06/07 People behind discovery Annual Review The Medical Research Council 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.

01 Vision & hearing page 4 02 Neurobiology & neurodegeneration page 6 03 Mental illness & behavioural disorders page 10 04 Genetic diseases page 14 05 Cancer page 18 06 Heart disease & stroke page 22 07 Obesity & diabetes page 26 08 Infections & the immune system page 30 09 Public health page 34 10 Turning research into healthcare page 38 Supporting careers in medical research

For almost a century, the Medical Research Council (MRC) has employed and funded people who’ve made pioneering discoveries and improved the health of millions. Together these scientists, clinicians, support staff, technicians, nurses, business managers, administrators, engineers and countless other people have created an unsurpassed catalogue of achievement. Today, we employ more than 4,000 staff in our own research institutions and support about another 3,300 researchers and students on grants.

The MRC is an employer as well as a research funder. Some of our researchers start their careers on studentships or fellowships with the MRC. Others are supported on grants or in our units for a time before moving on. Many spend their whole career with the MRC. Our scientists work in many different research environments. These include hospitals, universities, medical schools, the biotechnology, diagnostics and pharmaceutical industries and MRC units, institutes and centres. The MRC also supports people who later in their careers might help move science into policy and practice.

In this year’s Annual Review we feature some of the discoveries made by MRC scientists during the past year. We also introduce you to some of the people behind these discoveries. Each of these people has a story to tell about the work they do and the career path they’ve taken. For instance, Viv Moffat at the University of Edinburgh, who previously worked as a mental health nurse, has just finished her PhD. She is contributing to a decade-long study of brain imaging and schizophrenia. Dr Rachel Batterham is an obesity and diabetes specialist, who spends much of her time undertaking research to try to find new ways to help the patients she treats. Professor Steve Brown runs the MRC’s Mammalian Genetics Unit at Harwell. He is researching the genetic causes of deafness. And Professor Jeanne Bell started her career in anatomy but then moved to pathology and neuropathology. For more than two decades she has been researching the effects on the brain of HIV and its treatment.

The wide range of training opportunities available to scientists means careers can be forged in various ways. For instance, the MRC Career Development Fellowship scheme provides early career post-doctoral scientists with training positions within MRC research units to help establish themselves as research scientists. Our Clinician Scientist Fellowship scheme gives up to five years of funding for post-doctoral scientists in universities. We offer training awards in particular areas where there are national shortages, such as biostatistics, stem cell biology and public health. We also run studentships, aimed at supporting post-graduate students, in collaboration with other research funders, universities and industry. This is just a snapshot of the MRC’s dedicated training schemes. For more information about these programmes and others, visit www.mrc.ac.uk/careers.

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… it’s important to develop scientists beyond their research … it’s less about a job for life and more about providing opportunities, skills and knowledge for life.

MRC Annual Review 2006/07 1 continued …

The MRC doesn’t just support scientific careers – we also have hundreds of people sustaining our research, working in administration, business, intellectual property and the many other roles needed to facilitate the best medical research. For example, over the past year we have increased training opportunities and expanded the national qualifications available for our animal technicians. We have also completed a trial training a group of staff to diploma level in management skills.

But we don’t work in isolation. We achieve much more when we work closely with other organisations to tailor the finest range of training and development opportunities available. The Department of Health (www.dh.gov.uk), the UK Clinical Research Collaboration (www.ukcrc.org), the Research Councils UK’s Research Careers Diversity Unit (www.rcuk.ac.uk/rescareer/rcdu), the other research councils (www.rcuk.ac.uk), universities and charities such as the Wellcome Trust (www.wellcome.ac.uk) are just some of the organisations we work with to make this happen.

As the UK landscape for medical research changes, the MRC is well placed to continue to foster the best scientists and the best science. The introduction of an Office for Strategic Coordination of Health Research (OSCHR) to oversee medical research in the UK means that, in the future, the MRC will work even more closely with the Department of Health’s National Institute for Health Research (www.nihr.ac.uk) and with other medical research organisations and industry. These changes will present more opportunities for training the next generation of medical researchers.

The MRC realises that it’s important to develop scientists beyond their research. These days, it’s less about a job for life and more about providing opportunities, skills and knowledge for life. What we do wouldn’t be possible without the people who make up the MRC. We hope that you’ll enjoy reading the stories of just a few of these people and finding out about some of our scientific achievements from the past year. Welcome Professor Colin Blakemore, MRC Chief Executive

In any career, nothing is more important than the people who teach you and the environment in which you learn. In my own career, I was very lucky in both respects.

I was the first person in my family to go to school beyond the age of 15. My parents knew nothing about higher education but were extraordinarily encouraging. I passed my 11-plus, went to an excellent grammar school in Coventry and won a State Scholarship to study medicine at Cambridge, which covered all my costs. The academic ethos of Cambridge was intoxicating for me, from a working-class background, unsure what I wanted to do with my life. It was the early sixties, just 10 years after the discovery of the structure of DNA. The realisation that, just a stone’s throw from where I was studying, Crick and Watson had revolutionised our understanding of life had a huge impact on me.

I won a Harkness Fellowship to study in the States after I graduated from Cambridge, and went to the University of California, Berkeley, to work with Horace Barlow, great-great-grandson of Darwin and one of the most influential neurophysiologists of the last century. Again, I found myself in an extraordinary environment. It wasn’t so much the quality of the facilities – techniques were pretty simple then. It was the passion and support of the others in the lab – not just the leaders, but the postdocs and the other graduate students, all learning from each other through the curious mixture of tedium and exhilaration that makes research such a remarkable career.

Luck is important, I must admit. And I was very lucky. My research was a goldmine: I finished my PhD in record time and was offered a tenure-track position at Cambridge at the age of 23. And I picked up my first grant from the MRC just a year later. That enabled me to set up my own lab, but I also benefited from collaboration with Fergus Campbell, Roger Carpenter and many others in Cambridge. I found myself in the middle of a little scientific revolution – the birth of neuroscience as a discipline in its own right. With a lot of support from the MRC over the years, I never looked back.

I sometimes regret not completing a clinical degree and not having the experience of a postdoctoral appointment. There were disappointments and challenges along the way (not least the 13 years for which I was targeted by animal rights extremists). But the joy of discovery, and the camaraderie of my research group, with young people from around the world, compensated for any problems.

Things are different today. Training has to be longer. Jobs are harder to find. Competition is more extreme. But medical research is still a wonderful career – a chance to comprehend things that no- one has ever understood before and to be part of a worldwide effort to improve the lives of others.

MRC Annual Review 2006/07 3 Name Robin Ali Name Robert MacLaren Education Undergraduate and PhD Born 14 November 1966 in Epsom, Surrey at University College London Education MB ChB, University of Edinburgh; Awards 2001 Sir Jules Thorn Award DPhil, University of Oxford for Biomedical Research Family Married with three children: William Current job title Professor of Human (3), Imogen (2) and Edward (6 months) Molecular Genetics Awards 2007 King James IV Professorship Time in current position 5 years of Surgery, 2005 Oxford Ophthalmological Field of research Development of Congress Founder’s Cup and Medal, 2005 gene and cell therapies for the Royal Society of Medicine Prize Meeting treatment of eye disease in Ophthalmology Ambition To make a real difference Current job title Clinician Scientist and to patients with visual impairment Honorary Consultant Career highlight Helping perform the world’s first retinal gene therapy treatment Blind mice see again Professor Robin Ali and Dr Robert MacLaren (see profiles) at the Institute of Ophthalmology/Moorfields Eye Hospital 01 Vision & hearing in London have overcome a major hurdle to restore vision in blind mice. Their work could have a significant impact on stem cell therapy, particularly for patients with untreatable eye diseases. The mice had photoreceptor loss, which is the cause Sight and hearing are two of our most important senses. But around two million people in of irreversible blindness in many human the UK have a sight problem and nine million are deaf or hard of hearing. That’s why vision diseases. In the retina, transplanted and hearing are important parts of the MRC’s remit. photoreceptors only need to make one short connection to repair sight but previous attempts to do this have failed. Profile Robin Ali, Institute of Ophthalmology, London Professor Ali and Dr MacLaren tried transplanting retinal cells at a later stage of “My undergraduate degree in genetics was followed by a PhD and postdoctoral research development – using photoreceptors taken that used genetic technology to develop models of various disorders in mice. Since joining from mice just before the retina was fully the University College London Institute of Ophthalmology in 1994, my research has focused formed. These integrated successfully into on eye disease and developing new treatments. I didn’t want simply to understand disease the retinas of blind mice and restored some processes. For the past five years we have become increasingly interested in testing new vision. Dr MacLaren said: “This research treatments in patients. I now feel certain that my research has a very clear aim and objective is the first to show that photoreceptor – which is to treat clinical problems – and I find that satisfying. I enjoy having tangible transplantation is feasible. We are now milestones that we can measure ourselves against to see our progress over the past 13 years. confident that this is the avenue to pursue to uncover ways of restoring vision to Three highlights of my career have all come fairly recently. In 2000 I published a paper that thousands who have lost their sight.” described how we were able to use gene therapy to correct photoreceptor defects in an animal model of retinal degeneration. Last year’s Nature paper about restoring sight in blind mice using cell transplantation was another high. And at the moment we are engaged in the Children listen up first clinical trial of gene therapy to treat a genetic defect that causes blindness in children. Poor listening in children has been linked As for the future, I’d like to build up a programme of clinical trials so that we can see more to a number of developmental disorders, treatments – particularly cell and gene-based therapies – through to clinical application. To including dyslexia and language impairment. people interested in medical research, particularly seeing it put into practice, I’d say that you There is evidence that difficulties in judging need to have as broad a perspective as possible and have to work well with large teams of the difference between sounds may lead to people with lots of different expertise. I think that this is crucial for success.” abnormalities in how speech is represented in the brain and, in turn, could contribute to these language learning problems. Profile Robert MacLaren, Institute of Ophthalmology/Moorfields Eye Hospital Researchers at the Institute of Hearing Research in Nottingham have found “My father was a photographer, which led me to develop an interest in vision during my that just one hour of simple training can childhood. Cameras are similar to eyes in many ways. Rod photoreceptors, for instance, are improve listening in children as young as six like the grains of emulsion which react to light on black and white film, while a cataract is years old. The finding could lead to ways similar to condensation inside a camera lens. to tackle the difficulties language-impared children have judging sound. I studied medicine in Edinburgh, finishing house jobs in 1991, and then went on to a PhD studying retinal regeneration at Oxford, funded by an MRC Clinical Training Fellowship. After that I began clinical training in ophthalmology, finally specialising as a retinal surgeon at Moorfields Making sense of background noise Eye Hospital in London. But in 2004 I decided to give up all clinical work to go back into the MRC and Wellcome Trust funded lab. I met up with Robin and started a retinal stem cell project that fitted well with my previous scientists at University College London PhD work. My colleagues all thought I was mad, giving up a good position where I was about to have discovered that in noisy places such become a consultant to work in a lab, initially with no salary. It was tough, but my wife was very as a pub, the brain juggles the possible supportive. Sometimes there’s nothing better than a life changing decision to focus the mind. meanings of a sentence until it decides which is the most likely. The research Today I divide my time between the lab and clinical practice. Treating patients with eye may lead to improved hearing for people problems is very rewarding, but I also know that most retinal diseases are incurable. It is who have cochlear implants. Dr Jonas devastating to tell someone that nothing can be done to save their sight, but if a patient Obleser said: “In a noisy environment, knows we’re working hard to find a cure, it makes it easier for them to deal with. Our recent when we hear speech that appears to be breakthrough with retinal precursor cells was a real boost and the positive publicity has given predictable, it seems that more regions many patients hope for the future. I have had letters of support from people all over the of the brain are engaged. We believe this world – for most, simply the knowledge that someone, somewhere, is working on a potential is because the brain stores the sentence treatment means that they are not facing their blindness alone. Clinical practice is very in short-term memory. It juggles the much based on evidence or established treatments, often with little room for imaginative different interpretations of what it has thought. With clinical research, however, you can really let your mind fly. It is very creative heard until the result fits in with the and you can shape the future.” context of the conversation.”

