Working together to improve human health 2004/05 Annual Review The Medical Research Council (MRC) is the UK’s leading publicly funded biomedical research organisation. Our mission is to:

● Encourage and support high-quality research with the aim of improving human health.

● Produce skilled researchers, and to advance and disseminate knowledge and technology to improve the quality of life and economic competitiveness in the UK.

● Promote dialogue with the public about medical research.

Welcome 1

Introduction 2

Working in partnership 4

Accelerating research 8

A sense of achievement 12

14 Cancer

16 Cardiovascular disease and stroke

18 Respiratory disease

20 Infectious disease

22 Neurosciences and mental health

24 The ageing population

26 Obesity, diet and diabetes

28 Health inequalities

30 Clinical investigation and trials

32 From discovery to treatments Welcome From Professor Colin Blakemore MRC Chief Executive

In this Annual Review you will read about some of the many achievements of MRC-funded scientists in 2004/05 and the partnerships that have made much of this vital work possible.

The research that we fund is aimed at tackling major challenges to human health. These range from potentially devastating infections such as AIDS and avian flu to the gradual increase in ageing-related diseases resulting from longer life expectancy.

But it is not enough for us simply to support and carry out the highest-quality biomedical science. We must relate what we are doing in the laboratory to clinical research involving patients and the work of the NHS. By focussing on medical research ‘in the round’, as a continuum involving interaction and two-way feedback between a variety of disciplines, we can ensure that our scientists’ discoveries are translated into health benefits for people as soon as possible.

As the leading public funder of medical research in this country, with a portfolio that covers the spectrum of biomedical and clinical sciences, the MRC is able to create timely, effective links between our fundamental science and clinical research. As a result, there are countless examples of MRC-funded basic research leading to major breakthroughs in patient treatment, from the discovery of monoclonal antibodies – now the basis of 30 per cent of new treatments – to magnetic resonance imaging, the most important diagnostic advance of the 20th century.

The strength of the MRC’s basic research is recognised worldwide. Clinical research is now an equally high priority for us, as shown this year by our commitment to clinical trials, population studies and a new partnership initiative in experimental medicine. In the year ahead and beyond, we shall continue to forge new working relationships with professional partners and the public. Together, we can achieve the MRC’s overriding aim – better health for everyone.

MRC Annual Review 2004/05 1 The MRC works across all medical research Introduction disciplines and with a wide range of stakeholders to improve human health

The Medical Research Council (MRC) is the UK’s leading publicly funded biomedical research organisation. We are funded by the UK taxpayer, but are independent of the Government. This gives us the flexibility to decide which research to support, taking into account both national needs and scientific quality. We work closely with the Health Departments, other government agencies, other research funders and the biotech industry. We fund world-class medical research in our own institutes and units, and in universities and teaching hospitals throughout the UK. The MRC’s portfolio spans the whole spectrum of biomedical science – from basic studies in the laboratory to clinical investigations in hospitals, GP surgeries and the community.

The changing face of medicine Over the years MRC scientists have been responsible for many groundbreaking discoveries that have dramatically changed how we think about disease and the ways in which medicine is practised. This year has been no exception. But, as the challenges facing medical science become ever more complex, it is vital that we do not stand still. The MRC is constantly evolving, in order to meet the new and often unexpected challenges inherent in medical science, to increase our overall effectiveness and to continue strengthening our relationships with stakeholders, including the general public.

The power of partnership From page 12 onwards this Annual Review describes a selection of MRC-funded scientific achievements during the last year, in nine health priority areas. Leading up to those pages is information about some of our key partners and how together we are increasing the speed with which new treatments and diagnostic techniques are developed from MRC scientists’ discoveries.

2 MRC Annual Review 2004/05 Working in partnership 4

Accelerating research 8

A sense of achievement 12

MRC Annual Review 2004/05 3 To help take forward our efforts at all levels, from basic research to clinical trials, Working in we involve a wide variety of stakeholders, partnership including the public. Today, the impact of rapid social and economic change – at a national and global level – makes the challenges facing scientists increasingly complex. What’s more, we are striving to ensure that MRC discoveries lead as quickly as possible to improved diagnostic tests, treatments and methods of prevention. All of which means that our “Working in partnerships – such as the examples presented below – are more crucial then ever. partnership is essential Reshaping the clinical research environment to make sure that The MRC is a major player in the UK Clinical Research Collaboration (UKCRC), which aims to establish this country as a world leader in clinical research. The investments by member organisations include the Health Departments, the NHS, the MRC, medical different funders are charities, patients and the biotechnology industry. Clinical investigation is an essential well coordinated and step in the journey from scientific discovery to patient benefit, and we are united in our commitment to making the very most of the unique opportunities that the UK mutually beneficial.” offers for such work. Professor Colin Blakemore, The UKCRC’s first step has been to identify ways to develop the research MRC Chief Executive infrastructure within the NHS and to make sure that the country has enough trained and qualified clinical researchers. We have also been addressing the need to streamline regulation and governance and to coordinate approaches to research funding across the member organisations. The MRC is well placed to help drive the UKCRC’s objectives forwards. Along with our strategic emphasis on funding clinical research, we have widely recognised expertise in the ethical governance of research investigations involving human

OUR PARTNERS AND STAKEHOLDERS

OST / TREASURY / DFID / OTHER GOVERNMENT DEPARTMENTS

RESEARCH PATIENTS COMMUNITY AND CARERS

RESEARCH PUBLIC AND NHS UKCRC COUNCILS MEDIA MRC UNIVERSITIES MRCT AND INDUSTRY UK HEALTH DEPARTMENTS

MEDICAL INTERNATIONAL CHARITIES

PARLIAMENTARIANS / POLICY MAKERS

MRC Annual Review 2004/05 5 Working in partnership

participants. UKCRC Chief Executive, Dr Liam O’Toole, spent ten years at the MRC in a variety of research management roles, and MRC Chief Executive Professor Colin “The creation of Blakemore brings a wealth of public communication experience to his role as chair of the UKCRC offers us the UKCRC’s Public Awareness Task and Delivery Group. an incredible Promoting prevention opportunity to reshape While diagnosis and treatment are vitally important, the ideal approach is to prevent ill health in the first place. This is the aim of the National Prevention Research the environment in Initiative, which was launched in October 2004 with a budget of £12m and will run which clinical research for five years. The Initiative is a broad consortium of charities, the MRC, other is conducted in research organisations and the Government, who have come together to find ways to prevent major diseases such as cancer, heart disease and diabetes. this country.” Our joint efforts will focus on ways to discourage unhealthy habits such as smoking Dr Liam O’Toole or excessive alcohol intake and to encourage a healthy lifestyle including more Chief Executive, UKCRC physical activity and a nutritious, balanced diet. MRC Chief Executive Colin Blakemore says, “Research in this area is complicated by the fact that we are dealing with real populations with a tremendous number of interacting variables such as diet, lifestyle, levels of stress and so on. However the potential payoff could be huge.”

All over the world Ever since the 1920s, the MRC has funded a range of international research collaborations. For example, at our research units in The Gambia and Uganda we work with African scientists on pioneering research into HIV/AIDS, malaria and other life-threatening infections. It is now more important than ever that our science has a global reach. Widespread international travel, movement of populations and the evolution of pathogens make it easier than ever before for infectious diseases to cross the world. GLOSSARY This year we have been focussing on developing existing links with scientists in South-east Asia. A panel of senior MRC scientists visited North Vietnam, China and Characterise To define the biological properties of particular kinds of stem Hong Kong in October 2005 to assess the potential for collaborative research into cells. avian flu and other emerging (and re-emerging) infections. This international Microbicides Substances which endeavour builds on the MRC’s pioneering work with Chinese scientists in 2003 to women can apply to the vagina to help investigate the immune system’s response to the SARS (Severe Acute Respiratory provide a barrier against HIV infection. Disease) virus. Stem cells Cells found in embryos and We also work closely with the Department for International Development, who are in adult tissues that have the ability to co-funders of our Microbicides Development Programme. The MRC has been a divide almost indefinitely to produce driving force in microbicide research, from initial tests in the laboratory of Professor more stem cells, or to differentiate (specialise) to form different kinds of Jonathan Weber at Imperial College London to the development of a microbicide tissues. gel now in the early phases of clinical testing in Africa. The trial, which is coordinated Stem cell line Cells descended from by our Clinical Trials Unit and Imperial College’s Clinical Trials Centre, is a superb an original stem cell that share that cell’s example of collaborative working. If found to be effective, the gel could save genetic characteristics. millions of lives.

