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Home , Frank Fenner, Gordon Ada, Gustav Nossal, Macfarlane Burnet, WEHI

Laboratory Animal Science Vol 49, No 5 Copyright 1999 October 1999 by the American Association for Laboratory Animal Science

Meeting Report

Macfarlane Burnet Centenary Symposium on and 3–5 August, 1999, ,

Abigail L. Smith

This meeting was one of several events in Australia to cel- edict from WEHI that urged its scientists to work on flu or ebrate the centenary of the birth of Sir Frank Macfarlane leave the institute, he began an illustrious career as an in- Burnet, fondly known as Sir Mac by his friends and col- fluenza specialist. He elucidated the nature of receptor-de- leagues. The meeting was held in Melbourne during the stroying enzyme, began to characterize the nature of week prior to the XIth International Congress of Virology in reasssortment, predicted that would have a seg- Sydney. Another centenary symposium, “ - An Aus- mented genome, and pioneered the use of embryonated eggs tralian discovery of worldwide importance,” will be held as substrates for vaccine production. Ada then spoke about later in the year in Brisbane, and the July 1999 issue of Mi- the major diseases in the contemporary world (HIV, , crobiology Australia, the journal of the Australian Society chlamydia) and the approaches that are being used to de- for , was published in Burnet’s honor. Sir Mac velop vaccines. In these latter initiatives, he stressed the util- won the in and in 1960 for ity of animal models. his hypothesis of immunologic tolerance, a phenomenon that Michael Alpers (Director, [PNG] In- was experimentally validated by , with whom stitute of Medical Research, Goroka) began his talk by say- he shared the Prize. Ironically, Burnet is best known for his ing that Burnet had a “love-hate relationship” with . work on . Carleton Gajdusek, the acknowledged authority on kuru Burnet received his medical degree from Melbourne Uni- and himself a Nobel laureate, was a postdoctoral fellow in versity in 1922 and was director of the Walter and the Burnet laboratory. Alpers talked about PNG-based stud- Institute (WEHI) in Melbourne from 1943–1965. Despite his ies of kuru and malaria, the former stressing many contributions to the disciplines of microbiology (Q fe- and the latter stressing vaccine development with the goal ver) and virology (lysogeny in ; Australian X of protection against severe, lethal malaria, not disease, now known as Murray Valley encephalitis), Burnet prevention. When transumption was recognized in the 1950s transformed the WEHI into an institute that stressed im- as the primary and perhaps only mode of transmission of munology. The Macfarlane was established kuru, the practice was banned. This year is predicted to be one year after his retirement as director. the first with no cases of kuru, a disease with a 40 year incu- Having gained international recognition, Burnet was in- bation period. vited to deliver the Dunham Lectures at Sir (Emeritus Professor, The University of in 1944. He was later offered a chair at Harvard but declined Melbourne) introduced (Emeritus Professor, and was fiercely dedicated to Australian science. Sir Mac The John Curtin School, ), well known to the labo- was knighted in 1951, was the founding president of the ratory animal medicine community for his pioneering work Australian Society for Immunology in 1959, and was named with ectromelia . Nossal told the audience that Profes- in 1961. Speakers at the symposium sor Fenner, whose career has spanned 55 years, was Sir included colleagues and protégés of the honored scientist. All Mac’s favorite protégé. Fenner then spoke of his Burnet “con- speakers and topics are listed; however, space limitations nection” — he joined Burnet at WEHI in early 1946, remain- prevent detailed accounts of all presentations. ing until 1952 when he joined the faculty at the “nascent” (Emeritus Professor, The John Curtin School, John Curtin School. Fenner then noted that the symposium Canberra) recalled that Burnet was about half way through honored Australia’s “greatest biologist,” a scientist who his medical studies when the influenza pandemic hit never put his name on a publication without having made a Melbourne. Burnet had a mild case, but was struck by the real contribution to the work reported. Fenner summarized enormous impact of the epidemic. In 1943, as a result of an the history of attempts to control rabbits, introduced to Aus- tralia in 1859 for sport hunting and, ultimately, very suc- Department of , Loyola University Medical Center, Brookfield Zoo, cessful pests. In 1888, a 25,000 pound prize was offered for Chicago Zoological Society, Chicago, Illinois control of the rabbit population. Even Louis Pasteur com-

