Memories of a Senior Scientist

Self and non-selfGeorg Wick

Section for Experimental Pathophysiology and Immunology, Laboratory for Autoimmunity, Biocenter, MedicalUniversity Innsbruck, Peter-Mayr-Straße 4a, 6020 Innsbruck (Austria), Fax: +43-512-9003-73960,e-mail: georg.wick@i-med.ac.at

Received 11 December 2008; accepted 12 December 2008

The early years

Life has been good to me! This is true both lookingback on my family, friends and private environment aswell as reflecting on my professional career. Thetransition to Professor Emeritus on October 1st 2007,after having served as Chairman of the Institute ofPathophysiology at the University of Innsbruck, nowMedical University of Innsbruck (MUI), since 1975,offered a unique opportunity to look back on myprofessional and personal life, and how each informthe other.Despite being born in 1939 at the beginning of WorldWar II, I nevertheless – at least in my perception –experienced a rather protected childhood. It only laterbecame clear to me that I was privileged to have been

born into an intellectual, liberal and cosmopolitanenvironment that was further extended when myfather decided to send me to a College in the Engadin,a high-altitude Alpine valley in Switzerland. There Ibecame integrated into a multicultural atmosphereand also fell in love with the fantastic natural habitatand its endless resources for all kinds of sports, one ofmy favorite daily past-times lifelong. As a matter offact, during my scientific career, some of my best ideasfor important experiments and new concepts seemedto arise during mountain biking, rowing or ski hiking.This period provided me with not only a solid educa-tional background but also, more importantly, a senseof fairplay succinctly summarized by our cricketteacher, the Scotsman Gordon Spencer: “winningwithout grimaces and losing without a wry face”. Iforged lifelong friendships there, and more impor-tantly, was inspired by the outstanding natural scien-ces program, led by renowned entomologist andschool headmaster Adolf Nadig (who had an amazingcollection of beetles!), to make medicine my life�swork. It is a direct reflection of the educationalexcellence of our college that I passed the Biologyexam during my first year of Medical Studies inVienna based only upon what I had learned in collegewithout ever looking into a medical biology textbook.I initiated my medical studies in Vienna in 1958 andgraduated 6 years later in 1964 after a most interestingmedical school tenure – during which the signal eventof my life occurred in meeting the woman who wouldbecome my wife, Traudi. This remarkable womangave me five wonderful children (three boys and twogirls), and a wonderfully supportive family that

Cell. Mol. Life Sci.DOI 10.1007/s00018-009-8789-z� Birkh�user Verlag, Basel, 2009

Cellular and Molecular Life Sciences

encouraged me to pursue my hobby, i. e., medicalresearch – a lifelong passion for which I even got paid.This period, when we were both students in Vienna,also laid the foundations for our joint interest incultural activities, notably music, theater and otherfine arts that, in addition to science and sports, hasshaped our lives.During my medical studies, I was very impressed bythe textbook “Differential Diagnosis” by Hegglin,then Professor of Internal Medicine at the Universityof Zurich, Switzerland. After graduation, and on theoccasion of a skiing trip to the Mont Blanc area withmy new bride, Traudi, I passed through Zurich for apersonal interview upon an invitation by Hegglin. Heoffered me a job, but only under the condition that Ifirst spend 2 years as a postdoc in a theoretical medicalresearch institute, preferably Experimental Patholo-gy. Although as it turns out, this job never material-ized, it was a decisive encounter in my professionallife. Upon returning to Vienna, I first had to find outwhere the Institute of Experimental Pathology ac-tually was, since it had not been mentioned as part ofthe regular medical curriculum. There I met AdolfLindner, Professor and Chairmen of the Institute, wholater became not only my boss, but also my fatherlyfriend. Starting in January 1965, I spent the next2 years at this Institute, which I discovered to be verywell equipped despite the difficult economic times.The first project assigned to me was an assessment of anewly developed diuretic, Furosemide, in young ascompared to old rats. Unfortunately, my supervisor onthis work turned out to be both incompetent andcompletely uninterested in my project, which mighthave discouraged some from further pursuing ascientific career. But life has its own rules, and boththe decision to embark on Experimental Pathology asa general discipline and the good fortune of havingstarted with a gerontologically orientated projectturned out to be beneficial 25 years later when Ibecame the founder and head of an Institute for AgingResearch. In 1966, I decided to join the Immunologygroup within the Institute headed by Carl Steffen, apost-war pioneer in this discipline. In Steffen�s labo-ratory, I met his laboratory chief, Rupert Timpl, whointroduced me to the field of collagen immunologyand was the first to show me how internationallycompetitive research really works. This fruitful col-laboration lasted until Rupert�s untimely death in2005, interrupted only during my tenure in the UnitedStates from 1967 to 1970. It turned out that the basicimmunological and biochemical expertise of Rupertand my own knowledge of general and experimentalpathology were a perfect match. We developed thefirst antibodies against various types of collagens andthe many different epitopes contained in/on these

molecules. We demonstrated their physiological andpathological distribution and function and, with out-side collaborators, discovered or co-discovered manynew collagenous and non-collagenous connectivetissue components, such as collagen type IV and itsnon-triple helically structured (“non collagenous”)domain-1 (NC-1), which we (in collaboration withGeorge Martin from the NIH) later identified as therelevant autoantigen in Goodpasture�s syndrome. Thenon-collagenous molecules that we identified byimmunological means included fibronectin (thencold insoluble globulin, CIG), laminin, nidogen andothers [1 –3].My own experience in immunofluorescence andimmunohistochemistry, acquired during my stay inBuffalo, NY (see below), gave us the opportunity toimpressively visualize all these components in normaland pathologically altered tissues, such as dermato-sparaxis (together with Bjçrn Olson, now at HarvardUniversity) and Steffen Gay (now in Zurich), togetherwith his wife Renate Gay, who joined Rupert�s groupafter an adventurous and dangerous escape fromcommunist East Germany [4].One of the pathological conditions that has alwaysfascinated me is fibrosis. The foundation for thisfascination was laid during my first forays in this areawith Rupert. Its later ramifications were strengthenedby communications with many other laboratoriesaround the world, the leaders of which regularly metat Gordon Conferences on Collagen. The only adverseeffect of my first 2 years with Rupert in Carl Steffen�sLaboratory was a constant fishy smell, because he sentme to all Viennese fish stores to collect fish bladders asa rich source for type I collagen (then called “acidsoluble collagen”). From 1966 to 1967, I also workedas an Intern at a peripheral Hospital for InternalMedicine in Vienna because I did not want to continuepure basic research without also having the invaluableperspective of some clinical experience. This was amost enlightening, interesting and humanly rewardingtime, and I believe that I was a capable and compas-sionate practicing physician. I was especially fortunatethat I had learned to inject and take blood in smallexperimental animals, which made the performance ofthese skills in human patients easy and painless. Theyrespected my skills without realizing that givingpainless injections was much less important thanknowing what you actually injected. I later decidedto return to basic research based on the perceptionthat clinical medicine – at least at that time – was tooempirical for a scientist who had been “spoiled” byfirst doing evidence-based research. However, I alsolearnt that clinical work required far less persistenceand was more immediately gratifying than research inthe inevitable moments of success, despite the tragic

2 G. Wick Self and non-self

failures that also occur. For a group leader inmedicine, I have found that it is much easier tomotivate colleagues working in a clinic than thoseengaged in basic research who have never enjoyed theexperience of helping patients. To take advantage ofthese two complementary, but quite different, per-spectives, I always found it helpful to assign twoprojects, or at least two facets of a given project, toeach student or postdoc to minimize frustration: Sinceeach high-risk project will encounter unforeseenobstacles or setbacks, it is encouraging to see sufficientprogress in the other project. I have also avoidedassigning more than one student and/or postdoc to thesame project so that everybody has the feeling ofintellectual responsibility for their “own baby”.

