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OUR RESEARCH OUR MISSION
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Introduction “At Barts and The London School of Medicine and Dentistry our outstanding research underpins our commitment to excellent education and clinical delivery, and has been transformed over the last five years under the leadership of our Warden Professor Sir Nicholas Wright. This has been confirmed by the outstanding results for Barts and The London in the 2008 Research Assessment Exercise. “Since 2003 there has been a 45 per cent increase in research grants and contracts. Research council grants have doubled, and £94.3 million in new grants awarded since 2005. In terms of 2006-7 research spend, the School ranked 11th among UK medical schools, exceeding that of many major metropolitan medical schools including Newcastle, Nottingham, Cardiff, Leeds, Sheffield and Southampton. We were joint first in the UK for success in the MRC Clinical Research Training Fellowship competition. “Barts and The London is the largest recipient of charitable income among UK medical schools. This increase has been in part due to the recruitment of world-class researchers, strategically appointed to add value to existing areas of excellence. Thus the School boasts world-leading groups in Cancer, Inflammation, Cardiovascular, Endocrinology, Epidemiology, Gastroenterology and Neuroscience research. “Academics in the medical school have been at the forefront of gaining National Institute for Health Research (NIHR) funding, and have just won a £6 million award for a Cardiac Imaging Biomedical Research Unit. With high quality staff, Barts and The London seeks to increase its funding from NIHR, MRC, Wellcome Trust, CRUK and the other major charities by at least 5 per cent per year.” Professor Tom MacDonald Dean for Research Barts and The London School of Medicine and Dentistry
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Contents: Bringing the Benefits of International Excellence to our Communities
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Queen Mary, University of London
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Our Education Mission
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Our Clinical Engagement
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Our Research Excellence
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Cancer
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Stem Cells
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Genetic Basis of Common and Rare Diseases
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• • • • • • •
Hypertension and Heart Disease Skin diseases Diabetes and periodic fevers Obesity Coeliac disease Down’s Syndrome Bone Marrow Failure
Infection, Inflammation and Repair
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Basic and Translational Neuroscience
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Dentistry
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Preventive Medicine and Public Health
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For further information visit:
smd.qmul.ac.uk
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Barts and The London School of Medicine and Dentistry
Bringing the benefits of international excellence to our communities
The 2008 Research Assessment Exercise results showed Barts and The London School of Medicine and Dentistry joining Oxford, Cambridge, Imperial College and University College London in the top 5 research-active medical and dental schools in England. According to rankings published in the Times Higher Education, Barts and The London scored consistently in the top five: • Dentistry was ranked 1st equal with Manchester based on 3* and 4* outputs, and 2nd overall out of 14 UK dental schools. • In Cancer, we were ranked 3rd out of 14 submissions in terms of 3* and 4* outputs and joint 5th in the UK overall, ahead of Oxford, Imperial, Kings College London and University College London • The Institute of Cell and Molecular Science, returned in Hospital Subjects, was ranked joint 1st with Cambridge and Edinburgh in terms of 3* and 4* outputs and was joint 7th overall out of 28, ahead of Manchester, Newcastle and Southampton. • The Wolfson Institute of Preventive Medicine, returned in Epidemiology and Public Health, was 2nd out of 21 in terms of 3* and 4* outputs, and 3rd overall, ahead of Oxford, University College London and Bristol • In Health Services Research, we were ranked 4th overall out of 28, ahead of Oxford, University College London and Kings College London • The William Harvey Research Institute, returned in Preclinical and Human Biological Sciences, was ranked 3rd in terms of 3* and 4* outputs, and 4th overall out of 13, ahead of Kings College London, Bristol and Nottingham.
At the heart of the School’s mission lies world class research, the result of a focused programme of recruitment of leading research groups from the UK and abroad, and a £100 million investment in state-of-the-art facilities. Research is focused on: • translation of basic research into man • cancer • cardiovascular • dentistry • inflammation • endocrinology/metabolism • immunology and infectious diseases • skin disease • genomics
Barts and The London School of Medicine and Dentistry offers international levels of excellence in research and teaching. We serve a population of unrivalled diversity in east London and the wider Thames Gateway, with a high prevalence of diabetes, hypertension, heart disease, tuberculosis and other chronic lung diseases, HIV, oral disease, and cancer.
• neuroscience
To follow the London Underground from Westminster to Canning Town, in health terms, is to see a reduction in life expectancy of one year for each station – an astonishing and scandalous six years in all. Barts and The London is committed to changing this situation.
The School is nationally and internationally recognised for research in these areas. Its fundamental mission, with its partner NHS Trusts, and other linked organisations, such as CR-UK, is to ensure that that the best possible clinical service is underpinned by the very latest developments in scientific and clinical teaching, training and research.
The School has almost 1,000 members of staff, consisting of over 650 academics and around 350 support staff. The School’s total annual turnover is approximately £86 million of which over £40 million is competitively awarded external research income additional to that received from HEFCE, placing Barts and The London in the top tier of research active medical and dental schools. Through partnership with our linked trusts, notably Barts and The London NHS Trust, and our associated University Hospital Trusts – Homerton, Newham, Whipps Cross and Queen’s (Romford) – the School’s research and teaching is informed by an exceptionally wide ranging and stimulating clinical environment.
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• gastroenterology • epidemiology • public health and primary care
We pride ourselves on being a School that is committed to: • achievement of international excellence in our chosen areas of research and education • and through this, in collaboration with our NHS partners, contributing to our uniquely complex and diverse social and clinical environment in east London and the Thames Gateway, which offers research, teaching and clinical opportunities unrivalled in the UK
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Barts and The London School of Medicine and Dentistry
Queen Mary, University of London
Barts and The London School of Medicine and Dentistry draws strength from being part of Queen Mary, University of London, one of London and the UK’s leading researchfocused higher education institutions.
Queen Mary was ranked ahead of several Russell Group institutions, including Kings College London, Bristol, Sheffield, Leeds, Nottingham, Birmingham, Southampton, Liverpool and Newcastle.
One of the largest of the colleges of the University of London, Queen Mary's 3,000 staff deliver world class degree programmes and research across a wide range of subjects in Humanities, Social Sciences and Laws, Medicine and Dentistry and in Science and Engineering.
Queen Mary has also excelled in several subject groups, being in the top five in many, including (in addition to the medical and dental subjects itemised on page 1):
Queen Mary, as a member of the 1994 Group of research-focused universities, has made a strategic commitment to the highest quality of research, but also to the best possible educational, cultural and social experience for its students. Indeed, we believe that a vibrant research environment means that our students have access to the world's leading experts in their chosen subjects. Like Barts and The London, Queen Mary's distinctiveness arises from its commitment to an engagement with international excellence in education and research and a twin commitment to bring that engagement to bear on its London and Thames Gateway environment through educational outreach and knowledge transfer projects.
• English Language and Literature (ranked 2nd ahead of UCL, Oxford and Cambridge) • Linguistics (ranked 1st ahead of UCL, Oxford and Cambridge) • Drama, dance and performing arts (ranked 1st for Drama, but 2nd equal in the unit of assessment with the department ahead of us not being entered for Drama) • Geography (ranked 1st equal with Bristol, Cambridge, Durham and Oxford) Queen Mary was also ranked in the top 10 in:
Queen Mary has been ranked in the top 14 universities in the UK and in the top 100 in the world and has consistently been in the top group of universities for year-on-year increases in funding from the Higher Education Funding Council.
• Law • Russian, Slavonic and East European Studies • Iberian Languages
The results of the 2008 Research Assessment Exercise confirmed Queen Mary’s place in the very top group of research-led universities.
• Metallurgy and Materials • Economics and Econometrics
According to tables published in the Times Higher Education, Queen Mary has been ranked 13th in the country out of the 132 institutions which submitted for the exercise. The Guardian placed Queen Mary even higher, 11th in the UK.
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Barts and The London School of Medicine and Dentistry
Our Education Mission
Barts and The London offers an innovative and distinctive educational experience to our 2,300 undergraduate and 1,000 postgraduate students, which we believe to be quite different to and richer than other London medical schools. We offer our students exposure to research and clinical environments with worldwide reputations; the exceptionally rich cultural and social diversity of east London; and a varied and innovative mixture of educational opportunities to accommodate different learning styles. Because of the distinctively complex health environment that characterises the communities served by the School, combined with the excellence of our research, academic and clinical activity, we are able to produce outstanding graduates who go on to great success in their careers. Our students develop into scientifically-based clinicians with the highest quality clinical skills and professional competencies, who are also compassionate leaders of healthcare delivery across the full range of clinical activity and who are confident and self motivated individuals possessing key skills for lifelong personal development. We have many distinctions and successes in education. • Outstanding results scored in recent teaching quality assessments
The School has introduced an innovative new undergraduate curriculum. Key features of the revised “Curriculum ’08” include an increased emphasis on the scientific basis of medical practice and the development of medical professionalism. Other features include a strengthening of the much valued integrated systems-based approach to learning, whilst retaining an emphasis on the development of excellent clinical and communication skills. The course aims to provide the School’s students with a range of core and self-selected learning opportunities in both hospital and community settings and includes interdisciplinary modules as well as a choice of projects and electives abroad. The School’s students are highly motivated, with their own autonomous Association (within the Queen Mary’s Students’ Union) headed by a sabbatical Student President. In addition to the usual sports, drama and special interest clubs and societies, the Association has developed close links with the local community, examples being the raising of funds to build and run a residence for students and elderly people to live and work together and the running of a ‘Teddy Bear Hospital’ scheme with local schools.
• Our Medical degree course achieved top scores in areas of teaching, curriculum, student support and learning facilities • Our Dental degree course was one of the few in the country to achieve a maximum score of 24 for teaching quality • A very positive recent General Dental Council report • The only Centre of Excellence for Teaching and Learning (CETL) awarded in London by HEFCE, investment of £3.15 million with City University in recognition of excellence in training 3,000 healthcare professionals across six disciplines • Barts and The London was one of the pioneer medical schools to offer a Medical Graduate Entry Programme, now also in Dentistry
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Barts and The London School of Medicine and Dentistry
Our Clinical Engagement
Barts and The London School of Medicine and Dentistry has highly productive relationships with all NHS Hospital Trusts and Primary Care Trusts in North East London. We are proud of our association with Barts and The London Trust, which was ranked as the country’s top teaching hospital in the Healthcare Commission’s Annual Performance Ratings in 2007. The £1 billion PFI redevelopment programme at the Royal London Hospital, Whitechapel and at Barts – the largest hospital building project in Europe - will provide a world-class environment for the School’s teaching and research activities. We were the first Medical School and NHS Trust in the UK to develop joint Clinical Academic Units to exploit synergies between the School and The Trust in the following specialities: • Cancer • Circulatory and Metabolic Sciences • Digestive Diseases • Dentistry and Oral and Maxillo-facial Surgery • Musculoskeletal
The biggest and most research active of the Clinical Academic Units are led by senior medical school staff, again demonstrating the close strategic relationship between Trust and School. In 2006 the UK Clinical Research Network and the Department of Health appointed eight Local Research Networks to support the delivery and conduct of clinical diabetes research. The network covering north east London is led by Professor Graham Hitman. It promotes research that will improve care for people with diabetes, aiming to increase public and patient involvement in diabetes research, and supporting workforce development. Areas covered by the North East London Network include: Barking & Dagenham; City & Hackney; Havering; Newham; Redbridge; Tower Hamlets; and Waltham Forest. It is based at Barts and The London NHS Trust.