MRC Annual Review 2006/07 5 Name Jeanne Bell Born August 1942 in Bishop Auckland, County Durham Education BSc (Hons) University of Newcastle; MB BS University of Durham; MD University of Newcastle; FRCPath London Family Married to Dr Denis Rutovitz MBE, one son, two stepsons, two stepdaughters and four grandchildren Current job title Professor of Neuropathology Awards 2007 CBE; 2001 Fellow of the Academy of Medical Sciences; 1998 Fellow of the Royal Society, Edinburgh Career highlight Establishing internationally recognised brain banks for infective dementias and, more recently, for control brains and psychiatric disorders 02 Neurobiology & neurodegeneration

The brain is the most complex and least understood organ in the human body. Together Understanding neurobiology with our nervous system, it controls everything our body does, including breathing, Neurobiology is the study of the cells of moving, talking and emotion. MRC scientists are working to understand our brain and the nervous system. It helps us understand nervous system, to try to find ways to stop them breaking down. how the brain and nervous system work and gives us insight into what is happening when things go wrong. Neurodegeneration is the progressive loss of structure or function of Profile Jeanne Bell, Western General Hospital, University of Edinburgh neurons (nerve cells) in the brain, for example, in Alzheimer’s and Parkinson’s diseases. “As a child I was taken to India by my parents who were missionaries. My time there imprinted me with the reality of poverty and that made me want to be a doctor. I suppose I imagined myself tending to the sick and curing people, even though I really had no idea what being a doctor was about, coming as I did from a non-medical family.

I went to medical school in Newcastle, which certainly shaped my career. On my first day I met the new Professor of Anatomy, R J Scothorne – he was one of those inspirational teachers who made his subject come alive. During my medical training I did a research based honours degree with him and then, after qualifying, I went back to anatomy. At that stage I thought I’d spend my career in teaching and research. I loved research.

In 1975 I moved to Edinburgh but found that anatomy wasn’t research driven as it was in Newcastle. Instead I found a research post in an MRC unit, investigating human miscarriage, and it gradually became apparent that what I was really doing was fetal pathology. An opportunity arose for me to be trained in pathology and I became a member of the Royal College of Pathologists in 1983 when I was about 40.

I’ve been in neuropathology in Edinburgh since 1984. I spend half my time as a diagnostic neuropathologist. This involves performing post-mortem examinations, as well as helping neurosurgeons with diagnosing brain tissue samples in the middle of surgical operations. For the rest of the time I am occupied with academic activities including teaching and research. For a while in my career I was a full-time researcher but I was never entirely comfortable Neurodegeneration protein found with that. For me, contact with patients is very important to provide the research direction. in HIV patients’ brains I will retire from clinical service this year but I expect to continue with research while my Many people with HIV/AIDS show some current grants are still running. level of cognitive impairment and now University of Edinburgh researchers Much of my research has been concerned with the effects of HIV on the nervous system. may have found a reason why. They The HIV epidemic was emerging in Edinburgh just as I started working as a neuropathologist compared brain tissue samples taken and I felt that it would have been wrong not to investigate this new disease. Three main from HIV patients before and after the groups of individuals were at risk of developing AIDS in the early days – gay men, drug users introduction of highly active antiretroviral and haemophiliacs. The MRC was interested in whether these groups fared differently, therapy (HAART) – the most effective particularly with respect to involvement of the brain. For reasons which are still poorly treatment currently available for HIV/AIDS understood, about half of Edinburgh’s drug users became HIV positive, compared with only – with samples from healthy individuals around one in 20 elsewhere. When the MRC set up brain banks to store tissue from infected of the same age and older. The results people for research, Edinburgh was the logical place to study drug-related HIV/AIDS. showed that many HIV-infected people had raised levels of a protein called One issue in brain banking is the shortage of control brains for comparison purposes. With hyperphosphorylated Tau, with the highest the support of the MRC I recently set up the sudden death brain bank to access the forensic levels found in those who had been treated post mortem service as a source of ‘normal’ brain tissue. For this I had to get the police, the with HAART. Hyperphosphorylated Tau Scottish Crown Office, the procurators fiscal and the local ethics committee on board. It protein is related to neurodegeneration took me nearly three years to win approval to approach bereaved families. Sometimes the and is commonly found in the brain of circumstances of death are particularly tragic and post mortem examinations in the very Alzheimer’s disease patients. Professor young are always affecting, but my responsibility is to perform a professional job to the best Jeanne Bell (see profile), who led the of my ability. We have just completed the two-year pilot study to see whether bereaved research, said the finding indicated that families would authorise us to retain tissue samples from their loved one for the purpose the virus and/or its treatment might both of research. We have been overwhelmed by the response – 96 per cent of the families we pose a risk to the brain, as treated patients approach agree to the donation and nearly one in five are prepared to donate whole organs.” live longer.

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Dementia gene discovery Vegetative state patient aware Young brains store Around 750,000 people in the UK have A woman left in a vegetative state memories differently some form of dementia. After Alzheimer’s following a car accident has shown MRC and Wellcome Trust funded disease, the most common type is awareness of her surroundings. Researchers researchers have found that adults may frontotemporal dementia (FTD), which led by Dr Adrian Owen of the MRC find learning more difficult than children affects one in 5,000 people, mostly aged Cognition and Brain Sciences Unit worked because their brains store memories between 50 and 60. Research led by Dr with colleagues in Belgium to use functional differently. To work out what influences Stuart Pickering-Brown at the University magnetic resonance imaging (fMRI) to map memory storage, Dr Nigel Emptage and of Manchester has identified a gene linked the brain activity of the woman. She was colleagues at the University of Oxford to FTD, opening up new possibilities physically unresponsive and fulfilled all the studied a process in nerve cells known as for diagnosis and treatment. The team criteria for a diagnosis of vegetative state long-term potentiation (LTP). It is thought discovered an association between FTD according to international guidelines. When to be the basis of learning and memory and a gene called progranulin, which the team asked her to imagine playing at a cellular level in the brain. When LTP is on the same chromosome as the tennis or moving around her home, scans occurs, the strength of signals transmitted dementia-linked tau gene. “While a lot of showed the woman was able to do this, accross synapses increases, and the next progress has been made in understanding activating various areas of her brain in the time the brain encounters the stimulus Alzheimer’s disease, relatively little was same way as healthy volunteers. that sparked it the first time, the synapses known about the genes linked to FTD,” respond more strongly and create a said Dr Pickering-Brown. “Yet about half “These are startling results. They confirm different pattern of signalling. of all people with FTD have other family that, despite the diagnosis of vegetative members with the disease. We know now state, this patient retained the ability The researchers focused on so-called ‘silent that many other cases are caused by errors to understand spoken commands and synapses’, which do not normally seem to in the progranulin gene. These results to respond to them through her brain respond at all when chemical signals pass mean that we should be able to develop activity,” said Dr Owen. “Her decision to through them. The results suggested that therapies to tackle this form of dementia.” work with us represents a clear act of silent synapses, which decrease in number intent which confirmed beyond any doubt as the brain matures, are needed to that she was consciously aware of herself establish fresh networks of memories in the Epilepsy and pain insights and her surroundings.” The technique may brain, while mature synapses recycle the Calcium channels straddle the outer allow doctors to identify patients who networks that are already there. “As we age, membrane of cells such as nerve cells. have some level of awareness, although it the reason our brains may find it harder to Their job is to let calcium in, which cannot definitively rule out awareness in record memories could be because there enables signalling between cells. Loss unresponsive patients. are fewer silent synapses,” said Dr Emptage. of part of a calcium channel called alpha2delta is to blame in a mouse model for a form of epilepsy and Why fish oil is good for the brain Ageing cats and Alzheimer’s ataxia – a disease affecting balance, Omega-3 found in fish oil is good for the Dr Frank Gunn-Moore at the University coordination and movement – and brain and scientists have now discovered of St Andrews has found that ageing cats the protein has previously been shown a reason why. Knowing that the protein can develop a feline form of Alzheimer’s to bind to gabapentin, an important syntaxin contributes to brain neuron disease very similar to the human disease. epilepsy drug. In collaboration with growth, Drs Frederic Darios and Bazbek His team studied samples of brain tissue Pfizer, scientists at University College Davletov, of the Laboratory of Molecular from cats that had died naturally with London led by Professor Annette Dolphin Biology in Cambridge, have found that undiagnosed neurological disease. They have unravelled the mechanisms of omega-3 is essential to the action of discovered Tau protein within the nerve alpha2delta. Their work also helped Pfizer syntaxin. They discovered that syntaxin cells of many of the cats’ brains. In to understand how gabapentin and a is directly activated by omega-3 and humans, Tau protein can create tangles related drug called pregabalin are of omega-6 (found in meat), and this in inside nerve cells in the brain which stop use in the treatment of pain caused by turn helps brain neurons to grow. The messages from being processed. Dr Gunn- damage to the nervous system, known as research could lead to new treatments Moore said: “The presence of this protein neuropathic pain. for neurodegenerative diseases such as is evidence that cats too may develop a Alzheimer’s or help victims of brain damage form of Alzheimer’s disease. If humans and spinal cord injuries. “Identifying or cats live in an environment with little the link between omega-3 and syntaxin company or stimulation, they are both at should allow us to find new consumable higher risk of dementia. However, if an substances that could be beneficial for owner plays with a cat, it is good for both neural growth,” said Dr Davletov. of them.”

8 MRC Annual Review 2006/07 During my medical training I did a research based honours degree… I loved research. Professor Jeanne Bell Name Eve Johnstone Born September 1944 in Glasgow Awards 2002 CBE for Services to Medicine; 2002 Stanley Dean Award (American College of Psychiatrists) for Research in Schizophrenia; 1999 Gildea Prize for Research in Schizophrenia Time in current position 18 years Current Job Title Professor of Psychiatry and Head of Division, University of Edinburgh Future ambition Within my lifetime, to gain a full understanding of the development of schizophrenia 03 Mental illness & behavioural disorders

Mental health conditions are some of the most common illnesses. MRC scientists are trying Brain images predict to decipher the mysteries of the mind, including exploring the physiological and genetic schizophrenia risk factors behind mental illness and behavioural disorders and looking for ways to combat them. Research by Professor Eve Johnstone and her team (see profiles) at the University of Edinburgh has shown that brain imaging Profile Eve Johnstone, University of Edinburgh can predict schizophrenia in at-risk people even before they develop symptoms. At the age of 20 I saw my first schizophrenic patient. At the time I thought psychiatry The finding comes from the MRC-funded was strange and I didn’t think I’d like it. But I was bowled over and fascinated by how this Edinburgh High Risk study, in which disease came out of the blue and how nobody could offer me an explanation for it. In 1974 200 young people at risk of developing I left Glasgow, where I had studied medicine and worked my first few years in hospitals, to schizophrenia have been followed for go to the MRC Clinical Research Centre at Northwick Park. I was to look into the finding that 10 years. The disease is known to have many of the schizophrenia patients there didn’t know how old they were. a strong inherited element, but there is currently no reliable test to predict a In 1976 we were the first to show conclusively that there were actual structural deficits in the person’s actual level of risk. brains of schizophrenia patients. There was a new brain scanner across the other side of London that we took the patients to. When we first took pictures, these people’s brains just didn’t look Throughout the course of the study right. So we did a control study which showed that there was definitely something wrong. the participants underwent regular brain scans, clinical interviews and The Edinburgh High Risk Study, which we’ve been working on since 1994, involves people psychological tests. The results showed aged 16 to 22 who are at high risk of developing schizophrenia because they have at least structural changes in the brains of people two relatives with it. We’ve seen many of them become ill over time. And we’ve shown that who went on to develop schizophrenia, for those who did become ill, there were slight differences in their brain scans years before even before they became ill. These they became ill and that these differences got more pronounced over time. changes distinguished them from healthy volunteers and from at-risk people who We couldn’t do any of this research without the participants. We share the results with did not develop the condition. them and their families throughout and have been surprised by how warmly they receive the findings – the idea that there is something demonstrably wrong with the brains. For the In related work, the group also found a mothers who agree to let their children take part, being able to see that their boy’s brain is gene called neuregulin that is developing differently has meaning when he starts to get ill. If you can see there’s something associated with the development of physically wrong, it means there’s a chance that you’ll be able to do something about it. schizophrenia. This too is linked to changes in brain function. For 33 years I’ve been supported by the MRC. The organisation believed I could do these things which others felt were perhaps over-ambitious and unattainable. The continuous support has Dr Dominic Job, who worked on the meant that one study could build upon another and it has been wonderful. After Northwick study, said: “Although there are no Park, my grant support began in 1989 when I was invited to come up to Edinburgh. I’ve stayed preventive treatments for the illness, here since, first on individual grants and then programme grants. I’m applying for my last one an accurate predictive test could help now, but it’ll only be for three years because then it’s time to retire. The highlights are when you researchers to assess possibilities for get to the end of these great big projects and it has worked – it’s marvellous every time. prevention in the future. By combining brain imaging with traditional clinical I’d tell people who are interested in a career like mine that they shouldn’t ever imagine they assessments it might be possible to can’t do it. Don’t believe that people are better or more skilled than you. You have to think detect people who are at highest risk of big and not be scared. the illness early on.”