A postdoc abroad

In the fall of 1967, I obtained a postdoctoral fellowshipthat allowed me to take Traudi and my first twochildren, Gregor and Veronika, to the Center forImmunology in Buffalo, a Center of Excellencefounded by Ernest Witebsky at the Department ofMicrobiology and Immunology, State University ofNew York at Buffalo (SUNYAB). Ernest Witebsky, aGerman Jewish scientist who, with great foresight,emigrated to the US already in 1933, had established alarge imperium of Microbiology and Immunology atSUNYAB that, at the time, represented the leadingforce in autoimmunity research worldwide. AlthoughWitebsky had just retired as the Chairman of theDepartment when I arrived, he still had amplefinancial support to continue his work with a smallgroup of three dedicated young postdocs, i. e., LasseNielsson, a Swedish colleague from the laboratory ofOchterlouny in Gothenburg, Ole Werdelin, fromCopenhagen, Denmark, and myself. Together withadministrative and technical personnel, we formed thecore of the Center of Immunology that was meant tobring together scientists from the outstanding immu-nological community in Buffalo. The biannual Con-vocations on Immunology organized by the Center ofImmunology always brought the worldwide leaders inour discipline to Buffalo. For me as the youngestpostdoc, this was an invaluable and critical opportu-nity to start networking, which later proved to be soimportant not only for myself, but also for themembers for my group. I was honored to be in thecompany of such pioneering scientists who weremaking seminal contributions to the field. I metMilan Hasek, the discoverer of immunological toler-ance in the chicken system (who personally showedme his ingenious parabiosis technique), who barelymissed receiving the Nobel Prize for this work. The

man who was awarded the Nobel Prize for thisimmunological topic, Sir Peter Medarwar, was also aspeaker at a Convocation and simultaneously dem-onstrated allotransplant immunity and tolerance inmice. My time in Buffalo was obviously the mostdecisive period in my early scientific life, especiallysince Ernest Witebsky graciously abandoned hisunderstandable reservations against everything thatcame from the German-speaking world: I was appa-rently the first postdoc with whom he started to speakGerman again! We developed a very close personalrelationship and I enjoyed many evenings in his homeand long discussions of our common scientific projectson autoimmunity, particularly the failure of theimmune system to distinguish “self” from “non-self”.This is a path I have deviated from only occasionally.Upon my arrival in Buffalo, he assigned a project tome that dealt with the elucidation of a Hashimoto-likeautoimmune thyroiditis in chickens that had beenobserved by Randy Cole, a geneticist at the VeterinaryCollege in Ithaca, NY. Randy first brought these birdsto Witebsky, the “king of autoimmunity”, because herightly felt that he might have developed a new animalmodel for thyroid autoimmunity. I was initiallydisappointed that I would be working with chickensinstead of soaring within eagles and saving humanlives, but within 2 weeks I was fascinated by thismodel, the so-called Obese Strain (OS) of chickens,and these birds determined the next 15 years of myscientific career in two ways: I became a fairly goodexpert in autoimmune disease in general, and auto-immune thyroiditis in particular, and I acquiredconsiderable knowledge of developmental and com-parative immunology with a focus on avian immunol-ogy.These were the times when Robert Good, then still atMinneapolis, Minnesota, developed the B-T cell con-cept based on his unique gift of incorporating exper-imental and clinical data into the formulation of newtheories. Since Max Cooper and other members ofBob�s Group regularly performed in ovo bursectomiesand thymectomies in chicks on the day of hatching,Witebsky sent me to Minneapolis to improve mytechniques in this area. Working on the OS chickenproject in the bustling scientific atmosphere in Buffaloresulted in what I consider to be two of my mostimportant scientific achievements: (a) We were thefirst to show that neonatal thymectomy of OS chickenssurprisingly resulted in the development of the mostsevere form of thyroiditis [5]. More detailed analysesof this phenomenon, which continued until well after Ireturned to Austria, suggested that there were twotypes of T cells, i. e., the effector cells that contributedto the autoimmune destruction of the thyroid, and“controlling T cells” that were able to suppress the

Cell. Mol. Life Sci. Memories of a Senior Scientist 3

former. We hypothesized that these “controllingT cells”, now designated as regulatory T cells, weredestined to leave the thymus during ontogeny laterthan the effector cells, and were therefore removed byearly thymectory, leaving the effector T cells in theperiphery unsuppressed and thus able to deploy theirdestructive potential. This work was cited by subse-quent authors, e.g., Shimon Sakaguchi, who repeatedthe thymectomy experiments in rodents. However,due to the fact that we made our discovery in thechicken system, which is not so widely used as ananimal model of human disorders, this finding did notreceive the recognition we humbly believe it deserved.(b) We also produced the first anti-B and anti-T cellsera by immunizing turkeys with chicken thymocytesor bursa lymphoid cells, respectively, and usingextensive cross-absorption procedures [6]. Thesepolyclonal sera not only proved to be specific invitro [7, 8], but could also selectively suppress Tand Bcell reactivity in vivo and consequently preventspontaneous autoimmune thyroiditis in OS chickens[9].Coming from a country with rather old fashionedtraditions of academic structures, the lack of hierarchyin seminars and scientific meetings (notably at theannual FASEB Meetings in Atlantic City) and theopenness of the American group leaders and chair-persons towards their postdocs were perhaps the mostsignificant facet of the culture shock that I experi-enced in the US. This was even more evident since wespent the irrational revolutionary late sixties in theStates with all the unrest on university soils that laterspilled to the rest of the world. The foreign postdocs inour Department were, however, too conscious of thefact that our stay in the US was only temporary toparticipate in the turmoil that took place at SUNYABand that we were responsible for the good use of ourfellowships by getting the maximum intellectualharvest from our unique association with a trulyworld-class scientific community.Finally, our stay in the US also forged an everlastinglove for this country and its way of life that was furtheraugmented by the birth of our third child, Natalie,adding an American citizen to our family.The unexpected premature death of Ernest Witebskyin the fall of 1969 was not only a blow to the Center ofImmunology in general, but also to his small group ofcollaborators in particular. His young postdoctoralfellows were deprived of a truly stellar mentor and weall had to stand alone after returning to our homecountries. I therefore never had the good fortune ofrelying on an outstanding scientist or teacher as mymentor, a fact that has made me appreciate the criticalservice a good mentor provides and I wanted toprovide that to my own students. In addition to trying

to convey the message that good science relies on thethree pillars of “innovation, diligence and passion”, Ialways also tried to teach my students “the art oflosing”, in Gordon Spencer�s spirit, and to be tolerantof other scientist, defining tolerance as the oftenuncomfortable feeling that the other person may beright after all.The atmosphere between students and mentorsshould be one of mutual respect and acceptance. Forthe mentor it is, of course, the ultimate reward to havethe student surpass the teacher in their given field. Inscience, as in other professional fields, it is alwaysimportant to ask “why do we not finish this project”rather than “why do we carry on with this project”? Inother words, the determination of appropriate andlogical break-off points, in my view is one of the mostimportant and difficult tasks of a group leader. As thehead of a group of competent people, I oftenconsidered it my task not to tell them what to do(they usually may know better than I) but rather whatnot to do.

