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Influenza is rightly perceived as a significant health risk, and the spread of H5N1 (bird flu) has provoked alarm as it spreads across the globe. The groups of Professor George Brownlee, FRS and Ervin Fodor have for the past decade been working on understanding the molecular mechanisms underlying the influenza virus replication and adaptation from one species to another. Here, post-doctoral researcher Dr Ruth Harvey explains their approach.

Influenza virus was first isolated in 1933, and it ion channel activity required by the virus for the still remains a public health and economic problem release of its RNA into the host cell, but today. Since its isolation there have been two resistance to this class of drugs is very common.

Influenza virus binding to major pandemics, ‘Asian flu’ in 1957 (H2N2 The new neuraminidase inhibitors (such as infected cell via subtype) and ‘Hong Kong’ flu in 1968 (H3N2 Relenza and Tamiflu) block release of new virus Haemagglutinin spikes on subtype), estimated to have killed a total of 1.5 particles from infected cells, but these drugs virus surface. million people. But we should not forget the only work if administered in the first 72 hours infamous ‘Spanish flu’ in 1918 (H1N1 subtype) after infection and there have also been reports that reportedly killed an estimated 20 to 40 million of resistance starting to emerge. We still need people. By contrast the current outbreak of ‘Bird more effective drugs or a better vaccine that flu’ has to date infected around 200 people with would be effective against any strain of virus. about 100 deaths since the first case in 1997. Influenza research at the Dunn School by The occurrence of influenza virus each year, and George Brownlee, Ervin Fodor and others led to the recommendation for annual vaccination of at the development of the reverse genetics system risk groups, such as the elderly or that allows the construction of ‘designer’ immunocompromised, is the result of antigenic viruses from potentially any combination of the drift – the ability of the virus, as with many RNA virus genome segments. This is a huge step viruses, to mutate rapidly. There is however a form forward for the manufacture of vaccine strains, of more drastic genetic change, caused when allowing vaccine candidates to be made that segments of two viruses from different sources re- are, for example, antigenically relevant in a high assort in a single cell. This is known as antigenic growth background. This new reverse genetics shift and essentially gives rise to a new sub-type system has been used to create a non- THE SIR WILLIAM DUNN of virus. Pandemics often follow such a shift. pathogenic seed vaccine against the H5N1 bird SCHOOL OF PATHOLOGY flu virus. The UK government plan now includes is a department of the University of Oxford The current vaccine used worldwide is a trivalent the manufacture of H5N1 vaccine from such a website: vaccine. Each year, the World Health Organisation seed stock if pandemic bird flu occurs in the UK. www.path.ox.ac.uk (WHO) predicts the influenza strains, (A – H1

Contacts: and H3 subtype and B) likely to circulate the Currently both Prof Brownlee’s group and Dr Professor Herman following year based on epidemiological data Fodor’s group focus on fundamental work, Waldmann, FRS collected worldwide. The three virus strains are attempting to elucidate the molecular mechanisms Head of Department Sir William Dunn School grown in chicken’s eggs and from these stocks of transcription and replication of the influenza of Pathology, a vaccine is prepared. The vaccine requires updating virus genomic RNA, the structure and function of South Parks Road each year and so there is a very tight time frame the virus RNA polymerase, and the involvement Oxford OX1 3RE for first deciding which strains to include and then of the polymerase in the adaptation of avian email: herman.waldmann@ path.ox.ac.uk producing the vaccines. This process means that influenza to mammalian cells. This research should there is always a chance that the viruses included in lead to a better understanding of how the virus Dr Eric Sidebottom the vaccine will be out of date by the time the works and why the function of the polymerase is Sir William Dunn School of Pathology, vaccine is administered, although the viruses are so essential for the virus. Such an understanding South Parks Road normally similar enough to give sufficient protection may lead to new drugs targeted to viral or host Oxford OX1 3RE against any new antigenically drifted strains. proteins. Such drugs would complement those Tel: (44) (0)1865 285751 email: eric.sidebottom@ presently available, and increase our ability to path.ox.ac.uk Two groups of drugs are used for the treatment combat the threat of any emerging influenza of influenza. Amantadine/rimantadine block an viruses, including bird flu. Fusion #5a:Fusion #5 13/11/07 09:32 Page 3

fusionTHE NEWSLETTER OF THE SIR WILLIAM DUNN SCHOOL OF PATHOLOGY ISSUE 5 . MICHAELMAS 2006 Contents

Editorial 1

Editorial News 2 The department continues to thrive scientifically against a background of escalating Siamon Gordon costs and taxation for access to University services. Lab Reunion 4

