Historical review: Sir Gustav Nossal immunologist and more

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    Figure 1. Sir Gustav Nossal. Sir Gustav Nossal has been a member of the Editorial

    Board of Immunology Today/Trends in Immunology since the journals inception,

    25 years ago.

    Review TRENDS in Immunology Vol.25 No.12 December 2004of ideas!activities, reputations and influences can spring.Gus, like one of his very early mentors Sir Macfarlane

    Burnet, has subscribed to the view that basic science isprimarily about ideas. Creating the right environment forscientists, to enable ideas to emerge, where vigorousdebate flourishes and where hypotheses are put to thetest and bureaucracy minimized is what scientific leader-ship is about. One of his best-known quotes is . theglittering prizes of success come to those who combineteamwork with high technology in a bubbling cauldron

    Despite the primacy of ideas in basic scientific research,Gus interests in translating and implementing (evencommercializing) the products, processes and services ofresearch have strengthened over time. He has involvedhimself deeply at the global level in both development ofnew vaccines and increasing population access to those inexistence, particularly childhood vaccines. A completepicture of Gus Nossals contribution to immunology willtherefore comprise laboratory-based scientific researchoutputs, efforts to translate discoveries to products ofscientists credibility and from which the other interests,

    ceptual and technological currency. This is the basis of aHistorical review: Simmunologist and mGraham F. Mitchell1 and Michael F. Good1Foursight Associates Pty Ltd, Level 2, 164 Flinders Lane, Melbo2Queensland Institute for Medical Research, 300 Herston Road,

    Sir Gustav Nossal, universally known as Gus Nossal, isAustralias best known medical research scientist andadvocate, who over the past five decades has influencedthe course of immunology. His research interests in thisfield commenced during PhD studies, and his accom-plishments centre around the cellular events of antibodyproduction. His scientific achievements are matched bythe energy he has devoted over his entire career topublic health; science in society; political, philanthropicand community support for science; global access toexisting vaccines and development of new vaccines; andthe personal and scientific development of colleaguesand young scientists. His contribution and philosophy ofscience, together with political influence, capacity toinspire and an extraordinarily engaging personality,place Gus Nossal in the top bracket of biomedicalscientists of the second half of the 20th century.

    For almost 50 years, and certainly over the 25-year historyof Trends in Immunology and Immunology Today, GusNossal (Figure 1) has consistently and proudly describedhimself in a multitude of forums as an immunologist andoccasionally, as appropriate, an Australian immunolo-gist. His professional life as such is a reflection of a deepconviction that, despite encyclopaedic scientific knowledgeand infinite capabilities, genuine interests in all branchesof medicine, major ongoing societal contributions andserious political influence, above all else, the essence of amedical researcher is deep expertise in a particulardefined research area. In one discipline, specialty orresearch endeavour, depth rather than breadth is para-mount and, by definition, must be accompanied by con-Gustav Nossal ore

    e, Victoria 3000, Australiaston, Queensland 4006, Australiacareers of a multitude of immunologists and medicalresearchers more broadly.

    Corresponding author: Graham F. Mitchell (graham.mitchell@foursight.com.au).Available online 30 September 2004

    www.sciencedirect.com 1471-4906/$ - see front matter Q 2004 Elsevier Ltd. All rights reserved. doi:10.1016/j.it.2004.09.007public health and commercial value and impacts on the

  • The B-cell immunologistLike many of us, Gus is best known among immunologistsfor his early research; unlike many of us, he has stayedpretty much with a line of research that commencedduring his PhD studies: the cellular events of antibodyformation, extending to immunological memory andimmunological tolerance. Moreover, the vast bulk of hisresearch work was performed at one institution, namelyThe Walter and Eliza Hall Institute of Medical Research(WEHI) in Melbourne. Being concerned with the inductiveevents of immune responsiveness and the detailedcharacteristics of antibody-producing cells and theirprecursor lymphocytes, he is primarily a B-cell immunol-ogist. A particular source of pride has been continuous(19621996) National Institutes of Health (USA) grantsupport (AI-03958) for studies on antibody production atthe single-cell level.

