Kerr, J. Austin

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Yellow Fever - The Saraswati of Virology

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Thomas Jefferson UniversityJefferson Digital CommonsYellow fever, a symposium in commemoration ofCarlos Juan Finlay, 1955 Jefferson History and Publications9-1955Yellow Fever - The Saraswati of VirologyJ. Austin KerrLet us know how access to this document benefits youFollow this and additional works at: http://jdc.jefferson.edu/yellow_fever_symposiumPart of the History of Science, Technology, and Medicine CommonsThis Article is brought to you for free and open access by the Jefferson Digital Commons. The Jefferson Digital Commons is a service of ThomasJefferson University's Center for Teaching and Learning (CTL). The Commons is a showcase for Jefferson books and journals, peer-reviewed scholarlypublications, unique historical collections from the University archives, and teaching tools. The Jefferson Digital Commons allows researchers andinterested readers anywhere in the world to learn about and keep up to date with Jefferson scholarship. This article has been accepted for inclusion inYellow fever, a symposium in commemoration of Carlos Juan Finlay, 1955 by an authorized administrator of the Jefferson Digital Commons. For moreinformation, please contact: JeffersonDigitalCommons@jefferson.edu.Recommended CitationKerr, J. Austin, "Yellow Fever - The Saraswati of Virology" (1955). Yellow fever, a symposium incommemoration of Carlos Juan Finlay, 1955. Paper 7.http://jdc.jefferson.edu/yellow_fever_symposium/7YELLOW FEVER-THE SARASWATI OF VIROLOGYDR. J. AUSTIN KERRDirector, Virus Research Center, Poona, India; Member of the Staff,International Health Division, The Rockefeller Foundation (beginning1926). Distinguished service in many parts of the world in investiga-tions and in applications of public health measures for the control ofinfectious diseases.Saraswati is the Hindu Goddess of Wisdom and Learning and is the con-sort of Brahma the Creator. Saraswati is usually portrayed with four arms,which provide a convenient framework within which to discuss yellow fevervirus and its relationship to the development of techniques for the study ofviruses in general, and the acquisition of knowledge relative to other viruses.This subject can be discussed conveniently under four headings: virology;immunology; zoology; and ecology. With apologies for any liberties I ma ytake, I am going to assign one of Saraswati's arms to each of the four dis-ciplines I have mentioned.Before I do that I should like to pay my personal tribute to CarlosFinlay. I would stress the fact that the acceptance of the validity of histheory that yellow fever was transmitted by Aedes aegypti made it possibleto eradicate yellow fever from Havana, from Cuba, from the Panama CanalZone and from the rest of the Caribbean littoral.The demonstration in 1901 by the U. S. Army Commission that yellowfever was due to a virus had little practical importance until the virus wascaptured alive and brought into the laboratory for study. This was first ac-complished in 1927 and the period of eight years from then to 1935 has beendescribed as the golden age of virology.Virology is the first of the major disciplines to which Saraswati may besaid to devote her arms. The isolation of yellow fever virus in Indian monkeysat the Rockefeller Foundation Laboratory in West Africa is one of the prin-cipal milestones of microbiology. This event, involving as it did one of thegreat pestilential diseases of mankind, captured the attention of investigatorseverywhere and greatly hastened the isolation of many new viruses in a veryfew years.If one lists all the virus diseases of man, a list which is now of quite con-siderable length, he finds that the only human viruses which were alreadyin captivity before the isolation of yellow fever virus were rabies, poliomyeli-tis and herpes simplex. Though not really a human disease, vaccinia mustbe added to this list because of its relationship to smallpox. Of the animal33J. A USTIN KERRviruses only foot -and-mouth disease had been adapted to a small laboratoryanimal prior to 1928.Consider some of the viruses which have been discovered, in addition toinfluenza, mumps, and chicken pox, since 1927. There is a host of arthropod-borne viruses starting with those most unfortunately named "equine enceph-alomyelitides." These three viruses are all American; they are known asEastern, 'Western and Venezuelan equine encephalomyelitis. Philadelphia iswell within the region in which the Eastern virus is periodically epizooticand epidemic.Then there is the group of five antigenically related viruses each froma different continent, all of which appear to be transmitted by one or anotherspecies of Culex mosquito: Japanese B. St. Louis, West ile, Ilheus, andMurray Valley. Japanese B is as common as measles in most of Japan and inmany other parts of the Orient, and West Nile is equally ubiquitous in partsof Egypt, as well as being periodically epidemic elsewhere in Africa. Nor canSt. Louis encephalitis virus be relied upon always to stay west of the Missis-sippi River.Mention must be made of a number of viruses isolated in Africa andSouth America as a by-product of the studies of yellow fever. These viruses,to a total of about eleven different species, were isolated from men, mosquitoesand monkeys over a period of about ten years in the course of yellow feverstudies.The virus of Bwamba Fever was the first to be isolated by Dr. Mahaffyin Bwamba Forest. It was my very good fortune