This is reflected in the expanson of 5 year the pressure on departments such as ours by Research Profile 6 programme grants which now total 11 on an enabling the overheads that are raised on annual basis. We are pleased to welcome Prof grants to provide support to the scientific Research Notes 7 Oreste Acuto who has joined us from the infrastructure rather than be consumed by the Dunn School Joins Pasteur Institute, and provides for the salary costs. With the Milstein Chair the Dunn European Drive for School will have five endowed Chairs and three community an expertise in cell signalling which New Cancer will create many opportunities for understanding externally funded senior appointments Therapies 8 how interactions with ligands outside of cells (Wellcome PRF, MRC Professorship and an MRC can be transmitted to changes within. This area Senior Scientists). With the advent of Full Development News 9 of research has broad relevance in areas of local Economic Costing, externally funded research ranging from Immunology, Cancer Cell appointments and endowed postitions are likely Size Matters 10 Biology to Cardiovascular Disease. The departure to be the longer-term salvation of departments NEW Faces 11 of Prof Jeffrey Errrington to head a major such as ours. Needless to say we will be seeking further endowed positions to maximize our microbiology initiative at Newcastle University Bird Flu Vaccines and has inspired an energetic search to find new financial viability. Reverse Genetics 12 leadership in the area of Microbiology, and we hope that this appointment will be completed in Finally, our congratulations to William James and the not-too distant future. Our hope is to use Quentin Sattentau for being awarded the Title this appointment to provide a nidus for the of Distinction of Professor, and to Nigel resurgence of British microbiology, and this will Saunders and Shona Murphy to Readerships. certainly be facilitated by the very powerful immunology groupings within the department Herman Waldmann, FRS, Head of Department whose research efforts interface closely with microbial pathogenesis.

Our fundraising efforts for the Cesar Milstein Chair in Cancer Research have now taken us to the £2m mark, leaving us just £0.7m off our target. We are sorry to have lost our Development Officer Susan Harrison who has now taken on a significant role as Head of Development at Lincoln college. I am pleased however that she continues to help us complete the fundraising for this important Chair.

Not only do such endowed Chairs enable Oxford

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News

Awards Grants Professor Herman Waldmann has been awarded Two major grants to support work on the Mary Tyler Moore and Dr S. Robert Levine microbicides in the department have been Excellence in Clinical Research Award by the awarded over the past few months. Juvenile Diabetes Research Foundation (JRDF). The award, made jointly to Dr Lucienne Dr William James has been awarded a Chatenoud, Prof J F Bach and Prof. Waldmann, programme grant by the US NIH to use the recognizes the contribution made to the Envaptin technology originating in his laboratory treatment of diabetes by the anti-CD3 antibody to develop microbicides targeting multiple developed by Herman Waldmann and Geoff Hale sexually transmitted infections. The award, at the Dunn School. totalling more than $3.5m, involves laboratories at the University of California, Los Angeles, and Another member of the Dunn School has been Leuven, Belgium in a concerted drive to take elected to the Royal Society. Professor Nicholas Envaptins from the laboratory to preclinical trials. Proudfoot, Brownlee-Abraham Professor of The aim is to isolate Envaptins targeting Herpes Molecular Biology, was elected in May 2005, Simplex virus Type 2 and Human Papilloma virus with the citation recognizing his pioneering work Type 16, to complement those targeting HIV, on polyadenylation and transcriptional already isolated by William James, and to put termination which has had a major impact on them through a development program involving current knowledge of the mechanism and control lead identification, medicinal chemistry of mRNA processing. refinement, formulation and ex vivo testing. The aim is to be able to offer a single preparation Prizes that will simultaneously protect against infection Marianna Papaspyridonos, from Dr David Greaves by multiple infectious agents. lab, was one of the finalists in the British Heart Foundation image competition feature on the Dr Quentin Sattentau’s group is one of the BBC Health Website. She used DNA microarray recipients of The Bill and Melinda Gates Grand technology to analyse gene activity in white Challenges in Global Health Awards. Together blood cells from diseased blood vessels. Each with others in a consortium coordinated by Dr spot in the image represents a single gene – the Robin Shattock at St George’s Hospital, London, brightest are the most active they have been awarded $19.5m over a five-

Graduate Student Symposium, 2005 The symposium was held on 2nd July and was attended by the Vice-Chancellor, Dr John Hood, for the first time. First and second year graduate students exhibited posters of their work, while third year students made presentations to the Department. Sponsorship for the day was provided by Serotec, TolerRx, Qiagen and Astellas.

