Remembering Michael S Neuberger (1953-2013)
2013; Springer Nature; Volume: 32; Issue: 24 Linguagem: Inglês
10.1038/emboj.2013.251
ISSN1460-2075
AutoresAntonino Cattaneo, Roberto Sitia,
Tópico(s)T-cell and B-cell Immunology
ResumoObituary11 December 2013free access Remembering Michael S Neuberger (1953–2013) Antonino Cattaneo Antonino Cattaneo Scuola Normale Superiore, Pisa, Italy European Brain Research Institute, Roma, Italy Search for more papers by this author Roberto Sitia Roberto Sitia Division of Genetics and Cell Biology, Università Vita-Salute San Raffaele Scientific Institute, Milano, Italy Search for more papers by this author Antonino Cattaneo Antonino Cattaneo Scuola Normale Superiore, Pisa, Italy European Brain Research Institute, Roma, Italy Search for more papers by this author Roberto Sitia Roberto Sitia Division of Genetics and Cell Biology, Università Vita-Salute San Raffaele Scientific Institute, Milano, Italy Search for more papers by this author Author Information Antonino Cattaneo1,2 and Roberto Sitia3 1Scuola Normale Superiore, Pisa, Italy 2European Brain Research Institute, Roma, Italy 3Division of Genetics and Cell Biology, Università Vita-Salute San Raffaele Scientific Institute, Milano, Italy The EMBO Journal (2013)32:3112-3113https://doi.org/10.1038/emboj.2013.251 PDFDownload PDF of article text and main figures. ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinked InMendeleyWechatReddit Figures & Info Michael Neuberger died in Cambridge on 26 October 2013, surrounded by his loving wife Gill and children, Saskia, Lydia, Thomas and Benjamin. He now rests in peace next to their house in Suffolk. A particularly aggressive myeloma ended most prematurely a life full of science, human relationships, fatherhood, joie de vivre, understatement and humour. ‘Shut up, you fat face’ Michael said once as he picked up the phone, thinking it was Franco Calabi playing yet another game. We realized it was not Franco when Michael turned purple and said ‘Oh, good afternoon Sir’ (it turned out he was talking to the Director General of the MRC). After a few minutes of total embarrassment, we started laughing, only to resume our discussion about antibodies. Michael was a gentle and generous person, an outstanding scientist and mentor. After his PhD in Biochemistry with Brian Hartley in London, Michael went to work with Klaus Rajewski in Köln, on César Milstein's recommendation that he should learn some immunology before joining the LMB in Cambridge. Here, Michael spent his brilliant career, soon becoming one of its pillars, as Joint Head of the PNAC Division and Deputy Director. His contribution to immunology and biotechnology research is legendary, his work always rooted in his profound interest in basic science. Moreover, his ground-breaking contributions on antibody expression and diversification have implications that go far beyond immunology, impacting cancer, virus biology and DNA stability. Michael's pioneering work on antibody engineering was an important part of what is often called the ‘antibody revolution’. In a landmark paper in 1984, the Fc portion of an antibody was substituted by an active enzyme moiety—as he put it ‘the introduction into lymphocytes of immunoglobulin-gene DNA that has been manipulated in vitro allows the production of novel antibodies’ (Neuberger et al, 1984). This simple yet powerful idea paved the way to derive the first chimaeric mouse–human (with Terry Rabbitts) and humanized (with Greg Winter) antibodies, and subsequently for inserting a human Ig locus into lymphocytes of transgenic mice and for redirecting antibodies to novel intracellular compartments. These experiments were made possible by the vectors that Michael engineered to study Ig transcription, an endeavour that led to discovering the IgH enhancer (Neuberger, 1983). Figure 1. Michael Neuberger (right) and César Milstein in the LMB library, 1998. With permission - Visual Aids LMB, MRC. Download figure Download PowerPoint While these advances sparked a revolution in biomedical research, industry and society, Michael considered them with great understatement a ‘divertissement’, satisfied to show the proof-of-concept. His lifetime ambition was to solve the antibody ‘GOD problem’ (generation of diversity). When Michael entered the field, at the beginning of the 1980s, the discovery of VDJ joining by Susumu Tonegawa and colleagues had relegated somatic mutation, one of the first theories put up to address GOD, somewhat to the back seat. In their classic Nature paper, Brenner and Milstein wrote ‘We cannot propose a definitive test of this theory apart from the direct demonstration of a cleaving enzyme and a mutagenic polymerase in precursor cells, which may not be easy to do’ (Brenner and Milstein, 1966). Indeed, it was over 30 years later that Michael demonstrated the mechanism responsible. By the end of the 90s, Michael's, César's and other labs had characterized many features of somatic mutation and the quest for the mechanism was heating up worldwide when, while studying class switch recombination, Tasuku Honjo and colleagues identified AID, proposing an RNA editing mechanism. This was, at first, an anticlimax for the Cambridge dream team. Yet, Michael was convinced that the new enzyme had to act on DNA and was directly