• Anaesthesia and Critical Care • Neurosciences • Trauma • Acute and Emergency Medicine • Paediatrics • Women’s Health • Cutaneous Medicine and Surgery • Clinical and Laboratory Sciences
The School has a strong commitment to providing the leading contribution to the NHS skills and education agenda across North East London and beyond into the Thames Gateway. Close relationships have been developed with Homerton, Newham, Whipps Cross, Queen’s (Romford) University Hospital Trusts. Strong working links have been developed with the Primary Care Trusts in north east London.
• Infection and Immunity • Patient Services
Dentistry also has links further afield in Southend, Essex, where it has established an innovative dental outreach centre, as well as in east London where another outreach clinic has been established on the Isle of Dogs. To strengthen the impact of our education and skills contribution to our communities, we are currently planning an innovative partnership, North East London Health, that will bring together education and training provision across Hospital and Primary Care Trusts in the subregion and will be a partnership between these bodies and The Barts and The London School of Medicine and Dentistry, with City University, the University of East London and London South Bank University.
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Redevelopment of the Royal London Hospital (artist’s impression)
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Barts and The London School of Medicine and Dentistry
Our Research Excellence
Over the past five years Barts and The London School of Medicine and Dentistry has been transformed into one of the top research institutions in the UK. Highlights include characterising susceptibility genes for complex diseases such as hypertension, diabetes and coeliac disease; identifying the genes responsible for Harlequin Ichthyosis; showing that stem cells can regrow liver, pancreas and intestine; the production of the Down’s syndrome mouse; showing that breast cancer screening reduces mortality; producing the evidence that folic acid should be added to bread in the UK, as happens in 31 other countries; and showing that vitamin D boosts immunity to tuberculosis Barts and The London School of Medicine and Dentistry has shown the largest increase in research funding in the last five years in the UK. The School has the highest amount of bluechip charitable income in the UK, and our research spend in 2006-7 placed us 11th in the Russell Group of medical schools. Our 2007-8 spend of £41.5 million represents a 20 per cent year-on-year increase, the highest in the UK, and moves us to 7th overall. Our current portfolio of 1001 awards totals £125 million, including seven programme grants from the MRC, seven programme grants from Wellcome Trust, and 12 programme grants from Cancer Research UK. Among our senior investigators, 90 per cent have at least one paper with greater than 100 citations and 14 of our senior researchers have, in total, an astonishing 309 papers with greater than 100 citations and individual “H factors” between 50 and 81. The School’s translational research strength has been recognised by, amongst others, the award of a NIHR Biomedical Research Unit in Cardiovascular Disease, with a £5.375 million grant awarded in 2008 to Barts and The London School of Medicine and Dentistry, and Barts and The London NHS Trust. More than 25 world-class researchers have been appointed at Professorial level since 2005, along with 50 new group leaders (Lecturers and Senior Lecturers). The 2008 Research Assessment Exercise results showed Barts and The London School of Medicine and Dentistry joining Oxford, Cambridge, Imperial College and University College London in the top 5 research-active medical and dental schools in England.
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According to ranking published in the Times Higher Education, Barts and The London scored consistently in the top five: • Dentistry was ranked 1st equal with Manchester based on 3* and 4* outputs, and 2nd overall out of 14 UK dental schools. • In Cancer, we were ranked 3rd out of 14 submissions in terms of 3* and 4* outputs and joint 5th in the UK overall, ahead of Oxford, Imperial, Kings College London and University College London • The Institute of Cell and Molecular Science, returned in Hospital Subjects, was ranked joint 1st with Cambridge and Edinburgh in terms of 3* and 4* outputs and was joint 7th overall out of 28, ahead of Manchester, Newcastle and Southampton. • The Wolfson Institute of Preventive Medicine, returned in Epidemiology and Public Health, was 2nd out of 21 in terms of 3* and 4* outputs, and 3rd overall, ahead of Oxford, University College London and Bristol • In Health Services Research, we were ranked 4th overall out of 28, ahead of Oxford, University College London and Kings College London • The William Harvey Research Institute, returned in Preclinical and Human Biological Sciences, was ranked 3rd in terms of 3* and 4* outputs, and 4th overall out of 13, ahead of Kings College London, Bristol and Nottingham.
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Selected Professorial Appointments made in the past five years Malcolm Alison Qasim Aziz David Baker David Beach Inderjeet Dokal Marco Falasca Gavin Giovannoni John Gribben Jonathan Grigg Ian Hart David van Heel Louise Jones Ajay Kakkar Ania Korszun Attila Lorincz
Professor of Stem Cell Biology Professor of Neurogastroenterology Professor of Neuroimmunology Professor of Cell Biology Professor of Haematology Professor of Signal Transduction Professor of Neurology Professor of Experimental Cancer Medicine Professor of Paediatric Respiratory and Environmental Medicine Professor of Oncology Professor of Gastrointestinal Genetics Professor of Breast Pathology Professor of Surgical Sciences Professor of Psychiatry Professor of Molecular Epidemiology
Tom MacDonald Ian MacKenzie Nic Maffuli Silvia Marino Aine McKnight Sussan Nourshargh Ken Parkinson John Pasi Costantino Pitzalis Ray Playford Denise Sheer Andrew Silver Ken Suzuki Bart Vanhaesebroeck
Professor of Immunology Professor of Stem Cell Science Professor of Sports Medicine Professor of Neuro-oncology Professor of Viral Pathology Professor of Microvascular Pharmacology Professor of Head and Neck Cancer Professor of Haemostasis and Thrombosis Professor of Experimental Rheumatology Professor of Gastroenterology Professor of Human Genetics Professor of Cancer Genetics Professor of Translational Cardiovascular Therapeutics Professor of Cell Signalling
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Charterhouse Square Campus
In addition to new senior staff, Barts and The London is placing particular emphasis on recruiting young researchers and supporting them to become stars of the future. You can read about some of them later in this brochure. The School has a fully-integrated Joint Research Office with Barts and The London NHS Trust which takes care of grant administration and, increasingly, is providing academics with assistance in the more complex types of proposals, such as EU FP7. Our Principal Investigators have protected research time in order to maximise their productivity and are co-located into
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research centres and environments of critical mass underpinned by state-of-theart core facilities in: Genomics; Functional Genomics; Proteomics: Imaging, Transgenic and Knockout mouse unit; and Structural Biology. A core Genomics and Proteomics Centre has been funded by the Barts and The London Charitable Foundation (£3.1 million including refurbishment). This Centre provides stateof-the-art facilities to support the School’s genomic and proteomics research programmes and associated bioinformatics. The recruitment of new high profile staff and the nurturing of our young researchers has led to a significant increase in the number of papers in world-class journals,
which increased from two in RAE 2001 to 124 in RAE 2008. We have seen a similar large increase in the number of MRC Training Fellows and Senior Fellows (27 in total). Some 200 researchers in the School were assessed for RAE 2008 and judged by external review to be producing high international quality research. Each of the School’s Institutes has been designed to co-locate congruent groups of research centres sharing common research goals, techniques and infrastructure, including materials, technical support and equipment and to provide maximum opportunity for interaction and co-operation with the relevant clinical activity.
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Barts and The London School of Medicine and Dentistry
Our Research Excellence
On the Charterhouse Square Campus, the School aims to deliver an internationally recognised centre of excellence in Cardiovascular and Cancer research, which will directly complement the clinical service delivery on the St Bartholomew’s Hospital site. Three Institutes are based in Charterhouse Square: the Institute of Cancer; the William Harvey Research Institute, majoring in cardiovascular research, genetics, pharmacology and endocrinology; and the Wolfson Institute of Preventive Medicine, majoring in molecular epidemiology and public health. The William Harvey Research Institute offers a vibrant, fully integrated clinical and basic science environment devoted to understanding basic pathogenic mechanisms and therapeutic innovation in cardiovascular, inflammatory and endocrine diseases. Since 2001 William Harvey investigators have published in high impact journals such as Nature, Nature Genetics, Nature Biotechnology, The Lancet, Circulation, Journal of Experimental Medicine and the Journal of Immunology, and spent over £33 million on research. These successes have led to the William Harvey being ranked amongst the top 20 pharmacological research institutions in the world based upon citations (according to The Scientist, 2004). The Institute of Cancer was founded in 2003 and under the leadership of Professor Nick Lemoine has rapidly developed into one of the leading centres in Europe. In Spring 2004 the School launched a Cancer Research-UK Clinical Centre on this campus, the first CR-UK clinical centre in the UK. In 2007 it hosted, in collaboration with the University of Cambridge, the CR-UK Molecular Pathology Training Programme. Also in 2007, with funding from the Department of Health, the Institute was awarded £2 million to establish the first Experimental Cancer Medicine Centre, to fast-track new cancer treatments. It is led by Professor John Gribben and Professor Nick Lemoine.
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The Wolfson Institute of Preventive Medicine at Charterhouse Square houses some of the most renowned figures in public health worldwide. Led by Professor Sir Nicholas Wald FRS, it has produced ground-breaking research on screening for Down’s syndrome, the role of folate in the prevention of spina bifida, and the ability of the “polypill” to reduce dramatically cardiovascular disease and stroke. The Cancer Epidemiology group, led by Professor Jack Cuzick, is a world leader in cancer prevention and among its achievements is showing that breast screening reduces mortality from breast cancer. The John Vane Building which houses most of the research staff at Charterhouse Square has undergone complete modernisation in the last three years, and a new Heart Centre is currently under construction which will be complete in 2009.
Another major development at Whitechapel is the QM Bioenterprises building, scheduled to open in 2009, adjacent to the Blizard Building, which will provide 40,000 square feet of space for small to medium bioscience companies. This will be available for QM researchers wishing to commercialise their research as well as those from other institutions. An exciting feature of this development is the webbased portal which will allow prospective clients and entrepeneurs to design and cost facilities on-line. The School is also redeveloping other sites to house the Centre for Health Sciences, to drive forward our primary care research agenda in the unique health care setting of east London, with its large immigrant communities. Our research strengths are: • translation of basic research into man • cancer • cardiovascular
On the Whitechapel Campus, a new landmark architecturally distinguished building for research into cell and molecular science opened in April 2005 (the Blizard Building). This exciting capital development houses the Institute for Cell and Molecular Science (ICMS), with laboratory and office accommodation for 400 research workers in disciplines which match the local clinical activities of The Royal London Hospital. The ICMS includes research centres of excellence in Skin Disease, Immunology and Infectious Disease, Gastroenterology, Surgery, Paediatrics, Diabetes and Neurosciences. A key feature of the design of the new build is the large open-plan laboratory and office accommodation which aims to ensure maximum flexibility and interaction between the research workers of the ICMS. A key element of the School’s investment strategy for this Institute is to encourage inter-disciplinary research through the development of themes which link multiple centres and thereby gain synergistic value.
