SrprnN,rsoR1992 MEMoRIAL LECTURE

PATRICK MANSON AND THE DISCOVERYAGE OF BIOLOGY

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 vector biology than Sir Patrick Manson (1844-7922).By demonstrating that mosquitoesbecame infected with micrdfilariae in the processoftaking a blood meal, he becamethe first to prove an associationbetween and pathogins causing human and animal diseases.He also contributed substantially to _the discovery of mosqiito transmiision of parasites and was a priAcipal force behind the founding of 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 vector biology.

INTRODUCTION forwardconcerning the relationshipbetween in- sectsand somehuman diseases.Philip and Roz- I consider it a great honor to have been se- eboom (1973) provided a detailed account of lected by the American Control As- theseearly observers,referred to by Boyce (cited "John sociationto presentthis year's memorial lecture, in Philip and Rozeboom1973) as the and a privilege to memorializethe contributions Baptists." However, as of 1875, no one had of Sir Patrick Manson to the field of vector demonstratedexperimentally any connection biology and mosquito control. I will attempt to betweeninsects and human diseasepathogens. review the life and scientific career of this un- By 1915,which I havechosen as the closeofthe usually productive physician and scientist, ex- discovery age, the relationship between arthro- amine the significance of some of his original pods and Texas cattle fever, nagana, malaria, discoveries,and place these discoveriesinto the , dengrre,plague, Rocky Mountain context of our current understanding of the bi- spotted fever, relapsingfever, trypanosomiasis ology of -borne diseases.We are pres- and had been defined and demonstrated. ently in an exciting period of advancesin our The periodended with the discoveryof understanding of the of vector- transmissionof bartonellosisby sand by borne diseases,spurred by the availability of Townsend, and the development of I'oa loa in researchtools that existed only in the imagina- Chrysopsby Leiper. By 1918,the generalframe- tions of scientistsjust 15-20 yearsago. However, work of the field of medical entomology was these advanceshave their roots in painstaking essentiallycomplete. A class held in 1918 to research done using primitive experimental train entomologistsin the subject to prepare methods and equipment over 100 years ago. We them for possible problems in troops owe much to the pioneering workers who were fighting in World War I bears a remarkable active from about 1875 to 1915. I have called resemblanceto the latest available medical en- this 40-year span the discovery age of vector tomology textbooks, complete with definitions biology. Entering this period, the role of arthro- of mechanicaland biologicaltransmission mech- pods as vectors of diseasepathogens was un- anisms(Pearce 1918). If there is one individual known. Known human were re- who can be identifiedwith the beginningof this stricted to helminths which could be seeneither amazing period, it is Dr. Patrick Manson with the unaided eye or with microscopesof low (Fie.1). magnification (by today's standards), and the role of invertebrates as intermediate hosts of LIFE AND CONTRIBUTIONS OF parasites was just being discovered. Leuckart MANSON had shown between 1858 and 1867that Cyclaps was the intermediate host of a fish nematode. Patrick Manson wasborn October3, 1844,in Pasteur had not yet expoundedthe germ theory Aberdeenshire,in northern Scotland. His father of disease,and the etiology of microbial diseases was the laird of a large estatecalled Fingast and was unknown. Numerous theories had been put a local banker. As a young man, Manson had a keen interest in natural history, including insect life (Manson-Bahr and Alcock 1927).He was l Fourteenth Annual AMCA Memorial Lecture de- educatedat the University of Aberdeen,receiv- livered at the 58th annual meeting of the American ing an M.B. degreein 1865at the ageof 21 and Mosquito Control Association,Corpus Christi, Texas, an M.D. a year later. One of his first posts was on March 16, 1992. as medical officer to the ChineseImperial Mar-

SEPTEMBER1992 MnuoRrll Lrc'ruRn 2t7 mosquitoescould be kept for extended periods theory relied heavily upon his observations of of time by providing water and a source of exflagellation, first observedby Laveran. It also carbohydrates.For whatever reason,he thought paralleled his erroneousperception that mos- that mosquitoesin nature, as was the casewith quitoes served only as intermediate hosts of his captive mosquitoes,took a single blood meal theseparasites, and not as agentsof transmis- and laid but a single batch of eggs in their sion. In spite of its faults, Manson's theory lifetimes. He thus reasonedthat filarial larvae involved severaloriginal and important insights: escapedinto the water from the bodies of dead One was that if