Research Changes Lives 2009-2014 Mid-term update on progress against objectives
July 2012
Contents Executive Summary ...... 3 Introduction ...... 11 STRATEGIC AIM ONE: Picking research that delivers ...... 13 Natural Protection...... 13 Tissue disease and degeneration ...... 19 Mental health and wellbeing ...... 27 Repair and replacement ...... 35 Genetics and disease ...... 43 Life course perspective ...... 53 Lifestyles affecting health ...... 59 Environment and health ...... 67 STRATEGIC AIM TWO: Research to people ...... 75 Translation of research ...... 75 Regulation, ethics, governance and working with decision-makers ...... 87 Communication ...... 93 STRATEGIC AIM THREE: Going global ...... 99 Partnerships and shaping the agenda ...... 99 Global Health ...... 105 STRATEGIC AIM FOUR: Supporting scientists ...... 113 Capacity ...... 113 Use of population-based data ...... 119 Research environment ...... 125
2 Executive Summary
The mid-term progress report evaluates progress against each of the specific commitments made to deliver the sixteen objectives in the MRC Strategic Plan, Research Changes Lives (2009-2014). Significant progress has been made against most (approx. 70%) of these commitments, whilst in some areas delivery is underway and advances are expected in the second half of the Strategic Plan period. The mid-term progress report gives an overview of MRC activities and the outcomes of MRC research with the aim of informing discussions on research priorities for the future. It is the first time that MRC has measured progress against strategic objectives in this way.
The following two examples illustrate the impact of MRC activities shaped by the Strategic Plan:
Addressing the ‘Natural Protection’ objective, which contributed to Theme 1 ‘Resilience, Repair and Replacement’ - the MRC, Wellcome Trust and Department of Health convened a meeting in 2009 to develop new or enhanced approaches to tackle the H1N1 flu pandemic. Three key studies were supported through a fast-track procedure, including the Mechanism of Severe Acute Influenza Consortium (MOSAIC). MOSAIC is the largest consortium of its kind, led by Imperial College with co-investigators in many UK locations. It has provided the clinical samples that led to the identification of the IFITM3 gene1, which is linked to the severity of flu infection and helps explain why flu becomes a life-threatening disease in some people whilst only having mild effects in others. MOSAIC has provided a template for such consortia worldwide leading to the establishment of a new global network, ISARIC2, supported by 6 international funding agencies across the globe, including the MRC, to understand the causes of severe respiratory diseases.
Strengthening the way we work with industry for the benefit of UK science is a key goal in the ‘Translation’ objective in Strategic Aim 2 ‘Research to People’. This objective is directly relevant to Government’s Strategy for UK Life Sciences3. A partnership established with the Association of the British Pharmaceutical Industry (ABPI) in 2009 has been the driver for a transformational relationship with industry. The £9.5m MRC-ABPI Inflammation and Immunology initiative represents the first time an MRC initiative has been co-designed with industry and a novel way of working bringing together the best of clinical science, well-characterised cohort studies and industry partners. Two disease specific consortia were established tackling Chronic Obstructive Pulmonary Disease (COPD) and Rheumatoid Arthritis. The closer and more productive interaction with industry in this successful pilot programme has shaped the stratified
1 Everitt A.R. et al. (March 2012). "IFITM3 restricts the morbidity and mortality associated with influenza.".Nature advance online publication. doi:10.1038/nature10921. PMID 22446628. 2 “New international consortium to prepare research community for future pandemics” http://www.wellcome.ac.uk/News/Media-office/Press-releases/2011/WTVM053638.htm 3 http://www.bis.gov.uk/assets/biscore/innovation/docs/s/11-1429-strategy-for-uk-life-sciences
3 medicine initiative, a £200m five-year 2011 initiative which has leveraged support from the Technology Strategy Board, Cancer Research UK and others to accelerate the adoption of stratified medicine in the UK4. The MRC/AstraZeneca Mechanisms of disease call5is an example of a novel outcome from such discussions. In a world-first this initiative has made available 22 AstraZeneca compounds to the academic research community to investigate disease mechanisms and determine whether these can be used for previously unknown indications.
A summary of the transformational developments relating to the sixteen objectives in the Strategic Plan ‘Research Changes Lives’ achieved since the plan was adopted in 2009 is given below:
Objective Key Developments 1. Natural protection Through the joint MRC-ABPI inflammation To explore resilience to disease and Immunology initiative we have and degeneration, established a new funding model that brings understanding how it may be together competing UK academic groups exploited for new interventions and companies to jointly address pressing that ameliorate disease research questions processes 2. Tissue disease and We have established effective international degeneration networks to address the bottlenecks in To advance knowledge in the neurodegeneration research through a Joint biology of ageing and Programming initiative and Centres of degeneration of human tissue; Excellence in Neurodegeneration to understand the mechanisms Major advances have been made in the and impact of chronic diagnosis and development of potential inflammation therapies for Creutzfeldt-Jacobs Disease6 Through the UK Brain Bank Network we have transformed the access to healthy and diseased post-mortem brain tissue for research, benefiting donors, patients and researchers Long-term MRC investment into fundamental stem cell biology has now led to the availability of badly needed disease models for neurodegenerative diseases7
3. Mental health and wellbeing The MRC led UK strategy for Mental Health To explore the relationship and Wellbeing has led the way in novel between mental health, thinking and the definition of a research wellbeing and resilience to agenda that looks beyond diagnostic disease processes boundaries of mental health disorders and investigates common traits8 Through industry engagement in studies awarded under the Experimental Medicine in
4 Stratified Medicine in the UK Vision and Roadmap http://www.innovateuk.org/_assets/pdf/publications/roadmap_stratifiedmedintheuk%20_final.pdf 5 http://www.mrc.ac.uk/Fundingopportunities/Calls/MoD/MRC008389 6 Detection of prion infection in variant Creutzfeldt-Jakob disease: a blood-based assay Lancet, (2011) Volume 377, Issue 9764, Pages 487 - 493, doi:10.1016/S0140-6736(10)62308-2 7 Retinoid-independent motor neurogenesis from human embryonic stem cells reveals a medial columnar ground state. 2010. Patani R et al. Nature Communications, doi:10.1038/ncomms1216 8 Sahakian BJ, Malloch G and Kennard C. Lancet, Volume 375,. pp1854 - 1855, 29 May 2010
4 Mental Health initiative we have developed a platform for future UK investment by the pharmaceutical industry
4. Repair and replacement We have established a portfolio of six early To translate the burgeoning phase clinical trials of adult stem cell knowledge in regenerative therapies through the Translational Stem medicine into new treatment Cell Research Committee and are pursuing strategies the critical developmental work to support human embryonic stem cell therapies The world’s first clinical grade human embryonic stem cell line has been deposited in the UK Stem Cell Bank Repair of the retina is starting to become a reality. MRC supported research has demonstrated evidence of functional recovery of damage in the eye through cell transplantation, providing encouragement for the development of stem cell therapies for debilitating eye conditions9. The first UK exploratory clinical studies using UK derived human embryonic stem cells to treat age- related macular degeneration are expected to start soon. MRC funded research has laid much of the foundation of stem cell advances today10 11, including recent advances in technologies to derive induced pluripotent stem cell lines12.
5. Genetics and disease Through a £9m investment into four High To use genetics, imaging and Throughput Sequencing Hubs we have biological indicators to equipped the UK research community to understand predispositions for capitalise on the major advances in next disease, and target treatments generation sequencing technologies to drive to disease subtypes forward tomorrow’s therapies. We have joined forces with other countries across the globe to accelerate progress in understanding gene function and the consequences of DNA modification for instance through partnership in the International Mouse Phenotyping Consortium.
6. Life course perspective Over £50m will be committed by MRC, the To drive forward Research Councils and health departments
9 Restoration of vision after transplantation of photoreceptors (2012), RA Pearson et al. Nature 485,99–103 doi:10.1038/nature10997 10 MRC Professor, Austin Smith received the Louis Jeantet prize in 2010 in recognition of his role in identifying the factors important in maintaining pluripotency http://www.jeantet.ch/e/prize/laureats_2010.php, Sir Martin Evans received the Nobel Prize in 2007 for pioneering work in stem cell research, much of this work was MRC funded http://www.mrc.ac.uk/Newspublications/News/MRC004058 11 Nanog is the gateway to the pluripotent ground state. Silva J et al (2009), Cell Aug 21; 138(4): 722-737 12 Inhibition of glycogen synthase kinase-3 alleviates Tcf3 repression of the pluripotency network and increases embryonic stem cell resistance to differentiation. Wray J et al. Nat Cell Biol. 2011 Jun 19;13(7):838-45. doi: 10.1038/ncb2267. Erratum in: Nat Cell Biol. 2012 May;14(5):555.
5 interdisciplinary research on multi-disciplinary collaborative ageing addressing health and wellbeing research projects funded through the MRC- from childhood to older age led Lifelong Health and Wellbeing cross- council programme
7. Lifestyles affecting health Through investment into addiction clusters To explore resilience to disease as part of a £6.5m initiative we have and degeneration, significantly increased collaborative research understanding how it may be capacity in addiction research, addressing exploited for new interventions the needs of policy makers, for instance that ameliorate disease contributing to the Home Office processes development of a new drug data warehouse, an essential national resource for the study of drug misuse. New cost-effective interventions have been13 developed that demonstrate substantial increases in the quit rates of smokers14 15.
8. Environment and health We have established the MRC-HPA Centre To explore the impacts of for Environment and Health, a major new changes in our environment on centre of excellence bringing together world health and wellbeing leading research at Imperial College and King’s College London to address policy needs; key outputs of the centre include the London Air iPhone16 “app” and Rapid Inquiry Facility
9. Translation of research We have firmly established translation as a To bring the health impacts of fundamental part of our core business fundamental research to people We have revolutionised the way we work more quickly with industry by jointly shaping innovative initiatives to accelerate the development effective treatment strategies MRC research has impacted on NICE and international clinical guidelines for the treatment of stroke patients. It is estimated that the NHS may save £7m and 320,000 hours of nursing time a year by cutting the use of stockings for approximately 80,000 stroke victims a year in the UK17.
10. Regulation, ethics, MRC’s comprehensive input into the governance and working with Academy of Medical Sciences review of the decision-makers regulation and governance of health To uphold and guide ethical research has contributed to the research practice and the establishment of a new Special Health
13 Nationally Integrated Quantitative Understanding of Addiction Harm (NIQUAD) http://www.medicine.manchester.ac.uk/healthmethodology/research/ndec/Projects/NIQUAD/ 14 Smoking cessation support delivered via mobile phone text messaging (txt2stop): a single-blind, randomised trial Free, C at al The Lancet (2011), Volume 378, Issue 9785, Pages 49 - 55, 2 July 2011, doi:10.1016/S0140-6736(11)60701-0 http://www.mrc.ac.uk/Newspublications/News/MRC008034 15 Placebo-Controlled Trial of Cytisine for Smoking Cessation; West, R et al N Engl J Med (2011) 365:1193-1200 http://www.mrc.ac.uk/Newspublications/News/Archive/MRC008199 16 London Air Quality Network http://www.londonair.org.uk/LondonAir/Default.aspx 17 Effectiveness of thigh-length graduated compression stockings to reduce the risk of deep vein thrombosis after stroke (CLOTS trial 1): a multicentre, randomised controlled trial Lancet, Volume 373, Issue 9679, Pages 1958 - 1965, 6 June 2009
6 highest standards of research Authority, the Health Research Authority, to governance; to enhance the streamline regulation and improving the regulatory process by providing cost effectiveness of clinical trials18 innovative approaches 11. Communication MRC media coverage in the national media To enhance communication with broadcast and print media and online has scientists, the public, policy- increased from 248 articles in 2009 to 2,496 makers and partners in 2011. 67,000 members of the public signed up to take part in the BBC Lab UK Brain Test Britain experiment using online games licensed from MRC research, making this the largest ever study of computer-based training.
12. Partnerships shaping the We have significantly increased joint funding agenda opportunities with other countries, investing To provide international over £9m since 2009 in areas adding value leadership in partnerships which to UK research enhance the competitiveness of the UK knowledge and health base 13. Global health MRC investments have made considerable To support global health contributions towards improving health in research that addresses the developing countries: inequalities in health which arise The DART clinical trial19 found that regular particularly in developing laboratory tests to monitor the effects of countries ART offered little additional benefits compared to careful clinical monitoring, which means that many more people with HIV can be treated for the same money. The Jinja trial20, involving MRC’s Unit in Uganda demonstrated that ART delivery for the treatment of HIV through a home-based care model is as effective as clinic-based delivery, again helping more people to receive effective treatment The FEAST trial21 showed that intravenous fluid resuscitation for African children in shock with severe infections does not save lives, which will help to improve clinical practice.
14. Capacity Key developments include: To strengthen and sustain a skilled research workforce The establishment of Doctoral Training through targeted support for Partnerships with Universities to strengthen excellent training and the accountability for the use of block Doctoral
18 http://www.acmedsci.ac.uk/p47prid88.html 19 DART study website http://www.ctu.mrc.ac.uk/dart/ 20 Rates of virological failure in patients treated in a home-based versus a facility-based HIV-care model in Jinja, southeast Uganda: a cluster-randomised equivalence trial; Jaffar, S et al. Lancet (2009), Volume 374, Issue 9707, Pages 2080 - 2089, doi:10.1016/S0140-6736(09)61674 http://www.mrc.ac.uk/Newspublications/News/MRC006233 21 FEAST trial shows fluid resuscitation for African children in shock with severe infections does not save lives (2011) http://www.feast-trial.org/node/342
7 development of world-class Training Grants allocated on the basis of research leaders University grant income and to optimise the alignment of training strategies with MRC’s priorities and each University’s research strengths. Strengthened engagement with industry through broadening the range of companies involved in the Industrial CASE studentship scheme, the creation of two Clinical Pharmacology and Pathology Programmes (recruiting up to 20 clinician PhDs over three years), and the launch of new MRC partnership awards to stimulate industry collaborations of existing fellows
15. Use of population-based UK Biobank, an internationally unique cohort data resource combining breadth and depth of To exploit fully the complexity measurements has opened for use by and benefits of population-based researchers in 201222. The £93m UK Biobank data; to maximise sharing and project follows half a million UK adults, linkage of data, and to develop which were recruited between the ages of data collection and storage 40 and 69. They have undergone detailed body measures (such as lung and eye function), provided blood, urine and saliva samples and comprehensive lifestyle information.
An MRC supported Aneurysm Screening Study23 showing that around half of all aneurysm-related deaths could be prevented by a nationwide screening programme has led to the launch of a national programme to detect AAAs early in 2009.
Four UK e-health research centres of excellence have been awarded through a 10 partner £19m MRC-led initiative. By combining clinical, research and social information they will enable transformational change in the development of treatments, improvement of drug safety and assessment of risk to public health.
16. Research environment In a unique partnership between the MRC, To provide a world-class major charitable funders, and London research environment Universities we are on track to establishing the £540m Francis Crick Institute, a major new national biomedical research institute for the 21st century We are in the process of transforming the
22 What makes UK Biobank special? http://www.thelancet.com/journals/lancet/article/PIIS0140- 6736(12)60404-8/fulltext 23 Screening men for abdominal aortic aneurysm: 10 year mortality and cost effectiveness results from the randomised Multicentre Aneurysm Screening Study BMJ (2009);338:b2307
8 way in which we support research by fully integrating a large proportion of our MRC Units within UK Universities (3 transfers have been completed and 12 are on-going)
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10 Introduction
In June 2009 the Medical Research Council published its new strategy ‘Research Changes Lives’ which set the framework by which MRC aimed to support medical research which increased the pace of the transition to better health.
RCL set the path for delivering better health and wellbeing through developing prevention interventions, new treatments for disease, producing well found policy guidance for research governance and ethics, and maintaining excellence in the basic research that underpinned these activities.
The four strategic aims and sixteen objectives set within them were designed to drive progress in support of MRC’s mission, and to deliver measurable impact.
Each strategic objective described a vision for the future and a statement of how MRC would achieve the objective. In this mid-term review each objective is examined and progress against the 83 specific commitments made to achieve these objectives is measured using the following coding.
√ Little new activity
Partial progress against √√ objective/delivery in progress Significant/good progress √√√ against objective
This is complemented by brief details of more than 220 outcomes realised since 2009 as a result of MRC funding with impact relevant to the MRC strategic plan. The information has been selected from the MRC e-Val dataset24 from data sweeps in 2009, 2010, and 2011. MRC e-Val data is compiled from feedback provided by over 3,000 MRC funded researchers from almost 100% of MRC funded research fellowships, grants and intramural research programmes active since 2006.
The mid-term progress report will serve as a reference point for strategic discussions by MRC Boards and Overview Groups to inform future research priorities for the next spending review period and the refreshed Strategic Plan, ‘Research Changes Lives 2’. It will be made available to the MRC and wider scientific community, other stakeholders and the public via the MRC web page to communicate MRC activities and outcomes and to seek inputs on future priorities. Progress is dependent on a number of
24 http://www.mrc.ac.uk/Achievementsimpact/Outputsoutcomes/e-Val/index.htm
11 factors including the strength of the field at the time when the Strategic Plan was published. Future priorities may lay in areas of significant progress or little activity, dependent on the opportunities and needs identified.
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STRATEGIC AIM ONE: Picking research that delivers
RESEARCH PRIORITY THEME ONE: Resilience, repair and replacement
Natural Protection
“Protecting ourselves: understanding innate resilience to disease and degeneration”
The human immune system protects the body throughout life, providing innate resilience to disease and degeneration. Understanding this – and how resilience breaks down with age or disease – is critical for developing new therapeutic advances for transplantation and the treatment of infectious diseases, autoimmune diseases and allergy.
Objective
To explore resilience to disease and degeneration, understanding how it may be exploited for new interventions that ameliorate disease processes.
Measuring up progress against commitments in Research Changes Lives
1 Fostering interdisciplinary environments linking geneticists, molecular biologist, modellers, clinicians, physicists and √√√ chemists 2 Launching a joint initiative in inflammation and immunity with industry √√√
3 New appointments in strategic areas to boost capacity √√√
4 Sustaining and developing centres of excellence in HEIs √√√
5 Partner with other funders and improve access to clinical facilities √√√
MRC’s investment in immunology and infectious diseases through the Infections and Immunity Board is approx. £100m per annum25.
Transformational developments
Through the joint MRC-ABPI inflammation and Immunology initiative we have established a new funding model that brings together competing UK academic groups and companies to jointly address pressing research questions
25 2009/2010 spend figure
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1. Fostering interdisciplinary environments
The MRC has awarded £28m to the University of Glasgow to support a new multidisciplinary Centre for Virus Research (CVR) including £6m contribution to a new building. The Centre combines MRC and University researchers and is well integrated into Glasgow University and linked up with other activities, including the BBSRC Institute for Animal Health and the Global Virus Network. The Centre covers a broad range of virus research and will expand research capacity in emerging viruses, which present a major health threat. The CVR has successfully attracted a major infrastructure award from the Wellcome-Wolfson Trust.
We have renewed our investment in the NIMR Immunity and Infections Division, which conducts world leading research aimed at understanding immunological responses at the cellular level and, viral, bacterial and parasitic infections.
2. Launching a joint initiative in inflammation and immunity with industry
Working jointly with the ABPI and companies we have launched an initiative in inflammation and immunology. Building on the outcomes of two disease focussed workshops bringing together key experts from academia and industry, we have invested £9.5m to establish two disease specific consortia in Chronic Obstructive Pulmonary Disease (COPD) and Rheumatoid Arthritis. The consortia are in the process of establishing cohorts of well-characterised patients in order to understand better disease mechanisms and possible drug targets. This is the first example of an initiative that was shaped in partnership with industry and brings together a large number of academic investigators across the UK with pharmaceutical and biotech companies to address jointly pressing research questions.
3. Sustaining and developing centres of excellence in HEIs, and 4. New appointments in strategic areas to boost capacity
We have renewed funding for the MRC Human Immunology Unit (HIU), MRC’s first University Unit, at a level of just under £20m over five years. The HIU has been re-structured under new Directorship and has benefitted from its new funding model through increased interactions within Oxford University and the NIHR Biomedical Research Centre. The Unit conducts internationally leading immunology research and applies the knowledge gained for the development of treatment strategies against infectious diseases, cancer, allergy, and autoimmune diseases. Innate immunity is key focus and a new group leader has been recruited to strengthen this area. A high profile programme leader for imaging has also been appointed and further recruitments are ongoing.
