SrprnN,rsoR 1992 MEMoRIAL LECTURE

PATRICK MANSON AND THE DISCOVERY AGE OF VECTORBIOLOGY

BRUCE F. ELDRIDGEI

Department of Entomology, (Jniuersity of California, Dauis, CA 95616

ABSTRACT. There have been few scientists who have had a greater impact on the history of vectorbiology than Sir Patrick Manson (1844-7922). By demonstrating that mosquitoes became infected withmicrdfilariae in the process oftaking a blood meal, he became the first to prove an association betweeninsects and pathogins causing human and animal diseases. He also contributed substantially to _thediscovery of mosqiito transmiision of malaria parasites and was a priAcipal force behind the foundingof the Lbndon School of Tropical Medicine and the Royal Society of Tropical Medicine and Hygiene.Manson's career is reviewedln historical context as well as in relation to modern concepts of vectorbiology.

INTRODUCTION

I consider it a great honor to have been se-lected by the American Mosquito Control As-sociation to present this year's memorial lecture,and a privilege to memorialize the contributionsof Sir Patrick Manson to the field of vectorbiology and mosquito control. I will attempt toreview the life and scientific career of this un-usually productive physician and scientist, ex-amine the significance of some of his originaldiscoveries, and place these discoveries into thecontext of our current understanding of the bi-ology of arthropod-borne diseases. We are pres-ently in an exciting period of advances in ourunderstanding of the epidemiology of vector-borne diseases, spurred by the availability ofresearch tools that existed only in the imagina-tions of scientists just 15-20 years ago. However,these advances have their roots in painstakingresearch done using primitive experimentalmethods and equipment over 100 years ago. Weowe much to the pioneering workers who wereactive from about 1875 to 1915. I have calledthis 40-year span the discovery age of vectorbiology. Entering this period, the role of arthro-pods as vectors of disease pathogens was un-known. Known human pathogens were re-stricted to helminths which could be seen eitherwith the unaided eye or with microscopes of lowmagnification (by today's standards), and therole of invertebrates as intermediate hosts ofparasites was just being discovered. Leuckarthad shown between 1858 and 1867 that Cyclapswas the intermediate host of a fish nematode.Pasteur had not yet expounded the germ theoryof disease, and the etiology of microbial diseaseswas unknown. Numerous theories had been put

l Fourteenth Annual AMCA Memorial Lecture de-livered at the 58th annual meeting of the AmericanMosquito Control Association, Corpus Christi, Texas,on March 16, 1992.

forward concerning the relationship between in-sects and some human diseases. Philip and Roz-eboom (1973) provided a detailed account ofthese early observers, referred to by Boyce (citedin Philip and Rozeboom 1973) as "John theBaptists." However, as of 1875, no one haddemonstrated experimentally any connectionbetween insects and human disease pathogens.By 1915, which I have chosen as the close ofthediscovery age, the relationship between arthro-pods and Texas cattle fever, nagana, malaria,yellow fever, dengrre, plague, Rocky Mountainspotted fever, relapsing fever, trypanosomiasisand typhus had been defined and demonstrated.The period ended with the discovery of sand flytransmission of bartonellosis by sand flies byTownsend, and the development of I'oa loa inChrysops by Leiper. By 1918, the general frame-work of the field of medical entomology wasessentially complete. A class held in 1918 totrain entomologists in the subject to preparethem for possible insect problems in troopsfighting in World War I bears a remarkableresemblance to the latest available medical en-tomology textbooks, complete with definitionsof mechanical and biological transmission mech-anisms (Pearce 1918). If there is one individualwho can be identified with the beginning of thisamazing period, it is Dr. Patrick Manson(F ie .1 ) .

LIFE AND CONTRIBUTIONS OFMANSON

Patrick Manson was born October 3, 1844, inAberdeenshire, in northern Scotland. His fatherwas the laird of a large estate called Fingast anda local banker. As a young man, Manson had akeen interest in natural history, including insectlife (Manson-Bahr and Alcock 1927). He waseducated at the University of Aberdeen, receiv-ing an M.B. degree in 1865 at the age of 21 andan M.D. a year later. One of his first posts wasas medical officer to the Chinese Imperial Mar-

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mosquitoes could be kept for extended periodsof time by providing water and a source ofcarbohydrates. For whatever reason, he thoughtthat mosquitoes in nature, as was the case withhis captive mosquitoes, took a single blood mealand laid but a single batch of eggs in theirlifetimes. He thus reasoned that filarial larvaeescaped into the water from the bodies of deadmosquitoes and that human hosts were infectedby drinking water infested with filarial larvae.Thus Manson went astray in attempting to dis-cover the complete life cycle of the frlarial par-asite of man. That he failed to do so in no wayminimizes the importance of his monumentaldiscovery, however. When viewed in the contextof the time when it was made, and the resourcesavailable to Manson at the time, the discoveryis even more amazing. However, had Mansondemonstrated the complete transmission cycle,the significance of his discovery would have beenunchallenged, and he would have avoided someofthe adverse criticism he received later by someof his contemporaries and by some historians.