blood containing malarial para- mosquitoesand that human hosts were infected sites were to be taken in by mosquitoes,then in by drinking water infested with filarial larvae. the gut a transformation of the parasite would Thus Manson went astray in attempting to dis- occur leading to a life form capableof infecting cover the complete life cycle of the frlarial par- a human host. Another was that this transfor- asite of man. That he failed to do so in no way mation would only occur in certain speciesof minimizes the importance of his monumental mosquitoes.It remainedfor McCallum in Amer- discovery,however. When viewed in the context ica to show in the caseof Haemoproteusin birds of the time when it was made,and the resources that the "flagellae" were male forms and that available to Manson at the time, the discovery female forms were also present, with fertiliza- is even more amazing. However, had Manson tion taking place in the invertebrate host (Garn- demonstrated the complete transmission cycle, ham 1971). In 1894, a young surgeonby the the significanceof his discoverywould havebeen name of Ronald Ross visited Manson at his unchallenged,and he would have avoided some home, beginning a collaboration which was to ofthe adversecriticism he receivedlater by some Iast 4 years, involve constant exchangesof let- of his contemporariesand by somehistorians. ters (about 100) and specimens,and culminate In 1883,while Manson was still working on in the demonstration,by Ross, of mosquito filarial development in mosquitoes,a reviewer transmission of malaria. As late as 1896, when for the journal Veterinarian madethe suggestion Bigrrami forwarded his own mosquito hypothe- that the mosquito might transmit filarial larvae sis, Manson still believed that mosquitoes did to human hosts in the course of biting. Unfor- not transmit malaria directly becausethey fed tunately, Manson did not see these remarks on blood only once.However, Bignami believed (Manson-Bahrand Alcock 1927),and it was not although mosquitoes transmitted malarial par- until 1900 that Low confirmed mosquito trans- asites to people, they did not become infected mission of filarial larvae. from people(Harrison 1978). Manson moved to Hong Kong in 1883,thus Manson's involvement with malaria transmis- bringing to a close the most productive period sion by mosquitoes culminated in a series of of his research on filariasis. In Hong Kong, experimentscarried out in London and Rome in Manson founded a medical society,a dairy farm 1900. Manson designed these experiments to and a school of medicine (Manson-Bahr and prove to skeptics a transmission mechanism Alcock 1927). In 1889, he moved back to Scot- which he now regarded to be an established Iand to retire. His retirement lasted only until scientific fact as a result of Ross' research.He 1890, when he moved to London to open a had some anopheline mosquitoes infected by medical practice. He also set up a crude labora- feeding on patients with Plasmodium uiuax at tory in his home and continued to study various the Santo Spirito Hospital in Rome brought to kinds of biological specimenssent to him from London, where they were permitted to bite his abroad. oldest son and a laboratory assistant. He also In 1892, Manson receivedan appointment at organized an expedition, conducted by Low, the Seaman'sHospital in London. He was given Sambon and Terzi. in which these individuals charge of a ward at the Albert Dock Hospital. were protected at night by mosquito-proofquar- He also established a small Iaboratory there ters at the Roman Campagnaat the mouth of which was to becomethe nucleusfor the London the Tiber River. After staying there during one School of Tropical Medicine. It was at this time entire malaria season,they did not come down that Manson first learned about malarial para- with malaria, although most everyoneelse in the "mosquito sites and developed his theory" of areadid (Manson-Bahrand Alcock 1927). malaria transmission. Manson was, in the words Historians have argued for years about the "possessed of Harrison (1978), of a truly creative significanceof Manson's role in the discoveryof mind that was always perceiving connections mosquito transmission of malaria, especially in and resemblancesbetween disparate phenom- contrast with that of Ronald Ross and Battista ena. . . ." Having been shown malarial parasites Grassi.Ross stated. in 1900:". . . it was Man- by a Dr. Plimmer, Manson drew parallels be- son'stheory, and no other, which actually solved tween these parasitesand filariae. His mosquito the problem" (Harrison 1978).Manson himself, 218 JouRNer,oF THE AupmcaN Moseurro CoNrnor- AssocrlrroN VoL. 8, No. 3 in 1909, said he should get credit not for the Leiper, Wenyon, Low, Castellani,Daniels and mosquitotheory, but for having discoveredRon- Manson-Bahr(Garnham 1971). ald Ross(Manson-Bahr and Alcock 1927).Har- Manson receivedmany awardsduring