• dentistry • inflammation • endocrinology/metabolism • immunology and infectious diseases • skin disease • genomics • neuroscience • gastroenterology • epidemiology • public health and primary care These are grouped in the rest of this brochure under the headings of: • Cancer • Stem Cells • Genetic Basis of Common and Rare Diseases • Infection, Inflammation and Repair • Neuroscience • Dentistry • Preventive Medicine and Public Health
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Professor of Cell Signalling, Bart Vanhaesebroeck see profile p16
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Barts and The London School of Medicine and Dentistry
Cancer
Cancer research is a leading strength of Barts and The London School of Medicine and Dentistry. World-class research into the disease at Barts and The London is being pursued in: • Institute of Cancer • Wolfson Institute of Preventive Medicine • Institute of Cell and Molecular Science This concentration of expertise makes Barts and The London one of the most significant power-houses of cancer research in Europe, and many investigators hold programme awards from CRUK and other funders. In Cancer, in the 2008 Research Assessment Exercise, we were ranked 3rd out of 14 submissions in terms of 3* and 4* outputs and joint 5th in the UK overall, ahead of Oxford, Imperial, Kings College London and University College London. The Institute of Cancer, led by Professor Nicholas Lemoine, has been the focus for substantial new investment in basic, translational and clinical cancer research over the past five years. The Institute represents one of the largest cancer research bodies in the UK with a total of 300 staff, raising some £45 million in grant income over the past five years, with £12.6 million spent in 2006/7 alone. Research in Cancer at Barts and The London is built on an integrated molecular and cellular approach to the problem of cancer in individuals and in populations.
Research strengths represented include: • therapeutic and diagnostic target identification and validation in both haematological and solid malignancies • clinical trials exploring new therapies • the development of novel molecular approaches for diagnosis, classification and treatment of human cancers
Facilities and Clinical Environment Institute of Cancer researchers are housed in an outstanding research environment on the Charterhouse Square campus, with significant investment from Queen Mary, the MRC and charities into new laboratories as well as new staff appointments. An extensive Infrastructure programme has provided state-of-the-art laboratories and offices. This working environment is multidisciplinary and well-resourced, promoting academic exchange and translational research at all levels. The Institute is also home to many of the laboratories of the Cancer Research UK Clinical Centre at Barts and The London. This was the first centre of its kind to be established and is one of the largest constellations of Cancer Research UK clinical and translational groups in the UK university sector. Cancer research at Barts and The London takes place close to the clinical care facilities for oncology at Barts Hospital. Barts was the first Clinical Cancer Centre recognised by Cancer Research UK and has been supported since 2004 by over £1.2 million per year of infrastructure funding. This was followed by the creation of the Centre for Experimental Cancer Medicine funded by a £2 million grant from the Department of Health and CR-UK, which provides infrastructure for translational research, from early to late phase clinical trials. The configuration of the Barts Hospital site as a Comprehensive Cancer Centre, to be completed in 2011 as part of Barts and The London’s £1.3 billion hospital redevelopment, the largest in Europe, will provide outstanding facilities for clinical research.
• investigations into the regulation of tumour spread and host anti-tumour responses.
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Barts and The London School of Medicine and Dentistry
Cancer
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Cancer research themes at Barts and The London Molecular Oncology and Imaging is an internationally recognised centre of expertise in gene therapy for cancer, with an active programme of clinical trials, as well as programmes for the identification of molecular biomarkers of disease progression and treatment response. It houses the state-of-the-art molecular imaging facilities for both preclinical and clinical studies. Cancer and Inflammation focuses on the link between cancer and inflammatory responses, in particular the role of immune cells and mediators found in experimental and human cancers. Cell Signalling is a world-class centre of expertise in both basic and applied PI3K signalling research. The programme focuses on the way in which uncontrolled PI3K signalling is one of the most commonly deregulated pathways in cancer. Experimental Cancer Medicine focuses on early phase trials of novel therapeutics developed in the Institute of Cancer, as well as recruitment into late clinical trials, including NCRN, pharma-sponsored and investigator-initiated clinical trials open at Barts and The London NHS Trust.
Some leading Barts and The London Cancer researchers Professor Nicholas Lemoine is the Director of both the Institute of Cancer and the Cancer Research UK Clinical Centre. He also leads the Centre for Molecular Oncology & Imaging, where the research of four groups focuses on the molecular pathology of solid malignancies, gene transcription biology, cell survival signalling, and molecular therapeutics including gene therapy and vaccine approaches. Professor Jack Cuzick (Wolfson Institute of Preventive Medicine), leads research into the screening and prevention of cancer. Key areas of interest are cancers of the breast, uterine cervix, prostate and colon. In these areas there are activities encompassing prevention studies, screening studies, treatment comparisons, prognostic factors for survival, and aetiological studies of risk factors for developing malignant disease.
Professor Jack Cuzick
Professor Frances Balkwill’s work has led to the realisation that cancers possess a complex cytokine network, that a pro-inflammatory tumour micro-environment is involved in tumour promotion and spread, and that there are strong links between the processes of chronic inflammation and cancer.
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Barts and The London School of Medicine and Dentistry
Cancer
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Professor Bart Vanhaesebroeck MSc, PhD Centre Lead, Cell Signalling Professor Bart Vanhaesebroeck joined the Institute of Cancer at Barts and The London School of Medicine and Dentistry from the Ludwig Institute for Cancer Research (University College London), to set up the Centre for Cell Signalling in June 2007. His research group’s key interest lies in understanding signalling through PI 3kinases (PI3Ks), combining fundamental research with efforts to translate findings into diagnostic and therapeutic applications. In previous work, the team proposed the now universally accepted classification and nomenclature of the PI3Ks (Philosophical Transactions of the Royal
Society of London 1996:351:217, TiBS 1997:22:267). They cloned the p110delta isoform of PI3K (PNAS 1997:94:4330), revealed p110delta-selective functions in cells (Nature Cell Biology 1999:1:69; Cancer Res 2003:63:1667) and generated mouse models to investigate the in vivo function of this enzyme. They have pioneered the use of so-called 'kinase knockin' mice in which the active site carries a mutation in an ATP-binding amino acid residue, leading to inactivation of the kinase. These provide a more adequate physiological model for the effects of small molecule kinase inhibitors than classical gene knockout approaches (Cell 2004:118:274; TiBS 2005:30:194). Their recent studies have revealed key functions for p110delta PI3K in adaptive immunity (Science 2002:297:1031), allergy (Nature 2004:431:1007) and leukaemia (Oncogene 2006:25:6648). Partly through these research efforts, p110delta has become a drug target in cancer, inflammation and auto-immunity. These discoveries were successfully incorporated into the drug development programme of Piramed and is now further developed by Roche. Application of the mouse knockin strategy has further allowed the team to uncover the first physiological roles of the p110alpha (Nature 2006:441:366, Nature 2008;29:453) and p110beta (PNAS 2008:105:8292) isoforms of PI3K. The team is also developing novel
methodologies to monitor the amount and activation of signal transduction enzymes, with focus on the PI3K pathway (PNAS 2006:103:8959, PNAS 2007:104:7809). Bart studied at the University of Ghent, Belgium, gaining a Masters degree (1985) in Biology (Physiology and Biochemistry) and a PhD (1990) in Molecular Biology. His PhD work, supervised by Drs. Walter Fiers and Johan Grooten, focused on immunology and signal transduction by cytokines. He then had to fulfil his military service which he carried out while working at University Hospital in Ghent in the Laboratories of Toxicology and Immunology. Following postdoctoral studies on signal transduction by Tumor Necrosis Factor, in the Laboratory of Molecular Biology in Ghent, and a brief stay at the University of Padova, Italy (with Professor Tulio Pozzan), he joined Mike Waterfield's group at the Ludwig Institute for Cancer Research in 1993 to work on PI 3kinases. Since 1998, he has headed the Cell Signalling Group at the Ludwig Institute for Cancer Research, in 2000, was appointed as a Lecturer, and in 2005 as a Professor at the Department of Biochemistry and Molecular Biology at University College London. Bart is a member of EMBO (European Molecular Biology Organisation) and has been a consultant for Serono (Geneva), PIramed, AstaZeneca and Intellikine.
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Barts and The London School of Medicine and Dentistry
Cancer
(cont)
Cancer research themes at Barts and The London (cont) Medical Oncology has a long and distinguished history in haemato-oncology, urological and paediatric malignancies, having led several pivotal trials in the treatment of these cancers. Tumour Biology is concerned primarily with understanding the role that cytoadhesion plays in modulating cancer spread and has focused particularly on the involvement of members of the integrin family of adhesion receptors. The Institute of Cancer has strong links with the Wolfson Institute for Preventive Medicine, in particular Professor Jack Cuzick’s randomised cancer prevention trials: the international IBIS-II breast cancer prevention trial (determining whether the aromatose inhibitor anastrozole has greater preventive effect than tamoxifen, with fewer adverse effects of treatment including thromboembolism); the CRISP-I trial of diindolymethane in women with mildly dyskaryotic smears in the prevention of cervical cancer; and the UK trial of chemo-prevention of endometrial cancer in genetically susceptible women (POET). The Wolfson Institute is the leading UK centre in the HPV vaccine trials sponsored by GlaxoSmith-Kline.
Some leading Barts and The London Cancer researchers (cont) Professor John Gribben leads the newly established Centre for Experimental Cancer Medicine. The main objective of the Centre is to provide a centre of excellence to facilitate translational cancer research from basic scientific discovery to the delivery of novel approaches to care of patients with cancer.
Professor John Gribben
Dr Claude Chelala’s research focuses on the development and application of computational solutions to cancer research including the design and implementation of a generic model for the organisation, integration and mining of complex data for cancer research. Dr Thorsten Hagemann’s major research focus is to understand the fundamental mechanisms by which TNFα signalling promotes cancer; with particular reference to the role of macrophages and their phenotype in carcinogenesis.
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Cancer
(cont)
Professor Iain McNeish MA PhD MRCP MRC Senior Clinical Fellow Professor of Gynaecological Oncology and Honorary Consultant in Medical Oncology Deputy Director Centre for Experimental Cancer Medicine Centre for Molecular Oncology and Imaging Professor McNeish joined the Institute of Cancer in May 2004. He trained in medicine at Oxford and did his PhD at
the Institute of Cancer Studies at the University of Birmingham. From 1998 to 2004, he combined training in medical oncology at Hammersmith and Charing Cross Hospitals with post-doctoral research at the Molecular Oncology Unit at Imperial College. The focus of his research is ovarian cancer, also his clinical sub-specialisation. His research programme focuses on abnormalities in apoptosis and cell cycle control in ovarian cancer as a target for gene and viral therapy. In particular, his group is studying the therapeutic potential of selectively replicating adenoviral vectors as therapy in ovarian cancer, and a phase I trial of one such virus, VTP1 (dl922-947) will shortly commence in the new Centre for Experimental Cancer Medicine Unit, which launched in Spring 2008. Further, his group is studying the mechanisms by which replicating adenoviral vectors induce cell death and whether this can be augmented with apoptosis inducers, such as chemotherapy or pro-apoptotic genes. His group is also looking at
methods of imaging viral activity in whole organisms using bioluminescence, fluorescence and PET imaging. Most recently, Professor McNeish was awarded an MRC programme grant and Senior Clinical Fellowship, worth ÂŁ1.7 million over 5 years, to continue his research on replicating adenoviruses. In particular, the Adenoviral EIA deletion mutant dl922-947 seems to work well in partnership with paclitaxel, a chemotherapy drug commonly used in ovarian cancer, but it is important to understand why, and whether other chemotherapy drugs may also combine well. The programme also seeks to understand how the immune system responds to dl922-947 in the abdominal cavity, where ovarian cancer grows. Finally, the reasons why some ovarian cancer cells do not respond well to dl922-947 will be explored, by studying the patterns of gene expression in sensitive and resistant cells, especially genes that control cell division.