The years in Vienna

Returning to Austria in 1970 was not easy. I hadseveral offers to join the Departments of InternalMedicine, Pediatrics, or Immunology and GeneralExperimental Pathology (Pathophysiology) at variousAustrian Universities, but decided to return to myformer home, the Institute for General and Exper-imental Pathology at the Medical Faculty of theUniversity of Vienna. With written permission ofErnest Witebsky, I had organized the shipment ofhatching OS chicken eggs to Vienna, and AdolfLindner, with all his good connections, was able toprovide space to raise a new colony at the VienneseVeterinary School. Originally, the veterinarians as-signed a box in the horse stable to my project, so mychickens were kept between the stalls of two impres-sive white Lipizzan stallions. This situation laterimproved and we ended up having our own chickenroom in the center of Vienna right next to the institute.In 1969, the Austrian Research Fund (�sterreichisch-er Fonds zur wissenschaftlichen Forschung – FWF)was founded as a very modest source of competitivegrants for all fields of research. I filed my firstsuccessful grant application already from the US,and this was the beginning of a continuous successionof grants from this organization that has been the mostimportant single factor for the establishment ofscientific excellence in Austria after World War II.The FWF was not only decisive for my own scientificcareer, but for those of many young members of mygroup who were recruited on the basis of FWF-funded

4 G. Wick Self and non-self

grants. Their consistent support of science allowed meto establish a proper scientific school, and formermembers of my laboratory are now spread all over theworld. Some will be mentioned in more detail below.From 1970 to 1975, I went through the academic ranksof University Dozent (Assistant Professor) and FullProfessor in Vienna while building up my ownImmunopathology Group focusing on autoimmunityand avian immunology. This was perhaps the mostinformal period of my scientific life, surrounded by agroup of bright and dedicated collaborators with goodsenses of humor. The group consisted of my firsttechnician, Renate Steiner, who not only played acentral role in establishing the OS colony andcontinuing to produce the first anti-B and anti-T cellsera worldwide, as mentioned above, but also techni-cally trained further postdocs, notably Boris Albini,Konrad Schauenstein from Austria as well as a formerBuffalo acquaintance, Roy Sundick, from the US.Boris and Konrad were among the most intelligentand educated people I have ever met and theirscientific brilliance combined with the fact that theywere both semiprofessional musicians created aunique laboratory atmosphere. In spite of all thehard work, there was enough leisure time for all of us.However, I personally never met a student or postdoclater enjoying an outstanding career who did not alsoshow up in the lab on weekends. Boris was the first todifferentiate lymphocyte subpopulations by means ofthe above-mentioned anti-Tand anti-B cell antibodiesusing the newly developed membrane immunofluor-escence technique [7, 8]. Konrad and Boris also soondiscovered their interest in the methodological as-pects of immunofluorescence, and the three of usstarted to organize Annual International Immuno-fluorescence Courses partly supported by the WorldHealth Organization (WHO). These courses attracteda large crowd of young immunologists whom we oftenlater met again as prominent leaders in the field. Wewere supported in these activities by a physicist, FritzHerzog, from the scientific department of what thenwas the Viennese Reichert Microscope Company.Roy Sundick was the first to draw our attention to thefact that the target cell for an autoimmune disease, inthis case the thyroid epithelial cell, deserved specialattention and, from a genetic viewpoint, play anequally important role as the autoreactive immunesystem attacking this cell, as detailed below. He alsoshowed that the extent of iodination of thyroglobulindetermined its autoantigenic potential [10, 11]. This isalso the reason why autoimmune thyroiditis is themost important thyroid disease in the US (vs thyroidcancer in Europe): In the US, iodine is added to salt,bread and water, thus people are ingesting three timesas much iodine as Europeans, where it is only added to

salt. The importance of the susceptibility of the targetcell to the autoimmune attack was later proven indetail in genetic experiments conducted together withKarel Hala.In 1975, I became Professor and Chairman of theInstitute for General and Experimental Pathology(later renamed Pathophysiology) and Immunology atthe Medical Faculty of the University of Innsbruck inthe mountains of Tyrol. Konrad Schauenstein was mydeputy chairman, while Boris left for the US tocontinue his career in Buffalo and join his family. Justbefore moving to Innsbruck, our last two children, thetwin boys Nikolaus and Marius, were born. Both arenow both MDs specializing in pathology and radiol-ogy, respectively. It gives me great pleasure to nowcollaborate on joint research projects with each ofthem.

The years in Innsbruck

The Institute for General and Experimental Pathol-ogy in Innsbruck turned out to be attractive for youngpostdocs and students from all over the world. Irecently counted all the master and doctoral thesesperformed during the 33 years of my chairmanshipand came up with the amazing number of 190. Wewere also able to recruit a large number of very giftedpostdocs, many of whom went on to successfulscientific, clinical or business careers either in Austriaor abroad. My greatest professional pleasure from thetime moving from Vienna to Innsbruck until today isthe optimal mentoring of my scientific collaboratorsas well as the members of the administrative andtechnical staff. Members who joined the institute asstudents or postdocs and later became internationallyrenowned figures in science include Beatrix Grubeck-Loebenstein (Innsbruck), Guido Krçmer (Paris), JosefPenninger (Vienna), Quing Bo Xu ( London), RichardBoyd (Melbourne), Reinhard F�ssler (Munich),Georg Schett (Erlangen), Stefan Dirnhofer (Basel),Yping Zou (Shanghai), Lukas Huber, Reinhard Ko-fler, Peter Berger, Pidder Jansen-D�rr, Andreas Vil-lunger and David Bernhard, all currently in Innsbruck,and many more. The achievements of these and otherformer members of our group are easily evident uponan internet literature search.The only academic member of the former Institute inInnsbruck who stayed on after my appointment wasSiegfried Schwarz, perhaps the most knowledgeableendocrinologist in Austria and with whom we editedtwo highly successful Pathophysiology textbooks.Together with Siegi, we not only performed excellentendocrinological research but also built a highlyspecialized diagnostic laboratory for clinical immu-