    The early yearsAs the focus of this article is the contribution of Sir GustavNossal to the field of immunology in the years since hiscontribution to the first issue of Immunology Today [1](i.e. the second half of his immunological life), we willsimply headline some of his early research contributions

    lymphocytes (B cells) from non-immunized animals isolated through

    Review TRENDS in Immunology Vol.25 No.12 December 2004666antigen-binding fractionation; Development of robust micromanipulation and other cell-separation techniques to visualize and study single cells (later,exploitation of carefully optimized limiting-dilution in vitro clonalanalyses); Demonstration of a switch in isotype from multivalent IgM todivalent IgG in individual antibody-producing cells without changein specificity for antigen; Contributions to immune response maturation from early IgM toIgG antibodies with subsequent antibody affinity increase; Demonstration of follicular localization of (radiolabelled) antigenin secondary lymphoid tissues (i.e. lymph nodes and spleen) androle of antibody; Demonstration of persistence of (radiolabelled) antigen on follicu-lar dendritic cells; Insights into the development of germinal centres from primarylymphoid follicles; Highlighting the importance of antigen characteristics (e.g. valency,solubility), antigen dosage (i.e. low- and high-dose tolerance) andage of exposure in tolerance induction; Demonstration through chromosome analyses of micromanipu-lated antibody-secreting cells that, in T cellB cell collaboration, only(Box 1), many through collaboration, which, incidentally,was always acknowledged, often lavishly.

    Among the numerous research contributions anddiscoveries of the early years outlined in Box 1, two havehad a major impact. First, the use of micromanipulationtechniques to study single antibody-producing cells, withthe data strongly supporting, if not proving, the clonalselection theory of Burnet. Second, the equally pain-staking pioneering work with Gordon Ada and other

    Box 1. Research contributions (late 1950s to mid-1970s)

    The one cellone antibody rule; more precisely, the one celloneantibody specificity rule; Absence of (radiolabelled) antigen in antibody-producing cells; Validation of the clonal selection theory of antibody formation,including the demonstration of unique specificity of individualB cells produce antibody.

    www.sciencedirect.comcollaborators that demonstrated the trapping of antigenon follicular dendritic cells of lymphoid follicles andgerminal centres i.e. follicular antigen localization.

    More recent researchIn the decade before his retirement from WEHI in 1996,his research discoveries, again through collaboration(primarily with PhD students, postdoctoral fellows andsenior technical staff), were predominantly in two areas the mechanisms of B-cell tolerance and identification ofkey decision points for tolerance induction over thedifferentiation history of nave and sensitized B cells. Wewill now outline the essential features of this morerecent work.

    If the mechanisms of immunological tolerance at theB-cell level are viewed as a spectrum, with the concep-tually straight forward and well-grounded clonal deletionof Burnet at one end, then the more complex, andseemingly risky, clonal anergy of Nossal is at the otherend of the spectrum. Inhibition of antibody production,and thus control of autoantibodies in particular, appar-ently comes in several guises: yet another example of thebody not investing in only one mechanism to achievecrucial biological, and thus evolutionarily important,outcomes.

    The work of Nossal et al. [2] on clonal anergy that beganin the late 1980s demonstrated that self-destruction wasnot the only choice available to B cells when inhibition ofantibody production is the desired outcome. Rather than aselective purging of the repertoire in a situation of B-celltolerance, antibody receptor-bearing B cells could still bedemonstrated. Clonal anergy, a selective silencing (ratherthan purging) in the repertoire, seemed to be an optionfor B cells, particularly at certain time points in theprocess of B-cell development and differentiation in bonemarrow and lymphoid tissues. Thus, B cells could beparalysed and, although still demonstrating specificityfor antigen, were prevented from progressing to high-levelantibody secretion.