The prizewinners are pictured with Dr John Hood (Vice-chancellor; extreme R), Professor Fiona Watt (CRUK and a former Dunn School graduate; 3rd from L) and Dr Chris Norbury (organiser; 2nd from R). Fusion #5a:Fusion #5 13/11/07 09:32 Page 5

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year period, to design and implement new Obituaries forms of HIV vaccine delivery, with the specific Helen Muir, who died in November 2005 at the aim of eliciting strong and persistent antibody- age of 85, started her career at the Dunn mediated immunity in mucosal sites. School, completing her D. Phil in 1947 and continuing as a post-doctoral fellow working on Dr David Greaves, Reader in Molecular the synthesis of penicillin. Later, she moved to Pathology, has recently been awarded a five the Kennedy Institute for Rheumatology, where year programme grant by the British Heart she developed her interest in osteoarthritis. She Foundation to study the role of inflammation in was made a Fellow of the Royal Society in cardiovascular disease. 1977. Her obituary in the Guardian mentions her love of fast horses and fast cars, and she is Professor Jeff Errington, FRS, has moved to remembered here as a striking and lively the University of Newcastle as Director of the Helen Muir scientist. Institute for Cell and Molecular Biosciences. Jeff has been at the Dunn School for more than 16 Jean Medawar, died May 3 2005, aged 92. years, and we wish him great success in this Brought up in Cambridge, Jean went to new position. Benenden school, in Kent, and won a scholarship to Somerville College, Oxford, to read zoology. After graduating she joined “I told you so” Florey's team in the Dunn School and took a Henry Harris and George Klein are still discussing BSc for work on the origin and development of the importance of differentiation in cancer 36 lymphocytes. years after the first Harris & Klein paper on suppression of Malignancy While at Oxford, she met Peter Medawar, later Sir Peter, the Nobel laureate for medicine and Nature (1969) 223, 363-8. Suppression of director of the National Institute for Medical malignancy by cell fusion. The first of 26 Research, and they married in 1937. They had Jean Medawar collaborative papers with Klein 1969-1980. 4 children who all survive. Jean, despite a very active career of her own, including Chairman of the Family Planning Association, cared for Peter Photograph taken in Oct 2005 at a meeting after his calamitous stroke in 1969, helping him on Cell Fusion & Cancer in Sweden. through 18 more exuberant and productive years. Fusion #5a:Fusion #5 13/11/07 09:32 Page 6

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Siamon Gordon Lab Reunion

David R. Greaves

On 21st September 2005 hundreds of immunologists converged on the Medical Sciences Teaching Centre in Oxford for the Society of Leukocyte Biology (SLB) meeting on Phagocytes and Innate Immunity. This meeting was preceded by a symposium to celebrate the contribution that Siamon Gordon has made to the study of innate immunity during his time at the Dunn School. The speakers and session chairmen were chosen to represent many of the key areas of research undertaken in Siamon’s lab at the Dunn School from the late 1970s to the present day and included several current members of the Gordon laboratory.