We have funded a new MRC Centre for Molecular Bacteriology and Infection at Imperial College aiming to understand bacterial infection and human resistance to design affective vaccines and drugs. The Centre comprises a high profile training programme for students and clinical research fellows, to strengthen future capacity in the field.
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5. Partner with other funders and improve access to clinical facilities
Funding for the MRC Centre for Transplantation at Kings College London, which seeks to improve the health of transplant recipients by targeting inflammatory and immune responses, has been extended for a further five years.
We have joined forces with other funders to address the rise in antibiotic resistance and hospital acquired infections. Joining with the Canadian Institute of Health Research we have each invested £2m into two joint Canada-UK collaborative research programmes to tackle antibiotic resistance. In partnership with other UK funders, we supported two infections research consortia through a second phase of the successful UKCRC Translational Infections Research Initiative. The consortia aim to develop tools for tracking MRSA and a mobile phone-networked self test for sexually transmitted diseases.
In partnership with NIHR we have developed a Strategy for Public Health Infection Research26, which was published in 2010 and sets out the vision for an integrated national approach to infectious diseases research that reflects the public health needs of the UK.
Together with the BBSRC and the Wellcome Trust we invested £6.5m to fund a series of projects aimed at understanding the development and spread of influenza A, including the H1N1 virus responsible for the 2009 “swine flu” outbreak. We extended the scope of the FluWatch surveillance programme, which examines flu transmission within English households, to include H1N1. We also supported the MOSAIC consortium, which examines the factors that contribute to the severity of flu in up to 500 people hospitalised during the flu pandemic. The COSI projects examined H1N1 transmission in pigs and the associated occupational risks of farm workers.
Research Changes Lives objectives in progress
We will increase our investment in “systems immunology” and are developing a funding initiative in this area. This will bring together immunologists, computer scientists, and epidemiologists to understand better how we can stimulate the body’s own defence mechanisms and how our ability to fight off infections changes over the life course.
We will work with partners in Europe to develop a co-ordinated European research agenda in antimicrobial resistance and we will increase engagement with industry in this area
Outcomes 2009-2012
New treatments/diagnostics in development Zaed Hamady A live bacterial drug delivery method27 for potentially (University of treating irritable bowel syndrome has shown promising Leeds) results in preclinical testing. Evaluation was carried out in an animal model of intestinal epithelial injury and colitis and was shown to reduce symptoms such as rectal bleeding,
26 http://www.nihr.ac.uk/files/pdfs/Public%20Health%20Infection%20Research%20Strategy.pdf 27 Xylan-regulated delivery of human keratinocyte growth factor-2 to the inflamed colon by the human anaerobic commensal bacterium Bacteroides ovatus Gut. (2010);59(4):461-9
15 weight loss and inflammation. Irwin McLean A mouse model of eczema which demonstrates many of the (University of hallmarks of human eczema was published in 200928. The Dundee) MRC-funded group was the first to do this despite fierce international competition from groups in the USA, Germany and Japan. The model has now kick-started new therapy development programs aimed at repairing or enhancing skin-barrier function. Myra O. McClure A sensitive and specific antibody test for Chlamydia which (Imperial College performs significantly better than commercially available London) and Paddy assays has been developed29. Funding is being sought to Horner (University use this assay in order to better understand the natural of Bristol) history of chlamydia infection. Andrew Gorringe A vaccine for meningococcal disease enriched in heat shock (Health Protection proteins. The HPA has developed a GMP-ready Agency) manufacturing process and built on TSB funded collaborative with ImmBio Ltd.3031, a Cambridge-based vaccine development company, and Bristol University. Further development of the vaccine is now supported by MRC DPFS funding. The product is currently undergoing preclinical testing. Elleanor Barnes An investigational adenovirus-based hepatitis C virus (HCV) (University of vaccine induced sustained T-cell responses and cytokine Oxford) production in a small Phase 1 study of healthy volunteers3233. No vaccine currently exists for HCV. It is estimated that 170 million people globally have chronic HCV which may lead to liver failure34. Support provided by MRC Developmental Clinical Study funding and the pharmaceutical company Okairos. Synairgen Plc. Synairgen plc. is developing therapies for respiratory (Southampton diseases with a focus on asthma and chronic obstructive University spin pulmonary disease (COPD) using an inhaled interferon out) approach. The founding technology stems from at least twenty years of development in the laboratories at the University of Southampton led by Professors Stephen Holgate, Donna Davies and Ratko Djukanovic, who have benefitted from MRC funding. In 2012 Synairgen announced promising results from a Phase II trial of inhaled interferon to protect asthma sufferers from viral infections35.
Research into policy Owain Hughes Department of Health has made a decision to adopt the (MRC Clinical quadravalent vaccine Gardasil into the National
28 Fallon et al., A homozygous frameshift mutation in the mouse Flg gene facilitates enhanced percutaneous allergen priming. Nat Genet 41: 602-608 (2009) PMID: 19349982 29 Pgp3 Antibody Enzyme-Linked Immunosorbent Assay, a Sensitive and Specific Assay for Seroepidemiological Analysis of Chlamydia trachomatis Infection Clin Vaccine Immunol. (2009); 16(6): 835–843 doi: 10.1128/CVI.00021-09 30 New vaccine could prevent deadly infections http://www.innovateuk.org/content/case-study/new- vaccine-could-prevent-deadly-infections.ashx 31 Profile of ImmBio Ltd http://www.mrc.ac.uk/Achievementsimpact/Profiles/GrahamClarke/index.htm 32 Novel adenovirus-based vaccines induce broad and sustained T cell responses to HCV in man. Science Translational Medicine 4(115):115ra1. (2012). 33 Vaccine vectors derived from a large collection of simian adenoviruses induce potent cellular immunity across multiple species. Science Translational Medicine 4(115):115ra2. (2012). 34 www.who.int/csr/disease/hepatitis/Hepc.pdf 35 Positive Phase II asthma clinical trial data (Synairgen press release April 2012) http://www.synairgen.com/media/1536/19%20april%202012%20Phase%20II%20press%20release% 20final.pdf
16 Training Fellow, Immunisation Programme, replacing the bi-valent vaccine University College Cevarix36. Working with the Health Protection Agency, Dr London) Hughes was able to use data collected from across the UK on the prevalence and cost of treating Recurrent Respiratory Papillomatosis to model potential cost savings emerging from adopting the quadravalent vaccine versus continuing with the bi-valent vaccine. These data were presented to the Department of Health and published in the BMJ37. Andrew Haywood Data from the MRC/Wellcome Trust funded “Flu Watch” (University College study38 was used by the HPA modelling group that estimated London) the number of cases of pandemic influenza. Via the joint committee on vaccination and immunisation (JCVI)these results have informed policy decisions on the UK response to the pandemic in 2009, and have continued to help with economic modelling and national vaccination strategies. MRC/Imperial At the outset of the Influenza H1N1 pandemic, the College Centre for MRC/Imperial College Centre, in collaboration with the WHO Outbreak Analysis and public health authorities in Mexico put forward and Modelling estimates for the transmissibility and severity of the new strain39. This work contributed the best available evidence to policy makers world-wide and, given the global impact of H1N1, was highly cited by other researchers.
Scientific Advances Dr Leo James Discovery that antibodies can attack viruses inside the cell (MRC LMB) as well as outside of it has overturned 120 years of thinking about the immune system40 and opened up new avenues for discovering anti-viral drugs. Anne O’Garra A genetic signature discovered in the blood of patients with (MRC NIMR) active tuberculosis (TB)41 may serve as the basis of future diagnostic tests and also sheds light on why some people are carriers and others go on to develop active TB disease. Peter Openshaw The Mechanism of Severe Acute Influenza Consortium (Imperial College, (MOSAIC) has enabled identification of a gene (IFITM3), London) variants of which are linked to life-threatening influenza. The work is the result of collaboration between intensive and critical care units across the UK, the Wellcome Trust Sanger Centre, and virologists and was published in Nature in 201242.
36 HPV vaccine to change in September 2012 (Department of Health 2011) http://mediacentre.dh.gov.uk/2011/11/24/hpv-vaccine-to-change-in-september-2012/ 37 Comparing bivalent and quadrivalent human papillomavirus vaccines: economic evaluation based on transmission model BMJ 2011;343:d5775 38 http://www.fluwatch.co.uk/ 39 Pandemic potential of a strain of influenza A (H1N1): early findings. Science. (2009) ;324(5934):1557-61 40 Antibodies mediate intracellular immunity through tripartite motif-containing 21 (TRIM21) PNAS (2010), doi: 10.1073/pnas.1014074107 http://www.pnas.org/content/early/2010/11/01/1014074107.full.pdf+html 41 An interferon-inducibleneutrophil-drivenbloodtranscriptionalsignature in humantuberculosis Nature. 2010 Aug 19;466(7309):973-7. 42 Everitt A.R. et al. (March 2012). "IFITM3 restricts the morbidity and mortality associated with influenza.". Nature advance online publication. doi:10.1038/nature10921. PMID 22446628.
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18 Tissue disease and degeneration
“Understanding the mechanisms of degeneration to enhance the treatments of the future”
As the proportion of older people in the population increases, we need new approaches to unravel the complex biology of ageing and to understand its links with frailty and disease. Throughout life, cells and tissues are subject to attack from long-term biological processes such as chronic inflammation. These cause serious tissue deterioration, which can be responsible for symptoms ranging from breathlessness in asthma to bowel disease.
Objective
To advance knowledge in the biology of ageing and degeneration of human tissue; to understand the mechanism and impact of chronic inflammation.
Measuring up progress against commitments in Research Changes Lives
1 Support enabling technologies such as cellular and positron emission tomography imaging, computational biology and √√√ tissue and brain banking 2 Addressing the interaction between molecular and cellular damage and effects across physiological systems and √√√ encouraging the integration of studies of damage across cell components 3 Study the impact of potential therapies on chronic inflammation to learn more about the underlying √√√ mechanisms of disease progression 4 Train more researchers to take an integrative approach to the study of molecular and cellular ageing processes, and √√√ build research excellence in neurodegeneration
MRC is the largest UK funder of neurodegeneration research with an annualised spend on grants of £41m43 in 2011 compared to £63m for the UK as a whole.
Transformational developments
We have established effective international networks to address the bottlenecks in neurodegeneration research Major advances have been made in the diagnosis and development of potential therapies for Creutzfeldt-Jacobs Disease44 Through the UK Brain Bank Network we have transformed the access to healthy and diseased post-mortem brain tissue for research, benefiting donors, patients and researchers
43 Figure excludes spend on students, fellowships and resources 44 Detection of prion infection in variant Creutzfeldt-Jakob disease: a blood-based assay Lancet, (2011) Volume 377, Issue 9764, Pages 487 - 493, doi:10.1016/S0140-6736(10)62308-2
19 Long-term MRC investment into fundamental stem cell biology has now led to the availability of badly needed disease models for neurodegenerative diseases45
1. Support enabling technologies such as cellular and positron emission tomography (PET) imaging, computational biology and tissue and brain banking
In 2011, Imanova Ltd was launched, a unique £43m joint venture with three London Universities and significant engagement from GlaxoSmithKline. Imanova will deliver cutting-edge Positron Emission Tomography (PET) imaging technologies to researchers in the UK and promote novel ways of working between academic and commercial researchers (see also mental health and translation).
A Computational Genomics Analysis and Training Programme has been established at the University of Oxford to train post-doctoral researchers in next- generation sequencing analyses and provide analytical capability to UK research groups (see also genes and disease).
We have established the UK Brain Banking Network, which co-ordinates the provision of post-mortem brain tissue to tackle the shortage of samples for research into neurodegenerative and other brain diseases. In 2011, we renewed investment into four existing MRC brain banks and the network co-ordinating centre. We set up a new bank for ‘control’ brain tissue, increasing the availability of healthy brain tissue for research and enhancing the value of the Brain Banking Network by providing a standard that can be used across different banks. We have also agreed to meet NHS research support costs for dementia brain banks to assist charities in the field. The network has played a key role in ensuring best practice in relation to ethical issues and consent whilst at the same time minimising the regulatory burden on researchers.
2. Addressing the interaction between molecular and cellular damage and effects across physiological systems
Investment into world leading prion research, through the £32m MRC Prion Unit (University College London) has provided new insights into the mechanisms of protein folding which are associated with dementias as well as Creutzfeldt- Jacobs Disease (CJD). Translational programmes at the Unit are well advanced in developing therapeutic approaches for CJD and these may be applicable for Alzheimer’s Disease, given the recent discovery of common molecular pathways in the development of these diseases.
£16m was awarded to three major collaborative programmes through a joint neurodegeneration call for proposals with the Wellcome Trust. The call focussed on research addressing the disease mechanisms of debilitating disorders such as Alzheimer’s Disease, Parkinson’s Disease and Motor Neuron Disease. The research programmes bring in cutting-edge research expertise outside these disease areas thereby building important research capacity.
We have invested £1.7m to support 5 research proposals investigating the mechanisms of Chronic Fatigue Syndrome/Myalgic Encephalomyelitis
45 Retinoid-independent motor neurogenesis from human embryonic stem cells reveals a medial columnar ground state. 2010. Patani R et al. Nature Communications, doi:10.1038/ncomms1216
20 (CFS/ME), which are still poorly understood. CFS/ME is a debilitating medical condition with a diverse range of symptoms including profound physical and mental fatigue. A key priority was to build up capacity in CFS/ME research by encouraging researchers working in related research areas to tackle this disease. 14 researchers new to CFS/ME have been funded to work in this field.
In response to our highlight notice in systems medicine we awarded a number of major projects, including a £2m programme to increase mechanistic understanding of the hypothalamic-pituitary-adrenal axis, an important stress response system in the human body.
3. Study the impact of potential therapies on chronic inflammation to learn more about the underlying mechanisms of disease progression
We have invested £1.5m to renew funding for the MRC Centre for Inflammation Research at the University of Edinburgh in 2010. The Centre conducts leading research investigating the regulation of inflammation, modulation of the immune system and tissue regeneration and pioneers the imaging of inflammation. Under new Directorship the Centre has increased its translational ambitions, including a new programme on tissue injury and repair.
We also renewed our investment into the MRC & Asthma UK Centre in Allergic Mechanisms of Asthma at King’s College London and Imperial College at a level of £2m. The Centre leads the way in research addressing the interaction of infection with the immune system and airways, effects of chronic inflammation, the genetics of asthma, and the development of new strategies for the prevention and treatment of respiratory disease.
A groundbreaking £4m asthma programme, equally co-funded by the MRC and GlaxoSmithKline (GSK), has been awarded to the MRC-Asthma UK Centre in Allergic Mechanisms of Asthma. The programme will investigate the often life- threatening interplay between allergy and viral infection using compounds in the GSK development pipeline to explore novel targets for treatments (see also translation).
We have expanded the remit of the MRC Lifecourse Epidemiology Unit, which was renamed from the MRC Epidemiology Resource Centre in June 2011 to reflect the evolution into a science-led unit. The Unit uses epidemiological methods to reveal how we can prevent common chronic diseases by looking at the different factors that are important at various stages of the lifecourse. It places an emphasis on musculoskeletal, metabolic and cardiovascular diseases.
4. Train more researchers to take an integrative approach to the study of molecular and cellular ageing processes, and build research excellence in neurodegeneration
As part of the cross-Research Council Life Long Health and Wellbeing (LLHW) programme, we have been the major contributor to an £8m investment to establish two LLHW Centres focussed on research into the ageing brain in Edinburgh and Newcastle. The aim is to understand better the ageing process and the factors that determine the risk of and the resilience to age-related neurodegenerative processes such as dementia and cognitive decline.
21 Jointly with Arthritis Research UK, we invested £5m into two MRC-Arthritis Research UK Centres for Musculoskeletal Ageing Research (see also lifecourse perspective).
MRC is the largest UK funder of neurodegeneration research with an annualised spend on grants of £41m46 in 2011 compared to £63m for the UK as a whole. A relatively small proportion (10%) is clinical research carried out on patients, reflecting the few available treatments in this area (figure 1). Proportionally MRC investment is highest in Alzheimer’s Disease and dementias, representing the major burden of these diseases. MRC also has significant investments in prion disease, which is also one of the human dementias, mainly through the MRC Prion Unit (figure 2).
Figure 1
Health and social care research 2%
Clinical research* 10%
Basic research 88%
*defined strictly as research in patients
Figure 2
MRC Break down by disease (annualised, major) Neurodegenerat Spinal Muscular Alzheimer ive general Atrophy disease & 21% 4% dementias 21% Spinocerebellar ataxia Motor neurone 1% disease Huntington's 7% disease Prion Parkinson's 13% 20% disease 13%
To further strengthen research excellence in neurodegeneration research and tackle the obstacles to progress we are working with international partners:
MRC has led the development of a research strategy for the European Joint Programming in Neurodegenerative Disease (JPND) Initiative on behalf of 25 member countries. The research strategy was launched in February 2012 and sets out the research priorities for the next 10 years, providing a framework for future co-ordination and investment in neurodegeneration research across
46 Figure excludes spend on students, fellowships and resources
22 Europe47. Joint Programming initiatives are designed to address grand challenges that are too large for one country to tackle and there is significant potential for leverage of funding from the European Commission to support research addressing the growing burden of neurodegenerative diseases. We have already been involved in the first JPND funding call seeking to harmonise biomarkers for use in future clinical trials across European centres and have awarded £0.9m to support UK participation in three studies.
MRC also administers the Centres of Excellence in Neurodegeneration (COEN) initiative on behalf of currently six international partners to promote innovation and the co-operative use of cutting edge technologies across countries to speed up progress in neurodegeneration research. So far we have contributed £1m to a total investment of £3.7m to support eight research projects spanning discovery science and preclinical research. In 2011 MRC and ABPI co-hosted a meeting with the Biopharmaceutical sector to explore opportunities for public-private partnerships.
We have led the development of research priorities for dementia research as part of the work programme of the Ministerial Advisory group in Dementia Research (MAGDR), which brought together partners from academia, charities, Government, carers, and industry. The MAGDR report, including a ‘Route Map for Dementia Research’ was published in 201148. In 2012 the Prime Minister set out his challenge on dementia and his determination to build on the strategy to deliver major improvements in dementia care and research by 2015. A dedicated Champions Group has been established to oversee the implementation of the Prime Minister’s commitments and to strengthen engagement between research and health and social care providers.
Our long term investment in fundamental stem cell science over the past decade is now starting to pay off, with induced pluripotent stem cells promising to deliver important new cell-based platforms for disease modelling and drug screening. We invested £0.7m for a translational award to develop a programme on Alzheimer’s Disease capitalising on these new technologies.
Support for research teams at the MRC Centre for Neuropsychiatric Genetics and Genomics has been enhanced for instance through a £1.1m strategic award to exploit the high profile discovery at the centre of two genetic risk factors for Alzheimer’s Disease49.
Research Changes Lives objectives in progress
Guided by MADGR we will increase our investment in dementia research from £16m in 2010/11 to £33m by 2014/15 to meet the Prime Ministers challenge of more than doubling publicly funded dementia research to an estimated £66m by 2015. Recognising that risk factors and disease pathways are shared between neurodegenerative disorders we work across disease areas to address the mechanisms of disease development We will identify new drug targets for neurodegenerative disease We will develop novel biomarkers to identify subgroups of patients with different prognosis or response to treatment
47 http://www.neurodegenerationresearch.eu/initiatives/strategic-research-agenda/ 48http://www.dh.gov.uk/en/Publicationsandstatistics/Publications/PublicationsPolicyAndGuidance/DH_ 127750 49 Genome-wide association study identifies variants at CLU and PICALM associated with Alzheimer's disease: Nat Genet. 2009 Oct;41(10):1088-93. Epub 2009 Sep 6. Erratum in: Nat Genet. 2009 Oct;41(10):1156.