    The above experiments were performed using foreignantigens known immunogens (and tolerogens). In thecase of autoantigens and maintenance of self-tolerance, itwould seem risky to foster the presence of reactive yetclonally anergic B cells that might have some antigen-presentation capabilities for T cells. Just as B-celltolerance apparently involves more than the purging ofB cells, mechanisms of T-cell tolerance appear to bemultiple, and it is feasible that anergic B cells might beinvolved in maintaining sensitized regulatory T cellsin immunological tolerance. Alternatively, it is inter-esting to speculate whether the elimination of autoreac-tive B cells with the capacity to bind and presentautoantigens, at least to sensitized T cells, provides arationale for the use of particular B cell-depletingmonoclonal antibodies in the treatment of autoimmunedisease (D. Tarlinton, pers. commun.).

    Across immunology, the impact factor of clonal anergyhas been modest. Despite the considerable uncertaintyaround the extent, nature and physiological importance of

    this phenomenon, the notion that B cells pass throughperiods of heightened antigen-dependent susceptibility to

  • negative signalling has clearly stood the test of time. It isan immunological paradigm. There are key decision pointsin B-cell differentiation where the consequences of antigenencounter are weighted towards either negative orpositive signals. Additional considerations will clearly bethe presence of T-cell cytokine products, danger signalsfrom microorganisms and Toll-like receptor-bearing cells,and other aspects of the microenvironment local to

    1950s, Gus has been a devotee of quantitation, as

    Review TRENDS in Immunology Vol.25 No.12 December 2004 667quantitative analysis is a key ingredient of analyticalrigour. Like his scientific contemporaries and SydneyUniversity alumni colleagues Don Metcalf and Jaq Miller,and in keeping with the approach championed by NielsJerne and Mel Cohn, Gus recognized early on that the bestway to address the uncertainties of biological phenomena(and certainly the sometimes problematic assays ofimmune responsiveness, despite being at least based onspecificity and thus having an inbuilt control) was to getthe numbers and do the stats. Little is black and white inbiology, and the area of grey is best accommodatedthrough rigorous quantitation, in this case over the timecourse of an immune response (e.g. numbers of antibody-producing cells and numbers of their precursor Blymphocytes). Of course, it was left to Jerne et al. [6] toprovide the ultimate means to compare in vivo immuneresponses at the cellular level at that time the plaque-forming cell assay for antibody production to sheeperythrocytes. How, for years, we longed for a comparable

    Box 2. Germinal centres

    The demonstration some years ago that germinal centres are sites ofhypermutation in Ig V genes brought Nossal and Adas follicularlocalization studies [2] back into focus. Antigen localization ismarkedly influenced by existing antibody levels, and the overallavidity of any new B-cell receptor would need to be such that itcompetes for antigen with the range of existing antibodies,presumably anchoring that antigen on the follicular dendritic cell.antigen-binding B cells (which, at the population level,will also display a spectrum of avidity for antigen). Thisline of work extended to Klinmans second window ofsusceptibility to tolerance induction [3], this time ingerminal centres (the sites of hypermutation in B-cell Vgenes) (Box 2), perhaps through apoptotic mechanisms [4].

    Virtually all of the work outlined above was performedin non-transgenic systems, with use of labour-intensiveflow cytometry and fluorescence-activated cell sorting andsingle-cell cloning analyses. Interestingly, confirmatorydata on clonal anergy have come from studies intransgenic mice [5]. Gus and co-workers have investedheavily in developing and adapting new technology butmost obviously, in devoting the necessary time to prelimin-ary work on optimizing techniques and reagents that aregoing to be the linchpin of future research. Interpretationof results must not be clouded by technological deficienciesand uncertainties; emphasis must be on what doeshappen versus what can happen.

    The numerate immunologistAs evidenced in his early publications at WEHI in the lateThere would thus be selection of B cells bearing mutated V genes ofprogressively higher binding site affinity.

    www.sciencedirect.comassay of T-cell numbers engaged over time in an in vivoimmune response: the significant impedance being thatwe did not have a clue what they produced.