In 1883, while Manson was still working onfilarial development in mosquitoes, a reviewerfor the journal Veterinarian made the suggestionthat the mosquito might transmit filarial larvaeto human hosts in the course of biting. Unfor-tunately, Manson did not see these remarks(Manson-Bahr and Alcock 1927), and it was notuntil 1900 that Low confirmed mosquito trans-mission of filarial larvae.

Manson moved to Hong Kong in 1883, thusbringing to a close the most productive periodof his research on filariasis. In Hong Kong,Manson founded a medical society, a dairy farmand a school of medicine (Manson-Bahr andAlcock 1927). In 1889, he moved back to Scot-Iand to retire. His retirement lasted only until1890, when he moved to London to open amedical practice. He also set up a crude labora-tory in his home and continued to study variouskinds of biological specimens sent to him fromabroad.

In 1892, Manson received an appointment atthe Seaman's Hospital in London. He was givencharge of a ward at the Albert Dock Hospital.He also established a small Iaboratory therewhich was to become the nucleus for the LondonSchool of Tropical Medicine. It was at this timethat Manson first learned about malarial para-sites and developed his "mosquito theory" ofmalaria transmission. Manson was, in the wordsof Harrison (1978), "possessed of a truly creativemind that was always perceiving connectionsand resemblances between disparate phenom-ena. . . ." Having been shown malarial parasitesby a Dr. Plimmer, Manson drew parallels be-tween these parasites and filariae. His mosquito

theory relied heavily upon his observations ofexflagellation, first observed by Laveran. It alsoparalleled his erroneous perception that mos-quitoes served only as intermediate hosts ofthese parasites, and not as agents of transmis-sion. In spite of its faults, Manson's theoryinvolved several original and important insights:One was that if blood containing malarial para-sites were to be taken in by mosquitoes, then inthe gut a transformation of the parasite wouldoccur leading to a life form capable of infectinga human host. Another was that this transfor-mation would only occur in certain species ofmosquitoes. It remained for McCallum in Amer-ica to show in the case of Haemoproteus in birdsthat the "flagellae" were male forms and thatfemale forms were also present, with fertiliza-tion taking place in the invertebrate host (Garn-ham 1971). In 1894, a young surgeon by thename of Ronald Ross visited Manson at hishome, beginning a collaboration which was toIast 4 years, involve constant exchanges of let-ters (about 100) and specimens, and culminatein the demonstration, by Ross, of mosquitotransmission of malaria. As late as 1896, whenBigrrami forwarded his own mosquito hypothe-sis, Manson still believed that mosquitoes didnot transmit malaria directly because they fedon blood only once. However, Bignami believedalthough mosquitoes transmitted malarial par-asites to people, they did not become infectedfrom people (Harrison 1978).

Manson's involvement with malaria transmis-sion by mosquitoes culminated in a series ofexperiments carried out in London and Rome in1900. Manson designed these experiments toprove to skeptics a transmission mechanismwhich he now regarded to be an establishedscientific fact as a result of Ross' research. Hehad some anopheline mosquitoes infected byfeeding on patients with Plasmodium uiuax atthe Santo Spirito Hospital in Rome brought toLondon, where they were permitted to bite hisoldest son and a laboratory assistant. He alsoorganized an expedition, conducted by Low,Sambon and Terzi. in which these individualswere protected at night by mosquito-proofquar-ters at the Roman Campagna at the mouth ofthe Tiber River. After staying there during oneentire malaria season, they did not come downwith malaria, although most everyone else in thearea did (Manson-Bahr and Alcock 1927).

Historians have argued for years about thesignificance of Manson's role in the discovery ofmosquito transmission of malaria, especially incontrast with that of Ronald Ross and BattistaGrassi. Ross stated. in 1900: ". . . it was Man-son's theory, and no other, which actually solvedthe problem" (Harrison 1978). Manson himself,

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in 1909, said he should get credit not for themosquito theory, but for having discovered Ron-ald Ross (Manson-Bahr and Alcock 1927). Har-rison (1978) states: "Both talents, and both men[Manson and Ross] were essential to the work."I believe this to be an accurate assessment.