471 Vol 49, No 5 Laboratory Animal Science October 1999 peted, but no one was awarded the prize. A colleague of (MV), the first virus shown to have immunosuppressive ca- Burnet’s suggested myxoma virus as a possible “temporary pabilities. The host cell receptor for LCMV and other control” agent; however, there was resistance to the proposal arenaviruses has been identified as ␣-dystroglycan, a because it was not known at that time whether the virus in- heavily glycosylated protein expressed on the basal side of fected humans. After many false starts, largely due to the cells. Clone 13, an immunosuppressive variant of LCMV, tar- fact that mechanical transmission by insects was not appre- gets interdigitating dendritic cells based on in situ hybrid- ciated, the potential of biological control was recognized. The ization studies; however, expression of very little detailed history of that effort was recounted and the devel- ␣-dystroglycan is sufficient to initiate infection. The clone 13 opment of host-determined genetic resistance noted. The virus-receptor interaction is high affinity: expression of 100- conclusion: myxoma did control, but not eradicate, rabbits. fold more ␣-dystroglycan is required for infection by the (Emeritus Professor, WEHI, Melbourne) Armstrong of LCMV. Limited numbers of changes in talked about “biological curiosities.” Prior to 1961, the role of amino acid sequence have been shown to affect the affinity the thymus in immunity was not appreciated — thymec- of binding of LCMV strains and variants. Immunosuppres- tomy of adult mice had no effect and thymus cells were inca- sive consequences may be related to the same amino acid pable of transferring immunity. Miller showed the effect of sequences. Oldstone emphasized that there has not been, thymectomy immediately after birth in 1961 and demon- until now, a good small animal model of MV infection, de- strated in 1962 that there were two types of . In spite the fact that Von Pirquet documented the immunosup- 1972, Sir Mac called Miller’s subjects, mice that had been pressive capacity of this virus in 1890. The World Health thymectomized and sublethally irradiated, “biological mon- Organization has targeted MV for eradication by the year strosities.” But the ultimate importance of the thymus was 2015. The virus currently kills 1 million people per year and shown by Zinkernagel in 1978: MHC restriction is imposed infects 40 million people per year. Immunosuppression, aver- intrathymically. aging 2 to 3 months in duration, can result from infection. Peter Doherty (Professor and Chair of Immunology, St. The CD46 molecule is the host cell receptor for MV, and mice Jude Children’s Research Hospital, Memphis) quoted Bur- transgenic for CD46 may be infected by MV intracerebrally, net: “Science to me is the finest sport in the world.” Noting intravenously, or intraperitoneally. Virus recovery may be that Sir Mac led WEHI out of virology and into immunology, accomplished by co-cultivation. Additionally, MV infection of Doherty quipped “We all make mistakes.” He then discussed CD46 transgenic mice results in suppressed re- his own current studies with the type 2 herpesvirus of voles, sponses to sheep erythrocytes, depressed primary cytolytic MHV-68, an agent taxonomically related to herpesvirus responses to vaccination and secondary responses to LCMV, saimiri, human herpesvirus-8, and Epstein Barr virus and enhanced susceptibility to Listeria monocytogenes after (EBV). The virus is lytic for epithelium, with primary repli- the sixth day of MV infection. Newborn CD46-transgenic cation occurring in respiratory epithelium, and remains la- mice infected with MV die, whereas adult transgenic mice tent in B cells and macrophages. Co-cultivation is necessary are immunosuppressed for an as yet undefined interval and for recovery of the agent from those cell types. As is the case die only if their immune systems are suppressed by a sec- for EBV, MHV-68 infection results in an increased number of ondary mechanism. This small animal model shows promise CD8+ T cells in peripheral blood. The facts that class II in facilitating our understanding of MV biology. knock-out mice die from MHV-68 infection and that anti- Colin Masters (Professor, Department of Pathology, Uni- body has been shown to be important in reactivation imply versity of Melbourne) spoke of “Mad Cows to Demented that all components of the immune system are necessary to People” in place of Stanley Prusiner. He discussed the simi- clear this virus, a potential animal model of EBV infection. larities and differences among Huntington’s disease, Doherty, while serious in dealing with the science, quipped “I Parkinsons’ disease, Alzheimer’s disease, and Creutzfeld- think of myself as part of the living fossil record;” as always, Jacob disease. Creutzfeld-Jacob disease occurs sporadically he had words of encouragement for young scientists in the in 10% of cases and is familial in 90% of cases. Despite the audience, noting that there is still plenty of work to be done. lack of evidence for blood-borne transmission of so-called Rolf Zinkernagel (Professor and Chair of Experimental “new variant” Creutzfeld-Jacob disease, the U.S. Food and Pathology, Institute of Experimental Immunology, Zurich), Drug Administration was expected to rule that individuals who shared the Nobel Prize with Doherty, was introduced by who had spent more than six months in the United Kingdom Professor Geoffrey Shellam as an “honorary Australian.” could not donate blood. As a result of the British experience, Zinkernagel’s talk revolved around what immunologic pa- the U.K. is outsourcing its blood needs to the U.S. rameters we can measure and what we should measure: Bob Blanden (Professor, The John Curtain School, what is important? He emphasized the new tools, most nota- Canberra) spoke on the evolution of immunologic diversity bly genetically altered rodents, available to biomedical sci- at the molecular level. Noel Warner (Becton Dickinson Bio- entists. His present hypothesis is that local lymph nodes and science, San Jose), Burnet’s last Ph.D. student, talked about antigen concentration are key regulators of the immune re- the translation of basic science research to the bedside. He sponse — the issues being: where, how much, and when? quoted Burnet, “... I hope that medical research will never Michael Oldstone (Chair of Neuropharmacology, The lose its contact with human realities” (Burnet, 1965). Kevin Scripps Institute, La Jolla) discussed the biology of lympho- Lafferty (“retired” Professor and Director, The John Curtin cytic choriomeningitis virus (LCMV), an arenavirus that tar- School, Canberra) spoke on self-tolerance and autoimmu- gets interdigitating dendritic cells, and of measles virus nity. After a very full day of scientific presentations, partici-