to visit Uganda for the firsttime last month and drive down the road at the base of Mount Ruwenzoriwhere in 1937 Dr. Mahaffy found African road workers suffering from afebrile disease which, greatly to his disappointment, proved to be not yellowfever. He inoculated blood serum from patients into the brains of mice whichhe kept in a field laboratory in tents by the roadside.Semliki Forest, Bunyamwera, Zika, Ntaya, and West Nile viruses wereisolated during the next few years from either mosquitoes, monkeys or man.West Nile is perhaps the most interesting because it represents a new phe-nomenon: the isolation of a micro-organism before the disease it caused wasrecognized.West Nile virus was isolated in 1940 in Uganda from the blood of anative woman who had a low fever and was never seen again, but it was no tuntil 1950-51 that the disease West Nile Fever was described clinically. Twothousand miles away, in Israel, recently arrived Europeans were laid low byan epidemic of non-fatal dengue-like fever which was identified as West NileFever. The infection is highly endemic in the rural population of the NileDelta in Egypt but it is so mild there that it is not identifiable clinically.34YELLOW FEVER-THE SARASWATI OF VIROLOGYMost of these viruses are still scientific curiosities, but there is no know-ing when one or another of them may become of importance as to the causeof an important new epidemic disease.If we accept the theory that man evolved from tree shrews, lemurs,monkeys and anthropoid apes, all of which have an arboreal habitat, it seemsprobable that he has also inherited some virus diseases transmitted by blood-sucking arthropods. Jungle yellow fever is in this group of parasitic diseasesand perhaps if we could find enough fossil mosquitoes it would be worth whilelooking for fossil virus particles.Following the isolation of yellow fever virus, there was a rather intensesearch for animals which were highly and usefully susceptible to importantviruses. This led to the discovery that the ferret-of all animals-was suscep-tible to influenza virus. The great usefulness of the rhesus monkey protectiontest in yellow fever, expensive and cumbersome though it was, stimulated thedevelopment and use of the same test in poliomyelitis, resulting in the acqui-sition of much information about the extent and degree of immunity to thedisease which was not immediately credible.These are two examples of the diversity of the stimulus which yellowfever gave to virology.Both the ferret and the rhesus monkey tests are now obsolete, havingbeen replaced almost completely by simpler and better tests, but only afterthey had served to unearth much basi c information. The thing that madeobsolete the monkey protection test for yellow fever was the discovery thatyellow fever virus could be cultured in the albino mouse if one inoculated thevirus directly into the brain of the mouse. The demonstration that yellowfever virus-which attacked the liver, kidney, and heart of man and the rhesusmonkey-also had a neurotropic component that produced a fatal encephali-tis in mice, really jarred the laboratory Brahmins of 1930.This finding made possible the mouse protection test for yellow fever,tens of thousands of which have been done in the search for neutralizing anti-body in the blood serum of man, monkeys, and other vertebrates.Once the albino mouse was known to be susceptible to yellow fever virus,it was not very long before ways and means were found to culture otherviruses, including poliomyelitis and influenza, in the mouse. Nowadays themouse has become largely obsolete in these two diseases, but it is still the mostuseful of all laboratory animals in the virology laboratory.'Ve come next to immunology, Saraswati's second arm. Long beforeCarlos Finlay entered J efIerson Medical College it was generally recognizedthat one attack of yellow fever protected a person against the disease for therest of his life. This belief received great support from the laboratory findingthat the blood serum of a person convalescent from the disease contained large35J. AUSTIN KERRamounts of neutralizing antibodies. Such antibodies were detected in theblood serum of persons who had suffered their attacks as many as 50 yearspreviously, and had subsequently lived in areas in which the disease didnot occur.The original monkey protection test was used to demonstrate that theyellow fever of the Americas was immunologically as well as clinicall y andpathologically identical with the yellow fever in Africa - a demonstration offundamental importance.Mention has already been made of the fact that the development of usableprotection, or neutralization, tests for yellow fever led to an intensive searchfor neutralizing antibodies in other virus diseases. There was a considerabledegree of success in this search, and the identity of several viruses was thusestablished.Early in the work with yellow fever considerable attention was given tothe use of the complement-fixation test. One of the most potent yello w feverantigens is the blood serum of rhesus monkeys that are acutely ill with thedisease; another excellent source is the brain tissue of mice inoculated withthe virus. The complement-fixation test has proved very useful, not only indistinguishing between different viruses but also, at different levels of sen-sitivity, for showing relationships of viruses.Finally, I must mention the hemagglutinating antigens of yellow feverand a number of neurotropic viruses, in which there is much interest atpresent. With these hemagglutinins it is possible to set up a