his life. rison (1978)states: "Both talents, and both men He wasknighted in 1903,and diedApr1l9,1922. [Manson and Ross] were essentialto the work." Alert to the end, he quoted poetry to those at I believe this to be an accurateassessment. his bedsidejust before he died. The discoveryofthe developmentofbancrof- Many parasites and mosquitoes have been tian filariae in mosquitoesand his participation named in his honor, including the genus- in malaria researchwere not the only contribu- Mansonia, Schistosomamansoni and. Manso- tions Manson made during his career. While in nelln. At the time of his death, he had published Amoy he discovered new speciesof filariae in over 160 scientific articles. domestic fowl, crows and mapies. His work Although after his death in 1922,Manson had with magpieswas done at considerablerisk be- his detractors. it is difficult to minimize the causethe bird was consideredsacred in China. significance of his pioneering discoveries.That It was believed that an ancient Emperor had they were made in crude surroundings and in entered a mapie (Manson-Bahr and Alcock virtual isolation from the scientific community remarkable L927).Later, Manson contributed to the discov- of his day bears testimony to the was a genuine pi- ery of the lung fluke, Paragonimus westermani, effort they required. Manson oneer in the field of tropical medicine and par- and he predicted that Chysopswere vectors of asitology. He will always be marked in some Loa lna 21 years before Leiper was able to dem- historians' minds by the discoverywhich he did onstrate the fact. In 1897,he demonstrated ex- not make: that the mosquito not only servesas flagellation in malarial parasites after discover- a host of filarial parasites, but as a vector as ing that the addition of borax to methylene blue well. Nevertheless,Manson's research in China would enable the visualization of chromatin. involving mosquitoes, their biologa and their was known as stain, and was This Manson's role as hosts of parasites,paved the way for all Leish- developedfurther by Romanowsky and that followed. man to becomethe well-known stains of those Manson was not only the first to demonstrate names. In 1902, Manson discovereda new spe- a role for mosquitoesin the life cycle of human cies of fluke, named by Sambon Schistosoma pathogens,he was also the first to point out that mansoni. He also made original discoveries in mosquitoes varied from species to species in Ieishmaniasisand trypanosomiasis. their ability to serveas intermediate hosts.This, Because Manson was concerned about the he showed,was partly becausemosquitoes dif- slow movement of scientific information relat- fered in their daily biting cycles,but alsobecause ing to tropical medicine, he felt that a school of filariae would not develop in some species.He tropical medicine should be founded. He was tested 4 species of mosquitoes in Amoy, and "miscarried" particularly distressedthat it was not until his found that filariae in all but one, return to London in 1893 that he first learned quinquefasciatus(Manson-Bahr and Al- about Laveran's discovery of malaria parasites cock1927). Here is the adviceManson gave Ross in 1880. He began to organize such a school in in a letter written in 1895:"Another hint I would 1897.The London School of Tropical Medicine give you. Send specimensof the mosquito for was establishedin 1899,in connection with the identification of species.Probably different spe- Seaman'sHospital at Albert Dock. In 1920,the cies of mosquito modify the malaria germ that School was moved into a new building in the the differing degreesof virulence dependon the University Quarter ofLondon. In the final years different speciesof mosquito that has servedas of Manson's active professional Iife he devoted alternative host to the parasite" (Manson-Bahr much time and effort to teaching and to the and Alcock 1927).These observationsare ac- administration of the School. In 1898 he wrote tually the forerunners of modern concepts of the first edition of the textbook Tropical Dis- vector capacity and vector competence. eases.Over the next 23 years, 6 more editions appeared.His son-in-law Philip Manson-Bahr MODERN CONCEPTS wrote editions 7 through !6. Man'son'sTropical Diseasesis now in its 19th edition. In 1907, Although the idea of vector specificity has Manson was responsiblefor the founding of the beenwith us for over 100years, only rarely have Royal Societyof Tropical Medicine and Hygiene particular patterns been fully described, let (then called the Society of Tropical Medicine). alone explained. Huff (1929),working with bird Manson was the guiding force behind many malaria, was one of the first to provide evidence projects in tropical medicine,and brought many that susceptibility of arthropod vectors to infec- famous parasitologists to the London School: tion by pathogensis under genetic control. Sub- SEPTEMBER 1992 