23 We will promote the use of induced pluripotent stem cells as disease models We will review our investments in systems medicine and stimulate research in this area
Outcomes 2009-2012
Scientific Advances David Beech Researchers have discovered that scorpion venom (University of (margatoxin) is 100 times more potent than any other Leeds) known compound at preventing a condition which causes heart bypass grafts to fail50. Sean Deoni (Kings Scientists have shown, for the first time, how our brain College) ‘wiring’ develops in the first few months of life51. Using a new imaging technique, the scientists monitored the formation of insulating layers around nerve cells, a process called myelination, which is vital for normal brain function. Damage to the myelination process is believed to contribute to a range of neurological and psychiatric disorders, including autism and intellectual disability. David Smith Research has shown52 that daily tablets of B vitamins can (University of halve the rate of brain shrinkage in elderly people who Oxford) suffer from Mild Cognitive Impairment (MCI). Around half of people with MCI develop dementia, mainly Alzheimer’s, within five years of diagnosis and it is hoped these findings could lead to a treatment to delay the onset of Alzheimer’s Maria Hernandez- A ‘full set’ of immunological markers in the blood has Fuentes (King’s been found which could be used to predict whether an College London) individual’s kidney transplant will be a long term success or whether it will fail53. This may help deliver more personalised care to kidney transplant patients in future, by safely modifying the amount of medication patients take to prevent rejection of the donor organ. David Sharp Research in stroke patients54 has shed light on how these (Imperial College) patients can recover cognitive function after their brains have been injured. In stroke patients who recover the ability to speak, there is increased integration between the frontal and parietal lobes of the brain – and this effect is also seen in normal people who are exposed to difficult listening conditions. John Burn/CAPP2 New studies have suggested that asprin may be more trial (University of effective in preventing cancer than previously thought. Newcastle) Researchers examined 1000 patients with Lynch syndrome, a condition that increases the risk of cancer,
50 Potent suppression of vascular smooth muscle cell migration and human neointimal hyperplasia by KV1.3 channel blockers Cardiovasc Res (2010) doi:10.1093/cvr/cvq305 51 Mapping Infant Brain Myelination with Magnetic Resonance Imaging Journal of Neuroscience (2011), 31(2): 784-791; doi: 10.1523/JNEUROSCI.2106-10.2011 52 Homocysteine-Lowering by B Vitamins Slows the Rate of Accelerated Brain Atrophy in Mild Cognitive Impairment: A Randomized Controlled Trial PLoS ONE, 5(9). DOI: 10.1371/journal.pone.0012244 53 Development of a cross-platform biomarker signature to detect renal transplant tolerance in humans J Clin Invest.2010;120(6):1848–1861. doi:10.1172/JCI39922. 54 Increased frontoparietal integration after stroke and cognitive recovery Ann Neurol. (2010) Nov;68(5):753-6. PMID:20687116
24 Peter Rothwell and found that the incidence of cancers in patients taking (University of asprin was very significantly reduced55. It was noted that Oxford) previous trials may not have followed patients long enough to discover this effect. Two subsequent systematic reviews examined the short-term impact of asprin56 and its effect on cancer metastasis57, to find that daily asprin may be beneficial both in the short term and potentially help in the treatment of some cancers. Miratul Muqit and MRC funded researchers have discovered a molecular Dario Alessi (MRC “switch” that sheds light on the progression of Parkinson's Protein disease58. Mutations in the genes encoding Pink1 and Phosphorylation Parkin have both been found to lead to Parkinson’s Unit, Dundee) disease, but none of the detail about how these proteins might work together was known. The team in Dundee discovered that, under particular conditions Pink1 acts to switch Parkin into an active form. Activated Parkin is important for clearing toxic proteins from the cell, and failure to do this is thought to lead to cell death. The discovery opens up new ways to intervene in the disease. Giovanna Malucci Researchers have identified a major pathway leading to (MRC Toxicology brain cell death in mice with neurodegenerative disease. Unit, Leicester) The study demonstrates synaptic loss at the earliest stage of neural damage and capacity to slow damage to the synapse. Using prion disease as a model, the team was able for the first time to block this pathway. They found this prevented brain cell death and increased survival in the mice. Work is now underway to determine whether this is a route to therapy in other neurodegenerative conditions. Michel Goedert The research at LMB has led to a better understanding of (MRC Laboratory of the composition of the characteristic filaments that Molecular Biology) accumulate in nerve cells prior to their death in neurodegenerative diseases. Mouse models developed in this work59 are a key part of programmes to develop new treatments for Alzheimer’s disease, and licensed via MRC Technology. Wilhelm Schwaeble Studies using animal models found a key role for the (University of protein MASP-2 in modifying the extent of damage to Leicester) heart tissue following a heart attack60. Inhibiting MASP-2 using an antibody, prior to an induced heart attack, resulted in significantly less damage. The research led to a large number of reports in the media worldwide about the possibility of a “simple jab to limit heart attacks and
55 Long-term effect of aspirin on cancer risk in carriers of hereditary colorectal cancer: an analysis from the CAPP2 randomised controlled trial Lancet, (2011) Volume 378, Issue 9809, Pages 2081 - 2087, doi:10.1016/S0140-6736(11)61049-0 56 Short-term effects of daily aspirin on cancer incidence, mortality, and non-vascular death: analysis of the time course of risks and benefits in 51 randomised controlled trials Lancet, (2012) Volume 379, Issue 9826, Pages 1602 - 1612, 28 57 Effect of daily aspirin on risk of cancer metastasis: a study of incident cancers during randomised controlled trials The Lancet, (2012) Volume 379, Issue 9826, Pages 1591 - 1601, 28 58 PINK1 is activated by mitochondrial membrane potential depolarization and stimulates Parkin E3 ligase activity by phosphorylating Serine 65Open Biol(2012) doi: 10.1098/rsob.120080 59 Modeling familial Danish dementia in mice supports the concept of the amyloid hypothesis of Alzheimer's disease ProcNatlAcadSci U S A. (2010); 107(17): 7969–7974. doi: 10.1073/pnas.1001056107 60 Targeting of mannan-binding lectin-associated serine protease-2 (Masp2) confers a significant degree of protection from myocardial and gastrointestinal ischemia/reperfusion injury. ProcNatlAcadSci USA (2011) doi: 10.1073/pnas.1101748108
25 stroke damage”, but also positive publicity for the University, the Wellcome Trust, the MRC and the company Omeros, that licensed the University intellectual property behind this potential therapeutic approach.
New Products/Interventions in development Hashim Ahmed MRC co-funded trial61 of high-intensity focused ultrasound (University College (HIFU) treatment for prostate cancer, showed that 9 out London Hospital) of 10 patients were free of cancer 12 months after treatment with no major side effects (incontinence or impotence). HIFU shows promise as an alternative to current treatments. Stephen Sacks Researchers announced in 2010 that they had tested a (MRC/Kings College 'protective shield' for transplanted organs62, extending Centre for their life and helping prevent them from being rejected in Transplantation) patients' bodies. This promising approach is now being tested in larger scale trials. Colin Baigent (MRC A new meta-analysis of 27 trials63 shows that the benefits Clinical Trials of statins extend to a much lower-risk group of people Services Unit) than previously thought. The authors suggest that all those over 50 years of age could benefit from statins to lower cholesterol, and the impact on reduction of cardiovascular disease greatly outweigh known side- effects of the treatment.
Research into policy Trial co-ordinated Interim results from the PR07 study64 have shown that by the MRC and combining radiotherapy and hormone therapy in patients conducted by the with high risk prostate cancer significantly improves the NCIC Clinical Trials survival rate compared with hormone therapy treatment Group at Queen’s alone. NICE is currently updating its guidance on the University, Ontario treatment of prostate cancer.
61 Focal therapy for localised unifocal and multifocal prostate cancer: a prospective development study Lancet Oncology (2012) doi:10.1016/S1470-2045(12)70121-3 62 Therapeutic Strategy with a Membrane-Localizing Complement Regulator to Increase the Number of Usable Donor Organs after Prolonged Cold Storage J Am SocNephrol 17: 1102–1111, (2006). doi: 10.1681/ASN.2005101116 63 The effects of lowering LDL cholesterol with statin therapy in people at low risk of vascular disease: meta-analysis of individual data from 27 randomised trials Lancet, Early Online Publication, 17 May 2012 doi:10.1016/S0140-6736(12)60367-5 64 Intergroup randomized phase III study of androgen deprivation therapy (ADT) plus radiation therapy (RT) in locally advanced prostate cancer (CaP). Journal of Clinical Oncology, (2010) ASCO Annual Meeting Proceedings (Post-Meeting Edition). Vol 28, No 18_suppl
26 Mental health and wellbeing
“Revitalising mental health research”
Mental disorder is widespread; at any one time nearly one in six UK adults has a common mental disorder such as depression. Depression is the leading global contributor to years lived with disability, and is associated with increased future risk of heart disease. The UK Government’s Foresight Mental Capital and Wellbeing Project65 called for greater recognition of the extent to which individuals’ cognitive resources affect their ability to prosper. Therefore in addition to the need to address the burden of mental ill health, there is a need for research that tackles questions concerning the relationship between optimal wellbeing, mental and physical health.
Objective To explore the relationship between mental health, wellbeing and resilience to disease processes.
Measuring up against commitments in Research Changes Lives
1 Continue to support and develop research across the √√√ breadth of neuroscience and mental health, with a particular emphasis on linking fundamental understanding of cognitive processes with behaviour, and addressing public health and goals for prevention
2 Form partnerships with other stakeholders to build √√ capacity, helping to address the decline in academic psychiatry and learn from advances in biological understanding, population-based studies and technologies 3 Contribute to developing UK brain imaging capability √√√ and its coordination, through support of skilled individuals and new technologies 4 Ensure more selective groups of people are recruited √√ to clinical trials to address more specifically the effectiveness of potential new treatments
5 Carry out multidisciplinary longitudinal (long-term) √√√ studies involving genetics, neuroscience, psychosocial risk factors, behaviour and physical health outcomes
MRC’s annualised spend on mental health grants in the 2011/12 financial year was £30m, a significant increase from £13m in 2005/6.
Transformational developments The MRC led UK strategy for Mental Health and Wellbeing has led the way in novel thinking and the definition of a research agenda that looks beyond
65 Foresight Mental Capital and Wellbeing Project (2008). Final Project Report. The Government Science Office, London
27 diagnostic boundaries of mental health disorders and investigates common traits66 Through industry engagement in studies awarded under the Experimental Medicine in Mental Health initiative we have developed a platform for future UK investment by the pharmaceutical industry
1. Continue to support and develop research across the breadth of neuroscience and mental health, with emphasis on linking fundamental understanding of cognitive processes with behaviour
We have expanded the neuroscience division at the MRC Laboratory of Molecular Biology by nearly 50%, committing £49m over 5 years. The division investigates the mechanisms underlying neurodegeneration, including the effects of abnormal tau protein on Alzheimer’s Disease.
Together with the Wellcome Trust we have renewed support for the University of Cambridge MRC-Wellcome Trust Behavioural and Clinical Neuroscience Institute at a level of £4.3m over 5 years (£2.7m MRC commitment). The Institute investigates the cognitive deficits underlying brain disorders, linking fundamental and clinical research.
We have appointed a new Director for the MRC Cognition and Brain Sciences Unit (Cambridge), supported at a level of £33m over five years and have strengthened the Unit’s expertise in developmental cognition. The Unit undertakes research into the neuroscience underlying attention, emotions and memory, including the development of a diagnostic methods and rehabilitative programmes for patients with Parkinsons Disease, Alzheimer’s Disease and vascular dementia.
In 2010, MRC published a comprehensive review of mental health research67, advising on the most important UK research opportunities for improving mental health. The priorities identified for the MRC were: Experimental medicine for mental health; population based approaches to identify risk factors for poor mental health and determinants of mental wellbeing; and increasing the flow of trainees into mental health research to build capacity.
2. Form partnerships with other stakeholders to build capacity, helping to address the decline in academic psychiatry and learn from advances in biological understanding, population-based studies and technologies
Jointly with the Medical Research Foundation (MRF) we have invested £2.2m into the MRF/MRC Psychiatry:Scottish Training in Academic Research (PsySTAR) Programme. PsySTAR will support nine clinical research training fellowships over seven years from 2012 to engage the next generation of academic psychiatrists with all the aspects of fundamental science and academic medicine that are needed to enhance innovation in the management of psychiatric disorders.
3. Contribute to developing UK brain imaging capability and its coordination, through support of skilled individuals and new technologies
66 Sahakian BJ, Malloch G and Kennard C. Lancet, Volume 375,. pp1854 - 1855, 29 May 2010 67 http://www.mrc.ac.uk/Utilities/Documentrecord/index.htm?d=MRC006848
28 To boost translational neurosciences research using PET brain imaging we have invested £1.8m to support three capacity building research projects. This includes an innovative training programme for advanced PET radiochemistry for tracer development.
We are also working with the Medicines and Healthcare products Regulatory Agency (MHRA) on building a regulatory framework that supports PET based research in the UK. An MHRA-PET expert panel on regulatory affairs has been set up to help UK researchers overcome regulatory problems associated with undertaking PET research. These activities complement Imanova, a £43m public private partnership providing a national hub for PET imaging (see tissue disease and degeneration).
We have invested into a 7Tesla Magnetic Resonance MRI scanner at the University of Oxford to support neurosciences research across the UK. The scanner provides images at a resolution that was not possible before.
In July 2012 we awarded £700k for a partnership grant building clinical research capacity in Magnetoencephalography, a technique for mapping brain activity by recording magnetic fields. EPSRC contributed additional funding to this study.
4. Ensure more selective groups of people are recruited to clinical trials to address more specifically the effectiveness of potential new treatment
The 2010 MRC review of mental health research identified experimental medicine in mental health as a key priority. Through a call for proposals targeted at early exploratory studies aimed at building confidence in concept for new therapeutic interventions we funded 13 proposals at a level of £3.8m. A variety of novel ideas were funded testing possible new treatments for mental disorders. A translational scientist was appointed in 2011 to stimulate collaborations between scientists from academic and private sectors and to write a report on future opportunities presented. The programme will help to underpin future activities in mental health research through the Stratified Medicine initiative.
The Stratified Medicine initiative, launched in December 2011, will establish disease focussed partnerships with the aim of identifying subgroups of patients who respond differently to treatment. A number of outlines in the mental health field have been shortlisted for further development.
5. Carry out multidisciplinary longitudinal (long-term) studies involving genetics, neuroscience, psychosocial risk factors, behaviour and physical health outcomes
Funding has been renewed for the Environmental Risk (E-Risk) study, which investigates how environmental and biological risk factors contribute to disruptive behaviours in children and teenagers by following twins through adolescence.
We invested £1.1m into 7 research projects through a mental health data sharing call for proposals. The projects combine existing data collected from cohort studies and other data sets in novel ways to answer research questions on the causes and factors that influence mental health.
MRC invests into a number of large-scale, data-rich cohort resources that are being used/will be used to investigate the development of mental health problems
29 at different stages of the life course. These include the new birth cohort, ALSPAC, and UK Biobank.
Research Changes Lives objectives in progress
Building on the successful pilot programme we will support further post- doctoral trainees in PET imaging
We are contributing to work led by the Academy of Medical Sciences to enhance psychiatric careers.
We are looking into the feasibility of establishing a new cohort study focussing on intellectual disability.
We aim to increase linkages between developmental biology and mental health.
In the light of the report compiled by the translator appointed under the experimental medicine for mental health project we will consider future activities to stimulate the development of therapies and partnerships with industry.
Outcomes 2009-2012
New treatments and diagnostics in development Alasdair MacLullich Built and piloted a new neuropsychological instrument for (University of the objective diagnosis of delirium, the DelBox68. Work Edinburgh) supported by MRC DPFS Portfolio Award Ed Watkins Developed a guided self-help package for treating (University of depression and demonstrated effectiveness via a trial69. Exeter) Further translation of the approach is now funded under a £2m NIHR Health Technology Assessment award. Trevor Robbins Researchers at the MRC-Wellcome Trust Behavioural and (University of Clinical Neuroscience Institute developed the CANTAB Cambridge) psychological assessment tool, which is used in clinics around the world to help diagnose Alzheimer’s Disease before symptoms develop. The CANTAB tests are marketed by Cambridge Cognition70. Jennifer Shaw MRC supported research has compiled a structured, (Manchester) intensive method of supporting people with severe mental illness upon their release from prison. MRC funding supported a feasibility study and the team has now secured funding from the NIHR health services delivery programme for a full trial71.
68 Development of a new neuropsychological instrument for the assessment and monitoring of delirium http://www.sdcrn.org.uk/node/272 69 Rumination-focused cognitive-behavioural therapy for residual depression: phase II randomised controlled trial. Br J Psychiatry, (2011). 199(4), 317-322 70 Cambridge Cognition Ltd. http://www.cantab.com/about-cambridge-cognition.asp 71 Critical Time Intervention for Severely Mentally Ill Released Prisoners: A Randomised Control Trial (CrISP) 2012 - 2016http://www.netscc.ac.uk/hsdr/projdetails.php?ref=09-1004-15
30 Scientific advances Declan Murphy The success of the UK multicentre neuroimaging network for (Kings College research in autism (MRC UK AIMS Program) has provided a London) springboard to obtaining funding under the EU Innovative Medicines Initiative (IMI). The IMI has agreed to support the largest ever academic-industry research project to find new methods for the development of drugs for autism spectrum disorder, at over £23m it is the largest award made for any mental health condition in Europe72. Paul Edison (MRC Positron emission tomography has become a powerful Clinical Sciences research tool in the field of neurodegenerative diseases. Centre) The PET neurology group at the MRC CSC has used the imaging agent [11C]Pittsburgh Compound B to study in vivo amyloid plaque load in Alzheimer’s disease73, and found that plaques may be forming at least ten years before onset of symptoms. 11C-PIB PET is being used in a number of programmes as a biomarker of the efficacy of anti-amyloid agents. However, the team at the CSC in collaboration with the MRC Prion Unit74 have confirmed that this approach cannot be used to examine PrP amyloid deposition in prion patients. Katya Rubia (Kings Researchers have used functional MRI and carefully College) constructed tasks to discover differences in brain function between children and adults with/without autistic spectrum and attention deficit hyperactivity disorders. These approaches have been used to test the efficacy of different drugs used to treat these disorders75. James MacCabe The finding that patients with bipolar disorder have better (Kings College cognitive performance than the rest of the population76. London) People with excellent school performance at age 15-16 have a four-fold greater risk of later bipolar disorder when compared with those with average school performance. Jozsef Csicsvari Research shows how spatial memory traces are learned and (MRC Anatomical stored by hippocampal place cells in the brain77. The Neuropharmacology understanding of these neuronal processes could help in the Unit, Oxford) formulation of drugs to maintain and improve memory in patients with conditions such as Alzheimer’s disease. Amanda Law Using an integrative, multidisciplinary approach and (University of supported with an MRC Career Development Award, Dr Law Oxford/US National identified a signalling mechanism and genetic network Institute of Mental associated with schizophrenia risk variation78. The findings Health) suggest this may provide a new target for therapy for
72 European Autism Interventions – A Multicentre Study for Developing New Medications (EU-AIMS) is led by Kings College, Roche and Autism Speaks http://www.autismspeaks.org/about-us/press- releases/research-academic-industry-drug-discovery 73 Carbon-11-Pittsburgh compound B positron emission tomography imaging of amyloid deposition in presenilin 1 mutation carriers Brain(2011) 134 (1): 293-300. doi: 10.1093/brain/awq310 74 C-PiB PET does not detect PrP-amyloid in prion disease patients including variant Creutzfeldt–Jakob disease J NeurolNeurosurg Psychiatry (2012);83:340-341 doi:10.1136/jnnp.2010.233692 75 Methylphenidate normalizes frontocingulateunderactivation during error processing in attention- deficit/hyperactivity disorder. Biol Psychiatry. (2011);70(3):255-62. Epub 2011 Jun 12. 76 Excellent school performance at age 16 and risk of adult bipolar disorder: national cohort study The British Journal of Psychiatry (2010) 196: 109-115 doi: 10.1192/bjp.bp.108.060368 77 The reorganization and reactivation of hippocampal maps predict spatial memory performance Nature Neuroscience 13, 995–1002 (2010) doi:10.1038/nn.2599 78 Common genetic variation in Neuregulin 3 (NRG3) influences risk for schizophrenia and impacts NRG3 expression in human brain. ProcNatlAcadSci U S A. (2010);107(35):15619-24.PMID:20713722
31 schizophrenia, and the discovery led to Dr Law being awarded the 2011Sidney R. Baer Jr. Prize79 for Innovative Schizophrenia Research. Francesca Happé A new study of nearly 6,000 pairs of twins suggests that the and Robert three core traits of autism are inherited separately, and to Plomin(MRC SGDP, varying degrees, both in individuals with autism and in the Kings College general population80. The study is based on a sample of 12- London) year-old participants from the Twins Early Development Study, a longitudinal study of twins born in the U.K. between 1994 and 1996.