Jonathan Austyn opened the meeting with homeostasis and recollections of the earliest days of the Gordon immune function (Taylor et al. Trends Immunol. lab and the production and characterization of 2005; 26:104-110). the first antibodies that specifically recognized tissue-resident macrophages that included the Annette Pluddemann, a current member of the F4/80 monoclonal antibody. The cell surface Gordon Lab, reviewed the long history of receptor recognised by F4/80, research into macrophage Emr1, turned out to be a novel scavenger receptors undertaken in TM7 protein that is the first the Dunn School before talking member of a family of related cell Recent research about her own recent research on surface receptors that play the role of the SR-A receptor in important roles in leukocyte in Siamon’s the recognition of Neisseria adhesion and regulation. Martin laboratory has meningitidis proteins. The SR-A cell Stacey reviewed the history of the surface receptor was originally expanding gene EGF-TM7 family led to the identified through its role in uptake and talked about the continuing discovery of an of modified LDL uptake and search for potential ligands for macrophage adhesion (Greaves & these receptors and reviewed important new Gordon J Lipid Res. 2005; 46:11- recent findings from the Emr1 family of cell 20) and recent work in Siamon’s knockout mouse which suggests a laboratory continues to identify yet role for F4/80 in peripheral surface proteins more physiologically relevant tolerance in the eye and gut (Linn that recognize ligands for this most promiscuous HH et al. J Exp Med. 2005; of macrophage cell surface conserved 201:1615-25). receptors. features of Luisa Martinez-Pomares, who has pathogens. Speaking in the SLB main meeting recently taken up a lectureship at Paul Crocker (University of Dundee) Nottingham University), presented talked about his research on Siglec an overview of the biology of cell surface receptors, which are another important macrophage cell expressed by many cells of the surface receptor, the macrophage mannose innate immune system (reviewed receptor, which has been extensively studied in in Curr Opin Pharmacol. 2005; 5:431-7). The the Dunn School. The detailed analysis of the prototypic member of this immunoglobulin different ligands recognized by different super family of receptors, Sialoadhesin, was first domains of the mannose receptor continues to characterized in Oxford when Paul Crocker and Jonathan Austyn, Luisa reveal new functions for macrophages in tissue Stuart Muklow were working in Siamon’s lab in Martinez-Pomares, Paul Crocker, Martin Stacey Fusion #5a:Fusion #5 13/11/07 09:32 Page 7

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the Dunn School. generous sponsorship for the meeting.

Recent research in Siamon’s laboratory has led Many of the Gordon Lab alumni and alumnae to the discovery of an important new family of have gone on to combine careers in clinical cell surface proteins that recognize conserved medicine with basic biomedical research. features of pathogens. The Clinician scientists were well prototypic member of this family is represented at the meeting and Dectin-1, the gene for which was included Alan Ezekowitz (Chief of cloned and characterized by Gordon Many of the Pediatrics at Mass. General Brown (Nature. 2001; 413:36-7). Hospital) who continues to study Gordon Lab Phil Taylor talked about the wide macrophage phagocytosis (e.g. range of pathogens recognized by alumni and Kocks C et al. Cell. 2005; 123:335- Dectin-1 and presented recent data alumnae have 46) and Lynn Morris (Head, AIDS on how pathogen recognition by Research Unit, National Institute Dectin-1 leads to macrophage gone on to for Communicable Diseases, activation. combine careers Johannesburg, South Africa) who spoke about her important work In addition to taking forward the in clinical on HIV/AIDS in South Africa. Wim cell biology of macrophages and medicine with de Villiers (Kentucky Medical their receptors other former Center, Lexington, KY) spoke about members of the Gordon Lab have basic biomedical his continuing interest in used molecular biology approaches research. macrophage scavenger receptors, to illuminate important aspects of while Satish Keshav (Consultant macrophage biology. David Vaux Gastroenterologist, Royal Free (Oxford) presented new approaches Hospital, London) talked about his to studying macrophage receptors work on inflammatory mechanisms using phage display and David Hume (University in inflammatory bowel disease and Derralyn of Queensland, Brisbane, Australia) talked about Hughes (University College Hospital, London) his long-standing interest in the regulation of talked about the role of macrophages in macrophage gene expression (Curr Opin lysosomal storage disorders, exemplified by her Immunol. 2006; 18: 49-53). The main meeting work on patients with Gaucher’s Disease. also saw the return of a Gordon Lab sabbatical visitor, Prof. Christopher Glass (UC San Diego), The Gordon Lab Reunion Symposium and the who has made important contributions to our Society of Leukocyte Biology meeting served to understanding of macrophage biology and remind us of Siamon’s many important transcriptional regulatory mechanisms. Another contributions to the study of innate immunity, distinguished sabbatical visitor to the Gordon not least of which is the international network lab, Dr Thomas Schall CEO of ChemoCentryx Inc. of scientists and clinicians who continue to (Mountain View, California) talked about study the cells and molecules they first chemokine receptors as a new therapeutic encountered under Siamon’s tutelage here in target in inflammatory disease and provided

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the Dunn School. sure to fail.