Cell. Mol. Life Sci. Memories of a Senior Scientist 5

nology, allergology and endocrinology that not onlyprovided a crucial link to clinical medical practice, butalso served as financial support for the institute.The years in Innsbruck were characterized by atremendous drive in research and teaching, and alsoby exuberant personal friendships between the mem-bers of the group. Scientifically, we concentrated onautoimmunity, developmental and comparative im-munology and immunoendocrinology. We were luckyto be able to rely on a perfect infrastructure of highlymotivated and competent technical personnel as wellas administrative expertise. Most importantly, Her-mann Dietrich, a veterinarian who specialized inexperimental animal medicine, took perfect care ofour precious chicken lines.In the field of autoimmunity, the intuitive work ofRichard Boyd and Guido Krçmer gave credence to thefact (mentioned above) that certain thymocyte sub-populations had an immunosuppressive effect [12,13]. In cooperation with the group of Ivan Roitt(London) and a joint graduate Student from Brazil,Lain Pontes de Carvalho, we provided experimentalproof for the original idea mentioned above thatT effector cells leave the thymus earlier than theregulatory cells, thus explaining the thyroiditis-en-hancing effect of neonatal thymectomy [9].In continuation of Roy Sundick�s work, the geneticexperiments of Karel Hala, a refugee from communistCzechoslovakia, opened a new outlook on the devel-opment of autoimmune diseases in general: in con-trast to most other groups worldwide, we not onlyemphasized the autoreactivity of the immune system,but discovered that a genetically encoded target cellsusceptibility to the autoimmune attack is mostimportant for the development of both organ-specificand systemic autoimmune diseases, a concept that hasgoverned all our research in this field to this day [14].In the fields of endocrinology and immunoendocri-nology, respectively, the interaction of highly compe-tent immunologists and endocrinologists bore fruit:Reinhard Kofler was the first to introduce theproduction of monoclonal antibodies to Austria. Heestablished hybridomas that produced antibodiesspecific for human glycoprotein hormones [luteinizinghormone (LH), follicle-stimulating hormone (FSH)thyroid-stimulating hormone (TSH) and human cho-rionic gonadotropin (hCG)] and used this new tool tovisualize the production site of these hormones [15].Later, Siegfried Schwarz, together with Peter Berger,extended this line of research and gained internationalrecognition by monoclonal antibody-based epitopemapping of glycoportein hormones [16]. These mapsalso formed the basis of the development of highlyspecific, sensitive and practically applicable immuno-assays. An interesting sideline of these studies was the

critical proof by Peter Berger and Stefan Dirnhoferthat the hCG-based anti-fertility vaccine sported bythe WHO could not work [17]. These results finallyled to the decision by the WHO to abandon thisproject. A most important discovery during this areawas made by Konrad Schauenstein, together withReinhard F�ssler, showing that the immunoendocrinecommunication via the hypothalamo-pituitary-adre-nal (HPA) axis was malfunctioning in the OS modelfor autoimmune thyroiditis [18], an observation latercorroborated by many other authors and ourselves,also in experimental rodent models in cooperationwith France Haour (Institut Pasteur, Paris) andAlberto Panerai (Milano).These data nicely complemented our new, above-mentioned concept for the development of auto-immune diseases, i. e., their dependence on thepresence of two sets of essential genes coding forautoreactivity of immune system on one hand andtarget organ susceptibility on the other. This geneticconstellation leads to a baseline expression of thedisease that can then be further modulated by otherfactors, such as endogenous steroid hormones (influ-encing the immune system) and iodine (determiningthe autoantigenicity of thyroglobulin in the targetcell). Together with Karel Hala and one of hisstudents, Nikolaus Neu, we were able to show that inthe OS, in contrast to, say, lupus, only a relatively smallnumber of genes is involved in the development ofthyroiditis; three to four dominant genes coding forautoreactivity of the immune system and one reces-sive gene being responsible for target organ suscept-ibility [19]. Since the chicken genome is now se-quenced, the exact identity of all of these genes will beunveiled in the course of an ongoing cooperative studywith the groups of Olli K�mpe and Olof Ekwall fromUppsala, Sweden.In subsequent experiments combining our knowledgein developmental and comparative immunology withthe endocrinological expertise, Oskar Lechner and theBrazilian postdoc Antonio Oliviera dos Santos dem-onstrated the extra-adrenal synthesis of glucocorti-coid hormones in the thymus [20], an unexpecteddiscovery that formed the basis for extensive futureinvestigations by Jan G. Wiegers on the effect of thesehormones on thymocyte maturation, differentiationand selection in mice.In technically demanding experiments, Josef Penning-er [21, 22] showed that positive selection in the thymustakes place within so-called thymic nurse cells, i. e.,thymic epithelial cells harboring immature T cells.Among the many methodological inventions devel-oped in the course of our scientific projects was thediscovery of a low bleaching immunofluorescenceexcitation device by Konrad Schauenstein and the

6 G. Wick Self and non-self

biophysicist G�nther Bçck using short laser flashes[23] instead of continuous excitation. This constituteda significant technical improvement that complement-ed our earlier invention of the multichannel micro-pipette [24].In the late 1980 s and early 1990 s, our interest indevelopmental and comparative immunology turnedfrom investigations of T cell development to the otherend of the chronological spectrum, i. e., age-relatedchanges of immune reactivity. Again applying amultidisciplinary approach, we successfully combinedthe known facts on age-related alterations of the lipidmetabolism with our immunological expertise. Thiswork was begun by Karin Traill, an experienced seniorpostdoc from the UK, who worked with me andsupervised a promising medical student, Lukas Huber.Lukas is one of the success stories from our institutementioned above. Upon finishing his thesis, he went toGermany and Switzerland before returning to Vienna.He is now Professor and Chairman of Cell Biology atthe Medical University of Innsbruck, and also acts asthe Managing Director of the Biocenter of which I amstill a member. This is a perfect example of the closingof a circle. Karin and Lukas together with G�ntherBçck and Hugo Wolf, who contributed their expertisein Physics and Biochemistry, respectively, were in-strumental in laying the foundations for our later largegroup in aging research. They clearly showed that age-dependent alterations of cholesterol metabolism en-tailed a high plasma membrane viscosity of whiteblood cells, including lymphoid cells, that correlatedwith a decreased mitogenic and antigenic response.Fluidizing plasma membranes again by removing freecholesterol and decreasing the molar ratio of choles-terol to phospholipids led to a “rejuvenation” ofimmune reactivity [25].Again, several important, and in this case alsoclinically relevant, methodological innovations ema-nated from this period of our research. These includedthe first demonstration of lipoprotein receptors onliving (lymphoid) cells by the use of fluorescentlylabeled lipoproteins, and the first measurements ofplasma membrane viscosity on a single cell level, bothapplying flow cytometry [26]. As a matter of fact, wehad a long controversial discussion with the editors ofthe Journal of Biological Chemistry until they under-stood that, in contrast to the Nobel Prize winningradiolabeling technique of Goldstein and Brown usingpurified membrane preparations, we were performingour experiments on living cells. It is, of course,rewarding to see that this approach is now thestandard worldwide over earlier methods [27].In the late 80 s, during one of my visits to China, I metand recruited Qingbo Xu, a promising young PhDworking on an atherosclerosis project at the Beijing