6 MRC Annual Review 2004/05 Working in partnership

Stem cell science IN BRIEF By investigating how stem cells specialise to form different organs and tissues, scientists are discovering more about how our bodies develop and repair themselves, International and about the cellular mechanisms underlying diseases such as cancer. This collaboration knowledge may in the future enable scientists to ‘direct’ stem cells to create healthy The World Influenza Centre at the MRC’s National Institute for Medical Research replacements for worn out or damaged cells, organs or tissues. monitors molecular changes in the flu 2004 saw two exciting developments in UK stem cell research. The first of these was virus that might threaten human health the opening of the UK Stem Cell Bank, which is funded by the MRC and the and develops prototype vaccines to Biotechnology and Biological Sciences Research Council, and hosted by the National protect against new forms of the virus. Founded in 1947, the Centre was the Institute for Biological Standards and Control in South Mimms, Hertfordshire. The first of four World Health Organization Bank stores and characterises ethically approved, quality-controlled stem cell lines for (WHO) Collaborating Centres for use by UK and overseas scientists. The other good news was the opening of our new Reference and Research on Influenza centre in Cambridge, set up to generate new insights into stem cell biology that that advise the WHO on the design of flu could lead to potential new treatments for diseases such as diabetes, Parkinson’s vaccines. Because the flu virus can mutate disease and multiple sclerosis. The MRC Cambridge Centre for Stem Cell Biology to form new strains, it is important that scientists are able to respond swiftly to and Medicine is co-funded by the Juvenile Diabetes Research Foundation International. emerging strains to help prevent flu The MRC is a founding member of the International Stem Cell Forum, which brings pandemics. The World Influenza together 16 funding organisations from around the world to promote global best Centre is centrally involved practice and knowledge in stem cell research. The Forum is chaired by MRC Chief in monitoring and Executive Colin Blakemore. planning defence against the current threat Banking on success from avian flu. Throughout the year we have continued to work with the Wellcome Trust, the Department of Health, and the Scottish Executive to develop the UK Biobank. This long-term national project will follow the health of 500,000 volunteers aged 40-69 for up to 30 years, beginning in January 2006. The aim is to build the world’s largest information resource on the effects of genetic, environmental and lifestyle factors on human health and disease. Participants will be asked to provide blood and urine samples and to complete a confidential questionnaire. These will be used to create a comprehensive databank that researchers can draw upon to study the progression of cancer, heart disease, diabetes, Alzheimer’s disease and other common illnesses.

Involving the public The public plays an essential part in the MRC’s mission to improve human health. Clinical trials, population studies and most experimental medicine would simply not be possible without volunteers – whether patients or healthy members of the public. And through listening to your views, concerns and ideas about medical research, we gain valuable feedback that can help to inform our strategic thinking. One way we are developing our dialogue with the public is through our Advisory Group on Public Involvement, made up of people drawn from all walks of life with a shared interest in medical research. In the past year we recruited 16 new members to form an extended network across different regions.

MRC Annual Review 2004/05 7 We are working ever harder to transform the results of basic research into practical Accelerating benefits for patients. But one thing remains unchanged – our dedication to supporting research first-class science. Focus on delivery Throughout 2004/05 we have been working hard to formulate the best ways to deliver the results of medical research quickly to our key beneficiaries: men, women and children, as patients in clinics, surgeries and hospital wards, and as healthy “Maintaining a individuals going about their everyday lives. continuum between Clinical research and public health research are crucial elements in the two-way translational process. During the last year we set up two new overview groups to basic and clinical help us develop our research portfolio in these important areas, and have funded 10 research is absolutely new clinical trials since November 2004. And whereas in recent years we spent central to our approximately £127m a year on clinical and public health research and training, we commitment to are increasing this support to £162m by 2007/08. translational research.” People power Professor Colin Blakemore But an injection of funds, no matter how substantial, is not enough unless we have MRC Chief Executive the right people to carry forward our plans. There is currently a shortage of clinical researchers in the UK, so we are working closely with the DoH Research Capacity Development Programme and the UKCRC to address this. We are increasing the number of clinical research training fellowships that the MRC awards annually from 30 to 50 by 2007. In addition, we are providing funds to train more nursing and allied health professionals, and to ensure that we have enough qualified people in related disciplines – such as health economics and statistics – to take our vision forward.

TRANSLATING RESEARCH INTO PATIENT BENEFIT

RESEARCH IDEA

PATIENT BASIC BENEFIT RESEARCH

HEALTH POLICY/ EXPERIMENTAL PRACTICE MEDICINE

HEALTH CLINICAL SERVICES TRIALS RESEARCH

MRC Annual Review 2004/05 9 Accelerating research

A two-way process It is a common misunderstanding to think of medical research as a one-way process, “The scientists here which progresses ‘from lab bench to bedside’ in a neat, linear fashion. In practice it is love the fact that they much more of a continuum, with insights from studies of patients feeding back into are not far from the work done in the laboratory and vice versa. Only in this way can researchers gain a true understanding of how disease and ill health develop, and be able to devise, patients with the test and refine new methods of diagnosis, treatment and prevention. disease they are studying, while young Research in translation clinicians can rub The MRC has always been closely involved in translational research, through which shoulders with top the results of research studies are developed into improved healthcare. The challenge now is to make this process a natural part of the culture of MRC science, scientists.” so that it becomes easier and quicker to move from fundamental discovery to clinical Professor Chris Haslett, application. By bringing scientists from different stages of the research continuum Director of the CIR together, we can facilitate exchange of ideas and help to give everyone a view of the goal in sight whatever their own special interest. This kind of synergy and cross- linking will help to hasten the journey from basic research through pre-clinical testing, clinical trials, regulatory approval, and into clinical practice.

Building on success One very effective way of fostering cross-links between scientists is to bring them together and facilitate their interaction in joint research centres. The new MRC/UCL Centre for Medical Molecular Virology, under the directorship of Professor Mary Collins, unites experts in basic, diagnostic, clinical and epidemiological research into viral diseases. This year scientists working there have published a stream of studies – on the immune response to HIV and hepatitis B, on a new way to diagnose severe acute respiratory syndrome (SARS) and on HIV transmission patterns among Britons in the first wave of the HIV epidemic, to name but a few. Another example is the Queen’s Medical Research Institute for Medical Sciences in Edinburgh, to which our Centre for Inflammation Research (CIR) relocated this year. The new purpose-built Institute is also home to the University of Edinburgh’s Centres for Reproductive Biology and for Cardiovascular Science, and is adjacent to the new Edinburgh Royal Infirmary. Under the directorship of Professor Chris Haslett, it is the first UK institute to bring together scientists in these three complementary areas to gain a complete picture of inflammatory processes and disease – from cells and tissues to animal models, human organs and patients.

Translating science into patient benefit The CIR is already delivering exciting projects born of the partnership between basic and clinical sciences. Clinical researcher and respiratory physician Dr John Simpson has discovered that a protein compound, elafin, has powerful antibacterial and anti-inflammatory properties that could protect lung cells against injury. With the help of £1m funding from the Sir Jules Thorn Charitable Trust, he is now looking at new ways to treat antibiotic-resistant pneumonia – a growing problem in intensive care units. Meanwhile, transplant surgeon Miss Lorna Marson is investigating ways to

10 MRC Annual Review 2004/05 Accelerating research

prevent the inflammation and scarring that can cause kidney failure after a transplant; her research involves inserting ‘intelligent’ scavenger blood cells into mouse kidneys to see if they quell the inflammatory process.

Regeneration and renewal During 2004/05 we have been working on plans to renew our world-renowned National Institute for Medical Research at a new site in central London. Our partner in this exciting venture is University College London, with whom we have a long and successful tradition of collaboration. The renewed institute will offer scientists a world-class research environment and foster collaboration with clinicians at the UCL Hospital and its associated research-based hospitals in London.

Illuminating the future Progress in medical science often depends on developments in equipment. For example, Max Perutz’s Nobel Prize-winning 1950s discovery of the structure of haemoglobin – a landmark in 20th century medicine – relied on the use of X-ray crystallography. Today, the MRC is involved in a multidisciplinary project to build the Diamond Synchrotron, a huge facility that produces X-ray beams of unprecedented brightness that enable scientists to look deep into the basic structures of life. Synchrotrons are key tools for determining protein structures, information that is vital for the design of the new targeted drugs that will be part of the future of medicine. Computer-generated image of the Diamond Synchrotron, which will be an indispensible Construction is well under way in Harwell, Oxfordshire, including a new resource for chemists and structural biologists research complex so that scientists from a range of disciplines can exploit working together to develop promising this cutting-edge technology. compounds into potential new drugs.

The vital link Our affiliated company, MRC Technology (MRCT), plays a crucial role in the journey from scientific discovery to clinical treatment, by working with the biotech industry to translate MRC researchers’ achievements into innovations in healthcare. One of MRCT’s greatest successes has been the development of therapeutic antibody products, based on research into monoclonal antibodies at the MRC Laboratory of Molecular Biology in Cambridge. Monoclonal antibodies have revolutionised medicine. Not only have they led to radically new treatments for breast cancer, leukaemia, asthma, transplant rejection and arthritis, but they also account for 30 per cent of new drug-based treatments in development worldwide. Building on this phenomenal success, in 2004/05 MRCT launched a Drug Discovery Group with the help of funding from the MRC. The Group’s expertise and state-of- the-art laboratory will greatly enhance our translational activities and accelerate the rate at which the public can reap the health benefits of MRC research in the future.