    It is fascinating to look back at the early publicationsfrom Gus on the one cellone antibody demonstrationsand the emphasis on the arithmetic; that is, the numberof micromanipulated antibody secretors isolated fromanimals immunized with two antigens and comparingthe number producing antibody specificity 1 versusantibody specificity 2 versus possible double producers,and making comparisons with the precise numbersobtained by others using different techniques [2]. More-over, quantitation was crucial in his determination of thecellular events of memory and tolerance, and the esti-mation of the number of antibody molecules produced by aplasma cell (10 000 per second) was another example.

    This ease and familiarity with numbers finds itsexpression these days in the speed with which Gus canzero in on the key features of a companys financialstatements, a skill apparently learnt as a young boy fromhis businessman father on Sunday nights, while pouringover the book of accounts! Although not particularlyrelated to numeracy, another key element of Gusapproach to science that he shares with Miller andMetcalf is getting citations right, and their students allacquired this message at an early stage in their studies.The major purpose of at least Chapter 1 in a PhD thesis isto understand the background science in enough detail tobe able accurately to ascribe a relevant finding to aparticular research group and to be able to cite it fromthen on. Few things are more annoying to a researchscientist than not being cited or being cited incorrectly.Few are concerned when the deficiencies of ones study arehighlighted in the literature. Scientists are doing thatwith their own work all the time as Gus has said, aresearch scientist should be his or her sternest critic, withemphasis on the evidence (it is interesting to speculatewhat politics would look like if this attribute was taken upby politicians!).

    The applied immunologistIn 2000 (incidentally, the year that Gus was Australian ofthe Year), he wrote that In the years 19501980 (as thefoundations of new immunology were laid and the fieldbecame a dominant force in biomedicine) the high priestsand priestesses of the discipline concerned themselvesmore with the academic end of the spectrum and lesswith the community-orientated approaches, which actu-ally had given birth to immunology. Things have changednow and over the last two decades . some of the bestminds of immunology (are) now heavily concerned withthe practical end.

    In the past 15 years or so, Gus has immersed himself inthe field of vaccines and vaccination through major, high-level involvement in World Health Organization (WHO),World Bank, UNICEF, Rockefeller Foundation and GatesFoundation initiatives. For example, he has been a keycontributor to the Global Alliance for Vaccines andImmunization, which evolved from WHO programs and

    the Gates-supported Childrens Vaccine Initiative in thelate 1990s [7]. Gus has been entirely global in his

  • Review TRENDS in Immunology Vol.25 No.12 December 2004668involvement, facilitating the development of multimilliondollar funding programmes and specific endeavours todevelop new vaccines and to increase access to availablevaccines. He has doggedly championed the merits ofcontinuing investments in parasite vaccines, especiallymalaria vaccines, believing this campaign to be a long-term pursuit with no easy pathway. We all learnt long agothat vaccine development involves a lot more thanidentifying a prospective target antigen in the targetorganism, and the frustrations around parasite vaccinedevelopment are obvious. This is not a field for thedilettante or faint hearted, and the long pathway requirescredible and incisive spokespeople for the endeavour(rather then breathless advocacy or, conversely, naggingnagging negativism) in multiple forums and advisorycommittees. Gus is such a spokesman and tirelesssupporter for the parasite vaccine approach, as well asan active supporter of those involved more broadly inaspects of vaccine development, ensuring vaccine avail-ability, and vaccine-based disease control programmes. Hehas countered the criticisms and faced the critics of theparasite vaccine field, who declare that it has been shorton the deliverables and long on the rhetoric.