Research into policy Matthew Ridd (MRC During his MRC-supported fellowship, Dr Ridd explored the Clinical Training influence of continuity on identification and care of patients Fellow, University with psychological problems in general practice81.He of Bristol) subsequently served on the development group for the new NICE guideline for common mental health disorders82, which highlighted the importance of continuity of care. Christabel Owens Dr Owens MRC funded work has highlighted the role of (Peninsula Medical social networks and the wider community in suicide School, University prevention83. This was explicitly acknowledged and built of Exeter) into the new National Action Plan for suicide in Wales84. William Kuyken NICE updated its full guidance on Depression in adults in (University of 200985 and took into account MRC funded research86on a Exeter) technique termed “Mindfulness-based Cognitive Therapy (MBCT)”. MBCT was shown to be as effective as anti- depressant medication in preventing a relapse, and was more effective in enhancing peoples’ quality of life. NICE recommended that MBCT be offered as an option for patients with recurring depression, and the NHS HTA programme has funded a £2m follow up trial of MBCT87 David Fowler NICE updated its guidance on interventions for the (University of East treatment and management of schizophrenia in adults in Anglia) and David primary and secondary care88 in 2009. At least two MRC Osborne (University funded trial platform studies influenced recommendations College London) that; Cognitive Behavioural Therapy (CBT) be offered to patients (Fowler), and that all patients with schizophrenia
79 Sidney R. Baer, Jr. Prize for Schizophrenia Research (Brain and Behaviour Research Foundation) http://bbrfoundation.org/outstanding-achievement-prizes#Baer 80 A multivariate twin study of autistic traits in 12-year-olds: testing the fractionable autism triad hypothesis Behav Genet. (2012);42(2):245-55. PMID:21927971 81 Patient-Doctor Depth-of-Relationship Scale: Development and Validation Ann Fam Med. (2011); 9(6): 538–545. doi: 10.1370/afm.1322 82 Common mental health disorders: Identification and pathways to care (The British Psychological Society and The Royal College of Psychiatrists, 2011) http://www.nice.org.uk/nicemedia/live/13476/54604/54604.pdf 83 Public involvement in suicide prevention: understanding and strengthening lay responses to distress BMC Public Health (2009), 9:308. DOI:10.1186/1471-2458-9-308 84 "Talk to me: A National Action Plan to Reduce Suicide and Self Harm in Wales". http://www.wales.nhs.uk/documents/talktomee%5B1%5D.pdf 85 NICE guidance (CG90) Depression: the treatment and management of depression in adults (October 2009) http://www.nice.org.uk/nicemedia/live/12329/45896/45896.pdf 86 MRC News “Treatment hope for people with recurring depression“ http://www.mrc.ac.uk/Newspublications/News/MRC005275 87 Preventing depressive relapse in NHS Practice through mindfulness-based cognitive therapy (MBCT) http://www.hta.ac.uk/1924 88 NICE full guideline CG81 “Schizophrenia: Core interventions in the treatment and management of schizophrenia in adults in primary and secondary care” (March 2009) http://www.nccmh.org.uk/downloads/Schizophrenia_update/CG82FullGuideline.pdf
32 are screened for cardiovascular risk factors (Osborne).
Public/policymaker engagement University of On a recent visit to Edinburgh, the Rt Hon. David Willetts MP Edinburgh Centre - the UK Minister for Universities and Science - met with for Cognitive CCACE Director Prof Ian Deary to discuss a publication from Ageing and the Centre on the genetics of intelligence in ageing. The Cognitive Nature paper89 describes the genetic contribution to stability Epidemiology and change in intelligence across the lifespan had generated (CCACE) some press interest. Peter Woodruff The Actor's Brain: Exploring the cognitive neuroscience of (University of free will. A book authored by Sean A Spence90. The book Sheffield) was facilitated by the MRC Career Establishment Grant held by Professor Woodruff. Nick Craddock Nationwide coverage of the setting up of the bi-polar (MRC Centre for disorders research network91, funded by the Wellcome Trust Neuropsychiatric and Stanley Medical Research Institute. Celebrities Stephen Genetics & Fry and Kerry Katona have contributed to efforts to recruit a Genomics) further 1000 participants to the study.
Commercialisation Neurocentrix Ltd. Neurocentrix92 is a virtual company built around the know- how of several MRC-funded researchers in the University of Edinburgh with expertise in neurological disorders; pain, mood and mental illness.
89 Deary et al. (2012).Genetic contributions to stability and change in intelligence from childhood to old age. Nature doi:10.1038/nature10781 90 The actor's brain: Exploring the cognitive neuroscience of free will (Sean Spence, 2009, Oxford University Press) http://www.oup.com/us/catalog/general/subject/Medicine/PsychiatryPsychology/?view=usa&ci=97801 98526667#Description 91 Bipolar Disorders Research Network http://bdrn.org/ 92 Neurocentrx website http://www.neurocentrx.com/
33
34 Repair and replacement
“From fundamental research to first preclinical and exploratory clinical studies”
Regenerative medicine is set to transform the opportunities for cell- and tissue- based therapies. Tissue engineering is the generation of a renewable source of transplantable tissue by combining the principles of engineering, physical science and medicine. Scientists are pursuing both replacement and regeneration techniques for repairing human tissue. Therapies can be inorganic, such as bone implants and hip replacements, or living tissue – transplantation or stem cells. Therapies are already being developed to treat neurodegenerative diseases; blood vessel blockage in heart attack, stroke or pulmonary embolism; and the repair of damaged tissue to help regain normal body functions.
Objective
To translate the burgeoning knowledge in regenerative medicine into new treatment strategies.
Measuring up progress against commitments in Research Changes Lives
1 Bringing scientists with skills in mathematics, physical and engineering science into the field √√
2 Culture cells for repair and undertake ‘first into human’ and early phase clinical trials √√√
3 Working with industry and regulatory agencies to further development of stem cell therapies √√
4 Explore use of stem cells as vehicles for drug delivery
√ 5 Work with industry on the development of stem cell technologies √√√
MRC’s spend in regenerative medicine research has increased from £23m per annum in 2007 to £37m per annum in 201093. Spend has increased across all categories including fundamental research, aetiology, and the development of and evaluation of treatments (figure 3). In volume terms, expansion of the portfolio is strongest in aetiological research and treatment evaluation (albeit from a low base).
93 Based on data for 2007 stem cell portfolio (including cancer stem cells and excluding endogenous repair) and 2010 Regenerative Medicine portfolio (excluding cancer stem cells and including endogenous repair).
35
Figure 3
2007 Stem Cell v 2010 Regen Med (Value)
25.0
20.0
15.0 2007
£m 2010 10.0
5.0
0.0
Health
Services
Aetiology
Treatment
Evaluation
Prevention
Disease
Treatment
Diagnosis
Management
Fundamental Development Detectionand
Transformational developments
We have established a portfolio of six early phase clinical trials of adult stem cell therapies through the Translational Stem Cell Research Committee and are pursuing the critical developmental work to support human embryonic stem cell therapies
The world’s first clinical grade human embryonic stem cell line has been deposited in the UK Stem Cell Bank
Repair of the retina is starting to become a reality. MRC supported research has demonstrated evidence of functional recovery of damage in the eye through cell transplantation, providing encouragement for the development of stem cell therapies for debilitating eye conditions94. The first UK exploratory clinical studies using UK derived human embryonic stem cells to treat age-related macular degeneration are expected to start soon. The first UK clinical safety studies testing human embryonic stem derived by Advanced Cell Technology in Stargardt’s disease, which destroys vision at an early age, are already underway.
MRC funded research has laid much of the foundation of stem cell advances today95 96, including recent advances in technologies to derive induced pluripotent stem cell lines97.
94 Restoration of vision after transplantation of photoreceptors (2012), RA Pearson et al. Nature 485,99–103 doi:10.1038/nature10997 95 MRC Professor, Austin Smith received the Louis Jeantet prize in 2010 in recognition of his role in identifying the factors important in maintaining pluripotency http://www.jeantet.ch/e/prize/laureats_2010.php, Sir Martin Evans received the Nobel Prize in 2007 for pioneering work in stem cell research, much of this work was MRC funded http://www.mrc.ac.uk/Newspublications/News/MRC004058 96 Nanog is the gateway to the pluripotent ground state. Silva J et al (2009), Cell Aug 21; 138(4): 722-737
36
MRC funded groups in Cardiff have studied the neurotransplantation of stem cells and are poised to begin clinical studies aimed at therapies for Huntington’s and Parkinson’s disease in the near future.
1. Bringing scientists with skills in mathematics, physical and engineering science into the field
A cross-disciplinary training programme stimulating links with the physical and engineering sciences has been awarded to the MRC Centre for Stem Cells and Regenerative Medicine in Cambridge.
Tissue engineering challenges will also be addressed through the UK Regenerative Medicine Platform (see below).
2. Culture cells for repair and undertake ‘first into human’ and early phase clinical trials
We have renewed our investment in the MRC Centre in Regenerative Medicine in Edinburgh, which focuses on organ-based regeneration. We have also contributed £3.8million to an overall award of £8.1m for a new Wellcome Trust-MRC Stem Cell Institute in Cambridge, which brings together existing investments to form a new world leading institute investigating the properties of stem cells and how these can be exploited for health benefits.
The UK Stem Cell Bank, which has received £2.3M renewal funding, now stores 90 human embryonic stem cell lines and has provided those to more than 80 researchers. A £3m investment to derive clinical grade stem cell lines led to the first world’s first clinical grade, xeno-free stem cell line being deposited in the UK Stem Cell Bank. The projects awarded are still ongoing and we expect ~25 more lines to be deposited by 2013.
The Translational Stem Cell Research Committee, a dedicated Panel to support stem cell research with clearly translational goals, has invested close to £22M since the beginning of 2009, including six clinical trials of adult stem cell therapies to address blindness, bone and liver repair, the activation of dormant cells in the body to treat Addison’s disease and the targeting of cancerous stem cells in chronic myeloid leukemia. Notable investments in pre-clinical research target repair of the liver, heart and muscular dystrophy.
£3M has been invested jointly with the British Heart Foundation to build translational capacity in cardiovascular stem cell research.
Capitalising on the first successful transplant of a trachea (windpipe) using the patient’s own bone marrow stem cells, MRC has awarded £1.2m to the successful team to develop the first clinical trial of tissue-engineered larynx (voicebox) transplants.
3. Working with industry and regulatory agencies to further development of stem cell therapies
97 Inhibition of glycogen synthase kinase-3 alleviates Tcf3 repression of the pluripotency network and increases embryonic stem cell resistance to differentiation. Wray J et al. Nat Cell Biol. 2011 Jun 19;13(7):838-45. doi: 10.1038/ncb2267. Erratum in: Nat Cell Biol. 2012 May;14(5):555.
37
To support the stem cell research community in developing safe and effective treatments, the MRC in partnership with the Department of Health has launched a web based ‘toolkit’ providing an interactive route map through the UK regulatory processes98.
The second ever clinical trial using human embryonic stem cells is expected to be conducted by MRC funded researchers at Moorfields Hospital in 2012, to treat age-related macular degeneration (AMD). The stem cell line to be used was one of the first to be deposited in the UK Stem Cell Bank and has been re-derived by Pfizer to meet the requirement for clinical studies. The decision by Pfizer to invest in the UK is an important endorsement of the quality of research here.
The same team will conduct a trial following a related approach with collaborators in the US to gain regulatory approval there. The trial is supported as part of a $200M call in partnership with the Californian Institute of Regenerative Medicine (CIRM) to which MRC contributed £5M to support UK-based research. In addition to the AMD study, a second project addressing acute myeloid leukaemia is also underway99.
4. Explore use of stem cells as vehicles for drug delivery
This has not been an area of major activity and the science in this field is at an early stage. It remains a potentially powerful technology for the longer term future.
5. Work with industry on the development of stem cell technologies
MRC is a partner, alongside BBSRC and EPSRC, in a £21.5m regenerative medicine programme run by the Technology Strategy Board to support key areas of commercial Research and Development. The first 14 projects totalling £8.5m have now been awarded. MRC has contributed £1.6m to five industry-led studies developing new tools and technologies for regenerative medicine research100.
MRC was a founder member of Stem Cells for Safer Medicines (SC4SM) a public private partnership applying stem cell technologies to test toxicological responses to candidate drugs. Following a successful pilot phase, the partnership has invested £5m for the establishment of protocols to develop human liver and cardiomyocyte cells and validate those for the testing of drugs.
Research Changes Lives objectives in progress
MRC has led, on behalf of other Research Councils and the Technology Strategy Board, the development of a comprehensive and co-ordinated strategy for UK research and development in Regenerative Medicine101. In line with the strategy we will establish a national programme in regenerative medicine
98 UK Stem Cell Toolkit http://www.sc-toolkit.ac.uk/home.cfm 99 International collaboration brings stem cell clinical trials a step closer http://www.mrc.ac.uk/Newspublications/News/MRC006435 100Projects to be funded through the “Regenerative Medicine Programme: Tools and Technologies and Regenerative Medicine Programme: Developing Therapeutics 2” funding competitions (December 2011) http://www.innovateuk.org/_assets/regenmed_results5dec11_final.pdf 101 http://www.mrc.ac.uk/Utilities/Documentrecord/index.htm?d=MRC008534
38 ensuring that Research Council funding is well connected with the TSB’s Cell Therapy Catapult Centre, which focuses on commercial development.
We will, in partnership with BBSRC and EPSRC, establish a £25m UK Regenerative Medicine Platform, which will tackle areas such as safety science, immune modulation, engineering challenges, cell function, acellular technologies, and delivery mechanisms to facilitate further the pull-through of advances in regenerative medicine research towards the development of treatments
We will continue to work with regulators to explore clinical trial challenges with the aim to improve regulatory transparency and trial design
We will increase our investment into research targeting the body’s own repair mechanisms (endogenous repair) to address the apparent mismatch between current funding in this area and the high potential in terms of future treatments
We will increase opportunities to develop the potential of induced pluripotent stem (iPS) cells, adult cells that are reprogrammed to an embryonic state using transcription factors. These cells can be used to understand illness and test possible treatments.
Outcomes 2009-2012
New Treatments in Development Robin Ali In 2010 MRC funded researchers demonstrated that Crx (University expressing cells can integrate into the retina and form new College London) cone photoreceptors102. In 2012 the group demonstrated that transplantation of immature rod-photoreceptor cells from young mice can restore a significant amount of vision in blind mice103. Steve Dunnett MRC funded Cardiff Brain Repair group has commissioned a (Cardiff new GMP laboratory for the handling of human tissues for University) clinical trials, and in 2011 submitted a license application to the human tissue authority to begin clinical trials of cell transplantation therapy for Huntington’s disease in 2012104. Paul Riley Thymosin beta 4 (Tbeta4) can be used to stimulate new vessel (University development in the damaged heart105. Professor Riley is a College London) former MRC Career Establishment Grant holder, and has obtained follow on funding from the MRC (although his group is largely funded by the BHF). A US company (Regenerx Inc.) has already completed a Phase 1 trial using Tbeta4, and is now planning Phase 2 studies for the treatment of myocardial infarction. Martin Wilkins Mesenchymal stem cells (MSC) can modulate the immune
102 Cone and rod photoreceptor transplantation in models of the childhood retinopathy Leber congenital amaurosis using flow-sorted Crx-positive donor cells; Lakowski, J. Hum. Mol. Genet. (2010) 19 (23): 4545-4559. doi: 10.1093/hmg/ddq378 103 Restoration of vision after transplantation of photoreceptors (2012), Pearson, RA et al. Nature 485, 99–103 doi:10.1038/nature10997 104 The Cardiff Brain Repair Group HD Transplantation Project http://www.cf.ac.uk/biosi/staffinfo/dunnett/hdprog.html 105 De novo cardiomyocytes from within the activated adult heart after injury Smart, N. et al. Nature doi:10.1038/nature10188 (2011).
39 (Imperial system in ways that are helpful to treat graft vs host disease in College) patients after bone marrow transplantation. Researchers at Imperial College are involved in a multicentre Phase I/II trial using MSCs. Stephen Sacks A membrane targeted anti-coagulant for intended use in donor (MRC/Kings kidneys transplanted into high risk (highly sensitised) College Centre recipients. Currently at proof-of-principle stage in rat model, for further development work funded under a £2.1m MRC DCS Transplantation) award.
New Scientific Advances An analysis by Thompson Reuters for BIS - “Taking stock of regenerative medicine” (published July 2011)106 showed that the productivity and citation impact of UK papers in the regenerative medicine field is high, second only to the US, and apart from Germany and Japan significantly ahead of the rest of the world. Ludovic Vallier(MRC For the first time researchers cleanly corrected a human senior Fellow, MRC gene mutation in a patient's stem cells bringing the Centre for Stem possibility of patient-specific therapies closer to reality. The Cell Biology, team targeted a gene mutation that contributes to both Cambridge) cirrhotic liver disease and lung emphysema107. Jeffrey Huang A new study108 finds that retinoid X receptor-γ promotes re- (Research myelination. Its function in oligodendrocyte progenitor cell Associate, MRC maturation sheds light on nuclear receptor signalling in Centre for Stem myelin development and paves the way toward therapeutic Cell Biology, ligands for myelin repair in Multiple Sclerosis. Cambridge) Tilo Kunath (MRC For the first time dopamine-producing nerve cells were Centre for grown from iPS cells from a Parkinson's patient109. This Regenerative provides a model for in vitro screening of potential Medicine, therapeutics and further study of neurodegenerative Edinburgh) diseases. International Stem ISCI is a worldwide collaborative effort to establish basic Cell Initiative110 criteria and techniques that will underpin the eventual (ISCI, Peter development of applications for human embryonic stem Andrews, Sheffield (hES) cells in human medicine. The ISCI database gathers University) together information on bone fide human embryonic stem cell lines from around the world. The data for the stem cell registry is available for researchers to download and analyse for themselves and has led to several important publications111
106 Taking Stock of Regenerative Medicine in the UK (BIS Office for Life Sciences/Department of Health, 2011) http://www.bis.gov.uk/policies/innovation/business-support/ols/news/regenerative- medicine-report 107 Targeted gene correction of α1-antitrypsin deficiency in induced pluripotent stem cells K Yasuet al. (2011) Nature 478, 391–394 doi:10.1038/nature10424 108 Retinoid X receptor gamma signaling accelerates CNS remyelination Jeffrey K Huang et al. (2011) Nature Neuroscience 14,45–53 doi:10.1038/nn.2702 109 Parkinson's disease induced pluripotent stem cells with triplication of the α-synuclein locus M J Devine et al. (2011) Nature Communications 2, Article number: 440 doi:10.1038/ncomms1453 110 http://www.stem-cell-forum.net/ISCF/initiatives/isci/ 111 Screening ethnically diverse human embryonic stem cells identifies a chromosome 20 minimal amplicon conferring growth advantage Nature Biotechnology 29, 1132–1144 (2011) doi:10.1038/nbt.2051
40 Maya Sieber-Blum Methods for the isolation, characterisation and ex-vivo (Newcastle expansion of human epidermal neural crest stem cells University) (hEPI-NCSC). hEPI-NCSC are multi-potent somatic stem cells that can be readily isolated from the bulge of skin hair follicles, and directed to differentiate into melanocytes, osteocytes and dopaminergic neurons. Professor Sieber- Blum moved to Newcastle from Wisconsin in 2008, and is building on promising results using hEPI-NCSC cells in a mouse model of spinal repair. Marios Politis (MRC A major obstacle to developing a transplant treatment CSC) which can relieve the symptoms of Parkinson’s disease is that people get jerky limbs after stem cell transplants. Researchers have found that this is because of malfunctioning serotonin cells in the area of the brain where the transplant had taken place112, and that the dyskinesia can be treated effectively with a drug that desensitizes serotonin nerve cells. Wilhelm Schwaeble Studies using animal models found a key role for the protein (University of MASP-2 in modifying the extent of damage to heart tissue Leicester) following a heart attack113. Inhibiting MASP-2 using an antibody, prior to an induced heart attack, resulted in significantly less damage. The research led to a large number of reports in the media worldwide about the possibility of a “simple jab to limit heart attacks and stroke damage”, but also positive publicity for the University, the Wellcome Trust, the MRC and the company Omeros, that licensed the University intellectual property behind this potential therapeutic approach. James Briscoe MRC researchers discovered that the Sox9 gene plays a National Institute crucial role in the development of the central nervous for Medical system114, which in the future may be exploited for the Research regeneration of damaged nerve cells in patients with strokes and for the modelling of the cellular components of Alzheimer’s Disease.
