MRC/University of Edinburgh Centre for Inflammation Research
Centre profile from the MRC Network publication issued Autumn 2005.
Inflammation is a fascinating topic. While being a crucial part of our defence against infection and allergens, it is also central to a range of diseases that lead to a huge amount of ill-health and death, particularly in the developed world. Scientists now know that inflammatory disease of different organs – for example, asthma in the lungs, glomerulonephritis in the kidneys, and vasculitis and atherogenesis in the cardiovascular system – involve similar inflammatory and scarring processes. Even a normal process such as menstruation may in fact be akin to an inflammatory process. As Professor Chris Haslett, Director of the CIR, explains: “Inflammation and cardiovascular biology go together hand-in-glove. Inflammation cannot occur without the presence of blood vessels. And many diseases of the heart and blood vessels, such as atheroma, are known to have inflammatory causes. Similarly, nearly every reproductive event, such as ovulation and menstruation and parturition is partly dependent on inflammatory mechanisms.”
Because of these similarities, inflammation research has much to gain from a crossdisciplinary approach in which different specialist groups investigate these common mechanisms. And, as the range of inflammatory diseases continues to increase, there is an urgent need to develop new and more effective treatments. However, in the past relatively few clinicians and scientists have been trained in the scientific disciplines necessary to define the pathogenesis of these diseases.
With this in mind, the CIR was created in 1999 under the directorship of Professor John Savill, building on the region’s existing strengths in inflammatory cell biology research, the funding from other agencies, and the strong support and financial backing from the university. Over the last five years the centre’s research capacity has grown steadily, through the appointment of Professor Chris Gregory, adding to the existing expertise of Professors John Savill, Chris Haslett, David Harrison, Neil Turner, John Mullins and David Porteous.
This year the CIR entered a new phase in its history. In July the centre was relocated in a new, purpose-built building – the Queen’s Medical Research Institute for Medical Sciences (QMRI) – adjacent to the new Edinburgh Royal Infirmary at Little France, less than three miles south of the city centre. Under the directorship of Professor Haslett, the QMRI houses the CIR, the University of Edinburgh Centre for Reproductive Biology (incorporating the MRC Human Reproductive Sciences Unit) and the University of Edinburgh Centre for Cardiovascular Sciences. The result is the first UK institute ever to bring together the full range of research areas needed to get a complete picture of inflammatory processes and disease in the body’s organs.
Why is inflammation sometimes so destructive? The natural short-term or acute inflammatory response is a protective response to insult or injury, but if this response fails to resolve (see box), chronic inflammation may lead to tissue damage and inflammatory disease. This transition from acute to chronic inflammation may occur because of defects in the resolution of inflammation. Research to date has indicated that resolution is an active process, involving suppression of the production of proinflammatory chemicals; blocking of the movement around the body of the cells involved in inflammation; promotion of apoptosis; and the phagocytosis – literally the eating – of cells involved by other specialised cells called macrophages. Apoptosis is defined in its strict sense as programmed cell death without initiation of inflammation – that is, without cells bursting to release cellular components to cause or amplify existing inflammation. These complex processes are critical to the successful resolution of inflammation and whether or not chronic disease ensues.
The aims of the CIR’s research are to characterise and manipulate these key control points in inflammation and to look at how inflammation is initiated. Furthermore, CIR scientists are investigating new approaches to promoting the beneficial regulation of established inflammatory responses in order to limit tissue injury. Another important area of research is aimed at understanding the molecular processes at work during normal resolution, as this will provide insight into inflammatory diseases in which these processes go wrong. And bringing the three research centres together under one roof has opened up exciting research directions, as there is such a close relationship between reproductive biology and inflammation. Professor Haslett explains: “Reproductive events that happen physiologically every month in women demonstrate the body’s natural potential for resolution of even massive inflammatory responses. We suspect that some reproductive diseases, such as dysmenorrhoea, spontaneous abortion and premature labour, could easily involve disorders in the control of inflammation. Our combined efforts should help people with these conditions.”