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Profile Viv Moffat, University of Edinburgh

After training as a nurse I worked for many years with children with learning difficulties. It fitted in well with having my family. A few years ago I became interested in research and applied for a six-month secondment developing a pain assessment tool for children with neurological impairment. I found that I enjoyed research and in 2002 a job came up here working on a study looking at ways of identifying early indicators of mental health problems in young people with mild learning difficulties. It also gave me a chance to do a PhD, which focused on mothers’ perceptions of quality of life and unmet need in the families of these young people.

Meeting so many people and learning about different approaches to research relevant to my background has been fantastic – as was submitting my thesis. There’s not always a lot of opportunity to get involved in research, if you’re a busy nurse for instance. But if an opportunity does come along, you should take it. I was seconded into my first job and that led to doing a PhD and then working on this study, and it’s been great. Born Kirkcaldy, Scotland Education Registered Learning Disability Nurse, Registered General Nurse, Lothian College of Nursing and Midwifery; MSc, University of Edinburgh Family Married with three daughters aged 20, 18 and 15 Current job title Research Nurse Time in current position 4 years

Profile Bill Moorhead, University of Edinburgh

“My background is in engineering. I used to work in the defence industry in electro-optics instrumentation. I obtained my Masters degree with Honours from Napier University in Edinburgh and then lectured at Napier on instrumentation and artificial intelligence before doing my PhD. As a postdoc I worked for Professor Janos Hajto, modelling amorphous silicon devices, which are used in electronics. I came here after Eve advertised for engineers to come and help with the brain imaging that was being done as part of her Education MSc (Hons), Napier University; schizophrenia research. PhD, Napier University Current job title Research Fellow It’s worked well. I’ve been able to advance my modelling software and apply it to three Field of research Feature based morphometry – this involves applying artificial intelligence dimensional brain imaging. The best thing about the work here is that so many disciplines to measure shapes within structural images are contributing to the research. The collaboration between disciplines is excellent and produced through magnetic resonance imaging I am delighted to be part of something that’s of real use and that will ultimately lead to Future ambition To make the tools and improvements in mental health care. Of course there are hurdles. Coming from a different methods I have proved successful here widely available to brain imaging experts background there’s a language to learn about the field you’re going into. You go out on a limb but it’s well worth it when you see the results.”

12 MRC Annual Review 2006/07 The highlights are when you get to the end of these great big projects and it has worked – it’s marvellous every time. Professor Eve Johnstone

Impact of genetics and Classifying drugs by harm Addiction on the brain environment on learning Harmful drugs are currently regulated Scientists have found that variations in Professor Robert Plomin heads the according to classification systems that brain chemistry may mean that some MRC-funded Twins Early Development are meant to reflect the harm and risks of people are more likely than others to Study (TEDS), which is tracking 15,000 each drug. However an MRC-funded study become addicted to drugs even before twins born between 1994 and 1996 has proposed new classifications based they begin using them. for 15 years. The study focuses on the on the amount of harm they actually do. early development of three common The study put alcohol and tobacco among Dr Jeff Dalley and colleagues at the psychological problems in childhood: the most damaging substances, above University of Cambridge studied changes communication disorders, mild learning cannabis, ecstasy and LSD. Professor David in receptors in rats’ brains for dopamine difficulties and behavioural problems. Nutt at the University of Bristol, MRC Chief – a neurotransmitter that affects Executive Professor Colin Blakemore and emotion, perception and movement. Rats In the first decade, the study found that colleagues identified three main factors which had not been exposed to cocaine genetic factors have a strong influence that determine the harm associated with but were naturally impulsive had fewer on how children learn the UK National drugs that can potentially be abused: dopamine receptors and were more likely Curriculum. The researchers have also physical harm to the user, tendency of the than other rats to self-administer cocaine discovered genes that are involved in drug to induce dependence and its effect when given the chance. The results language impairment, hyperactivity and on families, communities and society. showed a clear link between impulsive behavioural disorders, as well as genes Two expert panels then scored 20 drugs behaviour and vulnerability to drug that determine reading, writing and using this system – both provided roughly addiction, and that changes in dopamine maths ability. similar scores for harm. Professor Nutt receptors pre-dated drug use rather than said: “Drug misuse and abuse are major being caused by it. “The field of education has been slow health problems. Our methodology offers to accept genetics even though the a systematic process that could be used “The results show promise for helping evidence for genetic influence on learning by national and international regulatory to identify individuals most at risk of abilities and disabilities is now as strong bodies to assess the harm of current and developing a drug abuse problem. The as for any other behavioural domain,” future drugs of abuse.” next step is to determine the possible said Professor Plomin. “These findings genetic basis of the diminished supply of have important implications for diagnosis, brain receptors, which may provide new treatment and especially prevention of Depression keeps people low leads in the search for improved therapies learning disabilities and for nurturing Depression is a common illness. Leading for disorders such as drug addiction,” said learning abilities.” charities claim that it affects as many Dr Dalley. as one in five of us at some point in our lives. Now, researchers at Oxford Autistic people not psychopaths University have found reduced levels Scientists have found that autism and of a brain chemical called gamma- psychopathy are two seperate disorders. aminobutyric acid (GABA) in people with However, some people with autistic a history of severe mood disorder, even The collaboration spectrum disorder (ASD) also have after they are well again. psychopathic tendencies. But it was between disciplines not previously known whether these Professor Philip Cowen and Dr Zubin were part of the same disorder or two Bhagwagar used magnetic resonance is excellent and I am distinct problems occurring in the same spectroscopic imaging to compare GABA delighted to be part person. Researchers at the Institute of levels in healthy volunteers with levels Psychiatry at King’s College London and in people with a history of depression of something that’s the Institute of Cognitive Neuroscience or bipolar disorder who were now well at University College London have now and no longer being treated. “Our work of real use and that shown that ASD can be distinguished shows that recurrent mood disorders using cognitive tests of emotional and have an important and enduring will ultimately lead to moral understanding. Professor Uta Frith biochemical basis which goes some improvements in said: “This work reassures parents and way to explaining their high rates of carers that the possibility of committing recurrence,” said Professor Cowen. “The mental health care. particularly callous crimes is not a changes in GABA we have found might necessary component of autism.” also provide a target for the design of Dr Bill Moorhead drugs aimed at preventing relapse.”

MRC Annual Review 2006/07 13 Name Steve Brown Born 1955 in Dumfries, Scotland, grew up and schooled in Belfast Education MA and PhD from Cambridge University Awards Elected member of EMBO (European Molecular Biology Organisation) 2005; Fellow of the Academy of Medical Sciences (FMedSci) 2001 Current job title Director Time in current position 11 years Field of research Mouse genetics and mouse models of human disease, particularly the genetics of deafness

Name Nanda Rodrigues Born 1960 in Mumbai, India Education MSc; DPhil (Trinity College, Oxford); MBA (Oxford Brookes); Dip Marketing (Chartered Institute of Marketing) Family Husband Robert and daughter Evangeline (11) Awards Biotechnology Young Entrepreneurs Scheme Winner 2000 Current job title Scientific Business Manager DNA unravelled Cells are the basic building blocks of all living things, including humans. In the centre of each of our cells is a nucleus, 04 Genetic diseases which contains our DNA. Unravelled, this DNA would be around two metres long. That’s why it’s stored tightly wound around spool-like proteins and packed together into chromosomes that fit inside the cell. Every cell contains an exact copy of this DNA, with all our genes found along its length. In Countless human diseases are linked to faults in our genes. There are many different different cells, such as blood cells or muscle types of genetic diseases. Some, like cystic fibrosis, are caused by a mutation in a single cells, different genes are switched on and off gene. Diabetes is one of a number of diseases which can stem from interactions between depending on function and life cycle. different genes. And a person’s environment can cause a gene to mutate, sparking disease – such as certain cancers. Therefore, different approaches to therapy are needed. Hundreds of MRC scientists are spending their careers studying the genetics of human disease. Mouse reveals genetic cause for glue ear Profile Steve Brown, MRC Mammalian Genetics Unit, Harwell Professor Steve Brown and colleagues (see profiles) at the MRC Mammalian “I was always interested in science at school – discovering something new about how the Genetics Unit have found the first world works that no one else knew before is always a thrill. Scientists really do affect people’s evidence of a genetic cause for glue ear lives – providing a huge public service that will have an enormous impact in the future. It’s (otitis media). The condition is the most the combination of these factors that makes medical research such an attractive option. common cause of hearing problems and surgery in children in the developed A highlight of my career was in 1995 when, with my collaborator Karen Steel, I discovered world – half of children have an episode the first gene for one of the most common forms of deafness – caused when cells on of glue ear by the time they are 12 the surface of the inner ear go wrong. It was a major breakthrough and a big source of months old and a significant number satisfaction for me because at that stage very little was known in this area. A second high go on to develop a recurrent or chronic came 11 years ago when I was given the opportunity to run the research facilities here at form of the disease. Previous studies Harwell – it is one of the major mouse genetic centres in the world and we really are at the have shown evidence of genetic factors forefront of using the mouse as a genetic model of disease. at play, but have not been able to find the gene responsible. Day-to-day I do a lot of different things. As director, I might be involved in troubleshooting, meetings with staff, spending time thinking about how to improve the unit and how to get The team bred a mouse with hearing more money in. I’m always looking for ways to improve opportunities for my staff. I like to go loss, known as Junbo, and identified round talking to people in the lab, taking the temperature of the science but also of the staff to one of the rogue genes involved. Called find out how they’re getting on. I have an open door policy – I think it’s absolutely critical for a Evi1, the gene provides instructions director to be approachable. I travel a lot, sometimes every week. It’s good to get away from that help to build proteins which are where I am and gives me time to reflect. It’s also very important to meet other scientists and important for the body. When this goes find out about what they’re doing – it helps to generate new ideas for my own unit. Engaging wrong, instead of helping to build other with the public is another important part of my role. I’ve always been a great believer in talking proteins, the mutated version of Evi1 about what we do and what the effects of animal research are to the community, politicians causes inflammation in the inner ear. and other scientists. I was on the working party of the independent Nuffield Council on Professor Brown said: “Because the Junbo Bioethics looking at research using animals. I see this as an important part of my role as director mouse provides a model of how glue ear of this unit. Harwell has always been in the vanguard of telling people about what is going on.” affects children, I hope that it will help researchers to figure out new ways to tackle this disease.” Profile Nanda Rodrigues, MRC Mammalian Genetics Unit, Harwell

“I became interested in science as a way to solve the mysteries of life and cure disease. One of the highlights of my career came early on, when I won a Rhodes scholarship and moved from Mumbai to Oxford to study biochemistry. My husband-to-be followed me six months later and we both fell in love with Oxford. After my degree I got a three-year postdoctoral fellowship with Cancer Research UK to study colorectal cancer. That was followed by grants to study diabetes, spinal muscular dystrophy and other childhood diseases.