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Professor of Stem Cell Science, Ian McKenzie
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Stem Cells
Given their unique ability to replicate specific human cells and tissues, and their potential to cure disease and heal injury, the study of stem cells is a key component of the School’s research strategy. The School has teams working on internationally competitive research programmes in areas such as adult stem cell plasticity, stem cell re-differentiation and trans-differentiation cancer stem cells, bioreactors and stem cell amplification, and stem cell targeting. These programmes were brought together by the Initiative in Stem Cell Biology established by the School in 2006, with funding from Barts and The London Charitable Foundation. Designed to promote cross-collaborative research and to advance discoveries in this important field, the Initiative includes all the research centres within the Institute of Cell and Molecular Science, as well as the Institute of Cancer, the Institute of Dentistry, the William Harvey Research Institute, and bioengineering researchers based in the School of Engineering and Materials Science at Queen Mary. The Institute of Cell and Molecular Science, returned in Hospital Subjects, was ranked in the 2008 Research Assessment Exercise joint 1st with Cambridge and Edinburgh in terms of 3* and 4* outputs and was joint 7th overall out of 28, ahead of Manchester, Newcastle and Southampton. Research programmes investigate various aspects of stem cell biology, ranging from basic science to clinical application, and many of these studies have already made a significant scientific contribution. Research aims to answer key questions such as whether differentiated cells can revert to the stem cell phenotype, which adult stem cells are tissue specific and which can transit to other tissues via the circulatory system. An example of this is the work of Professor Sir Nicholas Wright who, with colleagues, demonstrated that hepatocytes (liver cells) can be produced from non-hepatic adult stem cells. Researchers in the The Centre for Cutaneous Research identified a number of key stem cell molecules that are important in epidermal differentiation, wound healing and signalling between hair follicles and the epidermis. Other ongoing investigations include identifying stem cell marker proteins and determining the specific cellular cues (known as homing and cell fate signals) that form the correct microenvironment for cell regeneration. These include gene encoding growth factors and developmental genes.
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(cont)
Well established stem cell groups within the Institute of Cell and Molecular Science and the William Harvey Research Institute include: • • • • • • • • • • • •
Intestinal stem cells Heart stem cells Epithelial stem cells Malignant stem cells Pancreatic stem cells Haemopoietic stem cells Hair stem cells Genetics of stem cells Mesenchymal stem cells Neural stem cells Embryonic stem cells Inherited stem cell disorders In keeping with the strategy of the Institute of Cell and Molecular Science to gain synergistic value through the development of interdisciplinary themes, in 2006 the Initiative in Stem Cell Biology was launched which traverses each of the component Research Centres within the Institute and extends beyond to incorporate researchers from other Queen Mary Departments (e.g. Bioengineering) and linked Institutes (e.g. Institute of Cancer). The aim of the Initiative is to consolidate and expand an internationally competitive research programme in areas including adult stem cell plasticity, stem cell re-differentiation and trans-differentiation, bioreactors and stem cell amplification, and stem cell targeting. The initiative is headed by Professor Ian MacKenzie.
Some leading Barts and The London Stem Cell Researchers Professor Ken Suzuki’s current work primarily focuses on translational research on stem cell therapy for treating heart failure using stem/progenitor cells with the firm aim of establishment of this therapy in the clinical arena. His work aims to understand stem cell therapy and refining current protocols which can help myocardial inflammation and regeneration, and myocardial protection against ischaemia-reperfusion injury using gene therapy and advanced technologies Professor Ian Mackenzie, whose research interests are the cellular mechanisms involved in the maintenance of skin and oral mucosa; stem cells; tissue renewal; and cancer. Professor Mike Philpott, who works on the role of stem cells in hair renewal. Professor Silvia Marino, who has published ground-breaking work on the role of neural stem cells in neuroblastoma. Professor Malcolm Alison who specialises in research into stem cell biology of the pancreas, liver and gastrointestinal tract. During the course of his work he has developed novel methods for lineage tracing in human tissue, specifically in liver and pancreatic stem cells, with particular reference to diabetes, end-stage fibrotic disease and cancer. Professor David Beach FRS has a long-standing interest in the mechanism of cell cycle control and its role in inhibiting the growth of cancer cells. He discovered the relationship between cyclins and cyclin-dependent kinases, specifically the tumour suppressor genes p21 and p16, and has more recently focused on the problem of cellular life span control, an extension of his work on cell cycle regulation. Professor Inderjeet Dokal has identified the role of telomerase and associated genes in the pathogenesis of the stem cells disorders which underlie aplastic anemias. Dr Anthony Mathur, William Harvey Research Institute, along with Professor John Martin, from University College London, runs a pioneering research project testing the ability of stem cells to reduce the number of fatalities among heart attack patients and to improve heart function after the event.
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Professor of Stem Cell Biology, Malcolm Alison
Emma Smith PhD student Centre for Cutaneous Research “I chose to come to Barts and The London School of Medicine and Dentistry partly because of the fantastic modern facilities at the Institute of Cell and Molecular Science (ICMS), it's exciting coming to work everyday in the space-agey Blizard building! Also there is a great sense of community here everybody is very friendly and enthusiastic.�
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Genetic Basis of Common and Rare Diseases
Barts and The London has one of the most significant groupings of medical genetic researchers, seeking to find and study the genetic causes of human diseases; including skin disease; diabetes; coeliac disease; obesity; Down’s syndrome; cancer; motor-neurone disease; hypertension, and heart disease. In the 2008 Research Assessment Exercise, the Institute of Cell and Molecular Science, returned in Hospital Subjects, was ranked joint 1st in the UK with Cambridge and Edinburgh in terms of 3* and 4* outputs and was joint 7th overall out of 28, ahead of Manchester, Newcastle and Southampton. The William Harvey Research Institute, returned in Preclinical and Human Biological Sciences, was ranked 3rd in terms of 3* and 4* outputs, and 4th overall out of 13, ahead of Kings College London, Bristol and Nottingham. Hypertension and Heart Disease The aims of research in this area are to understand the basic underlying pathogenic mechanisms associated with the initiation and development of vascular diseases, eg, atherosclerosis and hypertension. Professor Mark Caulfield, director of the William Harvey Research Institute is a pre-eminent figure in the genetics of cardiovascular disease. He is national co-ordinator of the MRC British Genetics of Hypertension Study. With Dr Patricia Munroe he co-ordinates this study on behalf of five other UK Professor of Clinical Pharmacology, Mark Caulfield universities (Aberdeen, Cambridge, Glasgow, Leicester and Oxford). He published the largest genome screen in human hypertension on 2010 sib pairs highlighting four regions that may harbour susceptibility genes for essential hypertension in The Lancet during 2003. The BRIGHT study is an active member of the MRC Human Sample Collection Initiative. With the Wellcome Trust Case Control Consortium, BRIGHT is partnering Oxford, Cambridge and the Sanger Centre to undertake pathfinder experiments for genome-wide association. Professor Caulfield is co-grant holder with Imperial, Cambridge and Oxford on the Wellcome Trust Functional Genomics Programme (£5.4 million) to develop observations on metabolic syndrome and translate these from experimental models to man. Professor Caulfield is also Deputy Chair of the London Biobank Regional Collaborating Centre and a member of Biobank UK Sample Storage Committee, Chair of Biobank UK Ethnicity Sub-Group, member of Biobank UK Measurement Sub-Group.
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Professor of Molecular Medicine and Diabetes, Graham Hitman
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Genetic Basis of Common and Rare Diseases (cont)
Skin diseases The main focus is hyperproliferative skin diseases such as the palmoplantar keratodermas (PPK) and ichthyoses. Professor David Kelsell’s team in the Institute of Cell and Molecular Science has identified the important role of proteins involved in the regulation and formation of epidermal cell junctions responsible for cell-cell adhesion, cell signalling and communication, key properties to maintain the normal cellular phenotype and tissue architecture. Additional research programmes include the investigation of genetic and molecular events occurring in Basal Cell Carcinoma.
The current research programme focuses on genes important to inflammation and pancreatic beta cells in a number of major resources including British/Irish as part of the Diabetes UK/MRC Warren2 collections, and from the South Asian subcontinent including younger adult patients from Bangladesh. The cell biology links to the genetic work with major interests in pancreatic beta cell metabolism and insulin secretory granule trafficking. Researchers here recently discovered that calpain-10 is a trigger for insulin release; current studies are extending to actions on the cytoskeleton and into other endocrine cell types.
A prominent success which has received extensive media attention is the identification of the gene that causes the debilitating skin condition Harlequin Ichthyosis. Many children born with the disease die within two days of birth: those that survive endure painful rituals of scrubbing and applying cream to their skin at intervals to prevent it from cracking and becoming infected. The research group’s findings will facilitate the prenatal DNA diagnosis of this life-threatening disorder, and also pre-implantation genetic testing. With further research, more effective treatments could also be designed for Harlequin children.
The strength and uniqueness of this research is the clinical focus of the work, spanning from basic science to clinical application. An emerging interest is in the prevention of diabetes that is especially relevant to the School’s local Whitechapel community. Clinical translational research that interfaces with the NHS has been strengthened by several initiatives including the setting up of the North East London Local Diabetes Research Network (co-led by Graham Hitman) and a recent award of an MRC, National Prevention Research Initiative grant to pilot methods for identification of people at risk of diabetes and prevention strategies in the local Bangladeshi population.
Diabetes and periodic fevers Barts and The London is at the forefront of the international gene discovery programme in diabetes, related disorders, and periodic fevers (including genomewide association scans, candidate genes, functional genomics and applied physiology) and can count among its achievements a number of seminal discoveries. Research is led by Professor Graham Hitman and an exciting new development is the recruitment of Dr Vardhman Rakyan to bring his groundbreaking work on epigenetics into our research portfolio.
Obesity Professor Graham Hitman was among a team of scientists to have identified a genetic link to obesity through a genomewide study of 2,000 people with type 2 diabetes and 3,000 controls. This study was part of the Wellcome Trust Case Control Consortium, one of the biggest projects ever undertaken to identify the genetic variations that may predispose people to or protect them from major diseases. Through this genome-wide study, the researchers identified a strong association between an increase in body mass index (BMI) and a variation, or
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"allele", of the gene FTO. Their findings were published in the journal Science. The study found that people carrying one copy of the FTO allele have a 30 per cent increased risk of being obese compared to a person with no copies. However, a person carrying two copies of the allele has a 70 per cent increased risk of being obese, being on average 3kg heavier than a similar person with no copies. Amongst white Europeans, approximately one in six people carry both copies of the allele. Coeliac disease Research led by Professor David van Heel has recently identified eight new genetic risk factors for coeliac disease - a disease affecting one in 100 of the population which is caused by an excessive immune response to wheat in the gut wall. Funded by the charity Coeliac UK, and the Wellcome Trust, and published in Nature Genetics, the studies have revealed that those suffering have a different spectrum of genetic risk variants in multiple genes that control the nature of the immune system response. Behind its success is the Human Genome Project - a massive international research project to reveal the entire sequence of genes of all the human chromosomes. Exploiting technological advances that have enabled comparison of variations across the human genome in large numbers of people, researchers studied over seven thousand individuals with and without coeliac disease, amongst British, Irish and Dutch populations. One of the key findings is that healthy individuals more often have a protective DNA sequence in the interleukin-2 and interleukin-21 gene region than individuals with coeliac disease. Interleukin-2 and interleukin-21 are cytokine proteins secreted by white blood cells that control inflammation. It is likely that the protective
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Genetic Basis of Common and Rare Diseases (cont)
DNA sequences leads to different amounts of these cytokines being produced providing defence against intestinal inflammation. Professor Van Heel has recently been awarded £1 million by the Wellcome Trust to continue this work.