hemagglutination-inhibition test quite similar to that of influenza, and to show that yellow feveris closely related not only to dengue virus but also to Japanese B and St. Louisviruses, among others.I mention this matter because yellow fever is the recipient in this in-stance, rather than the donor. Things have come full circle, and now aphenomenon which was perfected with a very different virus is shown to be ofvalue with yellow fever virus.Saraswati's third arm, to continue the analogy, is the broad science ofzoology with its two important branches: entomology and mammalogy. Studiesof the reservoir of jungle yellow fever in the forests of tropical America andAfrica led to a consideration of all the bloodsucking arthropods - ticks andmites as well as insects-and of all the warm-blooded vertebrates in the forests.Knowledge was scanty on many counts and the taxonomic problems were nu-merous both in entomology and in mammalogy. The taxonomists who per-formed the absolutely essential service of putting labels on insects andmammals, so that less erudite persons like doctors interested in yellow fevercould be sure that they, and everybody else, knew what species they were deal-ing with, inherited from their predecessors much that was useful, but therewere many important lacunae to be filled.36YELLOW FEVER-THE SARASWATI OF VIROLOGYThe taxonomists of today are paying off our indebtedness to Linnaeusand his contemporaries and successors by putting the taxonomy of many groupsof mosquitoes and mammals into definitive order--or at least so they think.Our grandchildren will know better about this than we do.The fourth arm of Saraswati may be said to represent the science ofecology, of which epidemiology is really only a minor subdivision. When Iwas a premedical student, ecology was something that girls who were majoringin botany had to take. I fear that we rather looked down on them. What thedeal is today, I must confess that I do not know, but I sincerely hope that thediscipline is receiving the attention which it richly deserves.Ecology is the science which deals with the relations of organisms totheir environment. The organisms may be plant, animal, or viral- giantsequoia trees, whales, or yellow fever virus. And environment means all as-pects of the environment-physical and biological.Now as far as Saraswati is concerned, all species have equal rank beforeher throne: yellow fever virus is just as important as Homo sapiens.Ecological studies are often oriented around a single species. The epi-demiologist orients his studies around man, whereas the ecologist could justas logically orient his work around a parasite that was causing trouble.As long as there was only urban yellow fever to consider, ecological studiewere rather crude. Things like the lowest temperature at which Aedes aegypt icould over-winter were about the upper limit of scientific elegance. But onceit became evident, in South America, that jungle yellow fever was contractedin places in which there were no Aedes aegypti, then ecological studies be-came more and more necessary, and more highly refined.The ecological studies on jungle yellow fever revealed very conclusivelythat though that disease was identical with aegypti-transmitted urban yellowfever in all ways, except its manner of transmission, there were several differ-ent epidemiological types of the infection. Once this fact was clearly recog-nized in regard to yellow fever-a disease which forced itself upon everybody'sattention because of its ability to kill, and to kill in horrible fashion-it servedto alert the people who were working on other virus infections to the possi-bility that similar or equivalent factors were operative in connection withother virus diseases. Truly, yellow fever has been a model for the study ofarthropod-borne virus infections.In su~mary, the acceptance of the fact that yellow fever was transmittedby Aedes aegypti made it possible to eradicate the disease from the Caribbeanlittoral. Twenty-five years later the isolation of yellow fever virus inauguratedthe golden age of virology. First there was the direct stimulus to pure virology-the isolation and identification of the viruses that caused a number of im-portant human diseases. Then the results with yellow fever led directly to37J . AUSTIN KERRa variety of important studies in a variety of other disciplines: in immunology;in zoology; and perhaps most important of all, in ecology. These studies hadto do with yellow fever, and they also had to do with other virus dise ases,more or less distantly related to yellow fever. Perhaps the most important ofall these contributions were those in ecology because they spurred medicalinvestigators to get away from the classical viewpoint of man as the point ofdeparture in their thinking. They underlined a refreshingly new point ofdeparture: the virus, into whose orbit man was wont to wander, sometimeswith very unpleasant results.The simpler problems have been solved, in virology, in epidemiology, inecology; the more difficult ones remain to be solved, in yellow fever as well asin general. Yellow fever virus cannot lead the pack forever. Some fine day,some other virus will provide the clue which will solve one or more of themany interesting and important questions about yellow fever which still re-main to be answered. When this occurs it will be more than poetic justice;it will be scientific justice of the highest order.38

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Yellow Fever - The Saraswati of Virology

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