Where are they now? Name: Luis J. Montaner (D. Phil. Student 1991–95) Name: Hugh Rosen D. Phil. Student and JRF Current position: Director, HIV-1 1984–1990 Immunopathogenesis Laboratory Associate Current position: Professor of Immunology and Professor, Immunology Program Chair, Committee for Advanced Therapeutics, One thing you learned from Siamon: Look at The Scripps Research Institute, San Diego the big picture before judging on an incremental One thing you learned from Siamon: step. Integrative thinking. Siamon tried to teach me patience and perseverance but he did not quite Name: Luisa Martinez-Pomares (Postdoc succeed! 1994–2005) Current position: Lecturer in Name: Lynn Morris D. Phil Student and postdoc Immunology/Microbiology, University of 1984–1989) Nottingham Current position: Head, AIDS Research Unit, One thing you learned from Siamon: Be National Institute for Communicable Diseases, generous and trusting. Johannesburg, South Africa. One thing you learned from Siamon: Always Name: Alan Ezekowitz (D. Phil. Student look at your cells.... 1980–1984) Current position: Charles Wilder Professor of Name: Matthew Collin (D. Phil student Pediatrics, Harvard Medical School 1988–1992 Chief of Pediatrics Partners Healthcare System Current position: Clinician scientist, Mass General Hospital for Children haematology, Newcastle Head of Laboratory of Developmental One thing you learned from Siamon: Immunology Enthusiasm and generosity carry the day One thing you learned from Siamon: How to write a paper Name: Peter Gough (D. Phil. Student 1994–99) Current position: Investigator, GlaxoSmithKline, Name: Satish Keshav (D.Phil. Student and Philadelphia, USA postdoc 1987–1996) One thing you learned from Siamon: Treat Current position: Senior Lecturer and your data like a new piece in a very big jigsaw – Consultant Physician, Royal Free and University by constantly trying to fit the pieces together College Medical School, London you'll end up making unexpected joins and have One thing I learned from Siamon: Cell biology a very interesting new picture. is about cells, and the golden rule is "look before you lyse". Name: Willem J.S. (Wim) de Villiers (D. Phil student 1992–95) Name: David Vaux (D.Phil. Student and postdoc Current position: Professor and Chief, Division 1978–81) of Digestive Diseases and Nutrition, University Current position: Lecturer in Experimental of Kentucky Medical Center, Lexington, KY Pathology, University of Oxford One thing you learned from Siamon: One thing I learned from Siamon: “Stay broad, Persistence and optimism. Bad experiments follow your intellectual curiosity and appreciate often have as much, if not more, educational the beauty of your cells” value as good ones – if you don't try, you're

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Research profile – David R. Greaves

David Greaves is Reader in Molecular Pathology, and combines his research into inflammation with undergraduate teaching on the BM course. He talked to Fusion about his scientific career.

