Blood has long played a pivotal role in both biological science and clinical medicine. Blood and the tissues in which it is formed represent the largest single organ system in the human body. Studies of the haematopoietic system continue to provide many of the key paradigms underlying stem cell biology, cancer and thrombosis. Moreover haematology touches every aspect of patient care from routine blood counts and blood transfusion to the highly specialised management of patients with leukaemia or haemophilia.
The largest concentration of haematological research in Cambridge is based on the Cambridge Biomedical Campus and includes 4 main themes: haematopoiesis, haematological malignancies, structural medicine/thrombosis and transfusion medicine. Research groups are based in the Cambridge Institute of Medical Research, the MRC Laboratory of Molecular Biology, the NHSBT building and in University Department of Pathology space in Addenbrooke’s Hospital. Major recent initiatives include establishing a £5.3M European Bloodomics Programme and a $6M Centre Grant from the US Leukemia and Lymphoma Society, the only such Centre in Europe.
Haematopoiesis. Haematopoiesis is the best studied adult stem cell system and an exemplar for other stem cell systems. A major focus is characterisation of the transcriptional networks that control the normal function and development of haematopoietic stem cells. A GMP facility has been established to support clinical stem cell transplantation. Haematopoietic stem cells are also targets for genetic lesions which perturb their normal behaviour and give rise to haematological malignancies. Indeed studies of leukaemia first gave rise to the concept that many forms of cancer contain their own malignant stem cells.
Haematological malignancies. Haematological malignancies are as prevalent as breast cancer and represent a major healthcare challenge. Their accessibility means that they include the best understood human malignancies and provide paradigms for less tractable tumours. Multiple groups are studying the molecular and cellular basis for a range of different haematological malignancies. These studies are employing a range of approaches including genomics, transgenics, transcriptional regulation and signalling, and are supported by a haematological malignancy sample bank in Addenbrooke’s. In addition a wide range of early phase and phase 3 clinical studies are ongoing.
Structural medicine and thrombosis. Structural biology gives an unparalleled insight into the molecular details of biological mechanisms, an insight that has the potential to lead to rationally-designed therapies in multiple areas of medicine. Both arterial and venous thrombosis represent major health challenges in the developed world. Cambridge groups are focusing on a combination of structural approaches, protein biochemistry and clinical epidemiology.
Transfusion medicine. Transfusion medicine is embedded in the NHS Blood and Transplant Centre. The major themes are megakaryopoiesis, platelet biology, transfusion-transmitted viruses and rapid diagnostics for resource-limited settings. In addition a joint National Blood Service/MRC Clinical Studies Unit has been established to undertake clinical trials in transfusion medicine.
Research activities are closely integrated with haematology in Addenbrooke’s with the head of the University department acting as chair of the Addenbrooke’s senior staff group. This provides a particularly strong base for translational research which is further enhanced by the fact that Cambridge is the sole tertiary referral centre for haematological disorders in the Eastern Region, and thus serves a population of approximately four million. As well as providing diagnostic and clinical services for the Cambridge area, haematology within Addenbrooke’s includes a regional Haemato-oncology Diagnostic Service, a regional Stem Cell Transplant Unit and a regional Haemophilia Unit.
Haematological research in Cambridge is multidisciplinary and extends well beyond the Clinical School and Addenbrooke’s. Collaborations have been established with scientists in the Gurdon Institute, the Wellcome Trust Stem Cell Centre and the Babraham Institute. Interactions are developing with the Departments of Physics and Engineering as well as with pharma and biotech companies. Particularly close links have been established with the Sanger Institute where several of the faculty are haematologists (honorary members of this department) and several groups are applying genome-scale approaches to the pathogenesis of haematological malignancies.