But I began to get disenchanted with the lack of career structure for the average scientist, particularly with having to keep applying for grants every three years. So I went back to do an MBA at Oxford and it was fantastic. It really opened up my eyes to so many avenues I didn’t know existed as a scientist. For the past five years I’ve been Scientific Business Manager at the Mammalian Genetics Unit. I don’t do any bench work anymore but I can still talk science to businesses and other scientists. I do miss the buzz of getting a good result but now I see the big picture. Whereas the thrill of seeing a single line on a gel used to be enough, now I get a kick from meeting people, solving problems and getting big grants in.”

MRC Annual Review 2006/07 15 04 Genetic diseases continued

Mouse genetics helps fight pain Gene links leukaemia and Mice make human blood proteins Professor John Wood at University movement disorder Researchers at the MRC Molecular College London and Dr Geoff Woods MRC researchers have discovered a Haematology Unit (MHU) in Oxford and at the University of Cambridge have missing link that helps explain how a Edinburgh University’s Institute for Stem identified genetic targets for developing gene called AF4 is involved in both Cell Research have genetically modified a new painkillers. Special damage-sensing ataxia – a disease affecting balance, mouse to study the blood disorder alpha nerve cells in our bodies detect tissue coordination and movement – and thalassaemia. People with the condition damage and relay messages of pain some particularly aggressive childhood have a shortage of alpha-globin protein, to the central nervous system. The leukaemias. Previous studies in mice have which is a crucial component of the researchers created a number of mice shown that mutations in the gene can oxygen-carrying molecule haemoglobin that were lacking different genes in these result in movement disorders by causing in red blood cells. As a result their blood damage-sensing cells, and discovered one a loss of brain cells, and in leukaemia by cells cannot transport enough oxygen that was essential for sensitivity to pain. impairing the development of immune around the body, causing some carriers to Subsequent human studies confirmed cells. Professor Kay Davies and her team be severely anaemic. that the same gene is also crucial for at the MRC Functional Genetics Unit in humans to feel pain. Oxford discovered some of the steps Using a new technique, the team replaced in the pathways between mutation in the mouse alpha-globin gene with a “New painkillers should emerge from this AF4 and these diseases. She said: “Our human version, so the animal produces the work. This is important because there are findings provide valuable insight into the human form of the protein. The Director estimated to be 40 million people in the contribution of the AF4 gene family to of the MHU, Professor Doug Higgs, said: developed world with chronic pain who leukaemia and neurodegeneration. The “At present much of our understanding of are intolerant or unresponsive to current work takes us a step closer to identifying human genetics relies on mouse models. painkillers,” said Professor Wood. The genetic targets for developing new ways This work represents an important step study was co-funded by the MRC, the to prevent and treat these and other forward in producing more authentic Biotechnology and Biological Sciences related diseases.” models of human genetic disease.” Research Council and the Wellcome Trust. In a related project, Professor Higgs’s team MS gene curbed by twin found that thalassaemia can result from a Understanding human Multiple sclerosis (MS) is an autoimmune change in a single letter of DNA whose job genome differences disease in which the immune system is normally to switch on genes. They found There is a great deal of variation in the attacks the body. An MRC study has this change led to haemoglobin genes human genome, including differences uncovered a battle being waged between being switched off when they should be in the number of copies of genes that a pair of twin genes always found in MS turned on. This mechanism could have wide people have. Such gene ‘copy number’ patients. The DR2b gene is responsible for implications for many common diseases. discrepancies are to blame for many triggering the immune system to attack inherited diseases. Professor Sir Alec the body’s own tissue. But it’s always Jeffreys, at the University of Leicester, found with its twin DR2a. This ‘good’ gene Potential cancer therapy in junk DNA has shown one way in which these dampens the negative effect of its twin When the human genome was sequenced changes might arise. His team developed by slowing down the immune system’s in 2001, around 34,000 genes were found. very powerful methods for detecting attack on the body. The remainder was labelled junk DNA as it even extremely rare deletions in human had no obvious function. However, RNA DNA. They used these methods to study Professor Lars Fugger, of the MRC Human (the mirror image of DNA, which is used and characterise spontaneous deletions Immunology Unit, said: “Overall this to pass on instructions to cells to build in a family of genes called the globin fight between the two genes reduces proteins) can be made from much of this genes. The results revealed events during the severity of MS symptoms. Exploiting junk DNA. Now in a study co-funded by cell division that resulted in deletion of the way the tempering gene works the MRC and the Wellcome Trust, Oxford areas of DNA and therefore copies of might lead to new treatments. The study University scientists have discovered that genes. “This work is fundamental to our will help understanding of how genes using some of this RNA to switch off a understanding of the origins of a major interact in other autoimmune diseases, gene called DHFR, that is involved in the class of disease mutation,” said Sir Alec. such as diabetes, rheumatoid arthritis control of cell division, might be useful for He is now studying other processes and psoriasis.” developing new cancer therapies.“Switching that can cause variation in gene copy off DHFR could help prevent ordinary cells number, including those that create from developing into cancerous tumour additional copies of genes. cells, by slowing down their replication,” said Dr Alexandre Akoulitchev.

16 MRC Annual Review 2006/07 Scientists really do affect people’s lives – providing a huge public service that will have an enormous impact in the future. Professor Steve Brown Name Rebecca Fitzgerald Born 1968 in Sheffield Education Medical training, Cambridge University; research at Stanford University, USA (MD received from Cambridge); postdoc and specialist training, Barts and The London Family Husband Shaun and four sons: Luke (10), Samuel (7), Jacob (4) and Tobias (2) Awards 2007 Sir Francis Avery Jones Medal; appointed Goulstonian Lecturer by the Royal College of Physicians and the Academy of Medical Sciences for 2007; 2004 Westminster Medal Current job title Group Leader (Tenure Track), MRC Cancer Cell Unit, Hutchison-MRC Research Centre Cancer explained Cancer develops when cells in certain parts of the body start to divide uncontrollably. This produces increasingly abnormal cells, which 05 Cancer build up into tumours that interfere with vital bodily functions. The four most common types are breast, lung, bowel and prostate cancer – these make up over half of all cases.

More than a quarter of a million people are diagnosed with cancer each year in the UK. Anti-vitamin A blocks The MRC works alongside charities, such as Cancer Research UK, other research councils, oesophageal cancer government and industry to fund and carry out crucial research aimed at understanding Barrett’s oesophagus causes the scaly and combating cancer. lining of the oesophagus to be replaced by a glandular lining like that of the stomach. It turns into oesophageal cancer Profile Rebecca Fitzgerald, MRC Cancer Cell Unit, Cambridge in up to 10 per cent of sufferers, but until now scientists haven’t known its cause. “I’ve always wanted to be a doctor. I remember when I was four, my family went on holiday Led by Dr Rebecca Fitzgerald (see profile), to Devon and we went to a tiny museum with various biological specimens in it. There was a researchers at the MRC Cancer Cell Unit premature cow fetus – I was fascinated by it. have found that treating the normal scaly tissue of the oesophagus with vitamin A I studied medicine at Cambridge and qualified in 1992 – the same year I got married – and provokes changes to Barrett’s cells. When then spent three years working at Addenbrooke’s Hospital. I was attached to the gastro the researchers later treated the altered department for some of the time and found two of the consultants there, Graham Neale tissue with drugs that stop vitamin A and John Hunter, particularly inspiring. from working, the cells reverted back to their previous state. “We are very excited Then my husband got a job at Stanford University in California. I decided to do research about these findings,” said Dr Fitzgerald. as I didn’t have the right qualifications to work as a doctor in the States. I spoke to George “Vitamin A inhibitors could allow us to Triadafilopoulos, an oesophageal cancer specialist at Stanford. He offered me a job but told reverse Barrett’s oesophagus, which would me I needed to get a grant. I managed to get one from the Association of International in turn prevent oesophageal cancer.” Cancer Research in Dundee to carry out research into oesophageal cancer – at the same time I registered to study for a research doctorate through Cambridge University. Then in 1999 I applied for an MRC clinical fellowship, which allowed me to finish my clinical training Screening test for mouth cancer and to change the balance between clinical work and research as I needed to. A new test shows promise as a simple and accurate way of detecting mouth By that stage I was completely sold on academia and research. I wanted to come back to cancer and precancerous mouth lesions. Cambridge and so applied for a position as a group leader at the new Cancer Cell Unit. I’ve The research could form the basis of a been here ever since. I spend a third of my time in the clinic seeing patients, and am based population screening programme for in and around the lab the rest of the time. Working with patients is particularly rewarding – it mouth cancer, which accounts for more really helps to focus my mind on my research. UK deaths than cervical and testicular cancer put together. The research was A high point of my career was when I won the Westminster Medal in 2004 for done by Dr Nick Coleman and team at the communicating my work to politicians and the public. As far as low points go, I think I’ve MRC Cancer Cell Unit in Cambridge and been very lucky. Juggling everything – research, work in the clinic, teaching and having four supported by Cancer Research UK. young sons – can be a struggle. But it’s a great career and the combination of clinical work and research is very inspiring. You have to be very determined, but I believe that if you The researchers developed a technique create yourself a niche and stick at it, the world is your oyster.” in which cells are scraped from the mouth to make ‘smear’ samples, similar to cervical screening. They then examined these for the presence of cancer markers called mini-chromosome maintenance (MCM) proteins, which are key to a cell’s ability to duplicate its DNA. MCM proteins were virtually always found in cancerous smears but not in normal smears.

Dr Coleman said: “Mouth cancer can be a very aggressive disease which is often fatal and requires disfiguring surgery. Development of a feasible test for the early detection of this cancer is an important advance, as the earlier a cancer is treated, the better a patient’s chances of survival.”