    It is now widely recognized that his contributions tovaccines and vaccination in recent years have beenmonumental, through involvement in key programmesand decision-making international bodies [8]. Going back30 years, it is not widely recognized that he had a decisiverole in establishing the UNICEFUNDPWorld BankWHO Special Program for Research and Training inTropical Diseases (the well-known TDR programme) inthe mid-1970s. His more recent activities at FoursightAssociates in Melbourne, concerning the commercializa-tion of Australian science and technology, have alsoincluded outputs from immunology, and biomedicalresearch more broadly (see www.foursight.com.au).Other professional contributions to international immu-nology and vaccinology include presidency of the Inter-national Union of Immunological Societies (19861989),Chairman of the committee overseeing WHOs Vaccinesand Biologicals Program (SAGE; 19932002) and Chair-man of the Strategic Advisory Council of the Bill andMelinda Gates Childrens Vaccine Program (19982003),which includes the Malaria Vaccine Initiative. Thisinvolvement with international programmes extends to araft of advisory and grants committees, WHOs Initiative inVaccine Research and, most recently, the Gates FoundationGrand Challenges in Global Health programme.

    There are very good reasons why Gus is in demand forcommittees that provide high-level strategic advice. Wehope it is obvious from this article (particularly thenext section) what those good reasons might be. HisAustralian credentials can also be useful in internationalforums, where the lighter touch of the New World can beuseful in committees, combined with a finely tunedantenna for group dynamics and where people are comingfrom. His use of vignettes and big picture reminders tolighten a heavy situation are legendary. A photographicmemory also helps in reminding people what they have

    said in the past, a sometimes uncomfortable experience forthe verbose.

    www.sciencedirect.comThe inspirational immunologistSome difficulty has been encountered in deciding on theappropriate adjective for this last section, which shouldhave more to do with the person himself. It is blindinglyobvious that attempting to discuss the person divorcedfrom the scientist is, in Gus case, singularly meaningless.Many contributions to immunology are linked with hispersonality, and we thus start with some general pointsabout the man.

    He derives enormous pleasure from seeing his scientificprogeny flourish and take their place in the scientificlimelight. The decision to act as a students supervisoralmost invariably means that he is willing to enter into alifetime contract with that individual, providing ongoingadvice, mentorship, support and, above all, friendship. Hehas the breathtaking ability to distil the outcomes of ameeting or seminar in a concise, understandable andinspiring manner. He also has a very keen sense ofoccasion, tailoring remarks to suit the particular audi-ence, without the slightest hint of a superior air if it is alay audience.

    For a person who has succeeded at the highest level inall his undertakings and by any criterion, he is dis-armingly approachable. Unlike most of us who relax byescaping from people, he appears to relax by being withpeople! His ease with everyone and habit of greetinganyone as a long-lost friend or potential new lifelongfriend has over the years provided headaches for hispersonal assistants and secretaries having to deal with amultitude of requests for follow-up meetings, favours andregular access.

    His extreme intellect and memory plus a prodigiouswork ethic are matched by equally high ethical standardsand capacity for good judgement (and expectations ofsimilar standards and performance in others). He also hasa very keen sense of fair play.

    Finally, he is one of the best science communicators,with the capacity to inspire, being invariably positive andauthoritative. There have been many occasions when wehave witnessed reporters rushing up to Gus at the end of aspeech for a copy of the text and merely finding three dot(bullet) points on a pink sheet.

    Gus Nossals profound grasp of science, medicine andthe history of immunology down to precise individualcontributions emerges in three particular circum-stances. (i) In the introduction of a visiting speaker at aWEHI seminar [combined with an opening question indiscussion time that sets an intimidatingly high standardfor the rest of the discussion an approach from whichGus never recoiled (despite urgings from others), believingseminars to be the pinnacle of the intellectual life ofthe Institute, and on display]. (ii) In the introductorycomments in a major grant application, with the proposedwork being placed in a logical context and the reader beingleft in no doubt about its potential global impact. (iii) Innominations of individuals for awards or in refereesreports, where promotion of the science and the individualcan be. Nossalian! One does hear reference to over-the-top. However, the amount of time Gus spends thought-

    fully nominating colleagues for awards, and dictating orpenning letters of support, has to be seen to be believed,

  • another indication of unparalleled generosity and innatekindness.