Medical College. Qingbo, with his charming wifeYanhua Hu, became my closest collaborator for thenext 12 years. During this period, he not only obtainedhis medical degree at the University of Innsbruck andwas promoted to the position of an Associate Profes-sor but, surprisingly and although not being a Ping-Pong player, was granted Austrian citizenship, whichlater allowed him to settle down freely within theEuropean Union. Qingbo is now a Professor ofVascular Biology at Kings College, London, wherehe successfully leads his large own research group.In 1975, I was the youngest Chairman of a Departmentat a Medical Faculty in the whole of Austria. Nego-tiating the conditions of my appointment with theFederal Ministry of Science and Research as a scientistinexperienced in academic management turned out tobe difficult and, in hindsight, I was much too modest inmy understanding of what would be required, andsubsequently in my demands. I was, however, able tointroduce a short paragraph into my contract thatallowed me – to my knowledge the only professor inAustria so allowed – to go on a one semester sabbaticalevery fourth year. I regularly took advantage of thisprivilege by going to what was then considered theMecca of Immunology, the Basel Institute for Immu-nology (BII) founded and supported by Hoffman-LaRoche. My first of three sabbaticals at the BII tookplace under the directorship of the Nobel LaureateNiels Jerne, the next two under the auspices of its newdirector and now my long-term friend, Fritz Melchers.I took these sabbaticals as an opportunity not only tobroaden my scientific horizons, but also to stay abreastof new techniques in demand for our ongoing researchprojects. I spent my first sabbatical in the group of Auliand Paavo Toivanen, two eminent avian immunolo-gists from Finland who had invited me to test ourspecific anti-chicken B and T sera using the newlyavailable fluorescence-activated cell sorting (FACS)technique. Back in Innsbruck, we then got the firstsuch machine in Austria that was, and still is, success-fully run by G�nther Bçck. During my secondsabbatical at the BII, I was invited by Ivan Levkovits(who earlier had developed the limiting dilutiontechnique) to make use of his fantastic multistage2D-gel electrophoresis setup to study possible differ-ences between lysates of OS and normal chickenthyroid glands as a basis for the target organ suscept-ibility that we had observed in earlier experiments.This was my introduction to proteomics, a field ofresearch that had increasingly come into the center ofinterest in our lab, especially regarding our investiga-tions on the immunology of fibrosis, mentioned below.During my third and last stay in Basel, I joined thelaboratory of Louis du Pasquier, an expert in amphib-ian immunology. There, I completed my morpholog-

Cell. Mol. Life Sci. Memories of a Senior Scientist 7

ical assessment of thymic nurse cells by showing thatthey also existed in frogs, but that there was a clear-cutdecrease of the number of intrathymic nurse celllymphocytes from mice over humans and chickens toamphibians. In addition to the scientific harvest ofthese sojourns in Basel, it also became very clear thatexcellence in research can be achieved in small groupsin an institution with flat hierarchies provided that onecould recruit the brightest people from all over theworld who could then exclusively concentrate on theirresearch projects, supported by an efficient infra-structure and without having to continually divertattention, time and resources to preparing applica-tions for competitive grants. I have never againexperienced an atmosphere that paralleled the in-tellectual stimulation encountered at the BII. Duringthe first 10 years of its existence, three Nobel prizesemanated from this outstanding institution, i. e., NielsJerne, Georges Kçhler and Susumu Tonegawa. FritzMelchers was the optimal choice to succeed NielsJerne as the head of the institute, and former membersof the BII are now spread all over the world inimportant research positions. It is difficult to under-stand why Hoffmann-La Roche decided to close downthis jewel in 2000.After successfully completing my first 15 years as theChairman of Pathophysiology and Immunology at theUniversity of Innsbruck, the Austrian Academy ofSciences approached me to establish an Institute forBiomedical Aging Research under its auspices, also inInnsbruck. This was not only a distinctive honor, butalso a very timely proposal, since gerontologicalresearch was consistently gaining momentum interna-tionally in general and in our own group in particular.The Institute for Biomedical Aging Research (IBA) ishoused in a beautiful building that was adapted forresearch purposes.After an intensive recruiting phase, it was opened in1991 and remained under my directorship until 2003.Surprisingly, the IBA remains the only Institute of thiskind in the German-speaking world. It was organizedinto four sections: Immunology (led by BeatrixGrubeck-Loebenstein), Endocrinology (led by PeterBerger from the previous ImmunoendocrinologyGroup at the University), Molecular and Cell Biology(led by Pidder Jansen-D�rr) and Pathology (led bymyself). The IBA continues to be completely inde-pendent from the Medical School of the University ofInnsbruck, but enjoyed close academic ties throughmy joint appointment as its director, and by extensivecollaborative efforts at both the scientific and teachinglevels. In my group, Qingbo Xu became the leadingfigure, and attracted many compatriots from China.After a short period continuing our research on therole of an altered lipid metabolism in the age-

depended decline of immune responsiveness, wedecided to switch all our personnel and financialrecourses to a new project, i. e., the Immunology ofAtherosclerosis, which became a central theme for thenext 15 years. Based on in vitro work, animal experi-ments and longitudinal as well as cross-sectionalstudies in humans, we developed our new “auto-immune hypothesis” of atherosclerosis [28]. In es-sence, this hypothesis was developed based on theknown fact that inflammatory processes occur inatherosclerotic lesions. Our interest, however, wasexclusively focused on the very first, clinically inap-parent stage of the disease and our discoveries in thisarea were based on our broad knowledge of patho-physiology and cardiovascular diseases in general, andour background in immunology and autoimmunity inparticular. We showed that classical atheroscleroticrisk factors, the well-proven atherogenic role of whichwe, of course, did not deny, first act as endothelialstressors that induce the expression of a stress protein,heat shock protein 60 (HSP60), that is transported tothe endothelial cell surface and there acts as a “dangersignal” for preexisting adaptive and innate anti-HSP60 immunity. HSP60 is a phylogenetically highlyconserved molecule. Thus, an over 97 % homologyexists between HSP60 of different bacterial speciesand there is still an over 50 % homology betweenbacterial and eukaryotic HSP60, which at certaindomains of the molecule even exceeds 70 %. Everyhealthy person has protective adaptive and innateimmunity against microbial HSP60 as well as bona fideautoimmunity against biochemically altered autolo-gous HSP60. When this molecule appears on thesurface of endothelial cells injured by classical athe-rosclerotic risk factors, this danger signal triggers an

8 G. Wick Self and non-self

attack of preexisting anti-HSP60 immune mechanismson endothelial cells, subsequently leading to the first,still reversible, inflammatory stage of the disease [29].An interesting byproduct of this period of researchwas the discovery of the vascular-associated lymphoidtissue (VALT), i. e., mononuclear cell infiltrations atarterial branching points that can be found in babiesand young children as well as adults, and are accom-panied by a dense Langerhans cell-like network ofvascular-associated dendritic cells [30]. The VALTseems to fulfill similar functions as the mucosa-associated lymphoid tissue (MALT), i. e., protectingbodily surfaces, in this case the inner vascular surface,from potentially harmful exogenous and endogenousagents.The many invitations to prestigious meetings, such asGordon Conferences, Keystone Symposia, etc, reflectthe impact of our research in this field.Our overall project on the “Immunology of Athero-sclerosis” was again the basis of numerous medicaland PhD theses, postdoctoral projects, academicappointments and successful grant applications, in-cluding several very large recent grants that allow meas Professor Emeritus to continue my research with astrong group of young, international, eager collabo-rators. “The immunology of Atherosclerosis” also wasthe springboard for many successful academic careersof former collaborators of my group in addition toQingbo Xu, such as Georg Schett, now Professor andChairman of Rheumatology at the University ofErlangen, Germany. An especially close cooperationin this area developed with the groups of Josef Willeitand Stefan Kiechl from the Neurological UniversityClinic in Innsbruck within the framework of theirprospective atherosclerosis prevention study conduct-ed in the little town of Bruneck in Southern Tyrol(Italy), just across the border from Austria. Becomingpart of this so-called “Bruneck Study” not onlyallowed us to show that our concept translated fromanimal models to human patients, but also providedthe gateway to its successful application to theprevention of atherosclerotic disease in both anelderly population and in young cohorts [31]. Inrecent years, we also put great emphasis on the role ofcigarette smoke as a most important stressor ofendothelial cells making them a target for an auto-immune attack [32]. From our side, a dedicated groupof young scientists, Bernhard Metzler, Gunda Millong,Michael Knoflach, Blair Henderson and David Bern-hard, were instrumental in the great success of thisproject. For the many national and internationalcooperation partners, coauthors and friends engagedin our atherosclerosis project, Yehuda Shoenfeld at TelHashomer from Israel, is an excellent representativeexamples.