MRC Annual Review 2006/07 19 In related research, Professor Malcolm Dunlop at the MRC Human Genetics Unit in Edinburgh has developed a website to continued help clinicians decide how to treat patients 05 Cancer with bowel cancer. The site can also be used to assess whether other people are at risk of the disease. He analysed DNA from 870 patients who had been diagnosed with bowel cancer, and identified mutations in their so-called ‘DNA mismatch’ genes. Improving leukaemia survival Another reason to eat your greens Professor Dunlop then worked out the An MRC-funded clinical trial has shown It’s long been known that eating a impact of a mutation in any of these genes significant improvement in survival balanced diet improves health and can on survival and used this information to without relapse for leukaemia patients even protect against some cancers. develop a computer model to predict treated with a monoclonal antibody MRC-funded researchers at the University cancer risk. Data for around 6,000 people drug (called gemtuzumab ozogamicin) of Leicester have uncovered a possible have been entered into the website so far, combined with standard intensive reason why. They found that a molecule and the researchers are now collaborating chemotherapy. The study is the first ever in green vegetables such as broccoli and with scientists in Scotland, London and randomised trial of antibody-directed cabbage can inhibit the growth of breast North America to refine it further. chemotherapy for cancer. It is also the cancer cells and could even be used in first intervention to show any significant conjunction with drugs to help fight the benefit in randomised trials for patients cancer. “Dietary agents which can kill or Timing of tumours’ drug resistance with acute myeloid leukaemia for 20 years. slow down cancer cells do not affect Cancer cell resistance to chemotherapy normal cells. Combining them with drugs has generally been thought to happen Led by Professor Alan Burnett at Cardiff may enhance the drugs’ effectiveness and relatively late in the disease. However, Dr University, the trial involved 1,113 could allow reduced doses to be given to Selina Raguz and team at the MRC Clinical patients aged under 60. Preliminary patients,” said Professor Margaret Manson. Sciences Centre in London have shown results showed that risk of relapse was “Many chemotherapeutic drugs are toxic, that it occurs earlier than previously reduced from 54 to 39 per cent, while so the smaller the dose the better for the thought. The scientists developed a disease-free survival improved from 38 patient. As dietary substances like IC3 have cell-based model of the early stages to 49 per cent. Because this was achieved a proven track record of being safe for the of cancer and used this to show that with no side effects, the next stage of patient, we hope that the journey to clinical drug resistance can arise even before the research will involve studying higher trials will be relatively straightforward.” individual cancer cells form tumours. doses to try to improve recovery rates Next, the scientists plan to develop even further. The study, which is ongoing, diagnostic tests to detect the evidence of was sponsored by Cardiff University and Beating bowel cancer this – termed ‘chemotherapy resistance supported by Wyeth Research and was A worldwide clinical trial has found that signature’ – at the very early stages of carried out in 150 hospitals in the UK, radiotherapy can virtually eliminate the cancer progression. The research will Denmark and New Zealand. risk of bowel cancer tumours coming back help to predict a patient’s response when combined with successful surgery. to chemotherapy and so might have Researchers looked at data from 1,350 implications for cancer treatment. patients in the UK, Canada, South Africa and New Zealand. Traditionally, surgical removal of cancer in the lower bowel has Semen can worsen cervical cancer been the treatment of choice, but leaves a Cervical and uterine cancers could be risk that the tumour could return. aggravated by a hormone-like molecule called prostaglandin that is found in Dr David Sebag-Montefiore of the MRC semen, MRC research findings show. Clinical Trials Unit and team compared Prostaglandin is naturally produced by routine use of radiotherapy before surgery the cells that line the female reproductive with selective use afterwards. The cancer organs – its usual role is to help came back in only five per cent of patients regulate cell growth. However, it is also who had surgery before radiotherapy, found in semen, at 1,000 times higher compared with 17 per cent who had concentrations. A team of scientists surgery afterwards. And recurrence was led by Dr Henry Jabbour at the Human as low as one per cent in patients who Reproductive Sciences Unit in Edinburgh had the most effective surgery before discovered that semen prostaglandin can radiotherapy. “There are approximately influence the progression of cervical and 35,000 cases of bowel cancer diagnosed uterine cancers by enhancing tumour every year in the UK alone. These results growth. Dr Jabbour said: “This research show that giving a patient radiotherapy highlights the potential for a new before surgery gives them the best chance therapeutic approach that will inhibit the of survival in the long term,” said Dr action of both sources of prostaglandin Sebag-Montefiore. – those produced naturally by women and those introduced to the body by semen.”

20 MRC Annual Review 2006/07 Working with patients is particularly rewarding – it really helps to focus my mind on my research. Dr Rebecca Fitzgerald Name Philip Bath Born Maracaibo, Venezuela Grew up Venezuela, the Netherlands, Indonesia, Iran Education BSc (Hons), MB, BS, St Thomas’ Hospital Medical School; MD, King’s College School of Medicine and Surgery Awards Roger’s Prize, University of London Current job title Stroke Association Professor of Stroke Medicine Time in current position 9 years 06 Heart disease & stroke

Rates of heart disease and stroke in the UK are among the highest in the world. The MRC supports many studies into the causes of these conditions and ways to prevent and treat Heart attacks and strokes them. These range from basic molecular research in the lab aimed at understanding exactly To work properly, both the brain and the how heart disease and strokes occur, to clinical trials testing new therapies in patients. heart need a constant supply of blood. A stroke is caused by a blood clot suddenly blocking the flow of blood to the brain, meaning it is starved of oxygen. Similarly, a Profile Philip Bath, University of Nottingham heart attack is due to a blockage in an artery that takes blood away from the heart. Arteries “One week out of five I run the stroke ward in the hospital. Strokes cause horrible injuries; can become blocked suddenly by blood clots they kill a third of people within a year and leave another third disabled. The rate of strokes or over time by a build-up of fatty deposits, goes up with age, as does poor outcome. known as coronary heart disease.

Research into the cause and treatment of stroke occupies the time I am not in the clinic. I’m currently working on two big MRC-funded clinical trials. Treating the stroke-damaged brain Last year the MRC funded the Efficacy of Nitric Oxide in Stroke (ENOS) trial. It was the Professor Philip Bath (see profile) culmination of projects that began in 1994 when I was at King’s College Hospital in London. and colleagues at the University of I moved to Nottingham to continue this work in 1998. We are studying using a daily skin Nottingham have discovered that bone patch to reduce blood pressure in acute stroke, so people who can’t swallow safely can also marrow stem cells may be able to repair be included. Altogether, we carried out three preliminary trials in a total of 137 patients. the damage done to the brain by a stroke, Getting the grant was a buzz. It was very big because the study will involve more than 200 centres in 30 countries and 5,000 patients. We are at the expansion stage right now, with Many patients lose the ability to move most effort being spent in recruiting more centres. The trial is growing all the time. after a stroke because nerve cells in the brain die while the oxygen supply is cut My other big trial is STEMS2, which is looking at getting stem cells into the brain to repair off. Because stem cells can form any type damage done by strokes. It’s a so-called regenerative, or ‘neuroreparative’, strategy. of cell and can renew themselves, they Neuroprotection, or minimising brain damage immediately after a stroke, is very difficult and have potential for treating such brain so far has failed to deliver. Drug companies have spent billions with little success. That’s why damage by helping to grow new cells. some of us are now investigating regenerative therapies instead. In a pilot study, the researchers used a STEMS2 uses bone marrow stem cells. There is evidence that some of these may have a drug called granulocyte-colony-stimulating role in renewing tissue and cells elsewhere in the body. Of course they have already been factor to release stem cells from the bone used extensively to treat people with blood diseases such as leukaemia, but mostly in young, marrow in 36 patients who had recently otherwise healthy people. So far we’ve been successful in safely using drugs to mobilise these had a stroke. They found that the method stem cells in older people’s blood. Next we want to take the cells out, label them with tiny did not cause any harmful side effects. particles of iron, and inject them back into the bloodstream to see whether they make it to the The next steps are to explore whether brain or not. We think that if they get to the brain, they probably won’t turn into new neurons these stem cells are able to travel to the to replace the damaged ones, but might motivate local stem cells to come and do the job. brain and to see if they can be directed to repair stroke damage when they get there. I feel like research makes me a more credible clinician – the fact that I’m seeing patients gives me an extra drive to help them. The downside is that it can be distracting to have to go off to the clinic when you’re in the middle of an exciting project. But I love my job. If you asked me what I’ll be doing any day next month I couldn’t tell you. You need to be a free thinker and prepared to put time in and be very focused. You get out of research what you put into it.

Trials, more than most research, can take years to deliver. So you need to have other projects on the go in case a trial falls over. The different life cycles of research projects are so interesting and varied. There are great highs and lows.

Nevertheless, building up my team from about 10 people a year ago to 23 now has been a real highlight. It’s exciting to gather a big group of people who are so focused on a project – and it shows we’re obviously asking the right questions at the moment.”

MRC Annual Review 2006/07 23 06 Heart disease & stroke continued

Stemming the effects of heart Common painkillers may raise attack and stroke heart attack risk I feel like research makes Heart attacks and strokes cause around MRC researchers have concluded that me a more credible half of all deaths in developed countries. high doses of some commonly used They strike when the blood supply to the painkillers could increase the risk of heart clinician – the fact that heart or brain is cut off. Scientists led attacks. Their findings were drawn from by Professor Mark Pepys at University the results of 138 clinical trials involving I’m seeing patients College London have previously shown around 140,000 patients. that stroke and heart attack damage is gives me an extra drive compounded by a molecule known as Professor Colin Baigent, at the University to help them. C-reactive protein. It is produced and of Oxford Clinical Trial Service Unit, circulates through the blood stream in worked with scientists at the University of Professor Philip Bath response to the injury. Rome La Sapienza. The team examined all trials in which the effect on the heart Now, Professor Pepys’s team has of painkillers called selective COX-2 Broken body clocks cause designed a new agent that is bound by inhibitors (coxibs) and non-steroidal anti- metabolic disease C-reactive protein and stops it from inflammatory drugs (such as ibuprofen) Scientists at the Laboratory of Molecular doing damage. “If it is approved for use, had been studied. The results showed Biology in Cambridge have found that shift it should reduce the severity of heart that high doses of the NSAIDs ibuprofen workers may have problems regulating attacks and strokes, leading to improved and diclofenac increased the risk of their bodies’ nutrient levels. Their disrupted survival,” said Professor Pepys. The next heart attacks, as did the coxibs. The body clocks are to blame. This may explain step is to develop the compound as a cardiovascular effect of another NSAID, why they suffer increased heart disease drug for regulatory approval and naproxen, was smaller. and metabolic illness. clinical use. Professor Baigent said: “Many patients Dr Michael Hastings and colleagues found with severe chronic arthritis depend on that our daily body clock determines which Severe mental illness linked to these drugs to stay physically active, enzymes are produced by the liver at which heart risk so it is important that they and their time of day and night. As a result, the People with severe mental illness have doctors can weigh up their benefits and liver’s ability to break down meals and deal an increased risk of dying from heart potential harm.” with potentially toxic substances follows a disease or stroke. The finding comes regular daily pattern. However, when this from research done at the MRC’s routine is disrupted, for instance in people General Practice Research Framework Inflaming stroke damage who do shift work, have jet lag or suffer on the world’s largest database of Inflammation or infection outside from sleep disorders, these metabolic anonymous long-term records from the brain might contribute to and cycles will be compromised. This means primary care. Scientists therefore worsen damage caused by stroke that there is a mismatch between when suggest that people with severe mental and neurodegenerative disease – and people eat and what their bodies can illness should be regularly checked for Professor Dame Nancy Rothwell and process, so that nutrients are handled less indicators of cardiovascular risk such as colleagues at Manchester University have effectively. For example, fats might not be high blood pressure. found the reason why. cleared from the blood stream and blood sugar levels will not be regulated properly. Professor Nazareth Irwin and Dr David The team studied mice with both a stroke Osborn at University College London said and inflammation mimicking infection “We discovered that around a fifth of liver that the results were particularly striking and measured their brain damage. enzymes show circadian rhythms, which for people under 50 years old, who had The results showed that inflammation means that the metabolic capabilities of a three-times higher risk. Importantly, dramatically worsened the injury. The the liver change dramatically between day the finding stayed true even after they inflammation produced a molecule called and night as different groups of proteins took into account medications the interleukin-1, which caused immune cells and enzymes are turned on and off in people were taking, smoking and social in the blood to invade the brain. “We can sequence,” said Dr Hastings. deprivation. The research has influenced now use this information in our clinical recommendations made by the UK’s studies to look at whether the molecules The study was co-funded by the National Institute for Health and Clinical we find important in the lab are good Biotechnology and Biological Sciences Excellence about managing schizophrenia indicators of disease in patients,” said Research Council, and involved the in primary care. Professor Rothwell. Universities of Leicester and Cambridge.