MRC Annual Review 2004/05 11 As we look back at our scientists’ many achievements during the year, we are A sense of determined never to lose sight of our single most important goal: to improve achievement human health. KEY CONCEPTS Advancing on many fronts Scientists today have unprecedented scope for exploring and identifying what Medical research includes a broad range keeps us healthy and what causes disease. As a result, they are developing new of activities aimed at improving or ways to diagnose, treat and prevent disease that even a few years ago would have maintaining human health. been difficult to imagine. Basic research explores living systems, both healthy and diseased, at a As we show in the pages that follow, during 2004/05 MRC-funded scientists have fundamental level. It includes cell and continued to make significant strides in understanding the origins and progress of molecular biology, biochemistry, anatomy, a wide variety of diseases. Often this work has involved close collaborations – for pharmacology, and so on. It is usually example, between researchers working at different points of the medical research carried out in a laboratory setting and continuum, with other funding organisations and government departments, with may involve isolated preparations of cells, scientists and volunteers in other countries, and with the biotechnology industry. tissues, animals, or human beings. Clinical research involves people. It includes direct examination of Health priorities individuals and populations and may To ensure that the research we fund has the greatest impact on human health, entail collecting samples and personal we have identified key health priorities on which to focus our efforts. These are: data, from both apparently healthy and ill ● Cancer people. Clinical trials of drugs or ● Cardiovascular disease and stroke interventions are a key activity. ● Respiratory disease Experimental medicine provides a ● Infectious disease bridge between gene-based discoveries ● and the development of a new drug or Neurosciences and mental health intervention. It may include investigations ● The ageing population in humans and/or animals – either to ● Obesity, diet and diabetes identify mechanisms of disease or to ● Health inequalities refute or confirm an idea about diagnosis ● Clinical investigation and trials or treatment. Within each of these areas, MRC scientists are working to understand how our Population sciences involve studying large groups of people to look for patterns individual genetic makeup interacts with lifestyle factors – such as diet, smoking, or mechanisms of health or disease, or to alcohol or drug use, pollution, work-related stress and our environment – to test the validity and importance of new determine our health. By approaching research in this integrative way we aim to discoveries or interventions. They can ensure that discoveries made by MRC-funded scientists lead as quickly as possible include randomised trials and case-control to benefits for human health. designs. Medical research constantly presents new and unexpected challenges. There will Translational research aims to turn basic discoveries into diagnostic tests, always be new frontiers to explore. As we show you discoveries made by MRC- drugs, devices, surgery and other funded researchers in 2004/05, we pay tribute to the years of painstaking scientific strategies as well as taking insights from work and the many different partnerships that have yielded these achievements. patient studies back to the laboratory.

MRC Annual Review 2004/05 13 Each year around 270,000 people in the UK Understanding learn that they have cancer. This figure could rise to 370,000 a year by 2020, making the cancer need for effective diagnosis, treatment and prevention more urgent than ever before.

In 2004/05 MRC scientists made significant progress in understanding the inbuilt sys- tem of checks that can stop cells turning cancerous, learnt more about the part played by inherited breast cancer genes, and identified a marker that could help doctors determine the outcome of cancer.

Divide and rule Cancer starts with DNA damage, either inherited or caused by the environment. If this damage goes unchecked, mutant proteins can form that cause cell division to go awry. Scientists are working to understand how the billions of cells in our bodies ‘talk’ to each other, a process known as intercellular signalling. This Learning more about the process of cell division, shown here in a breast cancer cell, will help in turn will help them to discover how doctors diagnose and treat cancer more precisely. cells sometimes evade the system of checkpoints that stops them dividing function in cell division. The discovery may two proteins involved in blocking cancer, uncontrollably. be relevant to understanding human but previously thought to work cancers that involve mutations in clathrin, independently, collaborate to put a stop to Dr Matthew Freeman, of the MRC such as certain types of cancers affecting the cell division cycle. Commonly used Laboratory of Molecular Biology (LMB) the lymphatic system or the kidneys. cancer drugs, such as Taxol, work through in Cambridge, identified a previously these proteins to control cell division and unknown checkpoint in the fruit fly and Focus on breast cancer prevent the multiplication of cancer cells. showed how intercellular signalling might Inherited alterations in two genes, BRCA1 Discovering how they work together may disable this. As the same signalling pathway and BRCA2, are involved in many cases of help researchers understand better how has been implicated in many human hereditary breast and ovarian cancer, but cancer treatments work, and why some cancers, his discovery could help explain scientists still don’t understand exactly tumours are resistant to them. how tumours grow and spread. how these lead to the diseases. Dr Steve Smerdon of the MRC National Institute Predicting cancer outcome Moonlighting protein assists cell division for Medical Research (NIMR) at Mill Hill, Tumour ‘markers’ – substances produced North London, found that BRCA1 might by cancer cells – in the blood or urine, can A team led by Dr Stephen Royle, another interrupt protein-to-protein interactions. be used to screen for cancer and to help researcher at the LMB, found that a Meanwhile Professor Ashok Venkitaraman predict its outcome. Dr Nicholas ‘three-legged’ protein, clathrin, is involved of the MRC Cancer Cell Unit, Cambridge, Coleman of the MRC Cancer Cell Unit in helping chromosomes to separate when discovered that BRCA2 is needed to found a marker protein, geminin, which cells divide. Clathrin’s normal job is to ensure that chromosome pairs separate when combined with other previously transport hormones, proteins and correctly as cells divide. identified markers, gave information about nutrients from the outside to the inside of the number of growing cells in tumours cells. However, it appears that it Other research by Professor and their rate of division in breast cancer. ‘moonlights’ to perform this other Venkitaraman’s team demonstrated how

14 MRC Annual Review 2004/05 MRC research |Cancer

The discovery, which was made in of structures of the most common p53 collaboration with Addenbrooke’s Hospital mutations, using a tool called nuclear NHS Trust, could help give breast cancer magnetic resonance (NMR) spectroscopy patients more accurate information about to analyse molecular structure. In March how aggressive their tumours are, as well 2005 Professor Fersht was awarded the as helping doctors to decide on the most Bader Award of the American Chemical appropriate treatment. The research was Society for his pioneering work on protein co-funded by Cancer Research UK. engineering, 90 per cent of which was funded by the MRC. Defending the body against cancer Where’s the switch? Every cell in the body has the ability to With the sequence of the human genome commit suicide if something goes wrong complete, researchers are now with the cell division cycle, a process concentrating on its architecture. DNA is known as apoptosis. However in cancer packaged with proteins into a material the mechanism that triggers this called chromatin within the cell nucleus. programmed cell death is often faulty. Researchers have been trying to find out The tumour-suppressing protein, p53, if open and closed regions of chromatin described as ‘the most frequently mutated correspond to whether genes are gene in human cancer,’ plays a pivotal part switched on or activated (expressed), at The pattern of chromatin distribution within in this process by calling a halt to cell any one time. Such knowledge could help the human genome could aid understanding of division if DNA is damaged. increase understanding of many diseases, cancer. Here chromosomes are shown in blue including cancer. Alterations in p53, therefore, not only and chromatin in green. deprive the body of a key natural defence Professor Wendy Bickmore of the MRC and enable cancer cells to grow, but are Human Genetics Unit, Edinburgh, and a also the reason tumours may resist team from the Wellcome Trust Sanger GLOSSARY treatment. The development of drugs that Institute, have come up with the first ‘bind’ onto p53 and increase or restore its architectural blueprint of the human DNA Deoxyribonucleic acid, the genetic activity would be a huge step forward in genome to show areas of tightly packed blueprint inside our cells needed for the the war against cancer. and open chromatin. manufacture of the proteins that keep our cells working properly. Dr Steven Gamblin of the NIMR Scientists previously believed that genes Genes Units of DNA that contain the showed that a process known as lysine that were switched on corresponded to instructions needed to produce proteins. methylation could disrupt p53 regulation, open regions of chromatin and vice versa. Genome The full set of instructions while Dr John Rouse, of the MRC Protein Professor Bickmore’s research, however, within an organism, containing all of its Phosphorylation Unit at Dundee, identified showed that there is no such simple genes and associated DNA. a protein, hPTIP, which controls p53 correlation. Instead, genes that need to be Proteins Large molecules responsible for activity and enables cells to survive rapidly switched on or off are held in the function of all living cells. For example DNA damage. regions of open chromatin structure. they defend cells against infection, control Professor Bickmore was elected a Fellow In another pioneering piece of research, chemical reactions such as those needed of the Royal Society of Edinburgh in Professor Sir Alan Fersht, of the MRC for digestion, do the mechanical work of recognition of her scientific excellence and cells and determine their structure. Centre for Protein Engineering in achievements. Cambridge, produced the first description

MRC Annual Review 2004/05 15 Coronary heart disease, the UK’s single biggest Secrets of the killer, claims nearly 114,000 lives a year. Stroke, meanwhile, is responsible for the death of heart and brain 60,000 people annually and is the largest single cause of long-term disability.

Achievements in 2004/05 included All change identifying a link between heart attack, Genes aren’t everything; lifestyle factors “The results of the stroke and respiratory infections, are the other side of the disease-causing groundbreaking discovering genes likely to be involved equation. A study by Dr Ulf Ekelund of the in the metabolic syndrome, elucidating a MRC Epidemiology Unit, Cambridge, research being key cause of brain death in stroke, and showed that people who were physically co-ordinated by the evaluating the effects of surgery on active were less likely to develop the MRC for the Food stroke survival. metabolic syndrome, regardless of their aerobic fitness or weight. The research, Standards Agency New take on an old which was carried out over a five-year should enable us to give hypothesis period, suggests that it is not necessary A study, led by Dr Liam Smeeth of the to pound the pavements or join a gym to clearer advice to the London School of Hygiene and Tropical gain health benefits. Just small changes in public on consumption Medicine, breathed life into the old idea everyday activity levels (things like riding of fats and that infection could trigger cardiovascular a bike, taking the stairs instead of the lift disease and stroke. or walking the dog) can make all the carbohydrates.” difference to the risk. Tom Murray, Head of Nutrition Scientists funded by the MRC, the British at the Food Standards Agency Heart Foundation and the Wellcome Diet is also a crucial factor in many Trust examined the medical records of diseases, which is why in May 2004 we more than 40,000 people who had launched a major four-year study to find Pinpointing the X-factor suffered a heart attack or stroke. They out the best dietary strategies to reduce Since they mapped the human genome discovered that the risk of suffering a the metabolic syndrome. The £2.7m study, scientists have isolated the gene mutations heart attack increased five-fold, while the one of the largest of its kind, is funded by underlying a great many single gene risk of having a stroke tripled, in the week the Food Standards Agency and led by disorders, such as cystic fibrosis and following respiratory infections such as scientists from our Human Nutrition Huntington’s disease. However, the pneumonia or bronchitis. There was Research centre in Cambridge, in identification of the genes involved in no increased susceptibility to heart partnership with scientists from Imperial common conditions such as high blood attack and stroke following College London, King’s College London, pressure, cardiovascular disease, diabetes flu and pneumonia the University of Reading and the and obesity, where many different genes vaccinations. University of Surrey. may play a part, has proved more elusive.