During the planning, establishment and running of theIBA, I was confronted with serving two scientificmanagement cultures, i. e., a Medical Faculty from aFederal University and the Austrian Academy ofSciences as an independent, non-profit organization.In contrast to the university, where good professionalmanagement was often hindered by science admin-istrators and academic members who, due to a lack ofindividual scientific success, chose to become influen-tial via participation in various Committees, theAcademy supported lean management, short decisionpathways, gentlemanly interactions with the directorsand employees of its Institutes combined with a goodsense of intellectual competition. The spiritus rectorof the IBA and the Chairman of its Scientific Boardwas Hans Tuppy who somehow, and at first uncon-sciously, influenced my entire professional life frombeing my teacher in Biochemistry in Medical Schoolto acting as the Dean of the Vienna Medical schooland then the Rector of the University of Vienna,President of the Austrian Academy of Sciences,President of the FWF and even Federal Minster ofScience and Research. This is perhaps a good occasionto thank him for his personal and scientific adviceduring many stages of my life. I would also like tothank the former President of the Austrian Academyof Sciences, Werner Welzig and as well as its successiveSecretaries General Karl Schlçgl and Herbert Mang,for their continuous interest in, and support of, theIBA, despite their not representing the naturalsciences in general and medicine in particular.

Back in Vienna as a research manager

In 2003, a high caliber search committee, again headedby Hans Tuppy, proposed me as a candidate for thepresidency of the FWF, and I made a principaldecision that in some ways conflicted with my overallplan for the rest of my academic life. I would nowspend part or all of this time as a scientific manager,albeit of the most prestigious organization in Austriathat supported all basic research in all disciplines ofthe humanities, from natural and technical sciences tobiology and medicine. In principle, the position of thepresident of the FWF is an honorary job considered torequire a 50 % time commitment. In my case, anadditional complication was the commute from Inns-bruck to Vienna and staying there at least 3 days perweek. I finally decided to accept the position afterconsulting with my wife and my children, the membersof my Department and my own research group. As afirst action after my election, I stepped down as theDirector of the IBA and as the head of the Exper-imental Animal Unit at the Innsbruck Medical School.

Cell. Mol. Life Sci. Memories of a Senior Scientist 9

In addition, the Dean of our Medical School andRector of the University of Innsbruck granted meexemption from my heavy teaching obligations. It was,however, again Hans Tuppy who advised me not tocompletely abandon research, and so I started work-ing 7 days a week for the next 3 years, dividing my timebetween research and science management.This was perhaps the most interesting time of myacademic life since I was confronted with all differentscientific fields and their excellent proponents on aNational and European level. The most surprisingexperience, however, was the completely un-Austrianefficiency, strict impartiality and professionalism of allmembers of this organization, ranging from the tele-phone operators to the Section Leaders and theSecretary General, Gerhard Kratky. The latter I waslucky enough to recruit for this important job, and heassisted me both with the internal reorganization ofthe FWF administration and the external representa-tion, including financial negotiations with the relevantministries. I was gratified to have the excellentqualifications of the Austrian civil servants confirmedin their dealing with matters of basic and appliedresearch, but I was surprised and disappointed by thescientific incompetence of the ministers involved inthese issues. They had never heard of the recipe ofVandever Bush, the science advisor of PresidentFranklin D. Roosevelt who set the stage in the US bystating that “support of basic research will entaileconomic success”. In contrast, during my term aspresident of the FWF, I had the impression that inAustria “building a successful industry was consideredthe basis for being able to afford the luxury of fundingbasic research”. Another, unexpected experienceduring my term as the FWF President was the pressureexerted by politicians and their staffs, ranging fromattempts to influence decisions about scientific proj-ects to bluntly connecting funding of the FWF withpolitical issues. However, after a few months ofscrutiny and meticulous note-keeping about suchinterference, it became clear to everybody that theseinterventions were counterproductive and I was notbothered further.A special upshot of the term of my presidency was theincreased representation of Austrian science in gen-eral and the FWF in particular on the Europeanplatform. These contacts were most effective via anorganization called European Heads of ResearchCouncils (EUROHORCS), in which general researchstrategies with a focus on funding policies werediscussed on a European level. For me, these encoun-ters were both interesting and enlightening, the latterbecause I recognized that the FWF had a veryprivileged position in this European concert; althoughour budget was much too small in relation to Austria�s

ranking as among the most affluent countries in theworld, we were the most politically independentorganization. The FWF can spend its low budget in acompletely autonomous way without consideringpolitical interference (in spite of the frustratingattempts mentioned above). Furthermore, we arethe only European organization of its kind that sendsout all research projects for expert review abroadrather than having the majority of the reviewingprocess take place within the national researchcommunity and unavoidable attendant bias. I havealways summarized these specific characteristics ofthe FWF as its “five jewels”, which are:

– full autonomy– a bottom-up approach of research projects only– an international peer review system– quality as the only selection criterion for grant

approval– all disciplines treated equally

My most important achievement as a president of theFWF at this very difficult period was perhaps keepingit autonomous in the face of enormous politicalpressure to fuse the FWF with a second organizationin our country that funds applied research. Inciden-tally, besides the ministries themselves, the AustrianCouncil for Research and Technology (Rat f�rForschung und Technologie – RFT), an organizationestablished to advise the government in matters ofresearch policy, was the most ardent advocate of sucha fusion, which reflected the unfortunate inclination ofthe RFT towards applied versus basic science. I amgratified that this position has changed and take somesmall pride in believing my resistance contributed tothis development. In hindsight, I also seem to havebeen successful in propagating the idea that “culture”does not equal “art”, but rather also comprises“science” and many other facets of human life. Forthis purpose I created a formula that, in a nutshell,encompasses the differences and similarities of art andscience, notably the fact that both are driven bycuriosity and thus have a common “surprise factor(SF)”[culture = (art + science) SF].This and all other achievements were only possiblebecause the scientific community gave me enthusiasticand constant support for which I am grateful.Spending time in Austria�s Capital also permitted meto enjoy all its cultural and social treasures again that Isometimes miss in the provincial town of Innsbruck,such as daily musical performances by top artists,abundant exciting theater premieres and exhibitions,not to mention the culinary treasures, such as a good

10 G. Wick Self and non-self

glass of wine at the famous Heurigen, where we oftenmet our friends old and new.