472 Meeting Report

pants were treated to a wonderful Australian dinner at Institute, University of California at San Francisco) talked which the guest speaker was none other than Louis Pasteur. about signal transduction events in T cells. David Balti- Peter Howley (Professor and Chair, Department of Pa- more (Professor and President, California Institute of Tech- thology, Harvard Medical School, Boston) discussed the biol- nology, Pasadena) spoke on “Cell life and cell death,” the T ogy of papillomaviruses, important because there are 5 x 105 cell-mediated and natural killer cell-mediated events in HIV new cases of human papillomavirus (HPV) infection world- infection. (Director, Biomolecular Research wide every year and HPV is the second most common killer Institute, Melbourne) discussed influenza and mo- among female . Howley’s talk emphasized the E6 and lecular intolerance. As a physicist and X-ray crystallogra- E7 genes of HPV, the genes most important to the transfor- pher, he studies the interactions of monoclonal mation process. and drugs with epitopes of influenza viruses, specifically Geoffrey Shellam (Professor of Microbiology, University how these interactions may lead to drug resistance. Donald of , Perth) was Sir Gustav Nossal’s first Henderson (Johns Hopkins University, Baltimore) dis- Ph.D. student. He described current studies of murine cy- cussed the eradication program; Erling Norrby tomegalovirus (CMV), a model for human CMV infection. (Secretary General, The Royal Swedish Academy of Sci- Transmission of mouse CMV occurs via saliva, milk, and ences, Stockholm) spoke about “New biology and the global sexual contact. Infected mice mount a good natural killer society;” and Sir Gustav Nossal addressed progress in glo- response; however, antibody appears to be a good marker of bal immunization. infection but not of clearance. Inbred mouse strains vary in Commentary: One clear theme in this conference was the their susceptibility to mouse CMV, with Kk being resistant use of small animal models and the utility of genetically al- and Dd being susceptible. A gene designated Cmv-1, found tered rodents for developing models where none have existed on the distal region of chromosome 6 (an area to which the in the past. Gordon Ada spoke about vaccine strategies for the natural killer cell region also localizes), mediates resistance world’s major diseases and specifically mentioned the role of in the spleen. C57BL/6 mice are Cmv-1r, and BALB/c mice animals in those endeavors: vaccine candidates will surely be are Cmv- 1s. Cmv-1 is closely linked to rmp, the ectromelia screened in appropriate animal models prior to clinical tri- virus resistance gene, and to the gene coding for herpes sim- als. Other speakers (Miller, Doherty, Zinkernagel, Marrack) plex type 1 resistance. have made major discoveries about the immune system using Bernard Moss (Director, Laboratory of Viral Diseases, the best characterized mammal known to man: the labora- National Institutes of Health, Bethesda) discussed current tory mouse. And others (Fenner, Oldstone, Shellam) have work on molluscum contagiosum virus, a poxvirus that is a used or are using natural virus-host combinations to clarify human pathogen causing persistent cutaneous neoplasms. our understanding of pathogenetic issues. The studies using The virus codes for 16 cell protein homologs, including im- ectromelia virus, LCMV, and mouse CMV have also shed munoglobulin domains, chemokine homologs, apoptosis in- light on how taxonomically related viruses may interact with hibitors, and an interleukin 18 binding protein that is a their human hosts. Perhaps the most exciting prospects were potent inhibitor of interleukin 18 activity. raised by Oldstone’s report on the development of the CD46 Bernard Malissen (Professor and Director, Centre transgenic mouse model for the study of measles virus. The d’Immunologie, Marseilles-Luminy) talked about genetic importance of such models was even more evident at the XIth and structural dissections of the T cell antigen receptor and International Congress of Virology in Sydney — genetically “checkpoints” in T cell development. Philippa Marrack altered rodents are fast becoming the models of choice for ba- (Professor, Howard Hughes Medical Research Laboratories, sic scientists specializing in virology. As a result of their con- Denver) discussed the differences in T cell responses of tributions to this and other biomedical disciplines, these young and old mice. Arthur Weiss (Professor and Chief of animals may already represent the largest and most valu- Rheumatology and Immunology, Howard Hughes Medical able “patient load” of laboratory animal veterinarians.

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