Commercialisation A recent EU-funded project on regenerative medicine that compared EU capacity, regulation and future prospects in this field with developments globally115 showed that the UK had the largest number of companies operating in this field in Europe. Compared with the UK’s closest competitor, Germany, there is a greater investment in the support services for cell therapy research and greater success in commercialisation of cells as tools for drug discovery and toxicity testing. Vitrosafe Ltd.116 Founded by MRC funded scientists in 2008, the company is (University of focussed on marketing the Vitrosafe system which is Newcastle) designed to meet GMP standards during laboratory processing of embryos and stem cells. It has successfully
112 Serotonergic Neurons Mediate Dyskinesia Side Effects in Parkinson’s Patients with Neural Transplants SciTransl Med(2010): Vol. 2, Issue 38, p. 38ra46 Sci. Transl. Med. DOI: 10.1126/scitranslmed.3000976 113 Targeting of mannan-binding lectin-associated serine protease-2 (Masp2) confers a significant degree of protection from myocardial and gastrointestinal ischemia/reperfusion injury. ProcNatlAcadSci USA (2011)doi: 10.1073/pnas.1101748108 114 SOX9 induces and maintains neural stem cells Scott, CE et al. (2010) Nat Neurosci. 13(10):1181- 9. 115 REMEDiE project (Science and Technology Studies Unit, University of York) http://www.york.ac.uk/satsu/remedie/reports/archive/ 116 Vitrosafe website http://www.vitrosafe.co.uk/
41 exported bio-processing systems to Canada, Europe and Thailand with an estimated value of around £1m and the founders have won a number of business and innovation awards. Fibromed Ltd. Researchers at the MRC/University of Edinburgh Centre for (University of Regenerative Medicine have discovered ways to increase the Edinburgh spin production of hepatocytes in regenerating liver tissue, key out) cells needed to repair liver function117. In part it is this expertise which led to setting up the spin out company Fibromed118 in 2011. Fibromed will provide tools and technologies to customers interested in predictive liver models. UK Stem Cell Bank The UK stem cell bank has contributed to the development of several commercial products including surface treatments to maintain cells in pluripotent states (Orla Protein Technologies) and microfluidics systems for screening research grade cell cultures for viral contamination (ABI virus detection cards). Pro-cure Pro-cure is a spin out company from the Yorkshire Cancer therapeutics Research Unit at the University of York, in part based on (York) research from the MRC funded prostate cancer collaboratives (led by David Neal and Norman Maitland). Recently the company has been developing siRNA inhibition of cancer stem cells. Che Connon Gel encapsulation of stem cells for distribution at ambient
(University of temperature and atmospheric CO2. This technology can Reading) replace cryopreservation of cells. Cells within gel remain viable up to 7 days whilst retaining their pluripotency. Follow-on funding from BBSRC to develop the technology. Cay Kielty (The The group has patented a Fibrillin-1 cell adhesion fragment University of and are now testing its use in vascular tissue engineering - Manchester) to support endothelial and smooth muscle cell adhesion. Bob Carlyon (MRC The team at MRC CBSU have patented a new algorithm for Cognition and improving the perception of pitch for people with cochlear Brain Sciences implants119. Further development is funded under a MRC Unit (CBSU), Technology development gap fund award. Cambridge)
117 Macrophage-derived Wnt opposes Notch signaling to specify hepatic progenitor cell fate in chronic liver disease; Boulter, LM et al Nature Medicine 18,572–579(2012)doi:10.1038/nm.2667 118 Fibromed website http://www.fibromed.co.uk/ 119 Priority application GB0910811.9 (Cochlear implant apparatus and method, June 2009)
42 RESEARCH PRIORITY THEME TWO: Living a long and healthy life
Genetics and disease
“From genetic discovery to epigenetics and mechanisms of disease”
We are beginning to understand the link between genetics and disease. The challenge now is to determine the biological relevance and mechanism of action of genes, and to develop this knowledge for clinical application. To do this, scientists will develop new biological markers for determining disease subtype, predicting risk of disease and response to treatment, and understanding the life- course of disease at the mechanistic level, and the development new interventions.
Objective
To use genetics, imaging and biological indicators to understand predispositions for disease, and to target treatments to disease subtypes.
Measuring up progress against commitments in Research Changes Lives
1 Investing in high throughput technologies to explore genetic √√√ variation 2 Work with partners to establish a coordinated programme √√√ of mouse phenotyping 3 Further investment in epigenetics and its clinical √√√ applications 4 Development of statistical methodologies to exploit fully √√√ existing research data 5 Investing in basic research in mitochondrial biology, to √√√ understand mechanisms of disease 6 Linking genes with disease mechanisms will help to find √√√ new targets for drug therapies 7 Assess associations between genetic variation in √ populations and infections and metabolic diseases and traits using epidemiological platform projects in Africa
Genetics and genomics research has remained a strong portfolio area for the MRC with an annual investment of close to £40m120 through MCMB.
Transformational developments
We have equipped the UK research community to capitalise on the major advances in next generation sequencing technologies to drive forward tomorrow’s therapies We have joined forces with other countries across the globe to accelerate progress in understanding gene function and the consequences of DNA modification
120 2009/2010 spend figure (last one available)
43
1. Investing in high throughput technologies to explore genetic variation
MRC has invested £9m into four High Throughput Sequencing (HTS) Hubs, an initiative to strengthen UK-wide infrastructure, capability and expertise in cutting edge DNA sequencing technologies. This will ensure that the UK research community can capitalise on the recent step change in sequencing technologies to better understand the genetic basis of diseases. In June 2012 two successful hubs in Scotland and the North of England received renewal funding to ensure long-term sustainability. In addition, we have awarded £2.5m to researchers at the MRC Functional Genomics Unit (Oxford) for a Computational Genomics Training Programme (see below).
2. Work with partners to establish a coordinated programme of mouse phenotyping
The UK is at the leading edge of mouse genetics research. We have renewed our investment in the Mammalian Genetics Unit and the Mary Lyon Centre at MRC Harwell at a combined level of £48m over 5 years. As part of this investment £3m was provided to re-invigorate the services provided by the Mary Lyon Centre to the UK research community and support the MRC’s partnership in the International Mouse Phenotyping Consortium (IMPC). The IMPC will phenotype mouse mutants in which each gene has been systematically deleted, generating models to enhance the understanding of gene function and disease, and for the evaluation of new drug targets and testing new therapeutics. The genes prioritised for deletion and analysis through the MLC correspond to major human diseases and research strengths in the UK; foci include neural, metabolic, musculoskeletal and malignant disease. MRC Harwell has also attracted an additional investment of £6 from the NIH to support these international efforts.
3. Further investment in epigenetics and its clinical applications
Epigenetics research focuses on heritable changes in gene expression caused by mechanisms other than modification of the DNA sequence, including chemical modifications to the DNA and associated histones, and also the action of microRNAs.
We have renewed funding for a dedicated Section in Epigenetics (£21m) at the MRC Clinical Sciences Centre (CSC) and have restructured the CSC to support a new third Section in Integrative Biology (£3.7m). This new Section will develop innovative imaging approaches to analyse cellular and physiological processes and investigate how these link to genomic and epigenomic data to influence disease. We have also made investments in next generation sequencing technologies that allow the high throughput analysis of epigenetic modifications of DNA and help support MRC’s participation in the International Human Epigenome Consortium.
The MRC has recently renewed its investment in the Human Genetics Unit (HGU) and Institute of Genetics and Molecular Medicine (IGMM) at Edinburgh University. The mission is centred around developmental genetics and human genetics in health and disease. Many activities involve epigenetic components, including a programme dedicated to understanding the role of epigenetics in development and disease (£2m).
44 Renewed investment at a level of £29m into the MRC Molecular Haematology Unit (Oxford) has also recently been confirmed. This includes a key theme to understand epigenetic programmes driving gene expression and cell fate.
Major support in this area is also delivered through the Research Boards and Panels and MCMB alone has invested over £3.5m in epigenetic research since April 2010. In addition to this the MRC, in partnership with the Wellcome Trust, supported the next phase of funding for the Avon Longitudinal Study of Parents and Children (ALSPAC). ALSPAC is a unique study investigating the influence of social factors, behaviours and genes on child health and development, and the health and well-being of the parents. The latest investment (£6m total) includes support for epigenetic studies to explore the changes in methylation patterns during childhood development and how these might predict later phenotypes such as body mass and cognitive function and influence on future disease. The investigators have attracted additional BBSRC funding to build an accessible resource for integrated epigenomics studies (ARIES), which will make epigenomics data openly available to the UK community.
4. Development of statistical methodologies to exploit fully existing research data
The MRC invests substantial funding through a number generic and specialist schemes to help to address the long-term, national need for enhanced skills in informatics and computational genomics to capitalise on the huge and complex datasets that have emerged in the post-genomics era.
Specialist fellowship schemes in methodology, statistics, and biomedical informatics have targeted investment to enhance training, career development and capacity building in the development and application of computational methods, statistics and informatics to tackle the burgeoning large ‘omics’ data sets. Through these personal awards, the MRC has invested more than £11m between 2009 and 2012. The three schemes were brought together under one umbrella in 2012.
The MRC Biostatistics Unit (Cambridge) has an on-going programme in bioinformatics and systems biology. Following the appointment of a new Director in 2012, the Unit will be developing programmes in statistical genetics as well as statistical genomics and high dimensional data.
Fellowships and grants addressing methodology for epidemiology and public health research and biological and health informatics are also supported through the Methodology Research Programme.
The Computational Genomics and Training Programme (highlighted above) builds upon the fellowship training activities and those supported through the Functional Genomics Unit, and links with the activities of the four HTS Hubs and BBSRC’s Genome Analysis Centre (Norwich).
5. Investing in basic research in mitochondrial biology, to understand mechanisms of disease
MRC has had a long standing investment in the fundamental biology of mitochondrial energy production. There is now growing evidence of the involvement of the mitochondria and their dysfunction in an increasing range of human diseases. In 2010 renewed investment in the MRC Mitochondrial
45 Biology Unit (MBU) at the University of Cambridge was confirmed (£36m), with a new focus on integrating cell biology and developing a clinical programme addressing questions relating to health and disease. A partnership between the MBU and MRC Centre for Neuromuscular Diseases to support a joint clinical training programme will help drive these ambitions. This direction of travel will be enhanced by the appointment of the new Director from the beginning of 2013, who will further integrate the basic strengths within the MBU with the wealth of clinical, genetic and biochemical data generated locally and in collaboration with major clinical activities in Milan.
6. Linking genes with disease mechanisms will help to find new targets for drug therapies
A substantial component of MRC investment is focussed on mechanistic understanding of the causes and development of disease to provide the basis for the development of new therapies through specialist funding schemes (see translation).
The Protein Phoshorylation Unit (PPU) is the MRC’s main long-term, strategic investment in cell signalling research with the specific intention of underpinning major partnerships with industry to identify new opportunities for drug development. It has an outstanding track record in fundamental and applied research in signal transduction. New therapeutics targeting MAP kinase kinase 1 and p38 MAP kinase are already in clinical trials for cancer and inflammatory diseases. The PPU, in partnership with the University of Dundee, established the Division of Signal Transduction Therapy (DSTT) as one of Europe’s largest academic-pharmaceutical industry partnerships to further the development of new drugs. The DSTT was renewed in 2012 with an investment of £14m over 4 years by 6 major pharmaceutical companies.
We have established a new MRC Centre for Neuropsychiatric Genetics and Genomics in Cardiff, which is dedicated to harnessing the genetics revolution for research into mental disorders, including schizophrenia and bipolar disorder, neurodegenerative diseases, and developmental disorders such as childhood depression.
MRC has jointly with NIHR invested £3.1m for a phase two clinical trial conducted by the UK Cystic Fibrosis Gene Therapy Consortium. This delivers a working copy of the defective gene in Cystic Fibrosis sufferers directly into the lung of patients via a fine mist created through a nebuliser. In addition, MRC has invested £1.2 to help the consortium to develop a potentially more efficient viral delivery method for the gene therapy. The investment helps the Cystic Fibrosis Trust through a funding shortfall and ensures that this important work, which has been developed over a decade, can continue.
7. Assess associations between genetic variation in populations and infections and metabolic diseases and traits using epidemiological platform projects in Africa
This has not been a major area of activity. Exploration of each of these different elements is currently being pursued in overlapping studies primarily in the MRC Unit in Uganda and in Tanzania through the Mwanza Unit for which MRC has provided start up funding.
46 The Wellcome Trust is a major investor in this field though the Human Heredity and Health in Africa Initiative.
Research Changes Lives work in progress
Chemical and synthetic biology offer exiting opportunities to develop new tools to explore biology in health and disease and also novel approaches in drug development: The establishment of a new Centre for Chemical and Synthetic Biology supported through the recent LMB QQR will allow exploitation of exciting new technology in synthesising proteins containing novel amino acids and create a critical mass in chemical biology that will be an ideal interdisciplinary training ground. The establishment of Bicycle Therapeutics in 2009121 through LMB offers new and exciting opportunities to develop selectable macrocyclic peptides as new therapeutics We will assist the UK community to capitalise on the major advances in super-resolution microscopy through strategic investment into next generation optical imaging technologies to help scientists to address previously unsolvable cell biological questions.
Outcomes 2009-2012
Scientific advances Philipp Holliger (MRC Scientists at MRC LMB have used enzymes to grow Laboratory of Molecular synthetic DNA strands which replicate and evolve just Biology) like the real thing122. The artificial DNA (“XNA”) carries normal nucleic acid bases on a backbone made using different sugars, and the team’s engineered enzymes mean the synthetic strands can assemble and replicate genetic messages with high accuracy. The aim is that these new molecules will help others to develop new drugs and nanotechnologies. Jason Chin (MRC Scientists at MRC LMB have re-engineered the process Laboratory of Molecular by which genetic information is translated into Biology) proteins, allowing the incorporation of amino acid building blocks not found in nature. This entirely new approach is being applied to synthesise protein therapeutics with the potential for improved treatment of diabetes and cancer. Dr Chin received the EMBO Gold medal in 2010123 for his work, and in 2012 his group successfully demonstrated that the genetic code of the fruit fly could be modified to produce proteins new to biology124, building on work in the nematode worm published in 2011125. Bazbek Davletov (MRC Scientists at MRC LMB have developed a new way of
121 Bicycle Therapuetics http://www.bicycletherapeutics.com/ 122 Synthetic Genetic Polymers Capable of Heredity and Evolution Science(2012): Vol. 336 no. 6079 pp. 341-344 DOI: 10.1126/science.1217622 123 EMBO Gold Medal 2010 recognizes Jason W. Chin - Synthetic biologist pioneered genetic code reprogramming http://www.alphagalileo.org/ViewItem.aspx?ItemId=75533&CultureCode=en 124 Expanding the genetic code of Drosophila melanogaster Nature Chemical Biology (2012) doi:10.1038/nchembio.1043 125 Expanding the Genetic Code of an Animal J. Am. Chem. Soc., 2011, 133 (36), pp 14196–14199 DOI: 10.1021/ja2054034
47 Laboratory of Molecular joining and rebuilding molecules and used it to refine Biology) the anti-wrinkle treatment Botox in an effort to improve its use for Parkinson's, cerebral palsy and chronic migraine. By breaking down Botox molecules into two separate building blocks, Davletov's team were able to produce them separately and safely, and then "clip" them back together again126. The work was supported by a MRC Technology development gap fund award. A partnership between MRC scientists have shown that cancer can develop in the MRC Cancer Cell people born with one defective copy of the BRCA2 Unit, the CRUK gene even when the second copy is still working Cambridge Research effectively in cancer cells. By studying the Institute and development of pancreatic cancer, this discovery not collaborators in Iceland only signals an entirely new approach to studying the origins of cancers associated with BRCA2, but could also help to improve treatment options for patients who are resistant to a group of drugs currently under development, known as PARP inhibitors. Zameer Cader (MRC An international study127partly funded by the MRC Functional Genomics used DNA samples from families around the world Unit) prone to migraines, and found the first genes known to be directly responsible for causing migraine rather than merely increasing risk. Akhilesh Reddy By looking for the first time for circadian rhythms in (MRC Centre for Obesity red blood cells128, scientists have discovered that the and Related Metabolic 'body clock' is hardwired into all living cells even Diseases) those which don't have DNA (i.e. red blood cells) - overturning the assumption that circadian rhythms are controlled by genes and showing that the same process governs circadian rhythms in all living things129. The work was supported by the Wellcome Trust with additional funding from the MRC, BBSRC, EPSRC, the French Agence Nationale de la Recherche, and NIHR. Yasuyuki Fujita (MRC Cell MRC researchers discovered that two genes, called Biology Unit) Mahjong and Lgl, could be star players in helping to identify how the body’s own cells fight back against cancer cells130. This discovery could lead to future treatments to make healthy cells better-equipped to attack cancer cells, an entirely new concept for cancer research. Martin Dyer (MRC CRLF2 is a cytokine receptor which is altered in a Toxicology Unit, subset of patients with B cell precursor acute Leicester) lymphoblastic leukaemia. Overexpression of CRLF2 is
126 SNARE tagging allows stepwise assembly of a multimodular medicinal toxin PNAS, (2010) vol. 107 no. 42 18197-18201 doi: 10.1073/pnas.1007125107 127 A dominant-negative mutation in the TRESK potassium channel is linked to familial migraine with aura Nature Medicine (2010) 16,1157–1160 doi:10.1038/nm.2216 128 Circadian clocks in human red blood cells Nature. (2011);469(7331):498-503. 129 Circadian rhythms persist without transcription in a eukaryote Nature. (2011); 469(7331): 554– 558.doi: 10.1038/nature09654 130 Involvement of Lgl and Mahjong/VprBP in Cell Competition. PLoSBiol (2010) 8(7): e1000422. doi:10.1371/journal.pbio.1000422
48 associated with poor prognosis in these patients and may play a role in other cancers131. Professor Dyer is developing antibodies that could be used to target CRLF2. This work is supported via a MRC Technology development gap fund award. John Rouse (MRC Protein A protein called FAN1 that acts like a pair of molecular Phosphorylation Unit) scissors to repair damaged DNA in body cells has been discovered132. The discovery could have major implications for reducing cancer cells’ resistance to chemotherapy. Tony Monaco (University Early findings from the international Autism Genome of Oxford) Project (AGP) indicate that losses and duplications of whole chunks of DNA at sites across our genomes are likely to play a role in autism spectrum disorders133. Phase 1 of the AGP represented an investment of £7.44 million over three years by Autism Speaks, MRC, and the Health Research Board of Ireland (HRB). Genome Canada and Autistica (UK-arm of Autism Speaks) also contributed funding, while the MRC played the central role in establishing the AGP partnership and the multi-partite funding arrangements. Stuart Cook (MRC CSC) Discovery of a network of genes for type 1 diabetes (T1D) and a ‘key player’ in this network134. The work took a systems biology approach in a rat model for diabetes. These results could eventually help researchers focus their efforts to improve drug treatments for type 1 diabetes as well as possibly having an impact on other diseases where inflammation plays an important role. Leonid Sazanov (MRC Scientists have identified the structure of the vital Mitochondrial Biology enzyme ‘respiratory complex I’, solving a key part of Unit) the puzzle of how our cells gain energy from food135. This discovery opens up new avenues of research into future treatments for neuromuscular diseases and for neurodegenerative diseases such as Parkinson’s. Mary Herbert and Doug Researchers used a pioneering technique to Turnbull (Newcastle successfully transfer DNA between two human eggs136. University) The technique has the potential to help prevent the transmission of serious inherited disorders known as mitochondrial diseases. Following this discovery there was significant media interest137 in the ethics of future applications of this work which would require a change in the law. The Government subsequently
131 Deregulated expression of cytokine receptor gene, CRLF2, is involved in lymphoid transformation in B-cell precursor acute lymphoblastic leukemia. Blood. (2009) Sep 24;114(13):2688-98. Epub 2009 Jul 29. PubMed PMID: 19641190. 132 Identification of KIAA1018/FAN1, a DNA Repair Nuclease Recruited to DNA Damage by Monoubiquitinated FANCD2 Cell (2010), Volume 142, Issue 1, 65-7610.1016/j.cell.2010.06.021 133 Functional Impact of Global Rare Copy Number Variation in Autism Spectrum Disorder Nature.(2010); 466(7304): 368–372. doi:10.1038/nature09146 134 A trans-acting locus regulates an anti-viral expression network and type 1 diabetes risk Nature (2010) 467, 460–464 doi:10.1038/nature09386 135 The architecture of respiratory complex I Nature(2010) 465, 441–445doi:10.1038/nature09066 136 Pronuclear transfer in human embryos to prevent transmission of mitochondrial DNA disease Nature, (2010) 465, 82–85 DOI:10.1038/nature08958 137 Three-person IVF' technique moves closer (BBC News 2012) http://www.bbc.co.uk/news/health- 16627043
49 asked the Human Fertilisation and Embryology Authority (HFEA) to conduct a public consultation on this area138. The Wellcome Trust have awarded the Newcastle Centre £5.8m to examine the safety of the approach. Dr Mark Five new genes have been found which cause an O’Driscoll(MRC/University extreme form of dwarfism, known as primordial of Sussex Centre for dwarfism. Findings from two research papers139 shed Genome Damage and light on how human body size is determined, and for Stability) the first time make a direct link between the copying and Dr Andrew Jackson of DNA in cells and body growth. The discovery could (MRC Human Genetics open up new avenues of research into how growth Unit) disorders occur and offer people with severe growth disorders a chance of better and earlier diagnosis. Robin Lovell-Badge (MRC MRC researchers in collaboration with scientists and NIMR) clinicians in Australia and the USA showed that Sox3 could act as a male determining gene if it was expressed incorrectly in the early developing gonads in mice140. This led to the finding that about 20% of cases of female to male sex reversal in humans (that are not due to SRY) have genome rearrangements around SOX3. This discovery has rapidly been adopted as a diagnostic tool. SpiroMeta consortium 5 new loci associated with chronic obstructive (led by Martin Tobin pulmonary disease (COPD)141 were identified by (Leicester) and Ian Hall analysing gene and phenotype information from (Nottingham)) 20,000 patients. Daniel Swerdlow An international genetic study142 partly funded by the (University College MRC has provided the strongest evidence to date that London) inflammation causes coronary heart disease (CHD) by demonstrating the role of the interleukin-6 receptor in this process. This opens the door to testing existing inflammatory drugs for the prevention of CHD.