Back to the lab and Professor emeritus

As mentioned, during this period of my life I wasrunning both my own research laboratory in Inns-bruck and the FWF in Vienna, and thus had theopportunity to experience both sides of academicactivities, bench work and discussions with studentsand postdocs on one hand and science management onthe other. When the time came to decide whether Ishould run for a second 3-year term and later possiblyfor a third period, this dual viewpoint played a criticalrole. It was quite clear to me that the part of my workat the FWF that I enjoyed most was that most directlyrelating to the research itself, e. g., evaluations ofprojects encompassing all disciplines with highlyqualified experts in the Scientific Committee(Board), laboratory visits, discussions with presidentsof Universities and the Academy of Sciences, meet-ings with the EUROHORCS and conferences onbroader issues on the European level. In long andlonesome reflections, I came to the conclusion that,despite my fascination with science management, theday to day life in the laboratory is my real passion, andwhere I want to devote the rest of my active life as ascientist. I am grateful for the unique experience ofhaving been part of the inner circle of national andEuropean research management, and would not havewanted to miss becoming aware of the broader socialand economic forces that can impact the conduct ofscience in significant ways. However, discussing newdata with members of my group, sitting at the micro-scope, interpreting and photographing interestingimmunohistological slides, writing scientific papersand engaging in lively critiques and discussions withmy colleagues in the lab and at scientific meetingswere closer to my heart. This life seems to be my truedestiny, and thus I decided to not to run for a secondterm, but rather fully concentrate on the two topics ofresearch that I am currently pursuing, “The Immunol-ogy of Atherosclerosis” and “The Immunology ofFibrosis”.Now in 2008, I can say that I did not regret mydecision. An additional incentive for returning toInnsbruck was the fact that I was ripe for retirement atthe end of 2007, so, in order to be able to continuedoing research, I had to sit down and start writinggrants again, which I did – keeping in mind the oldprinciple “win a few, lose a few”. Surprisingly, theseendeavors turned out to be unexpectedly successfuland I enjoy sufficient support for a group of about 8 – 9people for the next 3 –4 years, two thirds focusing on

atherosclerosis research and the remainder on theimmunology of fibrosis. With respect to atheroscle-rosis, my most successful grant application was one inwhich my role would be coordinator for an EU-fundedproject (10 million E) in Gerontology aimed atdeveloping vaccines against atherosclerosis and rheu-matoid arthritis based on the induction of immunetolerance against HSP60, i. e., the antigen that seemsto be instrumental in both of these diseases, albeit viasensitization against different arthritogenic and athe-rogenic epitopes, respectively. Blair Henderson, a verybright long-term colleague in the lab from NewZealand specializing in genomic analysis of pro- andanti-inflammatory factors involved in atherogenesis, isinstrumental in this large project together with nineother European groups.In the field of fibrosis research, together with Alek-sandar Backovic, a student and now postdoc fromSerbia, we have developed and patented a test basedon the “signature” of serum proteins deposited on thesurface of silicone breast implants and other silicone-coated implants, which identifies patients prone todevelop severe fibrotic peri-implant complications[33].Also, as part of our research on the immunologicalbasis of fibrosis, Roswitha Sgonc, a long-term memberof my group, in cooperation with Eric Gershwin,University of California at Davis (UCD) is success-fully continuing comparative studies in an avianmodel with a spontaneous disease resembling humanscleroderma, the UCD-200 line of chickens [34]. Firstin this model, and then corroborated in humanpatients, we made the important discoveries that (a)autoantibody-induced endothelial apoptosis ratherthan perivascular mononuclear cell infiltration is thefirst pathogenetic process in this crippling disease, and(b) post-inflammatory fibrosis is due to a lack of theanti-fibrotic cytokine transforming growth factor b2(TGFb2).In all our projects, the close proximity of our instituteto the major medical clinics has proven to be aninvaluable advantage, particularly in those concerningatherosclerosis and fibrosis. In addition to the neurol-ogists mentioned above, Raimund Margreiter, a pio-neer in transplantation medicine, and his group wereperfect partners for our atherosclerosis project, andHildegunde Piza-Kratzer, head of the Clinic for Plasticand Reconstructive Surgery of our university, and hercrew proved to be an optimal complementation forour research on the immunology of fibrosis.I now have a group of four postdocs, two graduatestudents, two technicians and a secretary, easy tooversee and enjoyable characters to spend time with.The lab is rather crowded, but crowding notoriouslypromotes interaction between scientists. As in the

Cell. Mol. Life Sci. Memories of a Senior Scientist 11

past, we do basic research without losing sight of theinherent medical problems. I also run a diagnosticlaboratory specializing in clinical immunology, aller-gology and endocrinology that provides a very effec-tive tool for clinical problem solving. Teaching, writingand lectures about our scientific results to scientificand well as lay audiences have always been a passionof mine that I will continue to exercise in the future.Reviewing this essay, I wonder if I should haveaccepted the Editor�s invitation. There is so much,and so many colleagues, friends and other importantpersons who have contributed to my scientific andpersonal life that I could not mention due to spacelimitations. I am especially fond of my technicians, theadministrative manager of the Institute for Patho-physiology, Pia-Ulrike M�ller, my competent loyaland efficient secretaries throughout the years, MargitKirchebner, Andrea Hohenauer, Anita Ender, Bar-bara Gschirr and Claudia Ram. There are so manycrucial people and seminal events that go unacknowl-edged in this article. On the other hand, I thought itwas interesting that I completely forgot about mem-berships, official positions, awards, etc. – apparentlynot so important in a broader perspective. I also couldnot mention all the guest scientists who visited our labover the years, and did not emphasize failures of myown or others despite the fact that we learn as muchfrom our failures as our successes.In the present stage of my life, the fact that I havebeen, and still am, involved in aging research and“successful aging” has turned out to be quite useful forthe planning and performance of my own agingstrategy. It gives me continuous pleasure to see myformer collaborators thrive and become highly suc-cessful group leaders and professors in Austria andabroad. Finally, Traudi and I now enjoy our moreindependent and relaxed life, both with each other andwith our ever enlarging family.

1 R. Timpl, I. Wolff, G. Wick, H. Furthmayr and C. Steffen,(1968) Immunogenicity and specificity of collagen VII. Differ-ences between various collagens demonstrated by cross-reaction studies. J. Immunol. 101, 725–729

2 G. Wick, H. Nowack, E. Hahn, R. Timpl and E. J. Miller, (1976)Visualization of type I and II collagens in tissue sections byimmunohistologic techniques. J. Immunol. 117, 298–303

3 G. Wick, H. von der Mark, H. Dietrich, and R. Timpl, (1986)Globular domain of basement membrane collagen inducesautoimmune pulmonary lesions in mice resembling humanGoodpasture disease. Lab. Invest. 55, 308–317

4 R. Timpl, G. Wick and S. Gay, (1977) Antibodies to distincttypes of collagens and procollagens and their application inimmunohistology. J. Immunol. Methods 18, 165–182

5 G. Wick, J. H. Kite, Jr. and E. Witebsky, (1970) Spontaneousthyroiditis in the Obese strain of chickens. IV. The effect ofthymectomy and thymobursectomy on the development of thedisease. J. Immunol. 104, 54 –62