It could now be easier, thanks to the efforts of an international team led by Professor Tim Aitman of the MRC Clinical Sciences Centre, Imperial College London.

The researchers used a combination of the DNA chip technique – microarrays – and another approach called linkage analysis to identify 70 genes that are likely to be involved in the metabolic syndrome in rats.

The metabolic syndrome, also known as syndrome X, is a cluster of factors that

16 MRC Annual Review 2004/05 MRC research | Cardiovascular disease and stroke

increases the risk of obesity, type 2 deposits and restores blood flow, can help diabetes, heart disease and stroke. These prevent further problems in patients who factors include insulin resistance, high blood have already had a stroke or TIA. But can pressure and raised levels of blood fats. such surgery help those without symptoms and do the potential benefits outweigh the The next step is to hunt for the same risks? This was what vascular surgeon Miss genes in humans. The method used Alison Halliday, of St George’s Medical could also speed up the identification School, London, set out to discover in the of susceptibility genes in other largest vascular surgery trial in the world. complex disorders. The trial, which compared immediate with deferred surgery in 3,000 patients in 126 hospitals across 30 countries, found that Surgery to unblock a narrowed carotid artery, Stroke benefits immediate surgery halved the risk of shown here, can halve strokes in many patients stroke, especially in patients under the age with ‘silent’ carotid artery disease. Calcium counts of 75. The potential benefits for patients Scientists have long thought that raised over this age were less clear-cut. the Stroke Association. Its results are levels of calcium in brain cells are Numerous European clinicians collaborated expected to have a major impact on the responsible for the widespread cell death in the trial, which was co-funded by the care of stroke patients all over the world. that follows a stroke. But the precise MRC and the Stroke Association. mechanism underlying this was, until Professor Sir Richard Peto, of the recently, unknown. MRC/Cancer Research UK/BHF Clinical Trial Service Unit & Epidemiological Studies Professor Pierluigi Nicotera of the MRC Unit in Oxford was also closely involved. Toxicology Unit, Leicester, has now revealed that the main problem lies not A STICH in time? with the influx of calcium, as was Until now, many doctors believed that previously thought, but with the surgery to remove the blood clot mechanism that removes calcium from the GLOSSARY created by supratentorial intracerebral cells. The finding could provide haemorrhage, one of the most deadly Carotid arteries Large blood vessels in opportunities for the development of forms of stroke, could possibly limit the neck that lead to the brain. drugs to reduce cell death, not just in brain damage and improve recovery. Intracerebral haemmorhage people who have had strokes, but also in New research has, however, overturned Stroke caused by blood vessel leaking into those with degenerative brain diseases. this theory. the brain. The most common type is supratentorial intracerebral haemorrhage. Preventing stroke In a trial led by Professor David Linkage analysis A technique that Carotid artery disease is a major cause of Mendelow, Head of the Department of enables scientists to hunt for gene both full-blown strokes and mini-strokes Neurosurgery at Newcastle General mutations in high-risk groups by looking at (transient ischaemic attacks or TIAs). It Hospital, researchers found that early known variations of DNA sequences that lie happens when the arteries in the neck surgery was no better in preventing death close by. become narrowed and blocked by an or severe disability than watchful waiting Microarray A tool to examine the activity accumulation of fat and cholesterol. with the option of a later operation. The of thousands of genes or proteins MRC STICH Trial involved 1,000 patients simultaneously on a microchip or glass slide. An operation known as carotid from 27 countries and was also funded by endartectomy, that removes the fatty

MRC Annual Review 2004/05 17 The UK is on the verge of a potential lung disease ‘time bomb’. Pause for Lung cancer, asthma, pneumonia and chronic obstructive pulmonary disease cause more deaths than coronary heart breath disease. Respiratory problems are the most common cause of chronic childhood illness, and account for a quarter of acute emergency hospital admissions.

In the past year MRC scientists have Particle physics Stress connection in identified a molecule that could lead to What part does air pollution play in childhood asthma better treatments for chronic obstructive asthma? A study led by Professor William Stress is a well-known asthma trigger, but pulmonary disease (COPD), discovered MacNee, of the University of Edinburgh, to what extent does it increase the risk of more about the links between air could go some way to providing the an attack in children? In research funded pollution and respiratory problems, answer. The researchers looked at the by the MRC, Dr Seija Sandberg, of and found evidence suggesting that effects of fine airborne pollutants, called University College London, asked 60 common household chemicals may particulate matter, on cells in the umbilical asthmatic children aged between six and trigger childhood asthma. cord and lungs. They discovered that these 13 to keep symptom diaries and to record raised the levels of clotting factors that peak flow measurements over an 18- Asthma attack thicken the blood, increased inflammatory month period. The children and their More than four million adults and a million activity and accelerated the death rate of parents were also interviewed to identify children in the UK suffer from asthma, immune cells. The study was funded by any stressful life events, such as illness, one of the highest rates in the world. the MRC, the British Lung Foundation separation or bereavement. Children were MRC scientists are studying the origins and the Cold Foundation. almost five times more likely to have an of asthma at all levels, from the part asthma attack within 48 hours of a played by genes to the contribution Pregnancy, the home and stressful event, and twice as likely to have of factors such as air pollution and childhood asthma another attack around six weeks later. household chemicals. Several studies led by Dr Judith Headley are helping to untangle the complex links between the environment and childhood asthma. She discovered that seven per GLOSSARY cent of cases of childhood asthma could be linked to mothers’ use of paracetamol Adenosine monophosphate (AMP) One of a number of messenger chemicals during late pregnancy. She also that regulate the function of many cells identified links between the use of thought to contribute to respiratory common household products, such as diseases such as asthma and COPD. bleach, paint stripper and carpet Bronchi The small airways in the lungs. cleaners, and wheezing in babies and Chronic obstructive pulmonary young children. In a third study disease (COPD) A collective term for she showed that the pertussis disorders, such as chronic bronchitis and (whooping cough) vaccine emphysema, in which the bronchi are does not increase the risk of blocked. Symptoms include difficulty later asthma or allergy. The breathing, wheezing and a chronic cough. studies were done as part of the Particulate matter Ultra-fine solid or MRC-funded Avon Longitudinal liquid particles in dust, mist, fog or fumes Study of Parents and Children that stick to the lungs when inhaled. (ALSPAC). For more findings from Peak flow measurement A measure this study turn to pages 28-29. of how fast an individual can blow out air after a deep inhalation. It shows how well the lungs are working.

18 MRC Annual Review 2004/05 MRC research | Respiratory disease

IN BRIEF

Diehard smokers Fifty years after making the connection between smoking and lung cancer, Professor Sir Richard Doll and Professor Sir Richard Peto showed that smoking shortens life by a decade. The 50-year follow-up of the British Doctors Smoking Study re-emphasises the benefits of quitting no matter what your age. The study was funded by the MRC, Cancer Research UK and the British Heart Foundation. Smoke gets in your eyes Smoking doubles the risk of blindness or partial sight due to age-related macular degeneration (AMD), according to an MRC study. The researchers calculated that smoking is responsible for 28,000 cases of AMD, which causes blurred The discovery of a protein molecule involved in central vision, in the UK. The research, Treating inflamed lungs Fifty thousand people are diagnosed with lung inflammation could lead to more effective part of the MRC Trial of Assessment and COPD in the UK each year, and 30,000 drugs to treat chronic lung disease. Management of Older People in the die from it. There is currently no cure and Community, was led by Professor Astrid few effective drugs with which to treat it. Fletcher of the London School of Hygiene Drugs called phosphodiesterase-4 selective and Tropical Medicine and was co-funded inhibitors (PDE4 inhibitors) can help by the Department of Health and the relax the tightened airways and reduce Scottish Office. inflammation by triggering the build up All about ADAM of a messenger protein called cyclic AMP A team led by MRC Professor Stephen (cAMP). However, the PDE4 inhibitor “This clinical analysis Holgate at Southampton University drugs that are already on the market previously identified a gene, ADAM33, often cause side effects such as headaches, could not have been which is strongly associated with scarring nausea and vomiting. undertaken without in the lungs as a result of asthma. The In a study funded by the MRC, Professor our long-term basic gene is linked to lung function in babies Miles Houslay of the University of and small children and the team is now science effort Glasgow discovered a protein molecule, beginning further investigations into how PDE4A4, which controls levels of supported by the it may cause scarring and whether it may messenger chemicals involved in lung MRC.” predispose individuals to develop asthma. inflammation. The research could lead Professor Miles Houslay, to the development of PDE4 drugs with University of Glasgow fewer side effects.