I arrived at the Dunn School of Pathology in therapeutic chemokine binding proteins that November 1993 having read Microbiology at could find application in the next generation of Bristol University, studied for my PhD in drug eluting stents used in coronary artery Biophysics at King’s College London and angioplasty. undertaken postdoctoral research at the Netherlands Cancer Institute in Amsterdam and Funded by a programme grant from the British the MRC labs in Mill Hill. Heart Foundation we are continuing our studies into the role inflammation plays in atherosclerosis. I had the good fortune to join the group of We are searching for new mediators of Siamon Gordon where I began to develop a macrophage recruitment and activation that might deep appreciation for the biology of represent new targets for the treatment of angina mononuclear phagocytes, a group of cells that and myocardial infarction (heart attacks). We are includes monocytes and macrophages. using gene arrays to study macrophage activation Macrophages are found in virtually all tissues of in response to modified LDL and cytokines we the body where they are important for tissue know are expressed in arterial disease. We have homeostasis but they also play a central role in identified two relatively new players in vascular diseases characterised by chronic inflammation inflammation, a C-type lectin expressed by such as tuberculosis, rheumatoid arthritis and macrophages in unstable atherosclerotic plaques coronary artery disease. in human arteries and an unusual chemokine called fractalkine/CX3CL1. In addition to studying In the summer of 1995 I shared a bench with a the mediators that initiate and sustain sabbatical visitor from California, Tom Schall, inflammation in the artery wall I am very who had just cloned the first cellular receptor interested in studying endogenous mediators that for a family of potent monocyte are important in the resolution of chronic chemoattractant proteins called CC chemokines. inflammation in vivo as this may give new insights We now know that chemokines direct the into diseases characterised by continued monocyte recruitment of different leukocyte subsets into recruitment and macrophage differentiation. sites of infection and inflammation and they represent an important target for the The Dunn School provides an excellent development of a new generation of anti- environment in which to pursue this research inflammatory drugs. programme and we benefit enormously from many interactions with the wider cardiovascular My own contribution to the field of research community in Oxford. Following a inflammation biology has been to show that national competition Oxford University was chemokines are important for recruiting awarded one of three BHF 4 year studentship monocyte/macrophages into atherosclerotic schemes and as Academic Director of this lesions found in human coronary artery disease. programme I will oversee the graduate training In work funded by the British Heart Foundation programme for a cohort of up to 12 students we have shown that broad spectrum blockade over the next four years. I also contribute to of CC chemokine activity dramatically reduces undergraduate teaching through organising macrophage recruitment into developing the BM General Pathology and Microbiology atherosclerotic lesions in arteries and vein grafts course and tutoring medical students at (Bursill et al. 2004 Circulation 110: 2460-6 and Hertford College. In addition to research, Ali et al. 2005 Circulation 112: I 235-41). We mentoring and teaching I also enjoy cooking, want to continue this work by engineering reading and cycling. Fusion #5a:Fusion #5 13/11/07 09:32 Page 10

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Research notes and findings

David Vaux is Lecturer in Experimental Pathology at the Dunn School and Lincoln College. His research is in the field of molecular cell biology. Here, he discusses a new project that has been generously funded by Tim and Kit Kemp through Lincoln College.

The development of particular cell types Microarray Facility in the department, Dr Malhas depends on expressing the correct pattern of then showed that these cells have altered patterns genes at the right time. When this goes awry of gene expression, including groups of over- normal tissue function is lost and abnormal expressed genes. Strikingly, one of these groups growth in the form of cancer may result. clustered on a chromosome that is normally tightly attached to the nuclear lamina (label at the edge of Gene expression patterns depend on local DNA the normal nucleus in the top picture). This factors, diffusible DNA-binding factors and, for suggested that the altered gene expression might simple organisms anyway, the position of a gene have been caused by detachment of the within the nucleus. In recent work funded by a chromosome from the lamina, a prediction that was research grant from Tim and Kit Kemp, Dr Ashraf beautifully confirmed by imaging this chromosome Malpas in my group has shown that similar position in the mutant cells (bottom picture). effects occur in mammalian cells. Working with a range of genetically engineered cells we first These results have implications for showed that defects in the nuclear lamina protein, understanding both normal and abnormal lamin B1, result in an unstable nuclear periphery. control of gene expression and may offer In collaboration with Dr Nigel Saunders of the important clues to understanding aging.

Dunn School joins European drive for new cancer therapies

Dr Gordon MacPherson’s group is part of a European-wide network to explore the potential of dentritic cell therapy to cure cancer, in a consortium headed by Dunn School alumnus Professor Jon Austyn, now at the Nuffield Department of Surgery in Oxford.

Dendritic cells are specialised cells of the immune such as Crohn's disease and ulcerative coloitis, system that trigger and control many types of and improving the efficacy of vaccines against immune response. There is considerable interest in intestinal infections. using them to treat cancer, HIV and many other diseases, and human trials in advanced cancer One main purpose of the network is to co- patients have already yielded promising results. ordinate existing work – standardising disparate trials so that the data can be studied as a The DC-THERA is a €7.6m initiative established whole, and eliminating duplication. The other is under the European Commission Sixth to educate the next generation of European Framework Programme. Over the next five years, experts in the field. the 32 European research groups involved will collaborate in order to translate laboratory ‘It’s too early to say whether this could prove a findings into clinical trials. In Dr MacPherson’s treatment not just for cancer but also for a group, the initiative will support work on whole host of other widespread diseases, but understanding the roles of dendritic cells in the the obvious potential is very, very exciting,’ said regulation of intestinal immune responses, with Professor Austyn. ‘If we get this right, the a view both to understanding intestinal diseases potential is enormous.’ Fusion #5a:Fusion #5 13/11/07 09:32 Page 11