Down’s mouse – their efforts complicated by the fact that the mouse versions of the genes on human chromosome 21 are awkwardly scattered across three mouse chromosomes. About two-thirds lie on mouse chromosome 16, the rest on chromosomes 10 and 17.
Down’s syndrome A world leader in Down’s leukaemia research is Professor Dean Nizetic from the Institute of Cell and Molecular Science. He is part of a London based team which achieved a genetic engineering first when it created a strain of mouse with an almost complete copy of chromosome 21. This unusual genome mimics the genetic makeup of people with Down’s syndrome. The research was published in Science.
Professor Nizetic and his colleagues - along with Elizabeth Fisher of the UCL’s Institute of Neurology and Victor Tybulewicz of the MRC’s National Institute for Medical Research – rather than trying to duplicate regions of the mouse genome corresponding to human chromosome 21, radically tried instead to put the human chromosome into mice.
The modified mouse will make it easier to understand the effects of Down’s syndrome, which is linked with types of leukaemia, heart disease and Alzheimer type symptoms relatively early in life. Researchers have spent over a decade trying to engineer a
David van Heel BM BCh MA DPhil MRCP Professor of Gastrointestinal Genetics David van Heel was appointed as Professor of Gastrointestinal Genetics at Barts and The London School of Medicine and Dentistry, and Honorary Consultant Gastroenterologist at Barts and The London NHS Trust, in 2006. He currently holds a Wellcome Trust Clinician Scientist Fellowship project,
That strain of mice, called Tc1, has about 92 per cent of DNA of the human chromosome 21. It also has a unique set of several characteristics of Down’s syndrome not seen in any other mouse model. Although there are no tests for mental retardation in mice, the Tc1 mice have deficits in spatial learning and memory, fewer brain cells with altered
functions, as well as skeletal changes similar to those found in Down’s syndrome patients and, most significantly, they have heart defects like those found in Down’s syndrome patients. The research could have major implications in understanding these conditions in people with Down’s and, in the longer term, in aiding efforts to understand and perhaps ameliorate other effects of Down’s. The research also has implications concerning cell proliferation, cell differentiation, neurodegeneration, and protection from cancer, by identifying the molecular pathways and proteins which are altered by trisomy 21. Professor Nizetic’s work is supported by a programme award from the Leukemia Research Fund. This research has a strong local history because Downs syndrome was first discovered at The London Hospital by John Langdon-Down in 1859.
grant funding from Coeliac UK and a Wellcome Trust Programme Grant. His main clinical interests are coeliac disease and Crohn's disease. Principally his research interests lie in the genetic causes of these diseases, and the functional/immunological consequences of these genetic variants on human biology.
Research Activity • Identification of disease susceptibility genes for human intestinal inflammatory diseases (coeliac disease, Crohn's disease, ulcerative colitis). A genome wide association study in coeliac disease was published in 2007, identifying novel risk factors in the IL2/IL21 gene region.
David was awarded a Natural Sciences BA at Cambridge University in 1990 and completed Clinical Medicine training at the University of Oxford in 1993. A Medical Research Council Clinical Training Fellowship led to a DPhil in inflammatory bowel disease genetics from the Wellcome Trust Centre for Human Genetics, University of Oxford in 2002. He then undertook postdoctoral research at Imperial College, and completed specialist training as a Consultant in Gastroenterology in 2004.
• Understanding how genetic variants in disease susceptibility genes lead to altered biological function and disease pathogenesis. • Immunology of Crohn's disease (focus on NOD1, NOD2 and innate immunity).
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Genome Wide Association Study (GWAS) Professor David van Heel's group carried out the first ever coeliac disease genome wide association study, published in the journal Nature Genetics in June 2007. The primary study was performed on a British sample collection, with replication of the major finding in a Dutch and an Irish sample collection. 310,605 single nucleotide olymorphisms (SNPS) were tested for association using Illumina's chip technology in samples from 778 coeliac disease individuals and 1,422 population controls (British 1958 Birth Cohort). Genetic variants in the IL2 / IL21 gene region were identified as risk factors predisposing to coeliac disease. Genome Wide Association Study Follow Up The group followed up 1,020 top associated SNPS from the British GWAS in a further set of 1,643 coeliac and 3,406 population control samples from Britain, The Netherlands and Ireland. This study was published in Nature Genetics in March 2008.
Bone Marrow Failure Professor Inderjeet Dokal, with close colleague Dr Tom Vulliamy, has pursued a research interest in the biology of aplastic anaemia and bone marrow failure, a group of paediatric disorders characterised by the inability to make adequate numbers of red blood cells. The conditions may lead to early death from infection or bleeding if adequate treatment is not given. Scientifically, the studies on this rare disease have made a connection with
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They identified seven further gene regions predisposing to coeliac disease. There are now nine coeliac gene regions identified, including the 2007 IL2-IL21 finding and the long-recognised HLADQ association. Of the nine regions, eight contain likely candidate genes involved in immune system function. This agrees nicely with what is known about the immunology of coeliac disease. It is understood how genetic variation influences biological function for HLA-DQ, and possible mechanisms were reported for two of the new findings: SH2B3 and IL18RAP. Interestingly there seems to be substantial overlap of gene regions with other autoimmune diseases, particularly four of the nine coeliac regions also predispose to type 1 (early onset) diabetes. David’s group has been awarded a grant from the Juvenile Diabetes Research Foundation to study potential common mechanisms of these diseases.
aplastic anaemia and the key enzyme telomerase, which maintains the telomeric ends of all chromosomes. It has been discovered that several key components of the enzyme are also mutated in different genetic subtypes of anaemia. These findings have not only shown the importance of telomerase in humans but have also provided the platform for better diagnosis and future treatment strategies The immediate and future research aims are to establish the genetic
Current Research Finding more disease genes will require analysis of thousands more samples. David’s team have formed a large collaborative group to enable this, and in February 2008, were awarded a major collaborative grant by the Wellcome Trust charity. The group’s current collaborators are based in the UK, the Netherlands, Ireland, Finland (genome scan samples), Spain, US, Hungary, Italy, Sweden, Norway (replication samples). Current aims are to: • Localise precisely from each region the disease causing genetic change ('fine-mapping'). The current markers we have identified for each region are probably just tagging (i.e. correlated with) the true causal variant. • Discover more coeliac disease predisposing genetic variants • Understand how the coeliac disease genetic variants are influencing biological function
basis of many uncharacterised cases of aplastic anaemia, determine their functional significance in aplastic anaemia, and explore how these may be manipulated for future treatment strategies. This work is supported by a Wellcome Trust Programme Grant which has recently been renewed for another five years and many of the papers have been published in Nature Genetics.
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Professor of Haematology, Inderjeet Dokal
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Professor of Viral Pathology, Aine McKnight see profile p34
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Infection, Inflammation and Repair
These inter-related fields of research are particularly strong at Barts and The London with world-class researchers in all the major Institutes of the School. In the 2008 Research Assessment Exercise, the Institute of Cell and Molecular Science, returned in Hospital Subjects, was ranked joint 1st in the UK with Cambridge and Edinburgh in terms of 3* and 4* outputs and was joint 7th overall out of 28, ahead of Manchester, Newcastle and Southampton. The William Harvey Research Institute, returned in Preclinical and Human Biological Sciences, was ranked 3rd in terms of 3* and 4* outputs, and 4th overall out of 13, ahead of Kings College London, Bristol and Nottingham. The School plays an integral role in the UK’s fight against TB through the Health Protection Agency’s Micobacterial Reference Unit, led by Professor Francis Drobniewski. The Unit’s work involves collaborations with academic staff in the School’s Centres for Infectious Diseases and Primary Care, as well as community health staff throughout east London. Barts and The London School of Medicine and Dentistry, and the Trust are recognised as being at the forefront of research and clinical practice in TB. The MRU detects, identifies and isolates mycobacteria the organisms which cause TB - and advises on treatment. Its research interests include all aspects of TB and related diseases - particularly the interaction of TB and HIV (a growing health concern) - both in the UK and internationally. It is one of a global network of 23 such units run by the World Health Organisation (WHO). Focus is on disease diagnosis, the molecular epidemiology of TB and HIV, understanding drug resistance and disease tropisms, and broader translational research and public health problems posed by these diseases both in the UK and overseas. An international group of staff work on collaborative national and international clinical, laboratory and public health topics relating to TB and HIV in Russia and Ukraine and in partnership with institutions in Africa. HIV Research led by Professor Aine McKnight focuses mainly on the interface between HIV and the immune system with regard to humoral immunity and a novel innate immune mechanism (Lv-2) that inhibits HIV replication after cellular entry resulting in abortive infection. She has mapped the two viral genes involved in overcoming this antiviral effect and is currently mapping the host gene(s) involved. Other current research interests lie in HIV tropism and coreceptor use. HIV infects mainly T-cells and macrophages through the use of CD4 and co-receptors usually either CCR5 or CXCR4 chemokine receptors. Recently, we have
shown that viral envelopes amplifed directly from plasma almost always additionally use a related chemokine receptor CCR3 just as efficiently as CCR5. Professor Aine McKnight is also among a number of scientists taking part in a $25.3 million international research consortium searching for an HIV vaccine. The grant is one of the largest awards in a $287 million, five-year programme of 16 grants provided by the Bill and Melinda Gates Foundation to establish an international network of HIV vaccine discovery consortia, known as the Collaboration for AIDS Vaccine Discovery. There is also extremely strong translational HIV research funded by the MRC and led by Dr Claudia Estcourt Immunology and inflammation in the gastrointestinal tract is the subject of Professor Tom MacDonald's research group. His principal research effort is to try to understand the reasons why individuals develop Crohn’s disease, a serious inflammatory disease of the gut. Professor MacDonald identified the key role of the cytokine TNFα in Crohn’s disease, which has led to successful new therapies. Principally funded by the MRC, BBSRC and EU FP7 and with a very strong European collaboration, MacDonald has published extensively in top journals on the control of TGFβ signalling in the gut. Ongoing studies are aimed at trying to tolerise gut T cells in Crohn’s disease to reset the immunologic thermostat, which controls immunity in the gut of healthy people. Professor MacDonald works alongside other immunologists such as Dr Dan Pennington (funded by the Wellcome Trust) and Dr Andy Stagg, the world leader in the study of dendritic cells in the gut. Inflammation research investigates the basic mechanisms controlling various components in inflammation and the potential to modify these using, for example, gene-therapy, anti-inflammatory peptides, and agonists and antagonists that target novel inflammatory pathways. These highly integrated programmes of research use a range of techniques from molecular biology and genetic engineering of cells and molecules, to in vivo models of inflammation, where we have a great strength. A strategic investment of £1.45 million has been made to create a new Centre of Experimental Medicine and Rheumatology with a strong research programme in joint and tissue repair and stem cell therapy, headed by Professor Costantino Pitzalis. The strong translational element of this grouping funded by Wellcome, ARC and MRC is tightly linked into the Barts and The London NHS Trust clinical rheumatology service.