MRC Annual Review 2004/05 19 Infectious diseases remain the leading cause of Warriors in the death in developing countries, while emerging infections and antibiotic resistance pose an fight against increasing threat to public health globally. infection

In 2004/05 MRC research led to changed stopped early after it was revealed that it the ‘binding sites’ of two antibodies that guidelines for the treatment of children reduced deaths by 43 per cent and prevent the malaria parasite from invading with HIV/AIDS, took scientists a step admissions to hospital by 23 per cent. red blood cells, using a new method of further towards a malaria vaccine, showed nuclear magnetic resonance (NMR) As a result of the findings the World that vaccination can prevent a deadly form spectroscopy. Dr Michael Blackman Health Organization and the Joint United of pneumonia in African children, and meanwhile determined the structure of Nations Programme on HIV/AIDS have identified an effective new drug treatment a molecule, AMA1, which Plasmodium changed their guidelines on the regimen for people with tuberculosis. falciparum uses to gain entry to red management of HIV-positive children in blood cells. countries such as Africa. Origins of AIDS These basic research studies could provide The origins of the HIV/AIDS epidemic the foundation for the first effective have puzzled scientists since the disease “This is a breakthrough vaccine for malaria, which affects first appeared in the early 1980s. A team, in medical research approximately 400 million people and kills led by Dr Jonathan Stoye of the NIMR, has around 2.5 million each year. now identified a potential clue. The team which can help to save found a difference in a gene that can make children’s lives all over Cell invasion certain kinds of monkeys immune to HIV. the world.” In other research, Dr Blackman led an The research revealed that a difference in international team that discovered a key The Rt Hon Hilary Benn, a single amino acid in the gene, way in which Plasmodium falciparum International Development Secretary TRIM5alpha, disrupted replication of the invades the body’s cells. The research HIV virus and so prevented HIV taking could be used to help develop improved hold in rhesus monkeys but not in humans. Malaria milestones drugs, for malaria and for other diseases As well as helping explain how HIV/AIDS The malaria parasite, Plasmodium caused by members of the Apicomplexan got a grip on the human population, the falciparum, is a complex organism with family, to which the malaria parasite discovery has implications for the several distinct life-cycle stages. It is this belongs. These include toxoplasmosis, development of gene therapy for complexity that has enabled it to escape a well-known cause of birth defects, HIV/AIDS. the vigilance of the immune system and and cryptosporidiosis, one of a number has, so far, made the development of a of opportunistic infections associated Saving the lives of children vaccine elusive. with HIV/AIDS. with HIV/AIDS Key discoveries made this year at our Discovery of the AMA1 molecule shown Around 1,300 children die from HIV and NIMR could, however, change this. here could aid in the development of a AIDS-related illnesses each day. In a trial Dr Tony Holder created a genetic map of malaria vaccine. funded by the Department for International Development, Professor Di Gibb of the MRC Clinical Trials Unit (CTU), London, found that a cheap, widely available antibiotic almost halved HIV/ AIDS-linked deaths in Zambian children.

The antibiotic, co-trimoxazole, was given to 540 HIV-positive children, aged between one and 14, in order to prevent opportunistic infections. The study was

20 MRC Annual Review 2004/05 MRC research |Infectious disease

IN BRIEF

Clue to infective mechanisms Scientists have discovered that a protein normally only found in the powerhouses of cells (mitochondria) is present in the parasite that causes amoebic dysentery. The researchers found that a structure called the mitosome also contains a mitochondrial carrier that transports an important chemical through the waterproof membrane that surrounds it. The research, which was carried out by Dr Edward Kunji and scientists from the MRC Dunn Human Nutrition Unit in Cambridge, the Royal Holloway, Vaccinating African children against pneumococcal pneumonia will save countless young lives. University of London, and the University of Newcastle, provides a clue as to how Preventing pneumonia Short course TB treatment the spread of infection may be tackled. Pneumococcal pneumonia kills over wins the day Traditionally, TB patients are put on an 1.6 million people a year, mainly in the Back to basics eight-month long course of drug developing world. A large clinical trial led Certain cells of the immune system can treatment. But the regimen is not always by Professor Felicity Cutts showed that genetically rearrange themselves in order well tolerated and some patients abandon vaccination could save the lives of the to generate different types of antibodies treatment resulting in the need for hundreds of thousands of children in capable of combating assault by foreign further courses, which can in turn developing countries at risk of this deadly bodies or antigens as they attempt to increase drug resistance. form of pneumonia. enter the body. Dr Michael Neuberger, of A trial led by Professor Andrew Nunn has the MRC Laboratory of Molecular Biology, The team followed 17,000 young children shown that a new six-month course of has taken an important step forward in in The Gambia, where pneumococcal treatment is more effective, and just as understanding the mechanisms exploited pneumonia is the leading cause of death in cheap, as the longer regimen. What’s by the immune system to ensure the children under two. Vaccination reduced more, just 4.9 per cent of patients on this production of customised antibodies mortality by 16 per cent and was 77 per regimen responded poorly, compared to following an encounter with antigens. This cent effective in preventing infection. There 10.4 per cent of those on the more basic science could eventually help in the was also a 37 per cent drop in the number traditional regimen. development of new treatment and of children with pneumonia. prevention approaches, including The trial was co-ordinated by the The trial, a four-year collaboration vaccination strategies, to antibody-based International Union against Tuberculosis between MRC scientists and colleagues at autoimmune diseases such as multiple and Lung Disease and the MRC Clinical the London School of Hygiene and sclerosis, rheumatoid arthritis and Trials Unit. The Tanzanian National Tropical Medicine, was co-sponsored by type 1 diabetes. Tuberculosis Programme has already the MRC and the USA National Institutes adopted the shorter regimen. If adopted of Health, with extra support from the Bill in other countries it could substantially and Melinda Gates Foundation. reduce the numbers needing re-treatment.

MRC Annual Review 2004/05 21 Mental health problems and other conditions involving Matters of the brain or mind affect many thousands of men, women and children. The psychological, social and the mind financial cost to individuals, their families and the country is incalculable.

MRC research completed in 2004/05 could aid the early diagnosis and treatment of schizophrenia, help inform decisions about cannabis, and enable the identification of young children with mild mental impairment.

Spotlight on schizophrenia One in 100 people in the world suffer from schizophrenia. The disease exacts a considerable emotional, social and financial toll on those who have it and their families. Ten per cent of sufferers commit suicide. It’s not known exactly what causes schizophrenia, but both genes and the environment play a part.

Since 1994, psychiatrist Professor Eve Johnstone has been studying what happens in the brains of people at a genetically high risk of schizophrenia, as part of the Edinburgh High Risk Study of Schizophrenia (EHRSS). Much of her that when participants were asked to Cannabis and psychosis research has involved examining brain perform a task involving sentence As with all multifactorial diseases, genes structure and chemistry using various completion, several areas of the brain are not the whole story in psychoses magnetic resonance imaging (MRI) functioned abnormally in those who went such as schizophrenia. Research by techniques to view their brains at work. on to develop schizophrenia. Professor Avshalom Caspi and Professor Professor Johnstone’s impressive research Terrie Moffitt, of the MRC Social, Genetic effort, which has been substantially Other research from the EHRSS found and Developmental Psychiatry Centre at supported by the MRC, led to her election that a genetic predisposition to the Institute of Psychiatry, King’s College as a Fellow of the Royal Society of schizophrenia was linked to a reduction in London, made an important discovery Edinburgh in 2005. grey matter in the frontal lobe of the that helps to explain how cannabis use brain, as well as to impairment of memory may trigger psychosis in genetically The anatomy of and other intellectual processes. A third susceptible individuals. schizophrenia study found that young people who Recent studies from the EHRSS have develop schizophrenia are more likely to In a study of 1,000 people from birth to shown that it is possible to predict be depressed, anxious or tense, even 32, the researchers found that those who members of high-risk families likely to when they are well. possessed a common variation in a gene develop schizophrenia and, just as sequence (polymorphism) had a five-fold These studies could open the way to importantly, those who are not likely to, increased risk of psychosis if they had used different or improved methods of years before the disease develops. cannabis frequently in their teens. diagnosis for schizophrenia, as well as In just one of many studies involving enabling doctors to intervene early to The increased risk applied to those who functional MRI (fMRI), researchers found delay or even prevent its onset. inherited a polymorphism in the COMT

22 MRC Annual Review 2004/05 MRC research | Neurosciences and mental health

gene, possessed by about a quarter of the In the first ever application of a technique in Cambridge have now shown that activity population. Around 15 per cent of those that allows scientists to scan the genome in the brain of a patient in a PVS was who had this gene variation later became for the whereabouts of thousands of gene similar to that of people without brain schizophrenic if they had smoked cannabis markers, Professor Plomin identified four damage when he heard words with more frequently during adolescence. regions likely to be involved in MMI in a than one meaning, such as “cricket”. This sample of 6,000 children. The research suggests that, although unable to respond, Genes and mild mental could eventually enable doctors to identify the patient was able to process what he impairment and help children with MMI well before it heard. The finding has considerable casts its long shadow over their childhood. implications for the classification, diagnosis Mild mental impairment (MMI) causes and rehabilitation of patients with PVS developmental delay, difficulties in learning following severe brain injury. in childhood and poor intellectual capacity Scanning the unconscious How best to treat people in persistent in adults. Professor Robert Plomin, also of vegetative states (PVS), who show no the MRC Social, Genetic and Development signs of detectable awareness, Psychiatry Centre, harnessed the has long been a source of controversy. techniques of molecular genetics to search Dr Adrian Owen and scientists from the regions of DNA for gene variations MRC Cognition and Brain Sciences Unit associated with the condition.