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Development News

As regular readers of Fusion will know, the complement work by other research groups in Dunn School’s development programme has the Department and contribute to further been concentrating on supporting the therapeutic breakthroughs. Fundraising for this department through the endowment of new Chair has been coordinated by an Appeal posts, in particular a Chair of Molecular Cancer Committee, of which Milstein’s widow Celia is Biology, named in honour of César Milstein, and honorary President. Ably chaired by Dr Claudio a fund to honour Norman Heatley. It is Cuello (McGill), the Committee has raised over heartening to report that we are making good £2m of the £2.7m required to endow a Chair at progress towards achieving both of these Oxford. Generous donations have been received positions, of which more below. I would like to from the EPA Research Fund, the EPA thank all those who have offered support for Cephalosporin Fund, GSK Research, Genzyme, these, or more general Departmental needs. and many individuals who worked with Cesar over the years. One of the unexpected The Norman Heatley Fund outcomes of the Appeal has been a renewed Norman Heatley (1911–2004) was a pivotal link with Argentina, through a post-doctoral member of the team which isolated and purified fellowship linked to the Chair, to be funded by penicillin, and a sociable and much-loved CONICET (the Argentine medical research member of the Department for most of his agency) and an MRC-sponsored Fellowship for working life. an Argentine scientist in the UK.

This fund for research in the basic biological If you would like to know more about either of sciences, which we are seeking to fully endow, these initiatives, please contact Professor got off to a good start when the Merck & Co. Waldmann – [email protected] Foundation agreed to donate $500,000 towards its establishment. Merck & Co. played a pivotal role in the commercial development of penicillin in the 1940s, and indeed Heatley worked with scientists at the company’s research headquarters in Rahway, New Jersey. It was a small sample of penicillin from there that was Making a gift to the used to treat Mrs Anne Miller, the first patient in the USA successfully treated for streptococcus infection using penicillin. The fund has also Dunn School benefited from many other donations from The Dunn School owes its existence to a philanthropic gift, from the friends of Norman, and former colleagues. To Trustees of Sir William Dunn, and over the years has been the beneficiary complete this fund, the Department seeks a of many acts of philanthropy, not least from those who have worked minimum of £130,000 – any help that former here. Any gift made to the Dunn School helps to further research here, members can give, either directly or with whether it is made to support a specific initiative such as the ones suggestions for potential donors – would be described on this page, or at the discretion of the Head of Department. greatly appreciated.

If you would like to make a gift to the Department this year, please use César Milstein Chair in the gift form enclosed with this edition of Fusion. Please make sure that Molecular Cancer Biology you have completed a gift aid form so that we can reclaim tax on your Named in honour of the co-inventor of gift, and note that if you are a higher rate tax-payer, you can also set monoclonal antibody technology, the Milstein your gift against your tax liability for the year. All gifts made to the Dunn Chair will ensure that the Dunn School is able to School from the USA are also fully tax-deductible, when made through recruit a leading scientist in the field of the University’s ‘giving vehicle’ there, the Americans for Oxford, Inc molecular cancer biology, which will both organization. Fusion #5a:Fusion #5 13/11/07 09:32 Page 12

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Size matters, to the immune system at least

A theory about the way in which the immune system identifies and responds to invasion has been confirmed in a Nature paper published last year (Nature, 436, 578- An infected cell is 582). Dr Kaushik Chaudhury, Mr David Wiseman, Dr Marion Brown, Professor Anton van examined by two T-cells der Merwe, all from the Dunn School, and Dr Keith Gould from Imperial College London, simultaneously. The bright show that a highly sensitive and specific immune response hinges on something as areas of the cell interfaces straightforward as large and small molecules jostling into size order. are areas where the T-cell receptors are gathering. Researchers have long wondered how exactly T- published by Nature. The model proposes that, cell binding triggers an immune response. T-cells because both T-cell receptors and the telltale are kept in check by a constant battle at their peptide MHCs are relatively small molecules, surface between the small molecules that trigger they can only come into contact and bind when the immune response and large, long molecules the bulkier CD45s are out of the way – in which such as CD45s which prevent the immune case the immune response can be activated response from being switched on. The spoilsport without impediment. CD45 plays a crucial role: the immune system can attack as well as protect the body, and The work was funded primarily by the Medical allergies and serious autoimmune illnesses are Research Council, while Dr Choudhuri was the results of the immune system being supported by the Wellcome Trust. activated inappropriately. How, though, do T-cells Mr Wiseman said: ‘What we have shown is a overcome the inhibitory effect of CD45s when whole new way that cells can control they do need to launch an attack on invaders? themselves. These are the earliest events in T- cell triggering, the key activation step in The answer is now shown to be the kinetic immune surveillance, and all it comes down to is segregation model, conceived at Oxford 10 years whopping great molecules being shut out of ago by Professors Anton van der Merwe and close contacts zones, simply by virtue of their Simon Davies, and confirmed in the study whopping greatness.’