    Gus has diplomacy skills in spades. We will simplyprovide what is one of his best-loved quotes for manyAustralians. As Deputy Chair of the Council for AboriginalReconciliation in the late 1990s, he was pressed by atelevision interviewer to say something critical about thePrime Ministers position. Gus response will come as nosurprise to his international immunological friends something along the lines of . we must remember thatthe PM is on a journey, a journey of discovery, and weshould defer judgement until he has completed thatjourney.

    In terms of WEHI and his 30 years as Director(19651996), we have no doubt that one of his proudestcareer achievements was to catapult the Institute from arelatively small but very successful boutique medicalresearch institution under the direction of a NobelLaureate, to an Institute of outstanding achievements inimmunology, haematology, cancer, transplantation, auto-immune diseases and immunoparasitology. The expansionof WEHI practically a cumulative doubling of staff everydecade of his Directorship reflected his vision for whatmedical research institutes can achieve in terms of

    the beneficiaries. The rate at which his own laboratory-based scientific contributions decreased as Directorshipresponsibilities increased was far lower than the rateat which his contributions to the careers and motivationof a multitude of younger scientists across immunologyincreased.

    Thank you, Gus, for your contributions to the disciplineof immunology, medical research more broadly, theoutputs of immunology particularly vaccines, and tothe practitioners of immunology that cadre of immunol-ogists who have been privileged to know you and to havebeen influenced by you.

    AcknowledgementsWe thank Ian Mackay, David Tarlinton, Paul Lalor, Maria Karvelas, JillVan Es and Pamela Dewhurst for discussions and Cathie Irvin, CzesiaMarkiewicz and Joy Chapple for assistance.

    References1 Nossal, G.J.V. (1980) Tumour immunology: doomed or just ailing? A

    prognosis. Immunol. Today 1, 5102 Nossal, G.J.V. (1995) Choices following antigen entry: antibody

    formation or immunological tolerance. Annu. Rev. Immunol. 13, 1273 Linton, P.J. et al. (1991) Tolerance susceptibility of newly generated

    S

    thidedis

    Review TRENDS in Immunology Vol.25 No.12 December 2004 669discoveries, technology and better health for all peoples.He spared no expense in keeping WEHI at the cuttingedge of technical capacity. His warm embrace of themolecular, unfashionable under previous leadership, andhis unswerving support for parasitic disease research aretwo stunning achievements from which WEHI derivedgreat international clout and from which major advancesin medical and scientific knowledge emanated. Finally, thevery strong administrative as well as scientific support ofhis high-achieving associates such as Metcalf and Millerhas also been obvious for decades and well recognized by

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    information, Elsevier is dedicated to linking researchers andst and deepest coverage in a range of media types to enhance

    covery, and the sharing and preservation of knowledge. Visit usmemory B cells. J. Immunol. 146, 409941044 Pulendran, B. et al. (1994) A form of immunological tolerance through

    impairment of germinal center development. Proc. Natl. Acad. Sci.U. S. A. 91, 26392643

    5 Goodnow, C.C. (1992) Transgenic mice and analysis of B cell tolerance.Annu. Rev. Immunol. 10, 489518

    6 Jerne, N.K. et al. (1963) The agar plaque technique for recognisingantibody-producing cells. In Cell-Bound Antibodies (Amos, B. andKoprovski, H. eds), p. 109, Wistar Institute Press

    7 Nossal, G.J.V. (2000) The global alliance for vaccines and immunization a millennial challenge. Nat. Immunol. 1, 58

    8 Nossal, G.J.V. (2004) A healthier climate for the funding of vaccineresearch. Nat. Immunol. 5, 457459. Breaking Boundaries.

    Historical review: Sir Gustav Nossal - immunologist and moreThe B-cell immunologistThe early yearsMore recent researchThe numerate immunologistThe applied immunologistThe inspirational immunologistAcknowledgementsReferences

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