MsMonrer,Lrcrunn 2r9 sequentworkers showedthat populations could studies with Jamestown Canyon (JC) virus to be selected for susceptibility, and also that date suggestan equally complex array of mos- considerable variation in susceptibility exists quito populations and viral strains. Brust and amongpopulationsofa numberofvector groups. Munstermann (1992) have recently shown that In the caseof severalparasitic diseases,genetic the Aedescornrnunis complex consistsof at least mechanisms for control of susceptibility have 3 speciesin the western U.S. About 657oof. our beendescribed (Lehane 1991). isolatesof JC virus have come from membersof For diseases,sorting out environ- that complex in California. Before we can sort mental factors of vector capacity from physio- out the vector relationships for CAL serogroup logical factors of vector competencehas a long viruses in California, we must answer a number way to go. This is partly becauseof the com- of fundamental questions involving the evolu- plexity of both vector and complexes, tion of mosquitoes as well as the evolution of with hundreds of viruses already described,and viruses. We must also learn more about the probably many more to be described.Just last underlying causeof vector competencein these year the first evidenceofa geneticcontrol mech- populations for CAL serogroup viruses. Only anism for vector susceptibilif to an arbovirus then can the apparently anomolouspatterns of was reported by Tabachnick (1991).The current vector susceptibility to be explained. status of our knowledge of vector-pathogenin- teractions in was well stated bv THE NEW DISCOVERY AGE DeFoliart et al. (1987): During the past few years there have many Such mosaicsof regional behavior under- interesting developmentsinvolving the genetic line the importance of detecting the exist- and molecular basis of vector competence of ence of speciescomplexes and intraspe- arboviruses,with the paceof discoveriesincreas- cific differences in population behavior. ing in the past 2-3 years. In fact, we are in Intraspecific population differencesin in- another discoveryage in vector biology. This age ternal vector competencehave been simi- holds the promise of discoveringthe underlying larly documentedfor the vectors of a num- cellular mechanismscontrolling the relationship ber of arboviruses.Possibly the most im- betweena wide variety ofvectors and pathogens. portant concept emerging from arbovirus As these mechanisms are defined, they can be research of the past decadeis that there meshedto biosystematic and ecologicalstudies are no simple stories. in a way which can explain not only the phys- iological basis of vector competence,but also the I am involved in a researchproject with James environmental basis for the broader questions Hardy, William C. Reevesand others at the UC of vector capacity. The editor of. the American Berkeley Schoolof Public Health. This research Journal of Tropical Medicine and Hygiene stated is proving to us that vector relationships for in the February 1992 issue: "The intimate rela- California and Bunyamwera serogroup viruses tionship between the insect vector and the in- in the western U.S. certainly do not represent a fectious agent it transmits remains a corner- simple story. We sampled populations of stone of laboratory and field studies in tropical squamigerfrom coastal salt marshes in Califor- medicine." nia becausethis speciesis a "sister species" to I wonder if Patrick Manson ever imagined Ae. irwrepittts and Ae. Snowshoe hare fitchii. what he was starting when he was working in (SSH) virus has been isolated from the latter his laboratory in Amoy. I suspecthe did, because species,and we thought Ae. sEnmiger might he was a very creative and imaginative thinker. harbor either SSH virus or a closely related We owe him much, and again, I thank this yet virus. We repeatedlyisolated an as unnamed association for the opportunity to share this (CAL) California serogroup virus closely related tribute to his memory. to California encephalitis (CE) virus ftom Ae. squanniger,but nothing from its closestrelative, Ae. increpitus, nor from any other speciespres- REFERENCES CITED ent in salt marsh habitats in California (Eld- Brust,R. A. andL. E. Mustermann.1992. Morphologic ridge et al. f991). To make matters more com- andgenetic characterization ofthe Aedes(Ochlcro- plicated, we found that populations of Ae. incre- tatus) communlscomplex (Diptera: Culicidae) in pitus in California differed significantly in NorthAmerica. Ann. Entomol. Soc. Am. 85:1-10. Christophers, 1960. (L.). yellow vector competencefor this CE-like virus (Kra- R. Aedesaegypti The fevermosquito: Its life history,bionomics and struc- mer et al. 1992),and on the basisofelectropho- ture.Cambridge Univ. Press,London. retic and morphological evidence, concluded DeFoliart,G. R., P. R. 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