New products/diagnostics in development SNPMaP (SNP SNPMaP143 uses DNA pooling on microarrays for affordable Microarrays and genome-wide association using tens not thousands of Pooling) microarrays. The SNPMaP package facilitates the extraction technique (MRC and processing of SNPMaP data in the popular R environment SDGP, Kings for statistical computing. College)
138 Views sought on changing the law to find cure for inherited mitochondrial disease http://www.dh.gov.uk/health/2012/01/mitochondrial/ 139 Bicknell, L. et al. Mutations in ORC1, encoding the largest subunit of the origin recognition complex, cause microcephalic primordial dwarfism resembling Meier-Gorlin syndrome. Nature Genetics (2011) doi: 10.1038/ng.776. Bicknell, L. et al. Mutations in the pre-replication complex cause Meier-Gorlin syndrome. Nature Genetics (2011) doi: 10.1038/ng.775 140 Identification of SOX3 as an XX male sex reversal gene in mice and humans Sutton et al.Published in Volume 121, Issue 1 (January 4, 2011) J Clin Invest. 2011;121(1):328–341. doi:10.1172/JCI42580. http://www.jci.org/articles/view/42580 141 Genome-wide association study identifies five loci associated with lung function Nature Genetics (2010) http://www.nature.com/ng/journal/vaop/ncurrent/pdf/ng.501.pdf 142 The interleukin-6 receptor as a target for prevention of coronary heart disease: a mendelian randomisation analysis Lancet, (2012) Volume 379, Issue 9822, Pages 1214 - 1224 143 Davis, O.S.P., Plomin, R., &Schalkwyk, L.C. (2009). The SNPMaP package for R: A framework for genome-wide association using DNA pooling on microarrays. Bioinformatics, 25, 281-283. doi:10.1093/bioinformatics/btn587
50 Richard Development of a new direct electron detector, now marketed Henderson (MRC by FEI144. The new detector allows researchers to see LMB) biologically significant detail that could not be seen before. Richard Researchers at the MRC CSC have initiated early phase clinical Festenstein (MRC studies of a drug that may correct the genetic disorder Clinical Sciences Friedreich’s ataxia (FA) with funding from Ataxia charities in Centre (CSC)) the UK, Ireland and France, the European Commission and MRC DPFS support145. FA is caused by the epigenetic silencing of the Frataxin gene, and MRC-funded researchers have recently identified histone deacetylase drugs that switch this gene back on in cells taken from FA patients. Francesco An MRC co-funded clinical trial146 demonstrated that a gene- Muntoni based drug, initiating “exon skipping” is effective in raising the (University levels of a shortened, semi-functioning dystrophin protein in College London) sufferers of Duchenne Muscular Dystrophy, a fatal muscle wasting disease in boys caused by a faulty dystrophin gene. Steve Brown Following research to define potential molecular pathways (MRC Mammalian involved in the pathogenesis of otitis media147, work is Genetics Unit) underway to test in vivo whether compounds inhibiting these pathways would be useful in treating the disease. Promising results led to MRC Technology filing a patent to protect this novel finding, and the work has been extended to verify the in vivo results by collecting clinical effusion samples from children with chronic glue ear. Current develop work has supplementary support from the Translational Research Initiative for Hearing scheme run by Action on Hearing Loss (formerly RNID). Mike Gait (MRC Mike Gait and colleagues have developed cell penetrating Laboratory of peptides (CPP) suitable for delivery of therapeutics. CPPs have Molecular the potential to deliver a broad range of peptide, non-antibody Biology) therapeutics overcoming a major bottleneck in their development. A study, partly supported by a MRC Technology development gap fund award, has already demonstrated the improvements that CPPs can bring to exon skipping approaches for the treatment of Duchenne Muscular Dystrophy148.
Commercialisation UK academia has provided some of the most important scientific and technical advances in genomics. MRC contributions include the structure of DNA, chemical sequencing, DNA fingerprinting and microarray technology149. These innovations continue to influence a multi-billion dollar international biotechnology industry. In
144 FEI's New Direct Electron Detector Revolutionizes Electron Microscopy of Biological and Other Beam-Sensitive Samples http://www.globenewswire.com/newsroom/news.html?d=169814 145 Pharmacodynamic studies of a histone deacetylase inhibitor in Friedreich’s Ataxiahttp://www.ataxia.org.uk/data/files/summary_of_festensteins_hdaci_study_for_website_approv ed.pdf 146 Exon skipping and dystrophin restoration in patients with Duchenne muscular dystrophy after systemic phosphorodiamidatemorpholino oligomer treatment: an open-label, phase 2, dose-escalation study Lancet, Volume 378, Issue 9791, Pages 595 – 605 doi:10.1016/S0140-6736(11)60756-3 http://www.thelancet.com/journals/lancet/article/PIIS0140-6736%2811%2960756-3/abstract 147 HIF-VEGFpathways are critical for chronicotitismedia in Junbo and Jeffmousemutants PLoS Genet. (2011);7(10):e1002336 148 Pip5 Transduction Peptides Direct High Efficiency Oligonucleotide-mediated Dystrophin Exon Skipping in Heart and Phenotypic Correction in mdx Mice Mol Ther. (2011) July; 19(7): 1295–1303. PMID: 21505427 149 MRC Stories of impact “DNA research” http://www.mrc.ac.uk/Achievementsimpact/Storiesofimpact/DNAresearch/index.htm
51 the case of high throughput DNA sequencing UK academia has made significant impact on the technologies in use today, and likely to be used in future. Two examples are detailed below. Hagan Bayley Development of protein pores as nanoreactors for observing (University of chemistry at the single-molecule level. The work partly Oxford) funded by the MRC has led to a spin out company, now called, Oxford Nanopore Technologies (ONT) with a focus on single molecule sequencing. ONT has grown to employ 95 staff and in 2012 announced it would market a new DNA sequencer the size of a USB memory stick150. The technology from Oxford Nanopore Technologies is being seen as transformative151 in a multi-billion dollar market. Raindance Inc. The company152 is based on microdroplet ‘emulsion’ technology invented by Andrew Griffiths at the MRC LMB (now at the ISIS institute, Strasbourg) combined with ‘microfluidics’ technology from Harvard University and the ESPCI in Paris. It is a unique combination of engineering and biotechnology devoted to developing novel microfluidics devices that may be used for a variety of applications. The company is based in the USA (Lexington, Massachusetts), and its primary focus is on the DNA sequencing market. Raindance has raised $82m in funding since 2007. Martin Webb Development of fluorescent biosensors based on engineered (MRC National proteins, to probe for various products of the ATPases and Institute for GTPase reactions, inorganic phosphate, nucleoside Medical Research) diphosphate and single-stranded DNA153. These novel sensors were patented in 2005, further developed using MRC Technology development gap funding, and have now been successfully licensed. Ubiquigent Ltd. Ubiquigent154 markets reagents, assays, services and (University of technologies developed by the Protein Ubiquitylation Unit of Dundee spin out) the Scottish Institute for Cell Signalling, set up by Sir Philip Cohen. The company employed its first three staff in 2010 (4 staff in 2012).
150 Company Unveils DNA Sequencing Device Meant to Be Portable, Disposable and Cheap (New York Times, February 2012) http://www.nytimes.com/2012/02/18/health/oxford-nanopore-unveils-tiny-dna-sequencing- device.html?_r=1 151 MinION™ a miniaturised sensing instrument (Oxford Nanopore Technologies website) http://www.nanoporetech.com/technology/minion-a-miniaturised-sensing-instrument 152 http://www.raindancetechnologies.com/about-us/molecular-biology-genome-sequencing.asp 153 A biosensor for fluorescent determination of ADP with high time resolution. Journal of Biological Chemistry 284, 33130-33138 PMID:19801632 154 New Venture co-founded with Professor Sir Philip Cohen to Focus on the Ubiquitin Proteasome Pathway, a Key Cell Signalling System with Significant Drug Discovery Potential http://ubiquigent.com/index.php/news-and-events/stemgent_ubiquigent_release
52
Life course perspective
“Stimulating novel interactions to promote research into healthy ageing”
Life expectancy continues to increase in much of the developed world at the rate of five or more hours a day. As we push forward the results from basic research into health benefits for society, it is important that we study diseases in the context of the entire age spectrum from birth to adulthood.
Objective
To drive forward interdisciplinary research addressing health and wellbeing from childhood to older age.
Lifecourse perspective
1 Study factors that influence age-related change at the molecular, √√ physiological system and individual levels, and that lead to increased risk of disease in later life; involving multidisciplinary research linking basic and population science 2 Partnerships between researchers and stakeholders from a range √√√ of sectors, including cross-council funding programmes, to translate discoveries and influence policy and practice 3 Drive forward the translation of scientific findings into benefits for √√√ public health through linking with other funders and stakeholders in the LLHW programme 4 Study large groups of people from birth for genome-wide √√ associations to exploit data on variation in the human genome 5 Understand the basic mechanisms of brain and cognitive √√ development in infants and young children to identify risk factors in infancy or adverse outcomes in later life
Transformational developments Over £50m will be committed by MRC, the Research Councils and health departments on multi-disciplinary collaborative ageing research projects funded through the MRC-led Lifelong Health and Wellbeing cross-council programme MRC funded cohorts are now working closely together in novel ways opening up possibilities to combine life course datasets to carry out larger scale genetic, physiological and behavioural studies to advance our understanding of the ageing process.
1. Study factors that influence age-related change at the molecular, physiological system and individual levels, and that lead to increased risk of disease in later life
Jointly with Arthritis Research UK, we invested £5m into two MRC-Arthritis Research UK Centres for Musculoskeletal Ageing Research. The Centres will investigate why musculoskeletal tissues decline with age, exploring both the risk factors and the biological mechanisms involved, and they will pioneer new
53 interventions to improve musculoskeletal health in old age (see also tissue disease and degeneration).
Together with eight other Research Councils and Health Departments we have launched a £5.5m initiative on promoting physical activity in older age through the MRC led LLHW programme (see below). The call for proposals opened in summer 2012 and will support research on the physiological effects of physical activity and sedentary behaviour and factors underpinning these behaviours in older populations.
MRC is sponsoring a workshop that will bring together researchers working on the biology of ageing, physiological systems, and metabolic and cardiovascular conditions with the aim of stimulating novel collaborations to understand the relationship between the biological ageing process and the development of age related diseases.
2. Partnerships between researchers and stakeholders, including cross- council funding programmes, to translate discoveries, and
3. Drive forward the translation of scientific findings into benefits for public health through linking with other funders and stakeholders in the LLHW programme
MRC led the development of a UK Strategy for Collaborative Ageing Research155 on behalf of the Lifelong Health and Wellbeing (LLHW), which brings together AHRC, BBSRC, EPSRC, ESRC and MRC in partnership the four UK health departments. The strategy was published in 2010 and identified areas where greater impact could be achieved through working across disciplines and sectors. Expert think tanks involving academics, policy makers and business were held in three of these areas (extending working lives, physical activity, and mobility and independence) to scope how best to support these priorities over the coming years.
Building on earlier investments, MRC has led Phase 2 and 3 funding calls on behalf of the LLHW cross-council programme in 2009 and 2011, respectively. In Phase 2 we awarded £4.5m to three major LLHW Research Collaboratives to develop interventions for self-management of chronic pain, rehabilitation after stroke or joint replacement, and promoting health and well-being post retirement. In addition, we have supported 10 Collaborative Development Networks, short- term capacity building networks with the aim of creating new multidisciplinary teams. In Phase 3 we invested £11.5m on seven five year research programmes addressing areas such as menopause, mechanics of ageing tissue, and frailty and ten two year pilot studies in diverse areas such as falls, public transport and mental health.
In partnership with ESRC we have launched a LLHW call for proposals for research partnership awards on extending working lives in summer 2012. This initiative will support collaborations of academic researchers with businesses or policy makers investigating critical issues associated with an ageing workforce within a workplace or policy setting. Outcomes from this applied research will inform future policy and practice relating to an increasingly ageing UK population.
A key prerequisite for scientific progress in ageing research is the availability of good (bio)markers to characterise ageing people. We are supporting a small
155 http://www.mrc.ac.uk/Ourresearch/ResearchInitiatives/LLHW/Ageingresearch/index.htm
54 team of researchers from a range of Universities to develop guidelines on (bio)markers of healthy ageing for use by the UK research community. The project will establish best practice for the use of markers through literature research followed by an international workshop.
4. Study large groups of people from birth for genome-wide associations to exploit data on variation in the human genome
MRC provides core funding for the 1958 Birth Cohort, which has been widely used as a control for Genome-wide Association (GWAS) studies.
The Avon Longitudinal Study of Parents and Children (ALSPAC) is used for genome-wide association studies.
Researchers at the MRC Centre for Cognitive Ageing and Cognitive Epidemiology at the University of Edinburgh have used GWAS studies to investigate the genetic contribution and stability of intelligence across the human life course156 .
5. Understand the basic mechanisms of brain and cognitive development in infants and young children to identify risk factors in infancy or adverse outcomes in later life
The MRC Cognition and Brain Sciences Unit, has appointed a new Director and has increased its focus on cognitive development. The Unit has also attracted BBSRC funding to conduct a longitudinal study investigating brain development.
We have renewed our investment into the MRC Social, Genetic and Developmental Psychiatry Centre (Institute of Psychiatry), which studies common psychiatric disorders that emerge in childhood and cognitive disorders such as learning disabilities and the autistic spectrum. We have supported a research programme in the Centre building on the Twins Early Development Study (TEDS) to investigate common psychological conditions in children, such as autism and Attention Deficit Hyperactivity Disorder (ADHD).
We have renewed the MRC Centre for Developmental Biology (King’s College London), which conducts research linking basic neurobiology to risk factors in developmental diseases.
Research Changes Lives Objectives in progress
We will, in partnership with the public and private sector, increase research on extending working lives
We will invest further funding into research on promoting physical activity in older people.
We will support collaborative research to understand how the biological ageing process impacts on age related diseases.
156 Deary et al. (2012).Genetic contributions to stability and change in intelligence from childhood to old age. Nature doi:10.1038/nature10781.
55 We are establishing a major new birth cohort, supported jointly by BIS, the MRC and ESRC at a level of £28m. This will recruit 90,000 women during pregnancy to study health and disease of their children over the life course. The study is currently in its development phase and piloting will start in January 2013.
Outcomes 2009-2012
Scientific advances Rachel Cooper Research157 has shown that grip strength, the speed we walk (MRC Unit for or rise from a chair and our ability to balance could be Lifelong Health indicators of how long we may live. The analysis used and Ageing) findings from 33 studies across the world (including the Hertford study and the 1946 birth cohort), covering data from over 50,000 men and women who were followed for up to 43 years. Andy Greenfield Mutations in a gene called MAP3K1 play a key role in sex (MRC Mammalian development disorders158. This discovery adds to the genes Genetics Unit) already known to influence a range of sexual development disorders. It could help with earlier intervention with treatments that will enable healthy puberty and fertility in later life by screening for this range of genes. Cathy Elks and 30 genes have been discovered which control the age at Ken Ong (MRC which girls reach sexual maturity159. Many of the genes Epidemiology responsible for puberty also play a strong role in how the Unit) body metabolises fat, establishing new biological links between going through puberty at a young age and being at increased risk of obesity. Hazel Inskip The chance of a child developing allergies or wheezing is (Lifelong related to how they grow at vital stages in the womb160. The Epidemiology research, also supported by the British Lung Foundation, Unit, reveals that foetuses which develop quickly in early Southampton) pregnancy but falter later on in pregnancy are likely to go on to develop allergies and asthma as children. Scientists believe this is due to changes in the development of their immune system and lungs. Andrew Steptoe People who leave education with fewer qualifications are (University prone to age more quickly, according to results from a study College London) of the telomere length in participants from the Whitehall II cohort161. Education is a marker of social class and the results suggest that long-term exposure to the conditions of lower status promotes accelerated cellular ageing, regardless of people’s economic status in later life. The work was funded jointly by the British Heart Foundation.
157 Physical Activity Across Adulthood and Physical Performance in Midlife: Findings from a British Birth Cohort (2011) American Journal of Preventive Medicine, Volume 41, Issue 4 doi: 10.1016/j.amepre.2011.06.035 158 Mutations in MAP3K1 Cause 46,XY Disorders of Sex Development and Implicate a Common Signal Transduction Pathway in Human Testis Determination The American Journal of Human Genetics (2010), Volume 87, Issue 6, 898-904 159 Thirty new loci for age at menarche identified by a meta-analysis of genome-wide association studies Nature Genetics (2010) 42, 1077–1085 doi:10.1038/ng.714 160 Patterns of fetal and infant growth are related to atopy and wheezing disorders at age 3 years Thorax(2010)doi:10.1136/thx.2010.134742 161 Educational attainment but not measures of current socioeconomic circumstances are associated with leukocyte telomere length in healthy older men and women. Brain Behav Immun. (2011) Oct;25(7):1292-8
56 LLHW Centre for Estimated the genetic and environmental contributions to Cognitive Ageing changes in intelligence across most of the human lifetime. and Cognitive The study162 found that genetic factors may account for about Epidemiology 24 per cent of changes between childhood and old age, and (Edinburgh) that the largest influence on changes in intelligence is probably environmental. The findings also suggest that many of the genes that affect cognitive ability in childhood also influence cognition in old age. Keith Godfrey Studies on the Southampton Women’s Survey have shown (MRC Lifecourse that epigenetic changes caused by maternal diet strongly Epidemiology influence a child’s adiposity up to 9 years of age and this Unit, University of effect is independent of mother’s weight or weight of the Southampton) baby at birth163.