24 MRC Annual Review 2006/07

Name Rachel Batterham Born November 1970 in Peterborough, grew up in Bourne in Lincolnshire Education BSc (Hons) in Physiology and Biomedical Science (Imperial College London); MBBS (Distinction) St Mary’s Hospital Medical School, Imperial College London; MSc (Distinction) Biochemistry and Molecular Biology (King’s College London); PhD Imperial College London. Awards 2005 G.J. Mendel Award for the top British young researcher; 2004 European Association for the Study of Obesity, Young Investigator Award; 2003 BUPA Foundation Research Award Current job titles Reader in Diabetes, Endocrinology and Obesity and Honorary Consultant 07 Obesity & diabetes

Obesity is one of the greatest threats to public health in the UK, but current therapies Hormone controls hunger are only of limited usefulness. There is strong evidence that diabetes, which is rapidly Dr Rachel Batterham (see profile) and increasing in prevalence, is caused by being overweight and obese. That’s why MRC her team have discovered why a high researchers, from molecular biologists to stem cell scientists to diabetes clinicians, are protein diet can help weight loss. The trying to find out why obesity and diabetes have become so common in recent years gut hormone peptide YY (PYY) helps to and how to prevent and treat them. regulate appetite by sending signals to the brain indicating fullness. The scientists have now found that PYY levels are Profile Rachel Batterham, Division of Medicine, University College London increased through eating high protein foods. They studied obese and normal “I’m trying to gain an increased understanding of the different behavioural characteristics weight people and found that a high of obese people, an understanding of their drives to eat and patterns of eating behaviour. protein diet brought about the highest My research is moving more towards linking these complicated factors with what’s going levels of PYY and the greatest reduction on at a molecular level. As a diabetes/obesity specialist I want to understand the reasons for in hunger. This led them to create mice obesity, whether it’s evolutionary, genetic or environmental. The thing I enjoy so much is that could not produce the hormone that my work has direct application to people. – these mice ate more food than normal mice and became obese. I always wanted to do medicine, since I visited my grandmother in hospital at the age of four. I trained at St Mary’s in London. During my medical studies, I took an additional BSc “To confirm the role played by PYY, in physiology which gave me my first brief glimpse of research. It was during a house job we then gave the PYY back to the PYY at St Mary’s that I decided to focus on endocrinology and diabetes – I thought this was a deficient mice. Their food consumption particularly interesting field encompassing a broad range of diseases and affecting all age went down to normal levels, as did groups. During specialist registrar training most doctors carry out a period of research. I their weight. And when they no longer undertook a PhD focusing on appetite regulation and loved it – I haven’t stopped doing received PYY, their food intake and research since. weight went up again,” said Dr Batterham. “This research suggests that an increase I went from my PhD straight on to my current MRC/Academy of Medical Sciences Clinician in the protein content of the diet may Scientist Fellowship. During this time I completed my specialist training in general internal help tackle obesity,” she adds. The medicine and endocrinology/diabetes. Currently I spend about 10 per cent of my time findings also suggest a possible cause seeing patients and the rest doing research. The ratio of lab to clinical research I do varies for the current obesity epidemic, as our with what I’m working on at the time and comes and goes with specific clinical trials. But diets have shifted from being protein mostly my job is very lab based – working with mice, studying hormones in human and rich in our hunter-gatherer days to mouse samples, microscope work, molecular biology and biochemistry. Because I enjoy it so carbohydrate-rich today. much, I work most weekends and even Easter and Christmas!”

Pancreatic cells found in unlikely place For the first time, scientists have discovered pancreatic beta cells – which make and release insulin to control the level of glucose in the blood – outside the pancreas. They found them in bile ducts outside the liver. Beta cells are often damaged or destroyed in people with diabetes – there is hope that beta cell transplants could be used to treat the condition, but until now donor pancreases were thought to be the only available source of these cells. The study, by Professor Jonathon Slack at the Centre for Regenerative Medicine at the University of Bath, has important implications for diabetes treatment.

MRC Annual Review 2006/07 27 07 Obesity & diabetes continued

Clues about appetite may Gene for young obesity Birth weight linked genetically help obesity A study of 300 children has shown that to diabetes Co-funded by the MRC, the Wellcome mutations in the gene for the leptin The association between reduced birth Trust and the Biotechnology and receptor are linked to obesity in three weight and many chronic diseases in later Biological Sciences Research Council, per cent of children with a severe early- life was first described by Professor David Professor Steve Bloom’s team at onset form of the condition. Leptin is a Barker 16 years ago. Now, Dr Timothy Imperial College London is also hormone that plays a role in regulating Frayling and co-workers at the University investigating ways to combat obesity. appetite and energy expenditure of Exeter have uncovered strong In one study, the scientists looked – mutations in its gene were first linked to evidence linking genes to birth weight at how a part of the brain called the obesity a decade ago. “This new finding and subsequent diabetes. hypothalamus regulates food intake. reinforces the message that if children They identified proteins – relaxin-3 and are exceedingly obese early in life, there The scientists studied DNA samples from neuropeptide S – that increase and is very likely to be a biological basis, and mothers and children taking part in large decrease food intake in rats. that this is likely to involve impaired population studies and found maternal molecular control of satiety centres in genes that can affect children’s birth In a second study, Professor Bloom and the brain,” said Professor O’Rahilly, from weight by up to 120 grams – equivalent colleagues uncovered the role of gut Cambridge, who led the work. He was to the effect of smoking four cigarettes hormones in the regulation of appetite. recently awarded an MRC Centre Grant to a day in late pregnancy. Low birth Building on their previous discovery that set up a translational centre investigating weight in turn increases the chances of gut hormones are important in regulating the causes and treatment of obesity and developing diabetes in later life. “Our food intake, they have now shown that a related metabolic disorders. papers provide the strongest evidence hormone called oxyntomodulin not only yet for how common gene variants that reduces food intake but also increases influence chronic old age conditions energy expenditure in both obese and Fruit flies help understand fatty such as type 2 diabetes also alter birth lean individuals. They have also looked liver disease weight,” said Dr Frayling. at why gut bypass surgery works, and Scientists at the National Institute found that it increases circulating levels for Medical Research in London have of oxyntomodulin and other hormones discovered the cells responsible for fat Slim people may have hidden fat thought to be involved in regulating metabolism in fruit flies, with implications People who look slim and fit may not be appetite. “This research might form the for the treatment of human diseases like as healthy as they appear, according to basis of the first truly effective medical diabetes and fatty liver. scientists at the MRC’s Clinical Sciences therapy for obesity,” said Professor Bloom. Centre in London. Professor Jimmy Bell Led by Dr Alex Gould, the team hopes and colleagues used magnetic resonance to exploit the findings to speed up the imaging to show that even slim people discovery of new drugs to treat human may carry a cushion of fat around their liver diseases. In humans, dietary fat is internal organs. stored in fatty tissue but can be retrieved and converted into energy during long Their work showed that up to 40 per I want to understand periods between meals. Many of the cent of the population could be carrying important steps in this process take place fat around or inside organs such as the the reasons for in the liver. Although fruit flies share liver, heart and pancreas. Disused muscle obesity, whether it’s many of our genes, those responsible may also be streaked with hidden fat for fat metabolism have previously been that could lead to serious conditions evolutionary, genetic a mystery. But Dr Gould’s team found like diabetes and heart disease in later fly cells called oenocytes that perform life. Professor Bell said: “Traditional ways or environmental. The similar fat-metabolising functions to of measuring body fat give people the human livers. wrong idea of how much fat they have thing I enjoy so much is as it says nothing about internal storage. that my work has direct Dr Gould said: “We also found that flies People have become obsessed with share more than 20 ‘fat-burning’ genes dieting but doing this without exercise application to people. with humans. These discoveries may help means they may be putting fat in the us understand more about how our own wrong places.” Dr Rachel Batterham bodies store and burn fat.”

28 MRC Annual Review 2006/07

Name Giovanna Mallucci Born June 1963 in London Education BA (Hons), Oxford University; medical degree, London University; PhD, Imperial College London Awards 2004 Royal Society of Medicine President’s Prize in Clinical Neuroscience; 2003 Queen Square Prize in Neurology Current job titles Programme Leader Track MRC Prion Unit; Honorary Lecturer, Institute of Neurology; Honorary Consultant Neurologist, National Hospital for Neurology and Neurosurgery, London Career highlight Reversal of prion disease in mice by knocking out prion protein 08 Infections & the immune system

In the UK and globally, infections by viruses, bacteria, parasites and even prions – small infectious proteins – cause illness, suffering and death. The MRC carries out research Understanding prion disease into many related areas: the transmission and control of infectious agents; how these Creutzfeld-Jacob disease (CJD) is a pathogens interact with our immune systems; how the immune system works; the neurodegenerative disorder in which abnormally shaped proteins called prions processes of infectious disease; and global health issues. accumulate in the brain and cause brain cells to die. Prions exist in two forms – healthy, present in all normal brains, and unhealthy, Profile Giovanna Mallucci, MRC Prion Unit, London which are infectious and cause disease. Examples include scrapie in sheep and BSE “When I was eight I read about Marie Curie and her work on radioactivity: I thought ‘that’s (mad cow disease) in cattle. The spread of what I want to do’. The whole process of experimentation and asking questions really BSE to humans caused a new prion disease, appealed to me. In 1982 I went to Oxford to read medicine – the way we were taught was by variant CJD (vCJD), which has killed more than total immersion in the basic medical sciences. I knew I wanted to go into research, but was 160 people in the UK since the mid 1990s. advised to finish my medical training first and to consider research as a clinician scientist.

After qualifying, I spent five years doing general medical training in hospital rotations, then began specialist training in neurology, which included doing a PhD. A period Mouse CJD symptoms ‘reversible’ of formal research during training was then conventional for hospital clinicians and Scientists have now found that stopping immensely valuable. the production of normal prion protein in the brains of mice which carry a disease I was interested in neurodegeneration and went to talk to John Collinge, who was then similar to CJD reverses the symptoms that at the Prion Disease Group at St Mary’s Hospital in London. I got a Wellcome training are induced by prion infection. fellowship to work with him there. For my doctorate I generated a mouse model to look at loss of function of the prion protein. I loved finding out that molecular biology tools really Led by Dr Giovanna Mallucci (see profile), do work – you can follow a formula and create a mouse model and find that it really does researchers at the MRC Prion Unit in produce the protein you want. London studied the effect of halting production of these naturally occurring The MRC Prion Unit was set up five years later and I stayed on after my PhD to continue proteins on the progression of prion working on this mouse model. From 2000 I spent half my time in clinical work, to finish disease in mice. In the early stages of my specialist training, and half carrying out research. I became more research focused disease, infected mice showed problems once I qualified. I now run a group looking at mechanisms of neurodegeneration in with memory and behaviour. However, prion disease and am a consultant with a broad interest in neurodegenerative diseases, mice which had the gene for normal particularly dementia. prion proteins switched off experienced a reversal in these symptoms. Dr Mallucci These two aspects of my job are so different – research is highly creative, it’s a real waiting said: “The challenge now is to be able game and you have to have a long-term vision. But clinical work keeps me in touch with the to detect early disease in humans and patients we, as researchers, are trying to help. to develop treatments that can remove normal prion protein.” My group is small, but despite this and my clinical commitments, I have been able to carry out an ambitious research programme. Being within the Prion Unit has enabled me to draw on expertise and resources which have made our breakthroughs possible.

I have two sons, aged eleven and nine. In some ways, I think this career has more flexibility than a purely clinical career. I have never felt compromised at work or raising the boys. I travel quite a lot to conferences and meetings – it’s an important part of what I do – it’s constructive and collaborative in a way that no other interaction is.

For me the highs come when we get results. Even if they’re not what we’re expecting and I have to take a step back and think about what’s happening, it’s incredibly liberating. Of course there are low points too. You have to be tenacious to cope with the long periods where things don’t seem to be working or going anywhere, and you have to carry others through these troughs. To anyone thinking about research as a career, I’d say go for it. But you have to be prepared to take a long-term view and see the big picture. It’s a creative job. It’s all about ideas and thinking – and being prepared to change your mind.”

