregoing, it would appear that the became a distinct and separate branch of helmin development of helminthology was a reaction to thology, the study of nemas, or nematology; worms affecting human beings and animals. names introduced by Cobb, from which there This is the impression all of us could have gained were numerous derivations: “nematologist―, from our college courses in biology and very “nematize―,“nematosis―,“nematicide.―Cobb likely also from graduate studies in parasitology. became ‘SeniorNematologist' in 1924 and ‘Princi 98 DONALD L. AUGUSTINE pal Nematologist' in 1928. The category ‘Nema sitism by transduodenal irrigation with hot tology' was expressly created for Nathan Cobb, physiological salt solution. This reflects the its meaning being restricted to studies on plant pattern of the Journal, as far as publication in insect-inhabiting and free-living nematodes. the field of helminthology is concerned, from Nematology, unfortunately, is still a much Volume I, 1921, to Volume XXIII, 1943. Papers underdeveloped science, but the reaction to on helminthological subjects made up approxi nemas is constantly gaining force. In 1950 the mately 10 per cent of our total scientific contri only agencies in the United States dealing exclu butions. sively with nemas were the Division of Nema A change, a concentration on certain phases tology in the United States Department of of helminthology, begins with Volume XXIV, Agriculture and the then-newly-established unit 1944. In this volume only six of the 57 contribu at the College of Agriculture and the Agriculture tions deal with helminths, but five of these Experiment Station of the University of Cali papers have to do with filariasis; and two of these fornia. Today, less than 9 years later, there announce filariasis in American troops serving have appeared departments, sections, or cur in the South Pacific area. Volume XXV, 1945, rently-given courses presided over by trained announces hyperendemicity of schistoeomiai@is phytonematologists (an even newer category) on Leyte Island, another theater of the war. in the universities or land grant colleges of Eighteen, or more than 22 per cent, of the Alabama, California, Florida, Maryland, New contributions deal with helminthiases; of these, York, North Carolina and Wisconsin. 12 have to do with filariasis and five with schisto I have to a large extent drawn attention to somiasis. Schistosomiasis and filariasis continue the actions and reactions of worms of earlier to be foremost subjects in The American Journal years. I should now like to consider briefly the of Tropical Medicine and Hygiene. Volume V nature of these forces today; first the magnitude of our new Journal published a total of 125 and then the variability; whether the forces contributions of which 44, or 35 per cent, are static, and if not static, what is the direction deal with helminth infections. Twenty-two of or, in other words, what is the trend. these papers are on schistosomiasis and four are To appraise the magnitude, let us examine on filariasis. The same pattern obtains today. the record, namely, “Helminthological Ab Number five of Volume VII, which has just stracts.― This exceptionally valuable source of appeared, contains fewer original contributions, information on all the many and varied applica 17, but three of these deal with schistoeomisisis, tions of helminthology began publishing in two with filariasis and three are concerned with 1932. In that year Volume I contained abstracts insect vectors of filariasis. The emphasis remains from 268 periodicals; 776 authors had published on host-parasite relationships, epidemiology and 873 papers. Volume V contained abstracts from control. 458 periodicals; 1,199 authors published 1,346 World War II is responsible for this trend; papers. Except for the war years there were concentration and markedly increasing activity steady expansion, more periodicals, more authors, concerning two tropical diseases which hereto more publications. Volume XX contains ab fore, in this country, were matters of special stracts from 696 periodicals; 2,113 authors interest to only a relatively few research workers, published 2,067 contributions. physicians connected with medical missions or I shall now point out the course helminthology with industrial firms operating in the tropics. has taken as it is reflected in the publications in World War II ushered in a sudden change. It our own Journals. First, let us turn to Volume was somewhat of a rude awakening to the fact XII, 1932, of the American Journal of Tropical that the whole world had shrunk, that our Medicine; this is, as you may recall, the year public health problems were no longer limited Helminthological Abstracts made its appearance. to continental U.S.A., and that the solution of A total of 39 papers were published, three of the health problems of the warm climates, which were on helminthiases, namely, one on particularly health problems of parasitic origin, skin hypersensitiveness to hookworm antigen, are of primary importance. From the outset one on complications of filariasis and elephan the reaction was international. Never has there tiasis and one on the treatment of intestinal para been greater impetus to mobilize the resources of THE WORM TURNED—ACTION AND REACTION the Free World to combat and abate disease and reaction. The reaction is clearly visible and dis to improve living conditions, not justintheTrop tinct; it is definitely equal and opposite to the ins, but in all parts of the world. The aim has been action. towards international friendship and peace, In closing, I want to express my deep apprecia international cooperation “Forsurvival instead tion to those who gave me the privilege of serving of destruction.― Surely, the worm turned; it as President of our Society. For me it has been keeps on turning; there is action and there is an honor, a very singular honor and pleasure.