6 G. Wick, B. Albini and F. Milgrom, (1973) Antigenic surfacedeterminants of chicken lymphoid cells. I. Serologic properties

of anti-bursa and anti-thymus sera. Clin. Exp. Immunol. 15,237–249

7 B. Albini and G. Wick, (1974) Delineation of B and T lymphoidcells in the chicken. J. Immunol. 112, 444–450

8 B. Albini and G. Wick, (1974) Proportional increase of bursa-derived cells in chickens of the Obese strain. Nature 249, 653–654

9 L. de Carvalho, G. Wick and I. M. Roitt, (1981) Requirement ofT cells for the development of spontaneous autoimmunethyroiditis in Obese strain (OS) chickens. J. Immunol. 126,750–753

10 R. S. Sundick and G. Wick, (1976) Increased iodine uptake byObese strain thyroid glands transplanted to normal chickembryos. J. Immunol. 116, 1319–1323

11 L. C. P. de Carvalho, J. Templeman, G. Wick and I. M. Roitt,(1982) The role of self-antigen in the development of auto-immunity in Obese strain (OS) chickens with spontaneousautoallergic thyroiditis. J. Exp. Med. 155, 1255–1266

12 R. L. Boyd, K. Hala and G. Wick, (1985) Interactions andquantitative analysis of immunoregulatory cells in the chickenthymus. J. Immunol. 135, 3039–3045

13 G. Krçmer, K. Schauenstein, N. Neu, K. Stricker and G. Wick,(1985) In vitro T cell hyperactivity in obese strain (OS)chickens is due to a defect in non-specific suppressor mecha-nisms. J. Immunol. 135,2458–2463

14 G. Wick, K. Hala, H. Wolf, A. Ziemiecki, R. S. Sundick, M.Stçffler-Meilicke, M., DeBaets, (1986) The role of genetically-determined primary alterations of the target organ in thedevelopment of spontaneous autoimmune thyroiditis in Obesestrain (OS) chickens. Immunol. Rev. 94, 113–136

15 R. Kofler, P. Berger and G. Wick, (1982) Monoclonal anti-bodies against human chorionic gonadotropin (hCG): Produc-tion, specificity, and intramolecular binding sites. Am. J.Reprod. Immunol. 2, 212–216

16 S. Schwarz, P. Berger and G. Wick, (1986) The antigenic surfaceof human chorionic gonadotropin as mapped by murinemonoclonal antibodies. Endocrinology 118, 189–197

17 S. Dirnhofer, R. Klieber, R. De Leeuw, J. -M. Bidart, W. E.Merz, G. Wick and P., Berger, (1993) Functional and immuno-logical relevance of the COOH-terminal extension of humanchorionic gonadotropin b : implications for the WHO birthcontrol vaccine. FASEB J. 7, 1381–1385

18 K. Schauenstein, R. F�ssler, H. Dietrich, S. Schwarz, G.Krçmer and G. Wick, (1987) Disturbed immune-endocrinecommunication in autoimmune disease. Lack of corticosteroneresponse to immune signals in obese strain chickens withspontaneous autoimmune thyroiditis. J. Immunol. 139, 1830–1833

19 G. Wick, G. Krçmer, N. Neu, R. F�ssler, A. Ziemiecki, R. G.M�ller, M. Ginzel, I., Beladi, T. K�hr and K. Hala, (1987) Themulti-factorial pathogenesis of autoimmune disease. Immunol.Lett. 16, 249–257

20 O. Lechner, G. J. Wiegers, A. Oliveira-Dos-Santos, H. Dietrich,H. Recheis, M., Waterman, R. Boyd and G. Wick, (2000)Glucocorticoid production in the murine thymus. Eur. J.Immunol. 30, 337–346

21 J. Penninger, K. Hala and G. Wick, (1990) Intra-thymic nursecell lymphocytes can induce a specific graft-versus hostreaction. J. Exp. Med. 172, 521–529

22 J. Penninger and G. Wick, (1992) Thymic nurse cell lympho-cytes react against self major histocompatibility complex. Eur.J. Immunol. 22, 79–83

23 K. Schauenstein, G. Bçck and G. Wick, (1980) Short timebleaching of fluorescein isothiocyanate. A possible parameterfor the specific binding of conjugates in immunofluorescence. J.Histochem. Cytochem. 28, 1029–1031

24 K. Schauenstein, G. Wick and H. Kink, (1976) The micro-membrane-immunofluorescence test: A new semiautomatedtechnique based on the microtiter system. J. Immunol.Methods 10, 143–150

12 G. Wick Self and non-self

25 K. N. Traill, L. A. Huber, G. Wick and G. J�rgens, (1990)Lipoprotein interactions with T cells: an update. Immunol.Today 11, 411–417

26 L. A. Huber, Q. Xu, G. J�rgens, G. Bçck, E. B�hler, K. F. Gey,D. Schçnitzer, K. N., Traill and G. Wick, (1991) Correlation oflymphocyte lipid composition membrane microviscosity andmitogen response in the aged. Eur. J. Immunol. 21, 2761–2765

27 G. J�rgens, Q. Xu, L.A. Huber, G. Bçck, H. Howanietz, G.Wick and K. N. Traill, (1989) Promotion of lymphocyte growthby the high density lipoproteins (HDL): physiological signifi-cance of the HDL binding site. J. Biol. Chem: 264: 8549–8556

28 G. Wick, M. Knoflach and Q. Xu, (2004) Autoimmune andinflammatory mechanisms in atherosclerosis. Annu. Rev.Immunol. 22, 361–403

29 Q. Xu, J. Willeit, M. Marosi, R. Kleindienst, F. Oberhollenzer,S. Kiechl, T. Stulnig, G. Luef and G. Wick, (1993) Association ofserum antibodies to heat-shock protein 65 with carotidatherosclerosis. Lancet 341, 255–259

30 G. Millonig, C. Schwentner, P. M�ller, C. Mayerl and G. Wick,(2001) The vascular-associated lymphoid tissue: a new site oflocal immunity. Curr. Opin. Lipidol. 12, 547–553

31 M. Knoflach, S. Kiechl, M. Kind, M. Said, R. Sief, M. Gisinger,R. van der Zee, H. Gaston, E. Jarosch, J. Willeit and G. Wick,(2003) Cardiovascular risk factors and atherosclerosis in youngmales ARMY study (atherosclerosis risk factors in maleyoungsters). Circulation 108, 1064–1069

32 D. Bernhard, A. Rossmann, B. Henderson, M. Kind, A.Seubert and G. Wick, (2006) Increased serum cadmium andstrontium levels in young smokers: Effects on arterial endo-thelial cell gene transcription. Arterioscler. Thromb. Vasc.Biol. 26, 833–838

33 Backovic, H. L. Huang, B. Del Frari, H. Piza, L. A. Huber andG. Wick, (2007) Identification and dynamics of proteinsadhering to the surface of medical silicones in vivo and invitro. J. Proteome Res. 6, 376–381

34 G. Wick, L. Andersson, K. Hala, M. E. Gershwin, C. Selmi, G.F. Erf, S. J. Lamont and R. Sgonc, (2006) Avian models withspontaneous autoimmune diseases. Adv. Immunol. 92, 71–117

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Cell. Mol. Life Sci. Memories of a Senior Scientist 13