IN BRIEF

Dyslexia gene identified derived from a single gene called KIAA0319. problem and our early studies suggest In a major breakthrough in understanding The researchers now want to discover exactly these may work for children, although more the origins of dyslexia, a team led by how the gene may disrupt reading and writing research is needed,” he commented. Professor Julie Williams and Professor ability. Michael O’Donovan from the MRC All ears Cooperative Group in Neuropsychiatric Half a world away Professor Karen Steel, MRC-supported Genetics at the University of Cardiff, ‘Left neglect’ is a phenomenon well known in researcher at the Wellcome Trust Sanger identified a number of gene variations adults with right-sided brain injury, for Institute, Dr Robin Lovell-Badge from the associated with dyslexia, most of which example as a result of stroke, who can act as NIMR and scientists from the University if the left-hand side of their world has simply of Hong Kong have discovered that the disappeared. Dr Tom Manly at the MRC gene SOX2 is responsible for sensory Cognition and Brain Sciences Unit, Cambridge, development in the inner ear. The research has shown that while a degree of left neglect was the result of 12 years of research on a is present in all children when they are bored, mutant mouse, dubbed Yellow Submarine. children with attention deficit hyperactivity The team found that SOX2 is needed disorder (ADHD) reach the point of left to switch on the function of the tiny hair neglect more quickly unless they are on cells in the inner ear that detect sound, stimulant medication. “We have no idea how movement and balance. In the long-term, many children are affected, if they grow out of SOX2 may be a useful tool in the it, or if it is permanent. However, there are development of treatments for deaf or some effective treatments for adults with this severely hearing-impaired people.

MRC Annual Review 2004/05 23 As average life expectancy increases all over the Learning globe, the need to know more about the causes about ageing of ill health and disease in later life becomes vital.

In 2004/05 MRC scientists made findings Barker of the Cambridge Centre for Brain dramatically relieve the crippling symptoms that could help improve the diagnosis Repair used functional MRI (fMRI) to of advanced Parkinson’s. and treatment of Parkinson’s disease, define the range of these ‘cognitive Recently Professor Aziz has discovered revealed possible mechanisms of memory deficits’ in people with early Parkinson’s. that implanting an electrode into another loss in diseases such as Alzheimer’s, and The MRC-funded research is part of an region of the brain, the pedunculopontine discovered how genes and the ongoing project at the Parkinson’s Disease nucleus, can reverse Parkinsonian akinesia. environment may interact in osteoporosis. Research Clinic, which is collecting data This is one of the most disabling symptoms about Parkinson’s patients in East Anglia. of Parkinson’s, involving difficulty starting Parkinson’s laws As well as fMRI, the project involves and maintaining movement. One of the most devastating diseases of assessing patients clinically, taking blood later life is Parkinson’s disease. One in 500 The research, which used monkeys, is now samples for DNA analysis, looking for people – around 120,000 individuals – in being translated into a possible clinical genetic risk factors and performing the UK have the disease, which causes treatment. Several patients in Rome have postmortem brain analysis. symptoms such as tremor, muscle rigidity had an operation that, if effective, could and slow movement. Relieving Parkinson’s benefit many patients with Parkinson’s who are currently untreatable. Mutations in mitochondrial genes are symptoms associated with an increased likelihood of Parkinson’s is caused by a deficiency of the Memories are made of this Parkinson’s and Alzheimer’s disease. messenger chemical, dopamine, in the brain. A part of the brain called the medial Dr Miguel Martins of the MRC Toxicology The drug, L-dopa, has long been used to temporal lobe is critical for memory. Unit and researchers from Cancer ‘unfreeze’ patients by restoring levels of Damage to this area, for example as a Research UK showed that, in mice, a dopamine. However, 20 per cent of result of Alzheimer’s, can be a key cause mitochondrial protein, Omi/HtrA2, is patients do not respond to the drug, and it of memory loss in old age. In research involved in protecting the nerve cells can also cause debilitating side effects. funded by the MRC and the Alzheimer’s that die in Parkinson’s. Collaborative Thirty thousand people worldwide have Research Trust, Dr Kim Graham and research with other European groups had an operation called deep brain Dr Andy Lee of the MRC Cognition and has shown that two German families with stimulation, pioneered by Professor Tipu Brain Sciences Unit, Cambridge, found Parkinson’s disease have a mutation in Aziz. It involves implanting an electrode that patients who had problems this protein. They are now being studied deep within an area of the brain known as remembering following brain damage to understand more about the role of the subthalamic nucleus. In carefully show different patterns of memory loss, Omi/HtrA2 in Parkinson’s. selected patients, the procedure can depending on the precise area of the Diagnosing Parkinson’s The typical movement symptoms of Parkinson’s are often accompanied by an impaired ability to think, perceive, reason or remember, especially in tasks involving organisation, setting priorities, managing time and making decisions. Dr Roger

Understanding how brain activity is affected in Parkinson’s disease could aid the rehabilitation of patients with memory problems.

24 MRC Annual Review 2004/05 MRC research | The ageing population

medial temporal lobe that is damaged. IN BRIEF Their findings will help increase Fit at 50 understanding of memory loss and have implications for the rehabilitation of Research from the long-running Whitehall II study has shown that staying physically patients with such problems. active at around the age of 50 is crucial Dr Graham gained the European Society for future health and well-being. Dr Eric for Cognitive Psychology’s 2005 Paul Brunner and Dr Melvyn Hillsdon, of the Bertelson Award, which is given for Department of Epidemiology and Public an outstanding contribution to Health, University College London, science by a young scientist. analysed the lifestyles of a group of relatively fit and healthy middle-aged Commenting on the award the jury working men and women. Those who said, “Dr Graham’s findings... have did two and a half hours of moderate challenged the dominant theories of long- Boning up on osteoporosis physical exercise or an hour of vigorous term memory.” Her more recent work, A discovery made by MRC researchers in activity a week were much more likely which unites insights gained from fMRI Southampton could have a strong impact to have remained fit and healthy nine with human data and animal models of on the detection and treatment of the years later, compared to those who were memory, is a superb example of an brittle bone disease, osteoporosis, that sedentary. The findings suggest that integrative approach to research. strikes one in three women aged over 50. being active at 50 can help to prevent The team, led by Professor Cyrus Cooper, disability, extend independent living and A time and a place for found startling evidence that some people increase the quality of life in later years. remembering may have a defect in a gene, GH1, which Whitehall II is led by Sir Michael Marmot, Distressing consequences of Alzheimer’s who is supported by an MRC clinical regulates the amount of growth hormone professorship. To find out more about disease such as amnesia and getting lost produced. This in turn affects bone the study turn to page 29. are a result of degeneration of a part of density. The team found, moreover, that the brain named the hippocampus, which the action of the gene could be partly Refining surgery enables us to recall things that happened moderated by factors such as diet in the In research into Parkinson’s surgery, in a particular place and time. womb and early childhood. Professor Paul Bolam and Dr Peter Magill of the MRC Anatomical Professor Neil Burgess heads an MRC- Neuropharmacology Unit, Oxford, funded group looking at the formation of identified a signature brain wave that the hippocampus, at University College “Our findings suggest could improve the precision of deep London. Working with Professor John that the impact of an brain stimulation. Currently, because of O’ Keefe, he studied the action of adverse genetic make-up the difficulty pinpointing the exact part hippocampal ‘place’ cells that encode of the subthalamic nucleus in which to information about the spatial environment. might be minimised by implant the electrode, the procedure Their research is a key early step in involves two operations and patients improving the understanding what goes wrong in have to be conscious. Their finding could environment in the hippocampal cells in diseases such as speed up the procedure and enable it Alzheimer’s. The next task is to examine to be done under general anaesthetic in womb.” a single operation. how nerve cells fire off in mouse models Professor Cyrus Cooper, of Alzheimer’s, and to begin to look at the MRC Epidemiology Resource Centre, effects of drugs on this. Southampton

MRC Annual Review 2004/05 25 Obesity and being overweight are Meeting the a growing threat to human health, not just in the UK, but throughout challenge of obesity the world.

During the last year MRC scientists established the structure of a microscopic ‘motor’ involved in generating energy in cells, shed light on the part played by brain chemicals and stomach hormones in appetite control, and helped clarify the role of diet and exercise in the development of diabetes in those with a genetic predisposition.