The discovery ofthe development ofbancrof-tian filariae in mosquitoes and his participationin malaria research were not the only contribu-tions Manson made during his career. While inAmoy he discovered new species of filariae indomestic fowl, crows and mapies. His workwith magpies was done at considerable risk be-cause the bird was considered sacred in China.It was believed that an ancient Emperor hadentered a mapie (Manson-Bahr and AlcockL927).Later, Manson contributed to the discov-ery of the lung fluke, Paragonimus westermani,and he predicted that Chysops were vectors ofLoa lna 21 years before Leiper was able to dem-onstrate the fact. In 1897, he demonstrated ex-flagellation in malarial parasites after discover-ing that the addition of borax to methylene bluewould enable the visualization of chromatin.This was known as Manson's stain, and wasdeveloped further by Romanowsky and Leish-man to become the well-known stains of thosenames. In 1902, Manson discovered a new spe-cies of fluke, named by Sambon Schistosomamansoni. He also made original discoveries inIeishmaniasis and trypanosomiasis.

Because Manson was concerned about theslow movement of scientific information relat-ing to tropical medicine, he felt that a school oftropical medicine should be founded. He wasparticularly distressed that it was not until hisreturn to London in 1893 that he first learnedabout Laveran's discovery of malaria parasitesin 1880. He began to organize such a school in1897. The London School of Tropical Medicinewas established in 1899, in connection with theSeaman's Hospital at Albert Dock. In 1920, theSchool was moved into a new building in theUniversity Quarter ofLondon. In the final yearsof Manson's active professional Iife he devotedmuch time and effort to teaching and to theadministration of the School. In 1898 he wrotethe first edition of the textbook Tropical Dis-eases. Over the next 23 years, 6 more editionsappeared. His son-in-law Philip Manson-Bahrwrote editions 7 through !6. Man'son's TropicalDiseases is now in its 19th edition. In 1907,Manson was responsible for the founding of theRoyal Society of Tropical Medicine and Hygiene(then called the Society of Tropical Medicine).Manson was the guiding force behind manyprojects in tropical medicine, and brought manyfamous parasitologists to the London School:

Leiper, Wenyon, Low, Castellani, Daniels andManson-Bahr (Garnham 1971).

Manson received many awards during his life.He was knighted in 1903, and died Apr1l9,1922.Alert to the end, he quoted poetry to those athis bedside just before he died.

Many parasites and mosquitoes have beennamed in his honor, including the genus-Mansonia, Schistosoma mansoni and. Manso-nelln. At the time of his death, he had publishedover 160 scientific articles.

Although after his death in 1922, Manson hadhis detractors. it is difficult to minimize thesignificance of his pioneering discoveries. Thatthey were made in crude surroundings and invirtual isolation from the scientific communityof his day bears testimony to the remarkableeffort they required. Manson was a genuine pi-oneer in the field of tropical medicine and par-asitology. He will always be marked in somehistorians' minds by the discovery which he didnot make: that the mosquito not only serves asa host of filarial parasites, but as a vector aswell. Nevertheless, Manson's research in Chinainvolving mosquitoes, their biologa and theirrole as hosts of parasites, paved the way for allthat followed.

Manson was not only the first to demonstratea role for mosquitoes in the life cycle of humanpathogens, he was also the first to point out thatmosquitoes varied from species to species intheir ability to serve as intermediate hosts. This,he showed, was partly because mosquitoes dif-fered in their daily biting cycles, but also becausefilariae would not develop in some species. Hetested 4 species of mosquitoes in Amoy, andfound that filariae "miscarried" in all but one,Culex quinquefasciatus (Manson-Bahr and Al-cock 1927). Here is the advice Manson gave Rossin a letter written in 1895: "Another hint I wouldgive you. Send specimens of the mosquito foridentification of species. Probably different spe-cies of mosquito modify the malaria germ thatthe differing degrees of virulence depend on thedifferent species of mosquito that has served asalternative host to the parasite" (Manson-Bahrand Alcock 1927). These observations are ac-tually the forerunners of modern concepts ofvector capacity and vector competence.

MODERN CONCEPTS

Although the idea of vector specificity hasbeen with us for over 100 years, only rarely haveparticular patterns been fully described, letalone explained. Huff (1929), working with birdmalaria, was one of the first to provide evidencethat susceptibility of arthropod vectors to infec-tion by pathogens is under genetic control. Sub-

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sequent workers showed that populations couldbe selected for susceptibility, and also thatconsiderable variation in susceptibility existsamongpopulations ofa number ofvector groups.In the case of several parasitic diseases, geneticmechanisms for control of susceptibility havebeen described (Lehane 1991).