New products/diagnostics in development Carole Ward Developed and patented a heart rate sensor specifically for (Nottingham new-born infants164. Preliminary work has demonstrated its University) utility on babies in intensive care. Further development is underway to assess accuracy, reliability and acquisition time. The aim is to improve resuscitation in those infants at greatest risk of short and long term sequelae. Most recent work supported by DPFS Portfolio Award The LOISS is a questionnaire used to assess sleep related Loughborough occupational impairment in both clinical and non-clinical Occupational populations. The scale has been adopted by the RCUK Impact of Sleep funded New Dynamics of Ageing "working late" project. Scale (LOISS)165
Research into policy David Edwards ‘Hypothermic neural rescue therapy’ – controlled cooling of (MRC Clinical the brain – reduces the risks of death and disability in infants Sciences Centre) suffering birth asphyxia and reduces cases of cerebral palsy in survivors166. It is estimated that this could affect 100 babies born each year in the UK167. In 2010 NICE issued full guidance168 that the treatment should become part of normal NHS practice. Through the Experimental Medicine funding call, the MRC has supported further developments of this therapy, including new imaging biomarkers and early phase studies of related treatments. Paul Little In 2009 NICE recommended169 that patients with low back (University of pain be offered a course of structured exercise, and cited the
162 Deary et al. (2012).Genetic contributions to stability and change in intelligence from childhood to old age. Nature doi:10.1038/nature10781 163 Epigenetic gene promoter methylation at birth is associated with child's later adiposity Diabetes. (2011);60(5):1528-34. 164 Heartlight - Acquisition Times for a Novel Forehead Heart Rate Sensor in Delivery Room Resuscitation of Preterm Infants Pediatric Research 70, 674 (2011) doi:10.1038/pr.2011.899 165 The Loughborough Occupational Impact of Sleep Scale (LOISS): a new instrument for research and clinical practice. Behav Sleep Med.(2011);9(4):243-56. doi: 10.1080/15402002.2011.606775. 166 Neonatal Medicine Group at the MRC Clinical Sciences Centre http://www.csc.mrc.ac.uk/ResearchGroupContent/ECN/NeonatalMedicinePastWork1 167 Results of the TOBY trial, MRC Clinical Sciences Centre News http://www.csc.mrc.ac.uk/NewsEvents/News/TOBYtrial/ 168 NICE interventional procedure guidance (IPG347) “Therapeutic hypothermia with intracorporeal temperature monitoring for hypoxic perinatal brain injury” (May 2010) http://www.nice.org.uk/nicemedia/live/11315/48809/48809.pdf
57 Southampton) Alexander Technique as of benefit to patients, based on results from the MRC-funded ATEAM study led by Professor Paul Little170.
169 NICE full guideline CG88 “Low back pain: early management of persistent non-specific low back pain” (May 2009) http://www.nice.org.uk/nicemedia/live/11887/44334/44334.pdf 170 Randomised controlled trial of Alexander technique lessons, exercise, and massage (ATEAM) for chronic and recurrent back pain: economic evaluation, Hollinghurst,S et al. BMJ 2008;337doi: 10.1136/bmj.a2656; MRC News “Trial finds Alexander technique helps reduce backpain” http://www.mrc.ac.uk/Newspublications/News/MRC004790
58
Lifestyles affecting health
“Working in partnership to tackle the lifestyles that affect health”
Over recent decades, researchers tackling behaviour related to health have studied ways to change lifestyles at an individual level. Although some initiatives have been successful, we need to develop more effective strategies, which have a greater focus on community, macro-level or multi-level interventions, taking into account social factors that play important roles in behaviour and lifestyle.
Objective
To determine the most effective strategies for tackling lifestyles that are detrimental to health.
Measuring up progress against commitments in research Changes Lives
1 Build networks, working towards understanding the √√√ interplay between lifestyle factors, health and wellbeing to deliver benefits to human health 2 Evaluate the impact of complex interventions on lifestyle, √√√ and set up partnerships between researchers and policy- makers 3 Offer increased support for intervention development and, √√ through continued partnership with the NIHR, for large- scale evaluations particularly of community, macro-level and multi-level interventions 4 Strive for increased coordination and connectivity across √√√ existing groups, and innovative, cross-disciplinary studies in addiction research 5 Interaction of genetics with lifestyle will be studied in √√ addictions, including smoking and alcohol. 6 Development of methodology research to support the √√ design and analysis of large-scale evaluations and help define public health interventions
Strategic initiatives in addiction research and the National Prevention Research Initiative (NPRI), have increased MRC spend in addiction (grants and fellowships) from 1.7m in 2006/7 to £4.8m in 2010/11.
Transformational developments
Through investment into addiction clusters we have significantly increased collaborative research capacity in addiction research, addressing the needs of policy makers.
New cost-effective interventions have been developed that demonstrate substantial increases in the quit rates of smokers (see outcomes)
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1. Build networks, working towards understanding the interplay between lifestyle factors, health and wellbeing
Further funding, at a level of £1m over 5 years, has been invested into the MRC Population Health Sciences Network (PHSRN), a network of 13 MRC Units and Centres in Population Health Sciences to encourage collaborative working. The PHSRN has led a variety of workshops and projects aimed at translating research into policy and practice. Building on their 2008 guidance for the development of complex interventions, PHSRN has published a translational route map for public health research in 2009 and guidance on the evaluation of natural experiments in 2011. The latter will help funders and users of public health evidence to decide how and when natural experiments can be used to good effect. An international workshop on methodology in population health research was organised by the PHSRN in April 2012 (see below).
2. Evaluate the impact of complex interventions on lifestyle, and set up partnerships between researchers and policy-makers
We have continued leading the National Prevention Research Initiative (NPRI), a consortium of 16 Government Departments, Research Councils and charities, tackling the health effects of behaviours such as smoking, poor diet, lack of physical activity and excessive alcohol intake. We have completed Phase 3 and 4 funding rounds of the initiative in 2009 and 2011. Phase 3 focussed on the environmental factors influencing behaviours. 15 awards were made at a total level of £12m across the funders addressing issues such as healthy eating and lifestyle in pregnancy, and an after-school programme to increase physical activity. 19 research projects worth £10m were funded in Phase 4, which specifically addressed the development and evaluation of interventions. Funded topics include the effects of different alcohol pricing policies, and the impact of affordable housing at the 2012 Olympic Village on residents’ physical activity.
MRC co-funds the Scottish Collaboration for Public Health Research and Policy with the Scottish Chief Scientist Office and in 2013 will assume the management of the UKCRC Public Health Research Centres, supported by a consortium of seven government and charity funders. The Centres play a an important role in the development and evaluation of complex interventions to tackle public health issues such as diet, exercise, alcohol, and tobacco and foster collaborations between researchers and policy makers.
3. Offer increased support for intervention development and, through continued partnership with the NIHR, for large-scale evaluations particularly of community, macro-level and multi-level interventions
Through the National Prevention Research Initiative (see above) we have supported a variety of projects addressing the development and evaluation of public health interventions. Examples include the development and feasibility testing of a community-based group intervention to prevent alcohol-related harm in young women and assessing the effectiveness of mass media campaigns in reducing smoking, second-hand smoke exposure and smoking related disease.
In discussions with NIHR we have agreed to target specifically investment towards early phase developmental work and feasibility studies that will inform future larger scale grant proposals testing interventions. Plans are currently under discussion.
60 4. Strive for increased coordination and connectivity across existing groups, and innovative, cross-disciplinary studies in addiction research
Since the launch of the MRC-led Addiction and Substance Misuse strategy in 2009171, we have jointly with ESRC invested £6.5m to support research in this area. This has included funding for small pilot projects, the development of addiction clusters bringing together researchers from different disciplines, and, in 2010, funding of four substantial research programmes based on the addiction clusters. The projects study drug addiction as well as alcohol abuse and include collaborations with policy makers and industry. A review of the eight remaining clusters conducted in 2011 concluded that the initiative had strengthened research skills and collaborations between researchers as well as innovative methodologies for policy oriented research. Due to the strategic initiatives in addiction research and NPRI, MRC spend (grants and fellowships) has increased from 1.7m in 2006/7 to £4.8m in 2010/11.
5. Interaction of genetics with lifestyle will be studied in addictions, including smoking and alcohol.
A number of grants in this field, including a study investigating the genetic influences underlying the risk for drug addiction, have been supported through the addiction initiative (above).
This is also an interest of the MRC Social, Genetic and Developmental Psychiatry Centre (Institute of Psychiatry), which has received renewal funding in 2010. Researchers in the Unit lead the IMAGEN project, a European study investigating risk taking behaviour in teenagers.
The health effects of modifiable risk factors such as alcohol and diet are also investigated by researchers at MRC Centre for Causal Analysis in Translational Epidemiology (Bristol) and studies using the Avon Longitudinal Study of Parents and Children (ALSPAC) are ongoing.
Researchers at the joint MRC/Wellcome Trust Behavioural and Clinical Neuroscience Institute, which has received renewal funding in 2010, have demonstrated a link between abnormal brain structure and drug addiction172.
6. Development of methodology research to support the design and analysis of large-scale evaluations and help define public health interventions
Methodological research addressing the design and evaluation of public health interventions is conducted at some of MRC’s major Units in population health sciences, including the MRC Epidemiology Unit and MRC Social and Public Health Sciences Unit and through MRC Population Health Fellowships.
The MRC Population Health Research Network, with the UKCRC Public Health Research Centres of Excellence and the Scottish Collaboration for Public Health Research and Policy recently held a conference on “Population Health, Methods and Challenges” bringing together over 300 members from the population health community to discuss challenges and new approaches to population health research methods.
171 http://www.mrc.ac.uk/Utilities/Documentrecord/index.htm?d=MRC006320 172 Abnormal Brain Structure Implicated in Stimulant Drug Addiction (2012) K.D. Ersche et al. Science: Vol. 335 no. 6068 pp. 601-604 DOI:10.1126/science.1214463
61 Three awards investigating methodological issues relevant to public health interventions addressing diet and exercise have been funded through MRC’s highlight notice on improved measurement methods for population science research.
Research Changes Lives objectives in progress
We will evaluate the outcomes of NPRI since its inception in 2004 to inform future priorities in prevention research.
We will provide additional funding for the UKCRC Public Health Centres of Excellence for a further five years.
We will increase our investment in the early phase development of public health interventions.
Recognising the growing health problems caused by alcohol misuse, we will hold a workshop exploring important research opportunities on alcohol misuse and its harms and the development of interventions. This will inform our future funding in this area.
We will also establish a capacity building programme, which will train future researchers in addiction research.
Outcomes 2009-2012
Interventions in use 'Mind, exercise, The MEND programme is designed by researchers at the nutrition and do it!' Institute of Child Health at UCL and offers a range of ways (MEND) to make life changes in physical activity, food, self- confidence and personal development. It has proven to be a model that is replicable throughout England and Wales and is now the most extensive child obesity treatment programme in the UK173. In 2011 it was reported that there were now 1000 MEND programmes delivered each year, and the approach had impacted upon 40,000 individuals to date. The MEND Foundation now delivers the programme internationally with activity in Australia and the USA.
New treatments and interventions in development Txt2stop trial Motivational and supportive mobile phone messages have (Caroline Free, been found to double quit rates of smokers after 6 LSHTM) months174. National A pill known as Tabex®, commonly available in parts of Prevention Eastern and Central Europe, can more than triple Research Initiative someone’s chances of quitting smoking for at least 12 funded trial of months175. cytosine.
173 http://www.idea.gov.uk/idk/core/page.do?pageId=6283972 174 Smoking cessation support delivered via mobile phone text messaging (txt2stop): a single-blind, randomised trial Free, C at al Lancet (2011), Volume 378, Issue 9785, Pages 49 - 55, 2 July 2011, doi:10.1016/S0140-6736(11)60701-0 http://www.mrc.ac.uk/Newspublications/News/MRC008034 175 Placebo-Controlled Trial of Cytisine for Smoking Cessation; West, R et al N Engl J Med (2011) 365:1193-1200 http://www.mrc.ac.uk/Newspublications/News/Archive/MRC008199
62 John Strang (Kings The “N-Alive” Trial176 is launched to test the effectiveness of College) in prison-based prescription of Naloxone (the heroin antidote) collaboration with for reducing by 30% overdose deaths in the four weeks the MRC Clinical after injectors' release from prison. The reduction of drugs- Trials Unit and related deaths has been a key target of UK Governments’ MRC Biostatistics Drugs Strategy, which at the last report was being failed. Unit
New scientific advances Nita Forouhi (MRC The MRC funded Public Health Sciences Research Network Epidemiology Unit) has compiled an online toolkit for diet and physical activity measurement177 which is widely used by researchers wanting to conduct high quality studies in this field. Ruth Loos (MRC Over the past 3 years the MRC Epidemiology Unit has Epidemiology Unit) collaborated in studies that have identified more than 10 genetic loci reproducibly associated with body mass index and waist circumference (for example as a member of the GIANT178 consortium). These new observations are followed up via physiological studies and the interaction of genetic susceptibility with lifestyle factors is explored. In the past year, Dr Loos’ group has contributed to the discovery of a further 20 loci associated with body mass index, 14 loci with waist hip ratio, and one locus with body fat percentage, furthermore MRC research has also shown that physical activity can attenuates these genetic effects179. The new loci may increase our understanding of the physiological pathways that underlie the risk of obesity and type 2 diabetes180. MRC Addiction The Home Office has launched the Drug Data Research Cluster, Warehouse181 following research demonstrating that it is Tim Millar, feasible to link relevant separate drug treatment and Manchester criminal justice databases in a secure and anonymous way, creating a resource with enormous potential for analyses that will advance knowledge and improve understanding of drug misusers and drug misusing offenders. Sheila Bird (MRC Biostatistics Unit) is a member of the project advisory board for the warehouse. Daniela De Angelis Research in primary care in Edinburgh182concluded that (MRC Biostatistics opiate substitution treatment in injecting drug users reduces
176 N-ALIVE Prison-based Naloxone-on-release randomised controlled trial to reduce heroin overdose deaths; NALoxoneInVEstigationhttp://public.ukcrn.org.uk/search/StudyDetail.aspx?StudyID=8032 177 Diet and Physical Activity Measurement Toolkithttp://www.dapa-toolkit.mrc.ac.uk/index.html 178 GIANT: Genetic Investigation of ANthropometric Traits http://www.broadinstitute.org/collaboration/giant/index.php/GIANT_Cohorts_and_Groups 179 Physical Activity Attenuates the Influence of FTO Variants on Obesity Risk: A Meta-Analysis of 218,166 Adults and 19,268 Children (2011) PLoS Med 8(11): e1001116. doi:10.1371/journal.pmed.1001116 180 A genome-wide approach accounting for body mass index identifies genetic variants influencing fasting glycemic traits and insulin resistance Nat Genet.(2012). doi: 10.1038/ng.2274 181 The Drug Data Warehouse: Linking data on drug misusers and drug-misusing offenders (home Office Research Report 63, March 2012) http://www.homeoffice.gov.uk/publications/science-research- statistics/research-statistics/crime-research/horr63/horr63-summary?view=Binary 182 Survival and cessation in injecting drug users: prospective observational study of outcomes and effect of opiate substitution treatment BMJ 2010;340:c3172
63 Unit) the risk of mortality, with survival benefits increasing with cumulative exposure to treatment. Treatment did not reduce the overall duration of injecting. The BMJ paper won the 2010 Royal Society for General Practioners and Novartis Research Paper of the Year Award. British Genetics of Extensive phenotyping of the MRC BRIGHT participants Hypertension allowed data to be contributed to a major new analysis of (BRIGHT) cohort the genetics of smoking habits183this refined the study (Mark association between smoking quantity and a locus that Caulfield, QMUL) includes three genes encoding the neuronal nicotinic acetylcholine receptor. Combining PET As an example of the new interactions stimulated by the imaging and MRC addiction cluster investments; Luke Clark (Cambridge) addiction research is collaborating with David Nutt and Anne Lingford-Hughes (Imperial) to access PET imaging approaches to investigate neurotransmitter involvement in pathological gamblers. All three investigators having received separate awards under the MRC Addiction and Substance Misuse Research strategy. Gunter Schumann MRC funded researchers at the Institute of Psychiatry, King’s (MRC SDGP, Kings College London, with colleagues from Brazil, and Sussex College) have identified that variations in a neurotransmitter receptor gene GABRA-A2 are associated with cocaine addiction184. Rajinder Singh Evidence that cannabis smoke damages DNA in ways (University of that could potentially increase the risk of cancer185. Leicester) Using a highly sensitive liquid chromatography-tandem mass spectrometry method smoking of 3-4 cannabis cigarettes a day was found to cause the same damage to bronchial mucus membranes as 20 or more tobacco cigarettes a day. K Ersche Research has begun to sort out whether personality traits (Cambridge such as impulsivity and sensation-seeking are a cause or University) effect of being dependent on drugs. A study186 carried out in sibling pairs shows that impulsivity is a behaviour that mediates the risk of stimulant dependence, whereas abnormal sensation-seeking is more likely to be an effect of stimulant drug abuse.
Research into Policy Sheffield Alcohol Research in the MRC CAPER Cluster has provided evidence policy model which has led to policy changes or promoted the re- (Petra Meier, evaluation of alcohol policy in Scotland and England. The Sheffield) research which shows that increasing alcohol prices reduces crime is cited in the new UK Government Alcohol Strategy187, and has influenced the minimum price set in Scotland188
doi:10.1136/bmj.c3172http://www.rcgp.org.uk/pdf/Winning%20Paper%20- %20Kimber%20et%20al.pdf 183 Meta-analysis and imputation refines the association of 15q25 with smoking quantity Nat Genet. 2010 May;42(5):436-40. Epub 2010 Apr 25. 184 Cocaine effects on mouse incentive-learning and human addiction are linked to alpha2 subunit- containing GABAA receptors ProcNatlAcadSci U S A. 2010 Feb 2;107(5):2289-94. Epub 2010 Jan 19. 185 Evaluation of the DNA Damaging Potential of Cannabis Cigarette Smoke by the Determination of Acetaldehyde Derived N2-Ethyl-2′-deoxyguanosine Adducts Chem. Res. Toxicol., 2009, 22 (6), pp 1181–1188 DOI: 10.1021/tx900106y 186 Drug addiction endophenotypes: impulsive versus sensation-seeking personality traits Biol Psychiatry. (2010);68(8):770-3. Epub 2010 Aug 1. 187 The Government’s Alcohol Strategy (March 2012) http://www.homeoffice.gov.uk/publications/alcohol-drugs/alcohol/alcohol-strategy?view=Binary
64 National A critical social marketing study189 showed that youths had a Prevention sophisticated level of awareness of, and involvement in, Research alcohol marketing and marketers were aware that marketing Initiative funded targeted young people. The research has impacted on policy study involving at the European level, in Scotland and been cited by the BMA Institute for Social and House of Commons Health Committee190 Marketing, University of Stirling and The Open University Sheila Bird (MRC Research has provided more accurate statistics on drug- Biostatistics Unit) related deaths, and projections for Scottish deaths through to 2015 under a range of scenarios. This is achieved through inkage of the Scottish Drug Misuse Database (SDMD) cohort to hospitalizations, HCV diagnosis and deaths and the ability to investigate rates of and risks factors for cause specific morbidity and mortality in national cohort of nearly 70000 drug users who accessed drug treatment or services in 1996- 2006. Terry Porteous A study showed that Scottish GP involvement in (an MRC/ESRC managing drug misuse had reduced between 2000 and interdisciplinary 2008, but that there was a small increase in compliance with fellow at national guidelines. The findings repeated a Scotland-wide Aberdeen) survey of GP practices, funded by the CSO (Scotland)191 to obtain trend data. Peter Vickerman Research has outlined the cost effectiveness of antiviral (LSHTM) therapy for HCV as a preventative approach for HIV in various settings and the results have engaged policy makers in the UK and Australia. The studies published in 2011192 examine the transmission of HIV and Hepatitis C (HCV) amongst injecting drug users. MRC SDGP (Kings Research that showed impulsivity predicted gambling College, London) behaviour in low socioeconomic status (SES) adolescent males was cited in the UK Office of Science and Technology’s Foresight Programme review article “Problem gambling and other behavioural addictions”.193 Chris Bonell (MRC Promoting an inclusive ethos in schools was found to Health Services reduce young people’s substance misuse194. The project Research and contributed to the argument that education policy and Health of the practice can have major impacts on substance use, teenage Public Fellowship pregnancy and pregnancy. The Department for Children,
188 Sheffield University study adjusts booze price impact http://www.bbc.co.uk/news/uk-scotland- scotland-politics-16812662 189 Gordon, R., Moodie, C., Eadie, D. and Hastings, G. (2010), Critical social marketing – The impact of alcohol marketing on youth drinking: Qualitative findings. Int. J. NonprofitVolunt.Sect.Mark., 15: 265– 275. doi: 10.1002/nvsm.388 190 Details of the impact of the NPRI study are included in the case study “Alcohol Marketing and Young People” available on the MRC website at http://www.mrc.ac.uk/Ourresearch/ResearchInitiatives/NPRI/Alcohol/index.htm 191 Management of drug misuse: an 8-year follow-up survey of Scottish GPs Br J Gen Pract. 2010 July 1; 60(576): 517–520. doi: 10.3399/bjgp10X514783 192 Prevention of HIV infection for people who inject drugs: why individual, structural, and combination approaches are needed. Lancet. 2010 Jul 24;376(9737):285-301. 193 Problem gambling and other behavioral addictions (foresight phttp://www.foresight.gov.uk/Brain%20Science/Problem%20Gambling%20and%20other%20Behavio ural%20Addictions.pdf 194 Pilot multimethod trial of a school-ethos intervention to reduce substance use: building hypotheses about upstream pathways to prevention. J Adolesc Health. 2010 Dec;47(6):555-63. Epub 2010 Jun 20.