The Queen’s Medical Research Institute, Edinburgh, near completion in July 2005(left), Human blood monocyte-derived macrophages, which are used in studies investigating the mechanisms by which inflammation normally resolves (right)
Quality training, quality facilities
Over and above its impressive research portfolio, the CIR aims to deliver added value within each major scientific goal. It achieves this in a variety of ways, including nurturing promising young scientists, stimulating research in strategic and priority clinical disciplines through training and using its strong science base to deliver new interface science.
The centre has an excellent record for training young clinician scientists, some of whom are from academically underrepresented disciplines that are applicable to inflammation. Many clinical specialties, such as anaesthesia and intensive care, are national priorities for research development. An interesting new development in 2005 has been the recruitment of Dr Gareth Clegg, the UK’s first clinician fellow from accident and emergency medicine. There are also growing training opportunities for non-clinician scientists. The CIR has extended its three-year PhD studentship programme to a four-year programme focused on inflammation research. And the CIR has invested in two non-clinical fellowships for outstanding young scientists. After successful completion of their fellowships, these individuals will have guaranteed permanent academic research posts at Edinburgh University. These posts should attract candidates of truly international potential.
All scientists working at the QMRI will soon be able to enjoy superb imaging facilities that will greatly enhance the translation of discoveries in cells and molecules into therapies for human disease. The CIR hosts the new optical imaging suite, containing state-of-the-art confocal microscopy, cell sorting, laser capture dissection microscopy, as well as optical projection tomography – an exciting new technique developed by Dr James Sharp at the MRC Human Genetics Unit in Edinburgh. The adjacent Chancellors Building houses a small animal imaging centre that incorporates a 7.4 Tesla small-bore magnetic resonance imaging (MRI) scanner, and will also have micro positron emission tomography (micro PET). In addition, plans are well advanced for an integrative human imaging centre in the QMRI basement. This too will contain cutting-edge MRI, as well as a cyclotron and PET facility.
Translating science into patient benefit
The CIR has established itself as a base for clinical translational research and experimental medicine. Scientists are excited at working in an environment where patients suffering from diseases under research are at the same site. Young clinician scientists are motivated to become trained in research and initiate new research based on their clinical experiences. In turn, research discoveries in the laboratories filter through to benefit patients in the co-located hospital. This integration of basic research with the clinical problems allows research findings in cells and molecules to be taken, potentially through animal models, into treatments to benefit patients. For example, Dr John Simpson initially showed that gene transfer of the antimicrobial antiprotease elafin could protect the lining of the lung against injury using a cell culture model. He then developed the approach in sheep and discovered it dramatically protected the lungs. With £1m funding from the Sir Jules Thorn Charitable Trust his work is now being translated for the human problem of ventilator-associated pneumonia.
An exciting new area of research, which has emerged out of the three centres working together, is macrophage cell therapy. This ground-breaking technique, being developed by Drs David Kluth and Jeremy Hughes, could provide a crucial advance towards therapies for patients with chronic inflammatory diseases of, for example, the kidney and lung. The principle behind the new technique is to genetically alter the normal behaviour of macrophages, outside of the body, so that when they are re-introduced they perform new functions and quell the inflammation.
Other interesting new developments include research that uncovers relationships between cancer and inflammation. Professor Tariq Sethi has recently shown that the growth and spread of the devastating tumour, small-cell lung cancer, is critically controlled by apoptosis and by inflammatory proteins interacting with integrin receptors on the tumour cell’s surface. Professor Chris Gregory has proposed that when tumour macrophages scavenge dying tumour cells, they become activated to suppress antitumour immunity – which could promote more tumours forming.A major aim of his team is to find a way of switching the activation state of these cells so they instead promote anti-tumour immune responses. Both these lines of research link naturally to the study of apoptosis – an internationally recognized theme of the CIR.
A wealth of opportunities
The good news for medical research in Edinburgh does not begin and end with the opening of the QMRI. Developments at the new institute have undoubtedly been a major catalyst in the creation of a major Biomedical Science Park next to the hospital, a partnership between the University of Edinburgh, Scottish Enterprise and City of Edinburgh. Land is currently being cleared for a £45m stem cell science building to be commissioned in 2008/09. So no wonder there is a buzz of excitement at Little France. With the integration of three internationally renowned research centres and the science park on the horizon, the possibilities for ground-breaking research to improve human health seem endless.