For arbovirus diseases, sorting out environ-mental factors of vector capacity from physio-logical factors of vector competence has a longway to go. This is partly because of the com-plexity of both vector and pathogen complexes,with hundreds of viruses already described, andprobably many more to be described. Just lastyear the first evidence ofa genetic control mech-anism for vector susceptibilif to an arboviruswas reported by Tabachnick (1991). The currentstatus of our knowledge of vector-pathogen in-teractions in arboviruses was well stated bvDeFoliart et al. (1987):

Such mosaics of regional behavior under-line the importance of detecting the exist-ence of species complexes and intraspe-cific differences in population behavior.Intraspecific population differences in in-ternal vector competence have been simi-larly documented for the vectors of a num-ber of arboviruses. Possibly the most im-portant concept emerging from arbovirusresearch of the past decade is that thereare no simple stories.

I am involved in a research project with JamesHardy, William C. Reeves and others at the UCBerkeley School of Public Health. This researchis proving to us that vector relationships forCalifornia and Bunyamwera serogroup virusesin the western U.S. certainly do not represent asimple story. We sampled populations of Aedessquamiger from coastal salt marshes in Califor-nia because this species is a "sister species" toAe. irwrepittts and Ae. fitchii. Snowshoe hare(SSH) virus has been isolated from the latterspecies, and we thought Ae. sEnmiger mightharbor either SSH virus or a closely relatedvirus. We repeatedly isolated an as yet unnamedCalifornia serogroup (CAL) virus closely relatedto California encephalitis (CE) virus ftom Ae.squanniger, but nothing from its closest relative,Ae. increpitus, nor from any other species pres-ent in salt marsh habitats in California (Eld-ridge et al. f991). To make matters more com-plicated, we found that populations of Ae. incre-pitus in California differed significantly invector competence for this CE-like virus (Kra-mer et al. 1992), and on the basis ofelectropho-retic and morphological evidence, concludedthat 3 species in the Ae. intrepittts complex existin California (Lanzaro and Eldridge 1992). Our

studies with Jamestown Canyon (JC) virus todate suggest an equally complex array of mos-quito populations and viral strains. Brust andMunstermann (1992) have recently shown thatthe Aedes cornrnunis complex consists of at least3 species in the western U.S. About 657o of. ourisolates of JC virus have come from members ofthat complex in California. Before we can sortout the vector relationships for CAL serogroupviruses in California, we must answer a numberof fundamental questions involving the evolu-tion of mosquitoes as well as the evolution ofviruses. We must also learn more about theunderlying cause of vector competence in thesepopulations for CAL serogroup viruses. Onlythen can the apparently anomolous patterns ofvector susceptibility to infection be explained.

THE NEW DISCOVERY AGE

During the past few years there have manyinteresting developments involving the geneticand molecular basis of vector competence ofarboviruses, with the pace of discoveries increas-ing in the past 2-3 years. In fact, we are inanother discovery age in vector biology. This ageholds the promise of discovering the underlyingcellular mechanisms controlling the relationshipbetween a wide variety ofvectors and pathogens.As these mechanisms are defined, they can bemeshed to biosystematic and ecological studiesin a way which can explain not only the phys-iological basis of vector competence, but also theenvironmental basis for the broader questionsof vector capacity. The editor of. the AmericanJournal of Tropical Medicine and Hygiene statedin the February 1992 issue: "The intimate rela-tionship between the insect vector and the in-fectious agent it transmits remains a corner-stone of laboratory and field studies in tropicalmedicine."

I wonder if Patrick Manson ever imaginedwhat he was starting when he was working inhis laboratory in Amoy. I suspect he did, becausehe was a very creative and imaginative thinker.We owe him much, and again, I thank thisassociation for the opportunity to share thistribute to his memory.

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Christophers, R. 1960. Aedes aegypti (L.). The yellowfever mosquito: Its life history, bionomics and struc-ture. Cambridge Univ. Press, London.

DeFoliart, G. R., P. R. Grimstad and D. M. Watts.1987. Advances in mosquito-borne arbovirus/vectorresearch. Annu. Rev. Entomol. 32:479-505.

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Kramer, L. D., W. C. Reeves, J. L. Hardy, S. B. Presserand B. F. Eldridge. 1992. Experimental vector com-petence studies ofAedes mosquitoes for CE and CE-like viruses. Am. J. Trop. Med. Hyg. In press.

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