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(cont)
became Fellow of the British Pharmacological Society in 2005. Sussan has acted as a committee member on the British Heart Foundation Project Grant panel (20022006), was a co-founder and committee member of the London Vascular Biology Forum (2001-2008) and is currently the Treasurer of the UK Adhesion Society and Programme & Fellowship Committee member for the American Society of Investigative Pathology (ASIP). Sussan Nourshargh PhD FBPharmacolS Professor of Microvascular Pharmacology Centre for Microvascular Research Professor Sussan Nourshargh was appointed Professor of Microvascular Pharmacology at the William Harvey Research Institute in 2007 to establish and head a new Centre focussing on Microvascular Research. Professor Nourshargh heads an internationally respected research group investigating mechanisms of leukocyte trafficking and regularly contributes to key national and international conferences. She was awarded the Quintiles Prize for outstanding contribution to Immunopharmacology from the British Pharmacology Society in 2001 and
Sussan Nourshargh graduated in Pharmacology from University College London in 1982 and obtained her PhD in Pharmacology from King’s College London in 1986. As her PhD project addressed mechanisms of neutrophil activation in vitro, she extended her interests in this area to the in vivo inflammatory scenario through postdoctoral work at the MRC Clinical Research Centre based in Harrow and then at the National Heart & Lung Institute (NHLI) in London where she was appointed to Lecturer position in 1988. Her continued productive research in the field of leukocyte migration resulted in the award of a Wellcome Trust Career Fellowship (1990) followed by a Wellcome Trust University Award (1996) with the latter leading to a tenured academic position
within NHLI at Imperial College London in 2001. During these periods she rose through the academic ranks and became Professor of Immunopharmacology at Imperial College London in 2006, the same year as she was awarded a Wellcome Trust Programme Grant to extend her work into mechanisms of leukocyte transmigration in vivo. Current research interests The group’s research focuses on the mechanisms of leukocyte trafficking into sites of inflammation and the consequence of this response on regulating the phenotype of emigrated cells (Ley et al., Nature Reviews Immunology., 2007; Nourshargh & Marelli-Berg, Trends in Immunology., 2005). Their principal experimental approach is the use of advanced imaging techniques (eg intravital and confocal microscopy) for analysis of leukocyte/vessel wall interaction in vivo. The team’s work is supported by The Wellcome Trust, The British Heart Foundation and funds from the EU and has been published in high ranking journals such as Journal of Immunology, Blood, Journal of Experimental Medicine, Nature Reviews and Science.
Suzanna McDonald PhD student Centre for Infectious Diseases “The Barts and The London SMD campuses combine some of the oldest history in London at the Bart's site in West Smithfield, whilst here at the Institute of Cell and Molecular Science in Whitechapel we have one of the funkiest buildings in science! The open-plan structure of the building creates interactions with multiple departments. The facilities and equipment within the school as a whole are worldclass, such as the Genome Centre, and our extensive array of imaging equipment.”
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The Biochemical Pharmacology group under Professor Rod Flower FRS and Professor Mauro Perretti, investigates the mechanism of action of anti-inflammatory drugs including Cox inhibitors (Nature Reviews Drug Discovery 2004) and especially the glucocorticoid steroids (PNAS 2002; Journal of Immunology 2003; Blood 2005). Much of the research investigates the pharmacology and the biology of Annexin A1, a protein that is induced by glucocorticoids and has profound immunomodulating properties. Funded by the Wellcome Trust (programme and projects; >£1.6 million) and the British Heart Foundation (£225,000 project), this line of research spans all aspects of Annexin A1 biology ranging from cell biology through to its role in human disease (Nature Medicine 2002; The FASEB Journal 2006, 2008; Blood 2006, 2007 and 2008; JBC 2007; Nature Reviews Immunology in press). Other major research areas evolve around galectins (fellowships of the Arthritis Research Campaign [ARC] UK; £600,000) and melanocortin peptides (£230,000, arc UK). Industrial funding derives from Unigene Corp (NJ; $1.2 million, with licencing of 2 patents), Action Pharma (£250,000 melanocortin research) and UCB (£180,000), with other drug discovery work funded by Heptagon Fund. A recent recruit is Professor Sussan Nourshargh who leads the Centre for Microvascular Research, funded by a programme grant from the Wellcome Trust and the British Heart Foundation. Professor Nourshargh’s work on imaging of inflammatory cells leaving tissues is world-leading and her discovery of endothelial junction proteins being expressed in the brain (published in Science) has opened up exciting new avenues of investigation. The Bone and Joint Unit is a leading centre for inflammation research, which, under Professor Yuti Chernajovsky, works on the development of gene transfer strategies for the treatment of rheumatoid arthritis and other autoimmune diseases via cellular engineering, molecular design and genetic engineering. The group has extensive funding from the ARC and MRC. One recent development has been the design of latent cytokines by recombinant DNA technology. The designed fusion protein between the latency associated peptide (LAP) of TGFβ and a cytokine with therapeutic potential are linked via a metalloproteinase (MMP) cleavage site which renders the cytokine inactive until it reaches a site of inflammation. The LAP provides a shell that inhibits the interaction of the cytokine with its receptors increasing its half life and ensures delivery to sites of disease.
(cont)
Some leading Barts and The London Researchers on Infection, Inflammation and Repair Professor Amrita Ahluwalia's work focuses on mechanisms of vascular homeostasis in inflammation and particularly the role of the endothelium. Recent research areas include studies investigating the role of endothelium-derived hyperpolarising factor (EDHF) in cardiovascular protection and the influence of sex on its activity, investigating the role of C-type natriuretic peptide as an EDHF, dissection of the mechanisms involved in vascular inducible nitric oxide synthase expression in sepsis, Investigation of the role of TRPV1 in vascular reactivity and mechanisms involved in nitrate and nitrite-induced bioactivity. Professor Ahluwalia’s work on the ability of beetroot juice to lower blood pressure attracted international attention. Dr Francesco Dell'Accio's research focus is cartilage biology and the biological repair/regeneration of adult articular cartilage. The findings that progenitor cells persist within adult synovial joints and in adult articular cartilage (Dell'Accio et al. Experimental Cell Research. 2003) and that the injured adult human articular cartilage deploys an early signalling response including modulation of the WNT and BMP signalling pathways (Dell'Accio et al. Arthritis Research and Therapy 2006) suggests that repair mechanisms persist in the adult joints. His current research is therefore focussed on the unravelling of the molecular signalling triggered by injury to the articular cartilage and playing a role in the repair mechanisms. Professor Bart Vanhaesebroeck is a world expert on the biology of PI3Kinases. The main interests of his group include signal transduction in cell migration, proliferation, survival, intracellular vesicular transport, in the context of cancer, inflammation and immunology, angiogenesis, metabolism and stem cell biology. Collaborative efforts with industry are under way in the preclinical development of isoform-selective small molecule inhibitors for PI3K to translate this preclinical work to early phase clinical trials. Dr Toby Lawrence trained with Michael Karin in San Diego, where he used molecular genetics to study the role of cell signalling pathways in the regulation of inflammation and immunity. These studies focussed on the role of IkappaB kinase (IKK) in the biology of inflammation, using tissue specific gene targeting to establish the specific role of IKK in the inflammatory response. The major research focus of the group is to understand the fundamental mechanisms by which inflammation promotes cancer, with particular reference to the role of stromal and inflammatory cells in carcinogenesis.
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Wellcome Trust, Arthritis Research Campaign, Nuffield Foundation, European Union (FP6) as well as other smaller medical charities. His clinical interests are mainly in immune/inflammatory rheumatic diseases including rheumatoid and psoriatic arthritis. His major research interests focus in the field of adhesion biology and in the pathogenetic mechanisms of damage and repair of joint tissues. Costantino Pitzalis, MD PhD FRCP Professor of Experimental Rheumatology Centre for Experimental Medicine and Rheumatology Professor Costantino Pitzalis was recruited to the William Harvey Research Institute at Barts and The London School of Medicine and Dentistry in 2007 to direct the Centre for Experimental Medicine and Rheumatology. Following early clinical training in Italy he came to England in 1985 as a Research Fellow to the Department of Rheumatology at Guy’s Hospital. Here he carried out full time laboratory research for 4 years that lead to a PhD at the University of London. He then went back to full time clinical training in General Medicine in the UK, gaining the MRCP in 1992. He returned to the Department of Rheumatology at Guy’s in 1993 as the Arthritis Research Campaign Lecturer/Senior Registrar. In 1996, he was awarded a Senior Lectureship/Career Development Award from the Wellcome Trust and in 2000 was appointed to the Chair of Experimental Rheumatology at King’s College London School of Medicine. Professor Pitzalis has published over 100 full papers, a large number in journals with an impact factor of 5 or above. He has been awarded over £4.5 million in peer reviewed grants in the last three years including funding from the MRC,
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Current research interests Professor Pitzalis’ principal interests revolve around the role of adhesion phenomena in the pathogenesis of immune mediated inflammation and how these processes can be modulated therapeutically both by conventional drugs e.g. glucocorticoids and new biologic agents. In addition, he has developed a novel platform technology: “the human/SCID mouse transplantation model” that has been successfully used for dissecting molecular mechanisms of inflammation and for targeting human synovial microvascular endothelium by in vivo phage display selection. More recently, with the recruitment of Dr Francesco Dell’Accio, the Centre has extended its interests in the field of cartilage biology with particular reference to the mechanisms of tissue damage and repair. Main research areas can be summarised as follows: • Tissue specific homing in the pathogenesis of chronic inflammation • Chemokines in cell migration and neo-lymphoneogenesis • Identification of novel of tissue specific targets using phage display technology to target human tissues transplanted onto SCID mice. • Functional studies of targeting cellular and molecular pathways of inflammation in the human/SCID mouse transplantation model.
• Regulation of inflammation by glucocorticosteroids and new biologic agents • Mechanisms of joint tissue damage and repair. The Medical Research Council invested £681,000 in developing a Pathobiology of Early Arthritis Cohort (PEAC). The goal of PEAC is to create a unique resource with high-density data including genomic and transcriptomic analysis coupled with detailed imaging and clinical phenotyping to enable scientists to examine the cellular and molecular mechanisms determining diverse disease severity and response to treatment in rheumatoid arthritis (RA). RA is one of the most important chronic inflammatory disorders in the UK. It affects approximately 1 per cent of adults, causes considerable morbidity, reduces quality of life and increases mortality and results in large medical costs (over £1.2 billion/year). This cohort will be of major interest to academia, industry and government bodies as it will represent an ideal platform for innovative clinical trials that will incorporate imaging and biological parameters to determine early efficacy on structural damage progression with significant clinical, research and healtheconomic benefits. Professor Pitzalis will lead a Consortium of 5 Centres of excellence including the MRC Centre for Immune Regulation in Birmingham (Prof C Buckley); the Centre for Rheumatic Diseases in Glasgow (Prof IB McInnes); the Kennedy Institute for Rheumatology Imperial College - London (Prof PC Taylor) and the Academic Department of Rheumatology – King’s College London (Dr E Choy) to develop PEAC.
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(cont)
In 2000, she won a fellowship (RCDF) from The Wellcome Trust to develop an independent research group to focus on non-coreceptor determinants of HIV replication in cells at The Wohl Virion Centre, University College London. She is currently a Medical Research Council (MRC) Senior Non-clinical Fellow (awarded in 2005).
Aine McKnight MiBiol MSc PhD Professor of Viral Pathology Throughout her academic career, Professor McKnight has been interested in HIV/AIDS. In 1987, she joined the team of Robin Weiss at the Institute of Cancer Research, London, to study the role of neutralising antibodies to HIV-1 and HIV-2 in pathogenesis. She was awarded an MSc in Immunology in 1990 by King's College, London, and a PhD by University of London (supervised by Paul Clapham) in 1996.