Risks of obesity More than a fifth of men and women aged 16 and over in England are obese, and a further half of men and a third of women are overweight. Worldwide, more than a billion adults are overweight and at least 300 million are obese. Obesity and being

GLOSSARY

ATP Adenosine triposphate. A high energy phosphate molecule used to store and release energy in cells. ATPase Adenosine triphosphate synthase. An enzyme responsible for converting the energy in ATP into the fuel The discovery of the structure of the molecular motor ATPase will enable scientists to understand that drives cells. how the body creates energy. Bacterium A microscopic organism overweight pose a major risk for chronic Although scientists have studied molecular composed of a single cell. As such it can diseases, including type 2 diabetes, motors for many years now, they still do provide a simple and accessible model for cardiovascular disease, high blood pressure not fully understand how they work. the cells of more complex organisms such as human beings. and stroke, and certain forms of cancer. Professor Sir John Walker, of the MRC Dunn Human Nutrition Unit, and Dr Insulin Hormone produced by the Andrew Leslie, from the MRC LMB, have pancreas needed for glucose to enter cells Power break where it is used for energy. Molecular motors, unimaginably tiny determined the structure of a key part of protein-based machines, convert energy nature’s smallest ‘rotary’ motor – an Insulin resistance A condition in which (usually stored in a molecule called ATP) enzyme called ATPase – in a bacterium the pancreas is still producing insulin, but the body cannot respond to and use the into a fuel that can be used by cells, in found in the gut. ATPase is needed to hormone. much the same way that an engine drives a persuade ATP to release its fuel. car. Molecular motors have many jobs – Neuropeptide Y A messenger chemical The research builds on previous work by from enabling sperm to swim, to making that is found in the brain and its Professor Walker, which won him the muscles move or turning light signals into periphery, which acts as a powerful 1997 Nobel Prize for Chemistry (with appetite stimulator. nerve impulses in the eye. Professor Paul Boyer). His latest finding

26 MRC Annual Review 2004/05 MRC research | Obesity, diet and diabetes

IN BRIEF will help scientists understand more about animal origin – reduced the risk of Premature baby = fat the molecular basis of many biological diabetes. Such a diet together with plenty adult? processes, including one of the most of physical activity also helped to lower Poor pre-natal growth is a risk factor for crucial: the way in which our bodies make fasting insulin levels in those with a later insulin resistance and type 2 energy from food. mutated gene linked to insulin resistance. diabetes, both of which are strongly Insulin resistance, in which the body is associated with an ‘apple-shape’, where Hunger, food and unable to use the insulin it produces, is a fat is stored around the waist. Using a body weight precursor to type 2 diabetes. new whole body MRI scanning technique, Professor Steve Bloom, of the Division of Dr Jimmy Bell’s team at the MRC Clinical The research reinforces dietary advice to Investigative Science, Imperial College Sciences Centre, London, found that step up consumption of polyunsaturated London has been examining the premature babies or those with poor fats and reduce consumption of animal fats. relationship between hunger, food and pre-natal growth already had this pattern It also increases understanding of the weight gain for a number of years. A key of fat distribution. relationship between genes and lifestyle in finding this year was that a brain chemical, insulin resistance, A tale of fat mice called neuropeptide Y, is important in the obesity and In type 2 diabetes, insulin action in control of food intake. He also discovered diabetes. muscle, fatty tissue and the liver is faulty that suppression of ghrelin, an appetite- and the function of ‘beta cells’ in the stimulating hormone produced by the pancreas is altered. MRC Fellow Professor stomach cells after a meal, is impaired in Dominic Withers and a team from those who are obese. These and other University College London showed that results could be used to manipulating an insulin ‘signalling’ molecule, called Irs2, in specific cells help develop effective in the brains of mice and in the insulin- drugs for obesity and generating part of the pancreas made anorexia. The research them fat and caused them to develop was funded by the MRC in partnership diabetes. with the Wellcome Trust and the Biotechnology and Biological Sciences How much did you eat Research Council. today? Dr Susan Jebb, of the MRC Human Fat of the land Nutrition Research centre, has discovered What part does eating fat play in the that adults and young people under-report development of type 2 diabetes? Does the their calorie consumption in dietary surveys by as much as a quarter. And kind of fat we eat matter? And what is the those who are obese are even more relationship between physical activity and sparing with the truth. The research, fat consumption in people at risk of type 2 which was co-funded by the MRC and diabetes? These were questions posed by the Food Standards Agency, prompted Dr Nicholas Wareham’s team at the MRC a revision in the way surveys are carried Epidemiology Unit, Cambridge. out in the National Diet and Nutrition Survey Programme. The team discovered that a diet high in polyunsaturated fats – found mainly in seeds, nuts and vegetables – and low in saturated fats – present in foods of

MRC Annual Review 2004/05 27 MRC-funded population studies, UK and Towards better overseas health departments, universities, and other research funders have a pivotal role in health for all the Government’s attempts to reduce health inequalities.

In 2004/05 discoveries have been made about the origins of adolescent depression, the importance of children staying in touch with their fathers after divorce or separation, the role of fish consumption during pregnancy on children’s language and communication, the influence of the work-life balance on mental health, and the effect of company reorganisation on employees’ health.

Roots of the blues Once depression takes hold it sometimes persists for life. It is vital, therefore, for doctors to find ways to identify young people at risk so they can be helped. region. It is helping scientists and doctors When did you last see Dr Thalia Eley of the Social, Genetic and to discover a great deal about how the your father? Developmental Psychiatry Research interplay of genes and the environment How important is it that children maintain Centre at London’s Institute of Psychiatry can influence health throughout life. The a strong bond with their natural father found that teenagers aged 12 to 19 with a MRC has co-funded the study with the when their parents separate? ALSPAC family history of depression and whose Wellcome Trust and the University of researchers led by Professor Judy Dunn parents had a low level of education were Bristol since 1991. These are just some of studied 162 children whose parents had more likely to become depressed. The the results of 39 studies ALSPAC separated. They found a direct link researchers found a gene, the serotonin published in the last year: between behavioural problems, such as transporter promoter, which seemed to aggression, delinquency, withdrawal and increase the risk of depression in teenage Left hand, right hand depression, and the amount and quality of girls, but only when these other risk Professor Vivette Glover asked mothers contact children had with their biological factors were present. The research is yet with toddlers aged three and a half which fathers. another example of how the effect of hand their children used for throwing a genes can be modified by the ball, drawing and other tasks, as part of an environment. ALSPAC study of 7,400 mothers and “This underlines the children. The results suggest that a woman importance of separated who suffers anxiety during mid-pregnancy is more likely to have a child who is mixed parents developing Children of the Nineties handed – one who uses either hand – and a good working that this may be associated with a range of Avon calling conditions such as autism, dyslexia and relationship over their The Avon Longitudinal Study of Parents hyperactivity. Measures to alleviate stress children’s needs.” and Children (ALSPAC), also known as and anxiety during pregnancy could reduce Professor Judy Dunn, Institute of Children of the Nineties, is tracking the the prevalence of mixed handedness, and Psychiatry, King’s College London health of 14,000 children throughout the of these associated problems.

28 MRC Annual Review 2004/05 MRC research | Health inequalities

A fishy story South Asian people actually tended to be Researchers found that regular fish more likely to undergo investigative consumption was linked to better language procedures for heart disease and to be on and communication skills in offspring at 18 secondary prevention drugs. The research months. The researchers found that was funded by the MRC with the USA toddlers whose mothers ate fish at least National Institutes for Health, the British once a week during pregnancy scored Heart Foundation and the Health and seven per cent higher in tests of word Safety Executive. comprehension than those whose mothers never ate fish. Equalising the work-life balance Juggling the competing demands of work and family can cause stress and put a strain on health. Dr Tarani Chandola and a team Whitehall II analysed the effect of the work-life balance on civil servants in the UK, Finland and From mandarins to Japan. They found that single fathers in all messengers three cohorts, and single mothers in the Since 1985 the Whitehall II study has Finnish cohort, had poorer mental health. sought to establish the effects of stress at This was partly explained by higher levels work, job security, change in the of conflict between their work and family workplace, the work-life balance and a lives. Overall Japanese women experienced whole range of lifestyle factors, on the the greatest conflict between work and health of civil servants at work and after family and had the poorest mental health, they retire. The results of this study and while Finnish women had the lowest its predecessor, Whitehall I, are now conflict and the best mental health. feeding in to policy discussions and Professor Sir Michael Marmot, who has The adoption of family-friendly working GLOSSARY led the research for the past 20 years, has policies, such as those used in Finland, Cohort study A research study that won the 2004 Balzan Prize for could potentially reduce the negative involves observing a large number of Epidemiology and has been invited to chair effects of stress on health caused by people over a long period of time to the Commission on Social Determinants of juggling work and family life. assess the incidence of certain diseases Health. Here are just a few of the study’s or outcomes in relation to their exposure findings in 2004/05: Going by the book to various lifestyle factors. The Whitehall II team has produced a 28- Serotonin A brain messenger chemical The heart has its reasons page ‘plain English’ guide, Work, Stress and sometimes known as the happiness People of low socio-economic status and Health: the Whitehall II study, in association hormone. Disturbances in serotonin are of South Asian origin are more likely to with the Cabinet Office and the Council of linked to depression. develop heart disease. But is this to do Civil Service Unions. It aims to stimulate Secondary prevention drugs Drugs with differences in their access to debate about ways to promote better used to treat those with established heart investigation and treatment? Apparently health at home and in the workplace. disease and those at a high risk of not, according to a Whitehall II team led To download a copy visit www.ucl.ac.uk/ developing it. by Dr Annie Britton. They found that whitehallII/research/Whitehallbooklet.pdf

MRC Annual Review 2004/05 29 While basic science is vital to understanding From research the origins of disease, at the other end of the research pipeline clinical trials – of drugs, surgical to practice techniques and other interventions – are equally important to human health.