NEW Faces

Alan Ezekowitz a blue against Cambridge. Recently, Alan’s It was a great pleasure to laboratory research has focused on the role of welcome Alan back to the innate immunity in host defense, using Drosophila Dunn School as the Newton- as an experimental system and combining classical Abraham Visiting Professor in forward genetics with the characterization of cell Medical, Biological and lines to study phagocytosis. Using primary cells Chemical Sciences for 2005–6. and cell lines, he has demonstrated that that this process in flies has marked similarities to the Alan was a DPhil student in Saimon Gordon’s lab process that occurs in man and mice. After several in the early 1980s (the photograph is from that years as Charles Wilder Professor of Pediatrics at time!). He made a big impact not only in the lab the Massachusetts General Hospital, Alan has but also on the cricket field where he was a taken up a new senior post determining scientific regular member of the University team and won policy at Merck. Fusion #5a:Fusion #5 13/11/07 09:32 Page 13

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Professor Oreste Dr Susan Lea Acuto She has recently been He took up his post at the appointed to a Lectureship in Dunn School on 1st March Chemical Pathology. She 2006. He is working in the recently moved into the laboratories recently converted laboratories vacated by Jeff from the old Lecture Theatre. Errington’s group. Susan has been working in the Department of Biochemistry Oreste was previously Head of the Molecular for 16 years and already has collaborations with Immunology Unit at the Institut Pasteur in Paris. several Dunn School laboratories, including those of Saimon Gordon, William James and Ariel After obtaining a doctorate in Immunogenetics in Blocker. Rome, he did post-doctoral work in the Biochemistry Department of the ETH in Zurich and The research of her group covers: in the Genetics Unit at the ISREC in Lausanne and • Structural biology to aid understanding of then moved as an Assistant Professor to the Dana host-pathogen interactions Farber Cancer Institute at Harvard Medical School in • Innate immunity, especially the Complement Boston. His involvement with the Dunn School goes system back more than 20 years, when at Harvard • Pathogen evasion of host immunity, University, he started to work on the T-cell antigen particularly serum dwelling spirochaetes receptor at the same time as Alan Williams. Susan writes: His current work revolves around the search for An understanding of the way in which an novel avenues in T cell signalling, the invading pathogen interacts with its host at a mechanisms by which the adaptive immune molecular level is an essential aid to understanding response is activated and regulated. the nature and extent of disease caused. My group aims to use a variety of techniques to He writes: probe the interactions that characterise different We study the molecular mechanisms of T cell disease processes. Central to this approach is the activation. The molecular information carried by use of X-ray crystallography to determine the antigen presenting cells and by cytokines is relayed structures of individual host or pathogen to the T cell through a complex network of components with a view in the longer term to membrane receptors and intracellular signalling examining the atomic structure of important components able to decode positive (activator) host-pathogen complexes. The major targets and negative (regulatory and tolerising) signals. are protein based but we are also involved in The outcome of these processes determines projects where folded RNAs provide the whether T cells become immediate effectors of the structural target. To aid understanding of immune response or memory cells, or are tolerised. biochemical and structural data we use a Our research is focused on understanding the role variety of other biophysical techniques and regulation of key components on the signaling (including surface plasmon resonance) to further machinery. Moreover, we search for new signaling characterise the biological systems under study. pathways by the use of mass spectrometry applied to intracellular protein complexes. Currently we are exploring new findings pointing at negative regulatory signals emanating from the earliest stages of T cell activation and at previously unexplored signalling pathways directing arginine methylation in T cells.

Oreste has a wife, who is also a research scientist, and a 14 year old daughter. They both will join him in Oxford later in the year.