The interests of Professor McKnight’s group focus mainly on the interface between HIV and the immune system with regard to humoral immunity and a novel innate immune mechanism (Lv-2) that inhibits HIV replication after cellular entry resulting in abortive infection. The group mapped two viral genes involved in overcoming this antiviral effect and is currently mapping the host gene(s) involved. With regard to humoral immunity to HIV-1 infection the group mainly focuses on the role of neutralising antibodies in controlling HIV-1 and 2
replication. They have shown that activation of the classical complement pathway by serum antibodies can be implicated in the control of primary HIV1 viremia. More recently they have shown that in acute infection, viruses develop with envelopes that are highly sensitive to serum antibody mediated neutralisation but eventually these viruses are replaced in the blood by ones that escape serum neutralising antibodies. The group also has strong interests in HIV tropism and co-receptor use. HIV infects mainly T-cells and macrophages through the use of CD4 and coreceptors usually either CCR5 or CXCR4 chemokine receptors. Recently they have shown that viral envelopes amplifed directly from the plasma almost always additionally use a related chemokine receptor CCR3 just as efficiently as CCR5.
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Basic and Translational Neuroscience
Neuroscience research activity at Barts and The London lies predominantly within the Institute of Cell and Molecular Science but is an important strength across the School. Research in neuroscience is focused on translational work in the fields of traumatic injury, degenerative disorders and neuro-oncology, building on both internal investment and external funding.
Traumatic and degenerative central nervous system injury. The Centre has an established reputation for work on degenerative disorders including motoneurone disease and traumatic injury to the spinal cord. This has recently been further strengthened with the establishment of a neuroimmunology group with a focus on multiple sclerosis (MS) and basal ganglia autoimmune diseases.
The Institute of Cell and Molecular Science, returned in Hospital Subjects, was ranked in the 2008 Research Assessment Exercise joint 1st with Cambridge and Edinburgh in terms of 3* and 4* outputs and was joint 7th overall out of 28, ahead of Manchester, Newcastle and Southampton.
Research ranges from cell and molecular studies in vitro, through in vivo rodent models, to clinical trials. This translational focus is facilitated by the presence of a full-time trials coordinator. Ongoing studies include root avulsion injury, molecular strategies to promote regeneration and hence link closely with the peripheral nerve work reviewed above. Studies on spinal cord injury include the use of fibronectin implants to fill cystic cavities and support axonal regeneration, strategies to promote regeneration after ventral root avulsion injury, and use of omega-3 polyunsaturated fatty acids (PUFAs) as neuroprotective agents. A phase 1 safety study of PUFA treatment in spinal cord injury is underway , as is a pilot clinical study in Alzheimer’s disease.
A major objective is to strengthen the links between academic and clinical activity in Neuroscience and, to this end, the establishment of a Neurology Clinical Outcomes Unit is planned, along with the formation of an acute spinal injury unit with close links to the Helicopter Emergency Medical Service and trauma work within Barts and The London NHS Trust. To deliver this agenda, the group has appointed a new head, Professor Gavin Giovannoni, a world-leader in neuroimmunology. Neuroscience research focuses on three interrelated topics: • The role of primary sensory neurons and effects of peripheral nerve injury • Traumatic and degenerative disorders of the central nervous system • Molecular mechanisms of development and central nervous system tumorigenesis - a new theme and one which reflects the importance of cancer both for the School and for Barts and The London NHS Trust Primary sensory neurons. Work here focuses on the fundamental role played by neurotrophic factors and cytokines in regulating adult dorsal root ganglion (DRG) cells, the importance of such factors in pain states, and strategies to promote peripheral nerve regeneration. Professor John Priestley’s group was the first to establish that nociceptive DRG neurons comprise two main subpopulations which differ in their growth factor dependence and expression of neuropeptides. This work is continuing, with further study of the properties of nociceptive DRG neurons, their expression of key transduction molecules and ion channels, and their response to injury. Professor Priestley’s group has shown that novel silks developed by Oxford Biomaterials can support neural regeneration. This work is now funded by a £250,000 grant from Kinetique, awarded to establish a start-up company (Neurotex) and develop silk-based conduits for peripheral nerve repair. The Centre’s pre-clinical studies are complemented by clinical studies on orofacial neuropathic pain, on perioperative pain relief and on arthritis.
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Key recent achievements related to motor neuron disease include the linkage of axonal transport defects to motor neuron loss in dynein mutations and gene array analysis of common mechanisms underlying motor neuron disease and cell death following spinal cord injury. The neuroimmunology group leads the field in studies of endocannabinoids in MS and the possible therapeutic use of cannabinoids in MS. They have also highlighted the role of anti basal ganglia autoantibodies in movement disorders, and are developing novel treatments for MS based on induction of immune tolerance.
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Professor of Neuroimmunology, David Baker
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Professor of Neurology, Gavin Giovannoni
Daniel Chew PhD student Neuroscience Centre “Like everyone who visits here, I was thoroughly impressed with the labs in the Blizard Building at Whitechapel, and this was my main reason for choosing to study a PhD at Barts and The London School of Medicine and Dentistry. With state-ofthe-art equipment, and open, integrated lab space, it provides an excellent place to undertake research.'
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Basic and Translational Neuroscience
Development and neuro-oncology: The molecular events that determine gene transcription and cellular differentiation are being studied, both in normal development and in tumour formation. Major themes currently under investigation include: the role of chromatin and nuclear architecture in transcription (Sheer); genetic defects associated with glioblastoma multiforme (Sheer); the molecular events that control cerebellar granule cell development and their contribution to the pathogenesis of medulloblastoma (Marino); and the role of neural stem cells and self renewal mechanisms in the ontogenesis of brain tumours (Marino). The latter studies provide a strong link with stem cell work in other research centres at Barts and The London.
(cont)
Some leading Barts and The London Neuroscience Researchers Professor Gavin Giovannoni’s research interests include: multiple sclerosis; immune-mediated movement disorders, and immune tolerance strategies. He is setting up a clinical outcomes unit which will build important bridges between neurology, neurosurgery and neurohabilitation. Professor Silvia Marino’s main research interest lies in progenitor cells and tumourigenesis, its role in brain development and how that gives rise to brain tumours. She works with mouse models using a translational approach to assess relevance in humans. Professor David Baker leads the field in the study of how cannabinoids effect symptom control in MS. The body produces its own cannabis-like molecules to control how nerves work. Professor Baker’s work involves manipulating the natural immune system so it can bind to the natural docking molecules and relax the nerves.
Professor Denise Sheer
Professor Denise Sheer’s research aims to understand the biology of the human genome and the contribution of genetic changes to cancer. A major focus of her work is on brain tumours, primarily in children, where she aims to understand the pathways that give rise to cancer, derive a molecular classification, predict responses to treatment and to identify targets for new forms of therapy.
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Barts and The London School of Medicine and Dentistry
Dentistry
Barts and The London is an international leader in oral and dental sciences and, in the 2008 Research Assessment Exercise, was ranked 1st in the UK for 4* and 3* outputs and 2nd in the UK overall, according to the Times Higher Education. Combining a strong tradition of clinical, epidemiological and public health research and a solid research base, Barts and The London is at the forefront of the advancement of dental care. Cutting-edge laboratories and first class facilities enable the work of these research teams and clinical trials to be carried out to the highest ethical and governance standards. Significant local research in dentistry includes internationally renowned work on the molecular biology of the periodontal pathogen, Porphyromonas gingivalis. This has attracted significant funding and current investigations include the development of novel antimicrobial achievements based on the understanding of microbial virulence factors in bacteria. Work on the aetiology and treatment of periodontal disease includes longstanding studies on the biology and application of growth factors of periodontal regeneration and wound-healing. In addition, work continues to understand host-bacterial interactions and the regulation of mechanisms of tissue damage, including bone resorption, during periodontitis. Large multi-disciplinary studies are taking place to identify and investigate the role of a range of risk and prognostic factors in aggressive periodontitis. A large tissue bank and database allows a complex modelling of the relative role of different risk and aetiological factors, including psychosocial and behavioural factors, clinical factors, microbiological and genetic factors and a range of proteomic markers. Clinical and non-clinical academics with expertise in conservative and paediatric dentistry, anatomy, biophysics, chemistry, crystallography, electronic engineering, epidemiology and materials science all work together to develop x-ray microtomography and other x-ray microscopes for new ways to look at the biology of teeth and bones in the mouth. Barts and The London is also at the forefront of research in oral cancers. Head and neck carcinoma, the sixth most common cancer worldwide, is a significant public health issue in the local population of east London. Public health and clinical research programmes are utilised to advance understanding in this area, and there is a particularly strong link in oral cancer with women at the East London Mosque. Longstanding research and implementation programs in tobacco cessation, including those addressed specifically at the unique public health issues in the local area, are a key part of the research agenda. The research provides a demonstrable practical impact on health service delivery whilst addressing the most important area of risk factor management in both primary care and specialist dental practice.
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Professor of Medicine in Relation to Oral Health, Farida Fortune
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Dentistry
(cont)
Some leading Barts and The London Dental Researchers Mike Curtis is Professor of Microbiology and Director of the Institute of Cell and Molecular Science at Barts and the London. He is an international expert in oral microbiology in particular the microbial pathogenesis of periodontal disease. His research, funded principally by the MRC and the NIH, has made fundamental advances in our understanding of the virulence mechanisms of periodontal bacteria. He was awarded the International Association for Dental Research Distinguished Scientist Award in 2005, was made an Honorary Fellow by the Faculty of Dental Surgery of the Royal College of Surgeons in 2008, and is currently the President of the British Society for Dental Research. Ken Parkinson is Professor of Head and Neck Cancer. His research, funded through the European Union and BBSRC, is focussed on the mechanisms of oral keratinocyte immortalisation and the influence of telomere dysfunction in oral cancer. His work has lead to the hypothesis that oral squamous cell carcinomas may progress by two distinct routes only one of which leads to cellular immortalisation. Professor Parkinson won the Golden Award at the European Head and Neck Cancer meeting in 2003. Farida Fortune is Professor of Medicine in Relation to Oral Health and Director of the Institute of Dentistry. In addition to an active role in oral cancer research she focuses on the aetiopathogenesis of Behcet’s disease, oral Crohn’s disease and oral-submucous fibrosis and related systemic diseases of immune dysfunction in the mouth. She has established one of the largest patient bases of these conditions which has facilitated the analysis of the immunogenetics of these multisystem diseases to identify the role of genetic polymorphisms in their aetiology and immunopathogenesis. Gareth Thomas is Professor of Oral Pathology. His research focuses on the regulation of cancer cell invasion by invasionpromoting proteins expressed by malignant cells and the mechanisms through which the tumour stroma influences
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invasion. In collaboration with colleagues in the CRUK funded Tumour Biology Group at the Institute of Cancer, he has identified the integrin αvβ6 as a target for tumour imaging and therapy and demonstrated a novel link between this ligand and cyclo-oxygenease enzymes: αvβ6 dependent invasion can be suppressed by inhibition of COX-2. In 2004 he was awarded a five year Clinician Scientist Fellowship from the Health Foundation to develop novel tumour therapies based on αvβ6 expression in head and neck cancer. Francis Hughes is Professor of Periodontology. His research interests include the role and mechanisms of risk factors in periodontal disease; the biology of osteoblast function and periodontal ligament cell lineage; the biology and clinical application of methods of bone and periodontal regeneration. His work on risk factors includes clinical studies of risk and prognosis and the mechanisms of the interaction of bacterial factors with host responses including cytokine production and bone resorption. These studies are facilitated by the assembly of a large well characterised cohort of subjects with aggressive periodontal disease established through MRC funding. He is currently President of the Pan European Federation of International Association for Dental Research. Dr Virginia Kingsmill, Clinical Senior Lecturer, was awarded a Department of Health Clinician Scientist Fellowship award to compare the structure, mineralisation and remodelling of the mandible with that of other bones with the long term aim of understanding the processes and mechanisms of alveolar bone remodelling indentate and edentulous jaws and the response to systemic regulatory factors. Dr Muy-Teck Teh is a Lecturer in head and neck cancer. His research interests are focused on finding new biomarker genes for predicting early oral cancer formation. Currently studies are based around a known cancer gene called FOXM1B using human oral keratinocytes cells as the research model. Early results have showed that FOXM1B may be an early cancer marker which is expressed at higher level in pre-cancer and cancer cells compared to normal cells. The future aim is to develop a diagnostic test using the Gene Chip technology that can guide treatment strategy.