In 2004/05 MRC researchers reported The researchers are now investigating the results that could improve the treatment impact of corticosteroids on disability in “This result has allowed of people injured in car crashes, help the six months following head injury and us to avoid the delay, thousands at risk of dying from the will perform a second trial (CRASH-2) rupture of one of the body’s main arteries, to investigate the extent to which anti- costs and side effects and bring faster relief to sufferers from clotting drugs may reduce major bleeding associated with using a back pain. after trauma and so save lives. treatment which is The work involved researchers from actually ineffective.” CRASH alert the London School of Hygiene and Globally, more than a million people die Tropical Medicine and the universities Dr Robert Davies, from head injuries each year and a similar of Birmingham, Edinburgh, Manchester Oxford Centre for Respiratory Medicine number are disabled, mainly as a result of and Oxford. car crashes. For the past 30 years people with head injuries have been treated with The drugs don’t work Bubble trouble anti-inflammatory corticosteroid drugs in Sixty-five thousand people a year from the Ruptured abdominal aortic aneurysms the belief that these could prevent life- UK and USA develop potentially life- (AAAs), in which a balloon-like swelling in threatening brain swelling. threatening pleural infection as a result of one of the body’s main arteries bursts, kill However, the results of the MRC CRASH pneumonia. The condition, in which fluid thousands of older men and women each trial, the largest-ever randomised, double- and pus accumulate in the membranes year. Professor Roger Greenhalgh, Chief blind trial of head injuries, showed that around the lungs, often affects the elderly, of Service for Vascular Surgery at the corticosteroids actually increase the risk of homeless and drug users. Hammersmith Hospitals NHS Trust, and death after head injury. Head of Vascular Surgery at Imperial Previous small studies suggested that College London, has been evaluating a The study, which involved 10,000 people administering the clot-busting drug, promising treatment technique with the from 50 countries, found that 21 per cent streptokinase, might help resolve pleural help of MRC funding. of those who were administered infection by breaking down pockets corticosteroids died within two weeks, of pus and thinning the fluid so it Conventional surgery for AAA involves a compared to 18 per cent of those can be drained more easily. deep abdominal incision. The new given a placebo. minimally invasive technique, endovascular But a large study of more than 450 aneurysm repair (EVAR), could help patients in 52 UK hospitals found patients avoid this complicated and that there was no reduction in potentially dangerous procedure. It death rates among those involves placing a Dacron graft within the administered streptokinase aneurysm, which is held in place with a over those given a placebo. stainless steel expandable ‘stent’, to There was also no difference in prevent the vessel walls collapsing. the need for drainage surgery Early findings from the trials, the largest or length of stay in hospital UK surgical trials currently in progress, between the two groups. show that, a month after surgery, the The study was supported death rate after EVAR is two thirds less by the MRC and the British than following conventional surgery. The Thoracic Society. trials have involved close collaboration

30 MRC Annual Review 2004/05 MRC research | Clinical investigation and trials

should help speed the progress of new treatments from basic research into routine clinical care, so improving the health and quality of life for people with cancer.

GLOSSARY

Anti-inflammatories Drugs that reduce inflammation and swelling in the body. Antifibrinolytic drugs Drugs that promote blood clotting by preventing the breakdown of clots and so reduce blood loss. Aortic aneurysm An abnormal ballooning of the wall of the aorta, the main artery leaving the heart, usually between surgeons and radiologists and are Dr Madge Vickers from the MRC General caused by arterial disease. also providing 14 national training centres Practice Research Framework. Corticosteroids Synthetic versions of for the use of the technique in AAA. the natural hormone cortisone, which is The truth about trials produced by the adrenal gland. BEAM of hope for back pain Clinical trials are the best way to find out Clinical trial A carefully designed study Back pain affects approximately if tests, treatments or other interventions to assess the safety and efficacy of a drug 17.3 million people in the UK, over one are safe and effective. Many people with or treatment strategy in humans. third of the adult population. Patients who cancer, for example, are alive today as a Dacron graft A synthetic material that complain of lower back pain to their GPs result of patients participating in clinical can be formed into a tube for use in are at the moment encouraged to trials over the past 30 years. According to replacing or repairing blood vessels. continue normal activities and avoid rest. researchers from the MRC Clinical Trials Double-blind trial A trial in which Researchers from the back pain, exercise Unit, more patients are taking part in neither the doctor nor the patient know and manipulation (BEAM) trial assessed the cancer trials in the UK than at any point in which treatment the patient is receiving, cost effectiveness of adding spinal the last three decades. in order to reduce bias. manipulation techniques such as The research, published in The British Placebo A dummy treatment. osteopathy and chiropractice, exercise Journal of Cancer, looked at clinical trial Randomised controlled trial (RCT) classes, or manipulation followed by trends between 1971 and 2000. It showed The ‘gold standard’ of clinical trials, RCTs exercise, to existing ‘best care’ practice. a sustained rise in the number of patients involve assigning patients at random into They concluded that spinal manipulation taking part in trials, together with a trend groups receiving the treatment under was a cost-effective addition, although investigation, a standard treatment or a towards larger, multi-centre investigations. manipulation alone probably gives better placebo. value for money than manipulation The team also found that the time taken Stent A small stainless steel mesh tube, followed by exercise. The trial was to complete trials has dropped from which when inserted into an artery, acts directed by Professor Ian Russell, around seven years to two years, as a as a scaffold to support the vessel walls. Professor Martin Underwood and result of increased recruitment. This trend

MRC Annual Review 2004/05 31 Turning scientific discoveries into healthcare From discovery demands considerable investment. MRC Technology (MRCT), our affiliated company, to treatments works with the biotechnology industry to achieve this.

Accelerating drug discovery to the interleukin IL-6 receptor. Actemra’s To drive forward translation of our pharmaceutical developers hope that it may “This has been a scientists’ fundamental findings into new soon be approved for use in rheumatoid breakthrough year for therapies, MRCT set up a drug discovery arthritis as well. us with two novel group in 2004 with the help of £9.5m MRCT also develops pioneering new funding from the MRC’s commercial fund. equipment for scientists, such as a medicines for the The group’s work will span all of the remarkable form of optical microscopy treatment of serious research that the MRC funds, including called optical projection tomography disease reaching the some disease areas that are usually (OPT). Invented by Dr James Sharpe at the neglected by the pharmaceutical industry. MRC Human Genetics Unit in Edinburgh, market, both the direct MRCT’s laboratories in North London OPT enables scientists to produce result of collaborations have been upgraded to provide the computer-generated 3D images of small between MRCT and necessary ‘state-of-the-science’ facilities, biological samples to reveal their full including high throughput screening complexity. Its many potential applications industry.” involving robots and other specialised include speeding up and improving the Dr Roberto Solari, CEO, MRCT techniques to search thousands of accuracy of medical diagnosis. compounds to identify which have the Many healthy returns potential for development into new drugs. KEY CONCEPTS MRCT initiates the ‘technology transfer’ of Two new treatments for MRC scientists’ discoveries by patenting Monoclonal antibodies Often referred serious disease the intellectual property and negotiating to as ‘magic bullets,’ these are custom- licensing agreements with biotechnology MRCT is renowned for its development of made protein molecules that have been companies, who then carry out further designed to home in on specific targets. ‘humanised’ monoclonal antibody therapies, research to translate this scientific They are made by stimulating a mouse’s using techniques first developed at the knowledge into new healthcare immune system to produce antibodies to MRC Laboratory of Molecular Biology in technologies. The resulting benefits for the target. The antibody-producing cells the 1980s. (See Key Concepts opposite.) human health can range from new drugs are made ‘immortal’ by fusing them with a cancer cell, which enables them to be This year two more humanised monoclonal to important advances in diagnostic or manufactured on an industrial scale. antibody drugs received marketing surgical techniques, depending on the Dr César Milstein and Dr George Köhler approval. Tysabri is the first of a whole nature of the original discovery. In this discovered how to make monoclonal new class of drugs for the treatment of way MRCT promotes the speedy antibodies at the MRC Laboratory of relapsing-remitting multiple sclerosis. development of innovations in clinical Molecular Biology (LMB), an achievement It marks a real breakthrough for the practice, but without the massive that earned them the 1984 Nobel Prize. treatment of this debilitating and investment usually needed for such work. Humanisation Before being used in distressing disease. The licensing income we receive through patients, mouse antibodies are usually modified. This technique, known as Another completely original drug, Actemra, MRCT is ploughed back into basic medical humanisation, was invented at the LMB has been launched in Japan as a result of research. In 2004/05 it was £28.5m, making by Sir Greg Winter. It involves the genetic technology transfer by MRCT. Developed the MRC’s rate of return on technology transfer of the active parts of mouse to treat Castleman’s disease, a rare transfer approximately three times that antibodies into human antibodies, so that condition affecting the lymph nodes, this achieved by USA universities and 15 times they are not rejected by the human body. inflammation-blocking drug is an antibody that achieved by UK universities.

32 MRC Annual Review 2004/05 Image credits: P7 Computer illustration of an influenza virus from the orthomyxovirus group. BSIP, Cavallini James, Science Photo Library. P11 Diamond synchrotron. Courtesy of Diamond Light Source Ltd. P14 Scanning electron micrograph (SEM) of a breast cancer cell dividing in the telophase stage of cell division (mitosis). Steve Gschmeissner, Science Photo Library. P15 Open chromatin structure. Professor Wendy Bickmore, MRC Human Genetics Unit. P17 3D computed tomography scan of a stenosis (narrowing) of one of the carotid arteries of the neck. BSIP, Gondelon, Science Photo Library. P20 AMA1 structure. Dr Michael Blackman, MRC National Institute for Medical Research. P21 Doctor examining a child at MRC Kaneba, Fajara, The Gambia. Felicia Webb. P24 fMRI brain activation maps of patients with Parkinson’s disease. Dr Roger Barker, MRC-University of Cambridge Centre for Brain Repair. P26 ATPase rotor. Professor Sir John Walker, MRC Dunn Human Nutrition Unit. P31 AJ Photo, Hop Americain, Science Photo Library. Medical Research Council 20 Park Crescent, London W1B 1AL Tel: 020 7636 5422 Fax: 020 7436 6179 www.mrc.ac.uk

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