MRC Annual Review 2006/07 31 08 Infections & the immune system continued

Treating TB and malaria together Insights into HIV rates in Uganda HIV vaccine enters early clinical trial The three major poverty-related diseases Uganda is at the vanguard of the struggle MRC scientists have completed the first that continue to destroy lives and against HIV/AIDS. In 1989, the MRC phase of a clinical trial testing a two-part communities across the world are HIV/ Uganda Research Unit on AIDS (based at HIV vaccine aimed at an African strain AIDS, tuberculosis (TB) and malaria. The the Uganda Virus Research Institute) began of the virus. This was a test on healthy burden of these diseases falls heavily on studies into the course of the disease. volunteers to determine whether the sub-Saharan Africa. New ways of treating Over time, these confirmed that it was vaccine triggers an immune response to all three are desperately needed. Now, possible to control the epidemic through fight the infection as required, and whether researchers at the National Institute for a well organised national programme and there are any unwanted side effects. Medical Research (NIMR) in London are collaboration between the government, investigating a new way to target both TB nongovernmental organisations, The vaccine comprised an initial injection and malaria, potentially providing a cost researchers and society. However, recent of DNA followed by a booster vaccine effective way to develop new drugs for results have shown that the significant based on the pox virus, both of which both diseases. Drs John Eccleston, Iain downward trend of Uganda’s HIV/AIDS deliver the same DNA fragment but in Wilson and Roger Buxton have found a epidemic has begun to reverse in some different ways. The results, in 24 uninfected set of biochemical reactions critical for areas of the country. The research, led by volunteers, showed that the regimen the survival of TB bacteria that are also unit director Dr Heiner Grosskurth, suggests stimulated immunity in most of the present in malaria but not in humans. that there may be several reasons for the volunteers – the next steps are to improve The next steps are to show that these change in the course of the epidemic, the strength and breadth of these immune reactions are essential for malaria to but it seems changing trends in sexual responses. The trial was carried out by Dr survive and to find drugs to stop them, behaviour may be particularly important. Nilu Goonetilleke, Dr Tomas Hanke and killing both organisms. This work has significantly contributed to Professor Andrew McMichael at the MRC an adjustment of policy and a boost to Human Immunology Unit and co-funded prevention activities in the country. by International AIDS Vaccine Initiative. Immune defence linked to rare disease Research into a rare genetic condition has New antibacterial drugs Gut feeling about the unexpectedly helped scientists understand Resistance to antibiotics is soaring, meaning immune system how the body defends itself against viral that new antibacterial compounds – to Scientists led by Sir Philip Cohen at the infections and the processes involved in which bacteria are not yet resistant – are Protein Phosphorylation Unit in Dundee autoimmune diseases such as lupus. Babies urgently needed. A team led by Dr Gabriel have increased understanding of the born with Aicardi Goutieres Syndrome Waksman at the Institute of Structural innate immune system, which defends (AGS) have problems closely resembling Molecular Biology at University College against attacks from disease. The work has those caused by viral infections such London and Birkbeck College has found a enabled them to provide information to as rubella when they are caught during new way to combat infectious bacterial the pharmaceutical industry that will help pregnancy. However, AGS is caused by diseases. Their work focuses on pili – hair- in the development of drugs for Crohn’s abnormal genes rather than a virus. like structures found on the surface of disease, an inflammatory gut disease. many bacteria that help them to attach Collaborative research involving scientists to the surface of host cells they infect. Dr Fifteen per cent of Crohn’s disease at the University of Leeds Institute of Waksman and colleagues have identified patients have mutations in a protein Molecular Medicine, the MRC Human a step in the formation of pili and have called NOD2. It works with an enzyme Genetics Unit and Cancer Research UK characterised a compound that can block called RIP2 to trigger the release of has identified four of the genes that cause this step, rendering a bacterium harmless. molecules that instruct the immune AGS. The genes make enzymes called system to attack bacteria. The scientists nucleases. When they don’t work properly, found that NOD2 and RIP2 might keep the absence of nuclease proteins triggers in check levels of normal gut bacteria, an immune response in a baby like that but that when this goes awry, levels rise seen in infection in the womb. and trigger the overactivation of other immune responses, causing Crohn’s Dr Yannick Crow of Leeds University said: symptoms. It was previously thought “During the normal life-cycle of our cells, that drugs that inhibit RIP2 might help to nucleases clean up naturally produced treat Crohn’s disease, but by determining waste DNA and RNA. Failure of this process exactly how RIP2 works, they now means that the body mounts an immune suggest the opposite is true. reaction against itself.”

32 MRC Annual Review 2006/07 Dysentery cells invade gut wall Amoebic dysentery causes about 10,000 For me the highs come when I get results. Even if deaths and serious disease in tens of millions of people worldwide every year. they’re not what I’m expecting and I have to take The disease is caused by an amoeba parasite called Entamoeba histolytica. a step back and think about what’s happening, it’s Drs Robert Insall and Mehreen Zaki at incredibly liberating. Birmingham University collaborated with Dr Nancy Guillen at the Pasteur Institute Dr Giovanna Mallucci in Paris to investigate how the amoebas attack the lining of the gut. They found that the amoeba parasites produce New ways to tackle malaria Flu clues may prevent pandemic repellent chemical signals which cause A group led by Dr Michael Blackman at Scientists at NIMR have been working to them to move away from one another, NIMR is collaborating with scientists in try to prevent and prepare for a future potentially resulting in an outward the Netherlands, France, the USA and flu pandemic. Bird flu, H5N1, has spread movement that is strong enough to force Germany to try to find new drug targets worldwide in birds and caused almost them through the gut wall. Importantly, for malaria, which causes three million 200 human deaths in the past few years. the researchers found that relatives of deaths and extensive illness every year. In Experts worry that the virus may mutate E. histolytica that do not cause dysentery one project, they are looking at how the to a form that can pass between humans, do not show the same chemical signals parasite grows in red blood cells. It binds with potentially devastating effects. and movement, suggesting that this is a to a cell, then sheds the sticky proteins driving force behind the disease. involved in binding before it can enter The scientists have discovered subtle the cell. The team has now identified variations in the structure of the H5N1 virus an enzyme that is responsible for this that could lead to more effective drugs. All Antiviral proteins reduce asthma risk shedding. Called PfROM4, it is a prime flu viruses have the proteins haemagglutinin MRC scientists have found that low levels target for the development of drugs. and neuraminidase on their surface – the of antiviral proteins are to blame for H and the N. Neuraminidase comes in nine increasing the likelihood of people with forms – it allows the virus to be released asthma having a severe attack if they Simple TB test a step closer from infected cells so it can infiltrate new catch a cold. They hope the discovery will Diagnosing and treating TB patients the ones. Two drugs currently available to treat lead to a new way of treating asthma. first time they visit a clinic is key to stopping flu – oseltamivir and zanamivir – both block transmission and reducing death rates from neuraminidase but they are based on the Professor Sebastian Johnston, from the disease in developing countries. Current N2 and N9 forms. Sir John Skehel, former Imperial College London, and colleagues TB diagnosis involves careful examination Director of NIMR, and team used X-ray tested cells from the lungs of volunteers of sputum using a microscope – but in rural crystallography to determine the structures with and without asthma. They found areas where there is no clinic, this has only of N1, N4 and N8, and found that the that when infected with a cold virus, 40 to 60 per cent accuracy. Another team three-dimensional structures of the active the lung cells from people with asthma at the NIMR worked with researchers at St sites of these proteins are different. These produced half the level of antiviral George’s Hospital Medical School in London results could lead to breakthroughs in new proteins called interferons. This increased to devise a new method of diagnosing TB drug development, potentially helping to the severity of asthma symptoms when infection that is 94 per cent accurate. The combat drug resistance. the volunteers were given a common cold test relies on indicators of infection known virus under experimental conditions. as ‘biomarkers’ in serum blood samples. The In a second study, the investigators team took serum samples from patients collaborated with scientists in Japan to Professor Johnston said: “The discovery with TB and used analytical and statistical work out the structural changes in the of this mechanism could be of huge methods to detect a biomarker signature H5N1 virus that may have allowed some importance in how we treat asthma that is unique to TB infection. strains to spread from poultry to people. attacks. Delivery of the deficient They found two specific mutations in the interferons by inhalers could be an ideal Dr Delmiro Fernadez-Reyes said: “Our haemagglutinin protein that allowed the way to treat and prevent severe attacks.” work opens the door to further research virus to recognise human as well as bird The researchers are now carrying out trials translating our findings to fast and reliable cells. Dr Steve Gamblin, part of the NIMR to test the safety of this new therapy. methods of detecting TB infection that team, said: “Together, these studies are could have a major effect on global health.” an integral part of H5N1 surveillance.”

MRC Annual Review 2006/07 33 Name Marion Henderson Born 31 August 1963 in Johnstone, Scotland Education BA (Hons), University of Strathclyde; PhD, University of Glasgow Family Married to Dr Tony Axon, researcher for the University College Union. Current job title Research Scientist Field of research Evaluating interventions that aim to improve sexual health in young people Future ambition To contribute to the reduction of sexually transmitted infections and unwanted teenage pregnancies 09 Public health

Our health depends on many things – such as where we live, our education, diet and Sex education study helps lifestyle. MRC scientists are working to understand more about how these influence our change policy wellbeing, and to find ways to change things that are bad for our health. A decade long study has revealed that a special programme of sex education can have a positive impact on school Profile Marion Henderson, MRC Social and Public Health children’s knowledge of sexual health and Sciences Unit, Glasgow quality of relationships, and can reduce the awkwardness felt by teachers. “When I was young I used to read my Dad’s undergraduate psychology books and my parents’ Reader’s Digest magazines. I loved articles about educational psychology and The SHARE – Sexual Health and helping children with problems. They were fascinating. I toyed with clinical psychology, Relationships – study, carried out by the but found the idea of helping people with established problems difficult. Now I’m more MRC Social and Public Health Sciences interested in preventing problems and keeping people healthy. It feels like a very positive Unit, has changed sex education policy way forward. in Scotland. The Scottish Executive has recommended the programme be made Contract research can be hard – for the first decade of my career I was based at Strathclyde part of the sex education curriculum University and had to keep applying for grants. I found that sometimes you weren’t allowed throughout Scottish secondary schools. to apply if you weren’t tenured to a university. It can be difficult not knowing what your next project will be, where you’ll be based and how you’ll pay your mortgage. So I got involved SHARE involves five days of teacher with the contract research staff committee of the University College Union – I ended up training. It combines discussions in marrying the chair! Things have changed for the better now for young researchers. Changes groups, information leaflets and the in legislation mean more jobs are now secure. development of skills to talk about sexual encounters. A randomised controlled For the past decade I have been working on a study of the sex education programme trial involving 160 teachers and more SHARE – sexual health and relationships – which negotiated access to NHS data than 7,500 teenagers showed that about pregnancies and terminations to remove self-reporting bias. It’s one of the first SHARE was preferred by teachers, who sex education studies in the world to use objective data like this. I think the study’s felt more prepared, and by pupils, who methodology and how it was conducted were really rigorous and we managed to do what felt that it improved the quality of their we wanted to do. Sex education and reducing unwanted pregnancies is a huge task for the relationships and reduced regret about government. I don’t think you can just take 20 lessons in schools and change something sexual relationships. However, the that’s a much bigger problem. Poverty of aspiration is an important factor. For people who programme was no more effective than are third generation unemployed and don’t think they can do anything else with their lives, conventional sex education in reducing they might think ‘Why not have a baby?’ at 16 or 17. Getting the final results of the study pregnancies or abortions. was brilliant. It was a 10-year investment of my life. In saying that, it’s not over yet – we still have a lot more data to analyse and write up. “Until now, evaluations of sex education have had to rely on young people If you want to enter into this career you should go for it. You need to be passionate about reporting their sexual behaviour, and it. It’s important to persevere, to recognise what your transferable skills are and to believe in have only followed them up for a short them. I’d recommend finding someone who can mentor you and trying to be part of a good period. This is one of the first studies team. I’ve been fortunate to have learned from and worked with scientists who inspired in the world that has used objective and motivated me. My PhD supervisors Patrick West and Gillian Raab were incredible, as information, in this case NHS data on has been my team leader at the MRC, Danny Wight. At the end of the day, you can’t do young women’s abortions,” explained anything on your own.” the lead researcher Dr Marion Henderson (see profile). “Unfortunately I think it was difficult for the SHARE programme to reduce conceptions or abortions as these are so strongly influenced by socio-economic factors. Effective sex education programmes would need to If you want to enter into this career you should go address fundamental socio-economic for it. You need to be passionate about it. divisions and would also benefit from involving parents.” Dr Marion Henderson