Research into organ transplantation in Cambridge covers the entire scientific spectrum from basic molecular and cellular studies through to large-scale clinical trials and related health service research. It is closely aligned to the internationally renowned multi-organ transplant centres based at Cambridge University NHS Foundation Trust and at Papworth NHS Foundation Trust. Together these two centres provide the most comprehensive clinical transplant programmes in the UK, offering kidney, liver, pancreas, small bowel, multi-visceral, heart and lung transplantation. Research strategy is aimed at addressing the two major clinical problems in transplantation, namely the severe shortage of available organs for transplantation and chronic graft rejection along with the side effects of non-specific immunosuppression. The principal goals are to maximise patient access to transplantation and to improve patient outcome by reducing post-transplant morbidity and graft loss.
The role of MHC gene products on transplant outcome
Research aimed at understanding the role of Major Histocompatibility Complex (MHC) gene products and Leukocyte Receptor Complex (LRC) genes on transplant outcome is being undertaken by groups in the University Departments of Surgery and Pathology, in close collaboration with the Department of Histocompatibility and Immunogenetics at Addenbrooke’s Hospital. The emphasis is on understanding how polymorphisms in MHC and LRC gene products influence the allograft rejection response with a view to improving organ allocation and/or refining immunosuppressive strategies. Stem cell and regenerative medicine has the potential to revolutionise clinical practise, but as with conventional tissue transplantation there are major immunological barriers to be overcome, and collaborative research between the Regenerative Medicine Group in the Ann McLaren Laboratory and the Department of Surgery aims to define the immunogenicity of various types of stem cells and find novel ways for overcoming the immune barrier to transplantation.
Mechanisms of allograft rejection and transplant tolerance
Multidisciplinary research groups, based principally in the University Departments of Surgery and Medicine, are undertaking studies using in vivo experimental models of organ transplantation to address key questions about graft rejection mechanisms and induction of transplant tolerance. A major focus of these studies is on the emerging role of B cells in the graft rejection response. The long-term goal is to develop clinically applicable strategies for induction of transplant tolerance, thereby avoiding the need for the long-term use of non-specific immunosuppressive drugs that are associated with an increased risk of infection and malignancy.
Evaluation of novel targets for therapeutic intervention
Chronic allograft vasculopathy is the major cause of transplant failure but is poorly understood and not prevented by available immunosuppressive therapy. Research groups in the Department of Medicine and Surgery are, as part of a collaborative research programme in cardiovascular biology between the University of Cambridge and Yale University, performing translational research in transplantation and vascular injury. The focus in this collaboration is on the evaluation of novel targets for therapeutic intervention in transplantation.
Clinical studies optimising organ preservation and assessing organ viability and function
The increasing use through necessity of organs for clinical transplantation that are sub-optimal has highlighted the need to find better ways of evaluating organ viability and predicting function after transplantation. Collaborations between researchers in Surgery, Engineering and Neuroscience have been established to evaluate new approaches for predicting organ viability and monitoring early function after transplantation. In addition the University Department of Surgery is undertaking clinical trials to determine the benefits of ischaemic preconditioning in liver and kidney transplantation and to evaluate ways of improving organ storage prior to transplantation.
Clinical Trials of novel immunosuppressive agents in transplantation
Cambridge has a long record of successfully piloting the introduction of novel immunosuppressive agents into clinical practice and was, for example, the first to use Cyclosporin and the monoclonal antibody Alemtuzumab in clinical transplantation, as well as one of the first centres to evaluate the mTOR inhibitor Sirolimus both pre-clinically and in kidney and liver transplantation. Investigator-led clinical trials of new therapies in transplantation remain a major area of research in Cambridge transplantation.
Health service research in transplantation
Clinicians in Cambridge are introducing and evaluating a range of new clinical initiatives and policy developments in organ transplantation. In addition, investigators in the Departments of Surgery and Medicine have well-established research links with the Division of Organ Donation and Transplantation at NHS Blood and Transplant. They are involved in a variety of collaborative research projects that make use of the extensive UK transplant data set. These include analysis of the clinical variables that influence outcome after organ transplantation, as well as evaluation of new schemes for organ sharing. The long-term aim is to maximise the benefits available from organ transplantation by improving patient selection and organ allocation.