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Lecturer in Head and Neck Cancer, Dr Muy-Teck Teh
Oluyori Adegun PhD student Centre for Clinical and Diagnostic Oral sciences “Prior to my PhD I undertook an MSc in Experimental Oral Pathology at Bart’s and The London School of Medicine and Dentistry. The driving force behind this choice was the School’s world renowned reputation for excellence in both teaching and research, particularly in the field of Dentistry. My experience was a very positive one; the teaching sessions were enlightening and the laboratory sessions in the new, state-of-the-art Blizard building were stimulating and inspiring. These experiences fuelled my interest and sparked my desire to continue in this field. Hence, it was a natural decision to continue at Barts and The London. “Bart’s and The London offers a fantastic opportunity to work in a multidisciplinary team, enabling development of a vast array of key proficiencies such as clinical, leadership, teaching, research and analytical skills, increasingly required in modern day Medicine and Dentistry. It also provides the opportunity to learn cutting edge/revolutionary techniques and the chance to work and collaborate with distinguished professionals, experts in their respective specialties.”
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Senior Lecturer in Preventative Cardiovascular Medicine and Consultant Cardiologist, Dr David Wald see profile p46
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Preventive Medicine and Public Health
Barts and The London is a world-leader in discovering and understanding the causes of disease so that these can be prevented. The key element is the study of whole populations to determine the incidence of disease in different groups: in men, in women, in younger people compared with older people, in people in different countries, occupations, or genetic background. All of this provides clues to the causation of disease: for example, the relatively recent discovery that the common neural tube birth defect, spina bifida, is caused by a vitamin deficiency that is present in many populations, including those in economically developed countries. Preventive medicine and public health are located in two Institutes within the School: the Wolfson Institute of Preventive Medicine; and the Centre for Health Sciences in the Institute of Health Sciences Education. The Wolfson Institute of Preventive Medicine, returned in the 2008 Research Assessment Exercise in Epidemiology and Public Health, was 2nd out of 21 in terms of 3* and 4* outputs, and 3rd overall, ahead of Oxford, University College London and Bristol. In Health Services Research, Barts and The London was ranked 4th overall out of 28, ahead of Oxford, University College London and Kings College London. The Wolfson Institute of Preventive Medicine With an international reputation, the Wolfson Institute is a leading world centre for research and teaching in epidemiology, preventive medicine, and public health. The main areas of research are cardiovascular disease prevention, cancer prevention, cancer screening, antenatal screening and perinatal epidemiology, smoking cessation, mental health and medical statistics. The Wolfson Institute is distinctive in that it captures scientific opportunities that arise from laboratory-based epidemiological and screening research into common diseases such as cardiovascular disease, cancer and congenital malformations through integrating epidemiology and statistics with pathology and clinical medicine. Much of the research is funded by medical charities including Cancer Research UK, Wellcome Trust, and the BUPA Foundation. The Institute comprises three centres: • Centre for Environmental and Preventative Medicine headed by Professor Sir Nicholas Wald • Cancer Research UK (CRUK) Epidemiology, Mathematics, and Statistics (EMS) Unit, headed by Professor Jack Cuzick • Centre for Psychiatry, headed by Professor Stephen Stansfeld Professor Peter Hajek heads the Academic Psychology section, part of the Centre for Environmental and Preventative Medicine which is based at Whitechapel and includes the Tobacco Dependence Research Unit. There is an active group of statisticians and a statistical advisory service headed by Professor Joan Morris. Over 150 staff work in the Institute, which houses state-of-the-art laboratories and screening suites. There is a focus on academic discipline, the translation of research into public health strategies and their practical implementation - all dedicated to the reduction of disease and disability. Research is conducted using a number of methods, such as large scale randomised prevention trials, screening research projects and epidemiological studies into the causation of disease. Teaching and research go hand in hand; there are study days and lectures in areas such as Down’s syndrome, Medical Psychology and postgraduate courses in Transcultural Mental Healthcare. Many discoveries and applications from the Wolfson Institute have been adopted by health agencies worldwide with staff playing a key role in translating research findings into practice.
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Preventive Medicine and Public Health
Examples of recent ground-breaking research include the development of Polypill, the drug treatment preventing myocardial infarction and stroke, for people aged 55 and over and to be taken as a single daily pill. Ranked as one of the top medical stories of 2003, this pill may reduce the incidence of heart disease and stroke by over 80 per cent. Barts and The London is also at the forefront of antenatal screening research. This has resulted in two major studies, the SURUSS study and the FASTER study, the largest worldwide project on the subject of antenatal screening, published in 2006. This study yielded results on the screening performance of different combinations of first and second trimester markers in antenatal screening for Down’s syndrome. It showed that the Integrated Test (combining first and second trimester screening), developed by the centre previously, has by far the best screening performance, detecting 85 per cent of affected pregnancies with a false positive rate of only one per cent. The National Down Syndrome Cytogenetic Register, maintained by the centre, is also a valuable resource, providing information on numbers of prenatal diagnoses and live births and the exact nature of the association between Down’s syndrome risk and maternal age.
(cont)
Some leading Barts and The London Preventive Medicine and Public Health researchers: Professor Sir Nicholas Wald FRS, Director, Wolfson Institute of Preventive Medicine, pioneered the field of antenatal screening for congenital malformation and made discoveries that form the basis of screening for neural tube defects and Down’s syndrome in early pregnancy. Recent research activities include screening and treatment for Heliocobacter pylori infection and subsequent stomach cancer, and screening and treatment of hypothyroidism in pregnancy. He is the innovator of the ‘Polypill’, a radical approach to the prevention of cardiovascular disease, for which trials are being developed.
Prominent in the work of cancer research have been trials of tamoxifen and more recently the aromatase inhibitor anastrozole, in the treatment of women with established breast cancer and as a primary prevention of breast cancer. A significant reduction in the incidence of breast cancer was discovered with tamoxifen, while the ongoing international trial is expected to show an even greater preventive effect from anastrozole in postmenopausal women at increased risk (see Cancer p14). Centre for Health Sciences The Centre for Health Sciences led by Professor Chris Griffiths is making remarkable strides in implementing a translational research strategy. Work to date has centred on the role of vitamin D in health and illness. Staff have established the Translational Research Unit for the MRC Asthma UK Centre in Allergic Mechanisms of Asthma (www.asthma-allergy.ac.uk.) Other collaborations include the Wellcome Centre for Clinical Tropical Medicine (http://www1.ic.ac.uk/medicine/about/institutes/tropical/), and with the University of California, Riverside (http://www.biochemistry.ucr.edu/faculty/norman.html). With a grant from the Newham Development Agency, Professor Griffiths established a randomised trial and cross sectional analysis examining the hypothesis that vitamin D favourably modified the immune response against tuberculosis. This work was the first randomised assessment of the therapeutic capacity of vitamin D, despite its use prior to the introduction of antibiotics. It also led to a series of important publications supporting the hypothesis, elaborating the mechanisms of action, and for the first time highlighting the role of neutrophils in the anti-mycobacterial immune response. [Martineau AR, American Journal of Respiratory and Critical Care Medicine 2007], [Martineau AR, Journal of Clinical Investigation 2007], [Martineau AR, Journal of Immunology 2007], [Martineau AR, The Journal of Steroid Biochemistry and Molecular Biology 2007]
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Professor Sir Nicholas Wald, FRS
Dr Anne Szarewski, Wolfson Institute of Preventive Medicine, leads research to study different markers for cervical screening, and also two HPV vaccine trials. Her team has developed two preventative vaccines that have shown great promise in clinical trials: one containing HPV types 16 and 18; the other containing types 6 and 11 in addition to 16 and 18.
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Preventive Medicine and Public Health
Dr David Wald MA MBBS MRCP MD Senior Lecturer and Consultant Cardiologist Dr David Wald is an Interventional Cardiologist with an interest in the prevention of cardiovascular disease. His clinical-academic aims are to bridge the interventional and preventive approaches to cardiovascular disease which are often viewed as distinct. He is co-ordinating a proposed randomised trial to assess the value of coronary angioplasty in preventing future coronary heart disease events among patients receiving angioplasty to treat an acute myocardial infarction.
Professor Jack Cuzick, PhD Wolfson Institute of Preventive Medicine
(cont)
Dr Wald conducted a randomised trial which showed the minimum fully effective dose of folic acid for serum homocysteine reduction, for which he was awarded the BMA Brackenbury Research Prize. He has been adviser to the Food safety Authority of Ireland in helping them reach a decision on dietary fortication with folic acid. Together with Professors Malcolm Law and Joan Morris of the Wolfson Institute of Preventive Medicine at Barts and The London School of Medicine and Dentistry he quantified the relationships between homocysteine, coronary heart disease, stroke and thromboembolic disease using meta-analyses of observational and genetic epidemiological studies. This was important because it specified the expected effect of folic acid intake on cardiovascular disease prevention which, in turn, showed how even the largest randomised trials of folic acid supplementation were underpowered to show the expected effect.
Together with the Director of the Wolfson Institute, Professor Sir Nicholas Wald, and Jonathan Bestwick also at the Wolfson, David showed that screening for familial hypercholesterolaemia, by serum cholesterol measurement, is effective if done in early childhood after the first year of life. The finding underpins a novel “child-parent� population screening strategy that screens children and their parents within the same programme. He is assessing imaging techniques like carotid ultrasound and CT scanning in screening for coronary heart disease to determine their value in medical practice.
Professor Cuzick has pioneered the field of chemoprevention of breast cancer. The IBIS I and IBIS II trials have been investigating first tamoxifen and then anastrozole for prophylactic treatment of breast cancer. He has more recently lead the introduction of aromatase inhibitors, both for the treatment of breast cancer where they represent a major advantage over tamoxifen, and as a better agent for chemoprevention. Professor Peter Sasieni, an acknowledged expert in survival analysis, has extended his work in steering the cervical screening
programme in the UK to playing a leading role in clinical trials of HPV testing both in the UK and Peru. He is the Director of the Clinical Trials Prevention Unit, recently established as the only unit specialising in cancer screening prevention.
David Wald coordinates the Polypill Prevention Programme, a novel service that adopts the Polypill approach in coronary heart disease and stroke prevention. With Professor Nicholas Wald and Professor Malcolm Law he collaborates in the development and proposed trials of the Polypill itself.
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