responsible for the mutations at G:C pairs. In a remarkable tour de force, he demonstrated deamination of cytosine bases on DNA by AID as the mechanism of somatic mutation (Petersen-Mahrt et al, 2002), as well as gene conversion (Harris et al, 2002) and class switching (Rada et al, 2002). The discovery of DNA deamination by AID provided the unifying missing piece of the GOD jigsaw and allowed many testable predictions to be made (Di Noia and Neuberger, 2002). Although there was no precedent for any physiological programme in vertebrates that depended on targeted deamination of DNA, invoking such a mechanism of AID action immediately suggested explanations for several previously unconnected observations. In Michael's words, the ‘DNA deamination model then simply fell out on us’, underlining that it was the result of a ‘resurgence of hypothesis driven research’, something that he felt intellectually and aesthetically particularly gratified by. Sharp, always quick to get to the core of questions and pervaded by natural empathy, Michael has been an ideal mentor for flocks of students and colleagues, whose only problem was to cope with his quick-fire thinking and even faster talking (and mumbling). But what a joy when one guessed right! And what a joy to see the Milstein–Neuberger–Winter trio share their different styles and accents to satisfy their thirst for knowledge and together drive the antibody revolution. Among the many awards and recognitions in Michael's much too short life, he enjoyed the rare privilege of sharing the membership of the Royal Society with his father, a distinguished glycoprotein biochemist. An EMBO member and a Fellow of Trinity College, where he was Director of Studies in Natural Sciences, Michael was recently elected as a foreign associate of the US National Academy of Sciences. A lover of music, when asked about his piano lessons, he generally smiled, quoting his teacher telling him ‘Michael, you might consider taking up another instrument’. He worked throughout his illness, saying that he found it convenient to have the hospital so close to the lab, so that he could shuttle between the two. In the last few months, he felt like Moses, having brought the people across the sea to the new LMB building but not being able to get there himself. In 1967 Niels Jerne wrote ‘as this younger generation of professionals is pressing rapidly towards the definitive solution of the antibody problem, we older amateurs had perhaps better sit back, waiting for the END’. Michael did provide the end of the scientific story of somatic mutation. ‘Now I imagine Michael knocking at the Heaven's door, apologising for being early’ said a friend, summarizing his sweet and natural kindness well. Far, far too early. References Brenner S, Milstein C (1966) Origin of antibody variation. Nature 211: 242–243CrossrefCASPubMedWeb of Science®Google Scholar Di Noia J, Neuberger MS (2002) Altering the pathway of immunoglobulin hypermutation by inhibiting uracil-DNA glycosylase. Nature 419: 43–48CrossrefCASPubMedWeb of Science®Google Scholar Harris RS, Sale JE, Petersen-Mahrt SK, Neuberger MS (2002) AID is essential for immunoglobulin V gene conversion in a cultured B cell line. Curr Biol 12: 435–438CrossrefCASPubMedWeb of Science®Google Scholar Neuberger MS (1983) Expression and regulation of immunoglobulin heavy chain gene transfected into lymphoid cells. EMBO J 2: 1373–1378Wiley Online LibraryCASPubMedWeb of Science®Google Scholar Neuberger MS, Williams GT, Fox RO (1984) Recombinant antibodies possessing novel effector functions. Nature 12: 604–608CrossrefWeb of Science®Google Scholar Petersen-Mahrt S, Harris RS, Neuberger MS (2002) AID mutates E coli suggesting a DNA deamination mechanism for antibody diversification. Nature 418: 99–103CrossrefCASPubMedWeb of Science®Google Scholar Rada C, Wiliams GT, Nilsen H, Barnes DE, Lindahl T, Neuberger MS (2002) Immunoglobulin isotype switching is inhibited and somatic hypermutation perturbed in UNG-deficient mice. Curr Biol 12: 1748–1755CrossrefCASPubMedWeb of Science®Google Scholar Previous ArticleNext Article Read MoreAbout the coverClose modalView large imageVolume 32,Issue 24,December 11, 2013"Striated boulder" – The Coyote Buttes section of Vermillion Cliffs National Monument in Arizona contains some of the most colorful and whimsical sandstone formations to be found anywhere on the planet. The picture was taken by Ian Parker of the University of California, Irvine, who is a neurobiologist and an avid wilderness photographer. Apparently, he is also still the only Fellow of the Royal Society to have completed the world's toughest footrace. More of Ian's scientific and non-scientific adventures can be found at http://parkerlab.bio.uci.edu. Ian originally submitted this image to The EMBO Journal Cover Contest 2011, where it received a lot of praise from the jury. If you would like to "win" the cover of The EMBO Journal, either with a scientific or a non-scientific work of art, be sure to visit http://covercontest.embo.org to find out how you can take part in our 2014 competition. But hurry up – the deadline for submission is only a week away, on 20 December 2013. Volume 32Issue 2411 December 2013In this issue FiguresReferencesRelatedDetailsLoading ...
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