MRC Annual Review 2006/07 35 Stress can make you fat Researchers have found that stress from everyday life can contribute to obesity. The finding came from the Whitehall 09 Public health II study, which has followed thousands of civil servants since 1985, seeking to continued establish the effects on health of stress at work, job security, change in the workplace and lifestyle factors. The results of the study and its predecessor, Whitehall Breastfed babies smarter because Low calcium can cause rickets I, are now influencing policy discussions. mums are cleverer The childhood disease rickets is The link between breastfeeding and a associated with vitamin D deficiency. It’s “This is the first study to show that baby’s intelligence, first discovered in characterised by softening of the bones daily stress influences the development 1929, may exist because mothers who which bend out of shape. But rickets has of obesity,” said Professor Sir Michael breastfeed are more intelligent, highly been reported in children in Africa and Marmot, who has led the research for educated and provide a more stimulating Asia who don’t have vitamin D deficiency. more than 20 years. home environment – not because of MRC scientists believe low levels of breastfeeding itself, as previously thought. calcium in the diet might be to blame. In the past year, Whitehall II has yielded many results. Another finding is that The finding comes from a study by the Dr Ann Prentice at MRC Human Nutrition employees who report that they are MRC Social and Public Health Sciences Research and colleagues investigated treated unfairly at work by their supervisors Unit in Glasgow and the University of the possible cause by studying a group suffer increased levels of mental illness. Edinburgh. Geoff Der said: “We analysed of children with rickets who attended a The researchers are now looking into the data from more than 5,000 children and clinic in The Gambia. They identified a effects of unfair treatment at work on 3,000 mothers in the USA and found that molecule called fibroblast growth factor rates of sick leave, inflammation in the mothers who breastfeed tend to be more 23 (FGF23) that is involved in regulating body and sleeping difficulties. intelligent. When this fact was taken into phosphate in the body, which bones need account, most of the relationship between to grow. Elevated levels of FGF23 cause In closely related research, results breastfeeding and the child’s intelligence too much phosphate to be lost from the showed that reports of stress at work disappeared. The rest was accounted for body. The researchers suggest that a diet were directly related to a combination of by other aspects of family background.” which is low in calcium may cause rickets health problems known as the metabolic by overstimulating production of FGF23. syndrome that makes people more likely The scientists also looked at families where “If further studies confirm this result, it to suffer diabetes and heart disease. one child was breastfed and another will inform worldwide clinical practice and “Obesity rates are higher among lower wasn’t – a good way to get results which dietary guidelines,” said Dr Prentice. socioeconomic groups. We found there are less affected by family background. were greater reports of work stress This confirmed the earlier findings – that among lower occupational grades, which the breastfed child was no more intelligent. Scottish knife crime has doubled may explain some of the reason for this,” Knife crime in Scotland is a public health said Professor Marmot. problem. Research has found that it has Mother’s calcium affects child’s bones more than doubled over the past 20 years. MRC researchers have shown that a Five times as many fast food mother’s diet is important in determining The study by Professor Alastair Leyland outlets in deprived areas how strong her children’s bones will be. and colleagues at the Social and Public The poorest areas of Scotland and England Low bone mass is linked to increased risk Health Sciences Unit in Glasgow gathered have more fast food restaurants than of developing osteoporosis in later life. A information from 2,151 murders that affluent areas. The discovery was made by team led by Professors Cyrus Cooper and took place in Scotland between 1981 researchers at the MRC Social and Public Caroline Fall at the MRC’s Epidemiology and 2003. The team looked for crimes Health Sciences Unit in Glasgow. They Resource Centre at the University of involving knives or similar objects. During found almost five times as many outlets in Southampton tested this hypothesis the period, the overall murder rate the most economically deprived areas of in a population in Pune, India. They increased by 83 per cent, and murder the city compared with the most affluent. assessed nutritional status in 797 rural using knives rose by 164 per cent. The Indian women 18 and 28 weeks into their researchers also found that homicide was Dr Steven Cummins of Queen Mary, pregnancies and then measured bone more common at weekends. University of London, MRC Fellow and mass in their children at six years old. collaborator on the study, said: “Easy Professor Leyland said: “It seems clear access to fast foods that may be lower Results revealed that children born to from our research that the rise of in price than healthier options in shops a mothers who ate more calcium-rich foods murders in Scotland is due specifically bus ride away, could influence people’s during pregnancy had significantly higher to an increase in the use of knives and dietary choices. Making unhealthy options bone mass than those born to mothers other sharp implements. This problem the easy ones to take in deprived areas who ate less calcium. The researchers particularly affects young men between may help fuel a rise in obesity and store up suggest that giving mothers calcium 15 and 34. Murders, along with suicide, health problems for the future – including supplements while they are pregnant might now represent a serious threat to public type 2 diabetes, heart disease and high improve bone development in children. health for this social group.” blood pressure.”

36 MRC Annual Review 2006/07

10 Turning research into healthcare

A challenge for medical research is finding ways to translate findings into clinical practice, by changing policy, If you’re naturally inquisitive and want to learn, getting new drugs to the market or introducing measures to prevent illness. science is unique. It’s not a routine job, every day One way the MRC does this is through is different… it’s the best job in the world. MRC Technology (MRCT), our affiliated technology transfer company. John O’Brien

MRCT works with MRC scientists to help commercialise their discoveries. Its Hitting back at tuberculosis Working with China to beat malaria ambition is to ensure that MRC research Scientists have identified potential new Dr Michael Blackman at the National leads to improved human health and drug targets for TB. Dr Elaine Davis and Institute for Medical Research is economic prosperity. Research by team at the National Institute for Medical collaborating with the Drug Discovery MRCT also provides starting points for Research started by developing a method Group at MRCT to try to find new drug the pharmaceutical and biotechnology to purify a protein, known as UvrD, targets for malaria. He has identified an industries to develop new drugs. Another that enables the TB bacterium to repair enzyme in the malaria parasite called focus is unmet medical need, including damage in its DNA. By doing this, UvrD is SUB1 that he believes to be a good diseases such as malaria and tuberculosis thought to help TB persist in a patient’s potential drug target. It appears to play (TB). The Development Gap Fund is a cells after infection. an essential role in infection. Dr Blackman translational fund managed by MRCT, has developed a screening test to look which is designed to increase the The scientists searched for chemicals for chemicals that might stop malaria commercial potential of MRC discoveries that inhibited the UvrD protein, stopping by acting against this target. MRCT and intellectual property. Last year MRCT it doing its job. They identified a number has helped set up a collaboration with invested £1 million in 11 new projects of ‘hits’, which are chemicals that showed the National Drug Screening Facility through this fund. potential in inhibiting UvrD. These may in Shanghai, which has screened its form the starting point for new TB drugs. own extensive library of compounds To highlight MRC discoveries and The research was funded by MRCT’s and identified a number of ‘hits’. The encourage more collaboration with Development Gap Fund. results have been sent back to MRCT for biotechnology and pharmaceutical investigation and further development. companies, MRCT has been holding quarterly ‘showcase days’ since New iron supplements do less harm December 2006. Each showcase day Iron deficiency is a common worldwide Taking flu by storm provides influential industry scientists problem with huge economic costs. Professor Tracy Hussell and her team at with unprecedented access to the In another MRCT funded project, Dr Imperial College London are working on latest MRC-funded research. Those Jonathan Powell at MRC Human Nutrition a novel way of combating flu symptoms. who attend can bid for funding from a Research has developed a method to They found that death and disease £3 million pot designed to encourage produce iron supplements without the due to infection is partly caused by a collaborative research between the usual side effects. “Most current iron rush of immune cells into the lungs, MRC and industry. It is hoped the supplements tend to promote intestinal which blocks air spaces and reduces the showcase days will help to fuel the next tissue-damage and are poorly tolerated,” amount of oxygen. Their new therapies generation of healthcare products. said Dr Powell. “They can also lead to decrease inflammation and so diminish increased problems with infection, this response. A new company has been In the last year, MRCT made £65 especially in developing countries.” set up, StormBio Inc, which is working million from licensing MRC researchers’ with the team on early clinical trials. breakthroughs. This brought the total An MRC patent has recently been filed for Professor Hussell said: “Flu remains a cash generated since 1998 to £299 this new method of producing mineral- major health concern – there have been million. Some of this revenue goes based materials for a range of biological three pandemics in the last century. back to the scientists who make the and therapeutic applications, of which We currently use vaccination and discoveries and the rest is used to fund producing iron supplements is just one reagents that interrupt virus division to more research, potentially leading to example. Other uses might include vaccine prevent infection but influenza becomes further breakthroughs by MRC scientists. components or artificial bones. MRCT and resistant to these by mutating. This is an In 2006/07, MRCT also filed 25 new the scientists are also talking to venture alternative strategy that does not target patents and made 39 new licensing capitalists about the potential of setting up the virus but reduces the host’s reaction agreements with industry. a company to take the technology further. to it. This prevents illness and death.”

MRC Annual Review 2006/07 39 10 Turning research into healthcare continued

Profile John O’Brien, MRC Laboratory of Molecular Biology, Cambridge

“When I left school after my A levels, my parents did not have the money so I couldn’t afford to go to university. I was offered a job at Lloyds Bank but turned it down because you have to wear a suit every day. The next day I went to an open day at the Babraham Institute and managed to climb onto the bottom rung of the ladder as a lab assistant.

I knew little about science, but the job taught me the bench skills I would eventually need to work on my own. I went to college one day a week to study for my Higher National Certificate in microbiology and biochemistry. I was studying from eight in the morning until after 10 at night and then back in the lab early the next morning. Then I approached Sir Barry Cross, the Director of the institute, about doing a biochemistry Honours degree on day release. I was the first person to be allowed to do this.

In 1996, I met Steve Hunt, then a neurobiology group leader at the Laboratory of Molecular Biology (LMB). Even though my background was cell biology and I had little knowledge of the brain, he took me on because of the skills I’d learnt at Babraham. Two years later I began Born May 1962 in London to study the gene gun after the one bought by LMB didn’t work very well on brain cells even Education BSc (Hons) Cambridge College though it was excellent for injecting DNA into chloroplasts – the powerhouses of plant cells. Family Kieran (6), Ella (4) and my wife Debbie How long in current position 11 years Current job title Research Support With brain cells, it was like shooting a clay pigeon with a 12-bore shotgun – it wasted Future ambition To be a first author on a ammunition and damaged the surrounding tissue. My job was to improve the gun’s Nature paper accuracy. For the past 10 years that’s what I’ve done, by developing a special barrel to reduce the gas pressure and target area. My eureka moment came over coffee with a retired police firearms expert who explained to me how the barrel of a gun works. Gene guns: improving science’s aim Last year I fulfilled a major ambition in giving a talk to the whole of LMB. Once a year the A gene gun is a tool used to insert institute holds a series of lectures by a couple of people from each division. I felt honoured to genetic information such as DNA into a be chosen to represent neurosciences. On the day I was so nervous I felt sick but it went well cell. Handheld and about the same size and I could answer people’s questions. That’s when someone told me I was a gene gun expert. as a domestic hairdryer, it was originally developed to create new strains of I feel really lucky. Throughout my career so much has depended on people giving me a plants. Now, John O’Brien (see profile) at chance. But I’ve also found out that you’ve got to keep at it. If you’re naturally inquisitive and the Laboratory of Molecular Biology in want to learn, science is unique. It’s not a routine job, every day is different. And if you’re Cambridge has improved the accuracy prepared to listen and learn and respect your scientist elders, it’s the best job in the world.” of the gene gun to create a precision instrument capable of firing DNA into a single cell. The gun is powered by a pulse of helium which pushes its genetic bullet through a cell’s membrane and into its nucleus. Mr O’Brien modified the angle of the holes in the original gun that allow helium to escape, reducing the recoil that causes tissue damage.

“The gun can now be used to insert DNA into smaller targets and deeper tissues. And in the future, a further modified design might make it possible to deliver DNA vaccines directly into human skin or muscle cells without damaging them,” he said. With help from MRCT, Mr O’Brien patented his modifications to the gene gun barrel and is planning to sell modified barrels to other scientists around the world who work with gene guns.

40 MRC Annual Review 2006/07 Photography throughout : Noel Murphy page 9 Brain bank slides page 17 Mouse brain samples page 20 ‘Sponge in a capsule’ for diagnosing oesophageal cancer page 21 Endoscopy tube forceps page 37 Sexual health study questionnaire page 40 Gene gun barrels

Photograph of Colin Blakemore (page 3): Chris Gloag

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