Michael Neuberger obituary | Science | theguardian.com http://www.theguardian.com/science/2013/dec/01/michael-ne... Search Michael Neuberger obituary Biochemist who discovered how antibodies are greatly improved KJ Patel theguardian.com, Sunday 1 December 2013 13.03 GMT Michael Neuberger developed mice that carried humanised antibody genes, with the aim of tricking the animal to produce humanised antibodies when confronted with specific targets. Photograph: MRC Laboratory of Molecular Biology The molecular biologist Michael Neuberger's research into antibodies did much to increase our understanding of how the body defends itself against microbes – single-cell organisms including viruses and bacteria. His own death at the age of 59 came, by sad coincidence, from myeloma, a cancer of the immune system leading to uncontrolled antibody production. When Neuberger was a PhD student at Imperial College London, his supervisor, Brian Hartley, suggested Neuberger visit the South African biologist Sydney Brenner at the MRC Laboratory of Molecular Biology (LMB) in Cambridge to collect some bacterial strains. Brenner spent several hours talking to Neuberger and the scale and scope of the discussion left his head spinning. As a consequence, Neuberger was drawn back to the LMB in 1980 and remained there for the rest of his career, eventually becoming its deputy director. 1 of 4 06/12/2013 12:46 Michael Neuberger obituary | Science | theguardian.com http://www.theguardian.com/science/2013/dec/01/michael-ne... But before that, Neuberger gained his PhD and on Brenner's advice spent two years in Cologne with Klaus Rajewsky. At the time Rajewsky was pioneering molecular techniques to understand the immune system. This experience led Neuberger to become interested in the biology of antibodies, proteins that are produced by B lymphocytes, a type of white blood cell, and are crucial in protecting us against microbes. Antibodies are remarkable molecules because they are tailor-made such that each individual antibody is directed to only one determinant – often a molecule specific to a microbe. This diversity is mainly achieved through a process of cutting and pasting back together a vast number of small gene fragments in the developing B lymphocyte. In Cambridge, the Nobel laureates César Milstein and Georges Köhler had achieved the isolation of an antibody of a single specificity and which can be produced in limitless quantities outside the body (mono-clonal antibodies). Neuberger began his research there against the background of these advances. He contributed significantly to knowledge of how B lymphocytes make antibodies, and these discoveries enabled him to genetically engineer antibody genes to produce novel types of antibodies. This work stimulated the subsequent development of therapeutic humanised antibodies by Neuberger's friend Sir Greg Winter. Neuberger's own specific contribution in this area lay in developing mice that carried humanised antibody genes, with the aim of tricking the animal to produce humanised antibodies when confronted with specific targets. Humanised antibodies are now transforming medicine and have engendered a multibillion pound industry. These advances ensured Neuberger's international reputation and his election as a fellow of the Royal Society in 1993. However, the most important of his numerous contributions to antibody research lay in the discovery of the mechanism by which the body greatly improves antibodies when the immune response to microbes is in full flight. In approaching this central problem, Neuberger knew that a process distinct from that of cutting and pasting of the antibody genes came into play when an antibody is in full demand. Something caused a tiny segment of the antibody gene to be showered with a vast number of alterations – or mutations. These mutations occurred at levels several million times higher than they do spontaneously throughout the rest of the genome in a cell. This process, known as somatic hypermutation, is crucial because the immune system can then exploit natural selection to enhance the efficacy of an antibody. At LMB, Milstein was already working on this, so they decided to collaborate. However, their approach was frustratingly slow. This prompted Neuberger to search for a much 2 of 4 06/12/2013 12:46 Michael Neuberger obituary | Science | theguardian.com http://www.theguardian.com/science/2013/dec/01/michael-ne... faster somatic hypermutating experimental system, and with a PhD student, Julian Sale, he made a breakthrough by discovering that certain B lymphocyte cell lines do indeed possess this property. The next step was to identify the hypermutator gene, but the race for this was cut short in 2000 by the identification by Tasuku Honjo of Kyoto University, Japan, of a gene called activation induced deaminase – or AID. Genetic inactivation of AID in man or mouse abolished hypermutation. The key question now shifted to defining precisely how the AID gene product mutated DNA. It seemed most likely that there was an indirect mechanism by which AID caused hypermutation, but these elaborate ideas led to considerable confusion. Neuberger then had the stunning insight that AID attacked DNA directly, stimulating the change of just one of the four bases in DNA. This tiny and subtle alteration, known as deamination, would then fool the normal DNA error-correcting mechanism to paradoxically introduce a mutation. Neuberger's lab confirmed his model and reported it in a letter to Nature in 2002. Up to his death, Neuberger co-headed a lab with Cristina Rada. Together they continued to study AID and its related molecules, specifically to understand how they were controlled so that they do not engage with DNA inappropriately. Indeed, it is now clear that when this happens, mutations rip through the genomes of cells, possibly explaining how they might subsequently become cancerous. Neuberger's deamination mechanism therefore has implications well beyond the alteration of antibody genes and for this reason he was awarded numerous international prizes. Michael was born in London, the son of Lillian and Albert Neuberger. His father was also an outstanding biochemist, and the PhD supervisor of the double Nobel prizewinner Frederick Sanger. For some years both father and son were fellows of the Royal Society. From Westminster school, Michael went on to read natural sciences at Trinity College, Cambridge, which he returned to as a research fellow in 1977 and later as director of studies. Despite his enormous scientific achievements, Neuberger was a very modest man with unique leadership skills. Those of us fortunate enough to have worked with him recollect visiting his tiny spartan office carrying our seemingly confusing data. One would then emerge with a sense of pure clarity, and of course a mountain of new experiments to do in order to pin down a discovery with absolute rigour. His students now run research teams at leading universities around the world. From 2002 onwards, Neuberger jointly headed the protein and nucleic acid chemistry division of the LMB, where previously Sanger, Milstein and another Nobel laureate, John Walker, had conducted their research. He ensured the continuation of its scientific 3 of 4 06/12/2013 12:46 Michael Neuberger obituary | Science | theguardian.com http://www.theguardian.com/science/2013/dec/01/michael-ne... vigour and world-class reputation. All this was achieved quietly, with no fuss, by force of personality and through a profound sense of duty. Neuberger was also sustained by a wonderful family life with his wife Gill Pyman, an Australian doctor, whom he married in 1991. She survives him, along with their two daughters and two sons. • Michael Neuberger, biochemist, born 2 November 1953; died 26 October 2013 More from the Guardian What's this? More from around the What's this? 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