65 at the London Schools and Families has expressed an interest in the work. School of Hygiene and Tropical Medicine)
Public Engagement BBC Horizon Research using the MRC ENU Mutagenesis programme, Programme October led by Howard Thomas (Imperial) has generated a 2010. 'A Decade of mouse model of alcoholism. Further work has the Human Genome' indicated that the same gene is associated with alcoholism in some human patients. The mouse is being studied in the MRC Addiction Cluster run by Dai Stephens. This model was used as an example of how the Human Genome project has influenced research. New Musical Express General reference was made to the work carried out at article on addiction the MRC SGDP Centre on addictions (Specifically, Mephedrone) in an article published in the press on 27 March 2010 UNAIDS/UNICEF/WHO Invited talk on access of injecting drug using women to meeting “Pregnancy, prevention of mother-to-child transmission of HIV Drug Addiction and services in Ukraine. Attended by clinicians, addiction HIV in Eastern Europe specialists, policy makers, patient groups. and Central Asia”, Yalta, Ukraine (Claire Thorne, MRC Centre of Epidemiology for Child Health)
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Environment and health
“Understanding the relationship between environmental exposures and disease”
During a period of environmental change, research has a major role to play in society’s ability to adapt in order to maintain levels of human health and wellbeing. The relationship between humans and the environment in areas such as air and water pollution, changing patterns of infectious disease, allocation of natural resources, housing, food security, obesity and traffic all require cross- disciplinary solutions.
Objective
To explore the impacts of changes in our environment on health and wellbeing.
Measuring up progress against commitments in Research Changes Lives
1 Expanding research support in environmental and health: √√√ building evidence on the impact of environmental change on health and wellbeing 2 Fund research using longitudinal cohort studies to study the √√√ impact of environmental factors on disease 3 Develop methodology to detect exposure, and to find √√√ biomarkers to indicate exposure to potential toxins 4 Understand the impact of social and ecological √√ environments and interventions on the patterns of infectious disease
MRC’s spend in Environment and Health research was £43m per annum in the 2009/10 financial year195, increased from £31m in 2007/8
Transformational developments
We have established the MRC-HPA Centre for Environment and Health, a major new centre of excellence bringing together world leading research at Imperial College and King’s College London to address policy needs; key outputs of the centre include the London Air iPhone196 “app” and Rapid Inquiry Facility (see below)
1. Expanding research support in environment and health research
In partnership with the Health Protection Agency we have invested £3m to establish the £5.6m MRC-HPA Centre for Environment and Health at Imperial College and King’s College London in 2009. The Centre’s goal is to improve the
195 Last spend data available 196 London Air Quality Network http://www.londonair.org.uk/LondonAir/Default.aspx
67 scientific knowledge needed to develop better environmental health policies. The many environmental factors investigated by the Centre include air pollution, nanoparticles, mobile phone base stations, water chlorination, and overhead power lines.
Training the next generation of researchers that have knowledge across the disciplines needed to address environmental health problems is an important priority. We have provided renewal funding (£2.2m) for the Integrative Toxicology Training Partnership, a national programme managed by the MRC Toxicology Unit, which fosters partnerships between academia, industry and government agencies through support of multidisciplinary studentships. 31 studentships and one fellowship have been funded so far. Awards support research into the development of allergic sensitization to chemicals, the risk of adverse birth outcomes from exposure to disinfection by-products in public water and the mechanisms of nanoparticle-mediated foetal toxicity. The MRC-HPA Centre for Environment and Health also makes important contributions to training of students and fellows, which benefit from the broad expertise represented at the Centre.
The MRC has led two major initiatives under the banner of the Living with Environmental Change (LWEC) partnership to build capacity across disciplines: the Environmental Exposure and Health Initiative and the Environmental and Social Ecology of Infectious Diseases (see below). LWEC has brought together UK Government Departments and Agencies, the Devolved Administrations, and Research Councils to co-ordinate funding in response to the most pressing challenges brought about by environmental change.
The Welsh e-health informatics research centre funded through the 2012 call for proposals in this area (see use of population-based data) places an emphasis on data linkage to inform public health research. Programmes of research include studying the impact of the environment on health, including the effect of urban housing regeneration on residents’ health.
2. Using cohort studies to assess the impact of environmental exposure on disease
In partnership with the Wellcome Trust, we have funded the Avon Longitudinal Study of Parents and Children (ALSPAC, £6m over 3 years) to develop and expand this international resource for population genomics and life-course epidemiology, including collection of new data and biomedical samples, and recruitment of the next generation. This enhanced resource has enabled researchers to assess the impacts of environmental exposure on health, supported by a range of funders.
We have supported the European Prospective Investigation of Cancer (EPIC) Norfolk (£2m over 5 years) to identify dietary, physical activity and other determinants of health and chronic disease, and to explore the interaction of genetic predisposition with environmental factors in health in this ageing cohort.
Through renewal funding for the MRC Lifecourse Epidemiology Unit, we have supported the Southampton Women's Survey, which investigates how a woman's food intake, exercise level and housing arrangements affect her and her children’s health.
68 A key aim of UK Biobank is to better understand the environmental influences on health and disease. In 2009 we have contributed £2.2m towards a £6m investment to enhance the resource with additional measurements, including more detailed dietary information. In 2011 we invested close to £12m (total funders contribution £25m) to extend the resource for a further five years to 2015 to develop the online access facility that will allow researchers to use the resource (see use of population-based data). We are supporting the Million Women Study at Oxford University, which investigates how lifestyle factors, including diet, affect women’s health.
3. Detecting exposure and understand the impact of environmental toxins
We have renewed funding for the MRC Toxicology Unit (£35m over 5 years) thereby revitalising toxicology research. New leadership is in place with a strengthened emphasis on systems approaches to examine the effects that occur following cellular exposure to toxic insults. Amongst others this includes research on the molecular mechanisms through which asbestos causes malignant mesothelioma, which can provide valuable clues on the potential toxicity of novel materials with related structures, such as carbon nanotubes.
Nanomaterials are contained in many consumer products but there remain uncertainties about their potential risks to human health. We have refreshed our nanotoxicology highlight notice to specifically encourage research proposals investigating the health impact of nanoparticles in a whole organism context with an emphasis on addressing the mechanisms of toxicity. Since 2009 we have invested £2.7m into three research projects covering a range of nanoparticles and a further proposal has been supported with funding from the Department of Health.
MRC has also refreshed its highlight notice on improved measurement methods for population science research. This encourages biomedical and population scientists to collaborate with scientists from other backgrounds such as physical scientists and engineers to develop innovative measurement tools. Six awards have so far been made at a total level of £5m with an emphasis on dietary exposure.
The Environmental Exposure and Health Initiative (EEHI) is jointly supported by the MRC, NERC, the Department of Health and DEFRA with the aim to support innovative, interdisciplinary research addressing the relationship between environmental pollutants and human health in order to advance the development of evidence-based policies. Four large, inter-disciplinary proposals were funded through the initiative with a total investment of £7m (MRC contribution £2.5m) including research on the effect of air pollution and weather on health.
Capitalising on the legacy of the Olympics, MRC and NIHR have jointly awarded £10m (£5m each) to investigators at Imperial College and King’s College London to develop the London 2012 anti-doping facilities into a new research Centre once the games have finished. The MRC-NIHR Phenome Centre will conduct metabolic screens to investigate how factors such as diet, the environment and stress affect the development of diseases and responses to drugs. The Centre is a unique partnership between UK Universities, NIHR Biomedical Research Centres, and industry leaders and combines high-throughput analysis and forensic quality control at an unprecedented scale. It was announced by Prime Minister David Cameron in August 2012.
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4. Understanding the impact of social and ecological environments and interventions on the patterns of infectious disease
The Environmental and Social Ecology of Infectious Diseases (ESEI) initiative addresses the human health threat arising from new and emerging pathogens. As the emergence and spread of diseases depends on animal and human activity as well as the physical environment we worked together with NERC, BBSRC, and ESRC to tackle this area. Following the award of a series of small catalyst grants to bring people together we jointly invested £9m (MRC contribution £4.2m) to support three major proposals investigating an emerging strain of malaria, modelling how infections move through the urban environment, and studying how behaviour affects pathogen transmission.
Research Changes Lives objectives in progress
Plans are underway to include measures of exposure of both mother and child in the new Birth Cohort study funded to a level of £28million by the Large Facilities Capital Fund, MRC and ESRC.
In order to determine future priorities in environmental health we have convened a workshop on tackling the effect of environmental exposure on chronic disease using air pollution as an exemplar topic in February 2012. This has highlighted the opportunities to bring together the best scientists and novel technologies to improve tools for the measurement of exposure that can be used in population studies. The workshop report will be published and promoted as MRC strategy, in partnership with other funders as relevant.
Outcomes 2009-2012
Research into Policy ALSPAC ALSPAC has supported research resulting in a wide range of potential policy impacts. In 2012 results from the cohort, which celebrates its 21st birthday this year, provided evidence that low levels of vitamin D in childhood increases the risk of developing depression later in life197. In 2011 data from the cohort was used to re-assure the public that swimming in chlorinated pools did not increase the risk of asthma or allergic symptoms198. ALSPAC data was also used in a 2011 Department of Education study199 highlighting the importance of language in early educational outcomes, which influenced a new national communication scheme. European EPIC is the largest study of diet and health ever undertaken,
197 Children as young as nine at risk of depression due to vitamin D deficiency http://www.bristol.ac.uk/alspac/news/2012/42.html 198 Swimming Pool Attendance, Asthma, Allergies, and Lung Function in the Avon Longitudinal Study of Parents and Children Cohort, Font-Ribera et al. Am. J. Respir. Crit. Care Med.(2011) vol. 183 no. 5 582-588 199 Investigating the role of language in children’s early educational outcomeshttps://www.education.gov.uk/publications/eOrderingDownload/DFE-RR134.pdf
70 Prospective having recruited over half a million (520,000) people in ten Investigation on European countries. 87,000 participants have been enrolled in Cancer (EPIC) the UK and this work is led by MRC supported groups in Cambridge and Oxford, with funding also from CRUK, BHF, NIHR and the European Commission. The study has been key to confirming that a combination four dietary factors (fibre, fish, red and processed meats) plays a major role in colorectal cancer etiology, in addition to alcohol intake, obesity and low physical activity. In 2011 results from the study200 showed that as many as 1 in 10 cases of cancer in men and 1 in 33 in women may be caused by past or current alcohol intake (in 2008, in the UK, this corresponds to 13,000 out of 304,000 cases). The results also highlighted that men that drank more than two standard drinks and women that drank more than 1 standard unit a day were particularly at risk, a threshold lower than the current NHS guidelines. Peter Farmer Professor Farmer has been chairman of the Committee on (University of Mutagenicity of Chemicals in Food, Consumer Products and the Leicester) Environment for ten years. The committee provides advice to Government via the Department of Health and Food Standards Agency on the mutagenic potential of specific chemicals201. Richard Sharpe Gave evidence to the US Consumer product safety (University of commission: chronic hazard advisory panel (CHAP)202. The Edinburgh) CHAP committee reports directly to the US Government and determines regulatory policy on the use of, and human exposure to, phthalates, which are ubiquitous environmental chemicals. David Coggon Professor Coggon has been chairman of the Committee on (MRC Lifecourse Toxicity of Chemicals in Food, Consumer Products and the Epidemiology Environment since 2008. The committee provides advice to Unit, Government via the Department of Health and Food Standards Southampton) Agency on the toxicity of specific chemicals203. Di Kuh (MRC A life course perspective is evident in the government’s white Lifelong Health paper Healthy Lives, Healthy People204, which emphasises the and Ageing Unit) importance of environmental influences in pregnancy and early postpartum life. Professor Kuh contributed to the 2011 RCOG Scientific Advisory Committee Opinion Paper 27 'Why should we consider a life course approach to women's health care' which considers the rationale for a life course approach to women’s health care more broadly and the implications for health service delivery.
Products in use MRC/HPA Centre The Centre brings together leading research groups both at for Environment Imperial College and Kings College London. The
200 Alcohol attributable burden of incidence of cancer in eight European countries based on results from prospective cohort study BMJ 2011;342doi: 10.1136/bmj.d1584 201 Committee on Mutagenicity of Chemicals in Food, Consumer Products and the Environment (COM) http://www.iacom.org.uk/index.htm 202 Chronic Hazard Advisory Panel (CHAP) on Phthalates Meeting (November 2011) http://www.cpsc.gov/about/cpsia/chap1111.html 203 Committee on Toxicity of Chemicals in Food, Consumer Products and the Environment http://cot.food.gov.uk/moreinfo/ 204 Healthy lives, healthy people: our strategy for public health in England (Department of Health 2010) http://www.dh.gov.uk/prod_consum_dh/groups/dh_digitalassets/documents/digitalasset/dh_127424. pdf
71 and Health Environmental Research Group (ERG) at King's College has exploited the rapid growth in use of smartphones to better inform the public about air quality in the capital. The London Air iPhone205 “app” displays the latest air pollution levels recorded at over 100 monitoring in the London Air Quality Network. The application depends upon the support and participation of the boroughs of London and has proved popular with the public receiving 500-1000 daily hits throughout 2010. Air quality is an immediate issue for people sensitive to pollution, for example those that suffer from asthma and other respiratory conditions. Information from the London Air Quality Network assists people in limiting their exposure to peak pollution levels in the city.
Scientific Advances MRC/CSO Social The SPHSU is at the forefront of research on the social and and Public Health environmental influences on health. In 2011 staff at the Unit Sciences Unit contributed to publishing studies that highlighted the effect of (SPHSU) in smoking in movies on adolescents206, the higher suicide rate Glasgow among men in Scotland207, changes in the patterns of Caesarian sections within Scotland208, how health inequalities change with age, and the effect of neighbourhoods on health. Paul Elliott (MRC- Development of Rapid Inquiry Facility (RIF)209, a powerful tool HPA Centre for for the investigation of emerging threats to environmental Environment and health. The RIF can analyse health statistics in relation to Health) sources of environmental pollution and map diseases in areas as small as local authority wards, census output areas, or even postcode areas. Selected RIF users include: INSERM, France; British Columbia Centre for Disease Control; Geneva Cancer Registry, Switzerland;National Institute for Public Health and the Environment, NL; National Institute of Health & Welfare, Finland; Florida and Utah Departments of Health, USA. Terrie Moffit Developed coding scheme and training materials to use (MRC SDGP, Google earth to observe research participants physical Kings College) environments210 Mandy Drake Exposure to excess stress hormones in the womb combined (MRC Clinician with chemicals commonly found in the environment might Scientist Fellow, increase the chance of boys being born with reproductive University of abnormalities211. Scientists at the University of Edinburgh Edinburgh) looked at the effects of dibutyl phthalate, a chemical found in glues, paints and plastics, on fetal development in rats and
205 London Air Quality Network http://www.londonair.org.uk/LondonAir/Default.aspx 206 High youth access to movies that contain smoking in Europe compared with the USA Hanewinkel et al. (2011)Tobacco controlhttp://www.smokefreemovies- europe.eu/downloads/Tob_Control_2011_050050.pdf 207 Trends in national suicide rates for Scotland and for England & Wales, 1960–2008 Mok et al. (2012) Br J Psych Published online ahead of print, doi: 10.1192/bjp.bp.111.092908 208 The influence of both individual and area based socioeconomic status on temporal trends in Caesarean sections in Scotland 1980-2000 (2011) Fairley et al. BMC Public Health 11:330 http://www.biomedcentral.com/1471-2458/11/330 209 Environmental Epidemiology and Small Area Health Statistics - at the MRC-HPA Centre for Environment and Health (Launched June 2009) http://www1.imperial.ac.uk/publichealth/departments/ebs/projects/eresh/ 210 Development and validation of an online systematic social observation tool for use in the assessment of children’s neighbourhoods. [E-Risk] https://adaptlab.soceco.uci.edu/systematic-social- observation/ 211 Glucocorticoids amplify dibutyl phthalate-induced disruption of testosterone production and male reproductive development Endocrinology. 2009 Nov;150(11):5055-64. Epub 2009 Oct 9.
72 demonstrated increased male reproductive abnormalities. Alan Lucas (MRC Long-term follow up of a cohort of infants exposed to Childhood aluminium while being fed parenterally (via a drip) found a Nutrition link to reduced bone mass in adolescence212, which is a Research Centre, potential risk factor for developing osteoporosis and hip UCL) fracture in later life. MRC Infant intelligence is more likely to be shaped by family Epidemiology environment than by the amount of omega 3 fatty acids in Resource Centre, breast milk or fortified formula. The results were obtained Southampton from a four-year follow up of the Southampton Women’s Survey funded by a research contract with the Food Standards Agency213. Jayati Das- Living in areas where higher proportions of people of the Munshi (MRC same ethnicity live alongside each other has been found to be training fellow in protective against depression and anxiety, despite the health services tendency of these same areas to be some of the poorest214. and health of public research, Kings College London) Paul Elliott (MRC- A study215 has shown that there is no increased risk of HPA Centre for developing childhood cancer if you live near a phone Environment and mast. The study analysed 1500 cases of childhood cancers Health) from the National Cancer Registry and studied the proximity to a mobile phone mast of their home address at birth.
212 Aluminum Exposure From Parenteral Nutrition in Preterm Infants: Bone Health at 15-Year Follow- up Pediatrics Vol. 124 No. 5 November 1, 2009 pp. 1372 -1379 (doi: 10.1542/peds.2009-0783) 213 Breastfeeding, the use of docosahexaenoic acid-fortified formulas in infancy and neuropsychological function in childhood – Archives of Disease in Childhood 2010 doi: 10.1136/adc.2009.165050 214 Understanding the effect of ethnic density on mental health: multi-level investigation of survey data from England BMJ 2010;341:c5367 215 Mobile phone base stations and early childhood cancers: case-control study BMJ 2010;340:c3077
73
74 STRATEGIC AIM TWO: Research to people
Translation of research
“Embedding translation as part of MRC’s core business”
We are driving the translation of discoveries from basic laboratory and clinical science into benefits for human health. Using these insights, we are further enhancing our knowledge of the fundamental pathways in health and disease. An essential component of this bidirectional process is sustaining strong support of the basic science that underpins it.
Objective
To bring the health impacts of fundamental research to people more quickly.
Measuring up against commitments in Research Changes Lives
1 Provide access to the required technology platforms and √√√ infrastructure to achieve translational activities
2 Embed the ethos of translation in academic communities √√√
3 Use expert input from partners and stakeholders to √√√ prioritise clinical, patient, scientific and industrial research needs and match these priorities to the translational research we support 4 Exploit the emerging opportunities from enhanced genetic √√ knowledge for more sophisticated approaches to early stage trials and use patient groups categorised (stratified) according to their characteristics, imaging and biological indicators
Since 2009 £79 million has been invested in DPFS and DCS translation funding schemes. In 2011 £180 million was committed to further translational activity through the joint MRC/TSB Biomedical Catalyst
Transformational developments
We have firmly established translation as a fundamental part of our business We have revolutionised the way we work with industry by jointly shaping innovative initiatives that bring together the best clinical scientists with patient networks and industry partners to drive forward the development effective treatment strategies MRC research has impacted on NICE and international clinical guidelines for the treatment of stroke patients. It is estimated that the NHS may save £7m and 320,000 hours of nursing time a year by cutting the use of
75 stockings for approximately 80,000 stroke victims a year in the UK216 (see outcomes).
1. Provide access to the required technology platforms and infrastructure to achieve translational activities
In partnership with NIHR, the Scottish Chief Scientist Office and Welsh Assembly Government we have invested £7.25m in thirteen disease cohorts across the UK to developing faster and better ways of involving small, well-defined, groups of patients in early clinical studies of disease mechanisms. A review conducted of the remaining eleven disease cohorts in 2011 concluded that the cohort provided a valuable resource to academic and industry researchers and had stimulated significant collaborative activity.
Through the Imanova partnership, we have put in place PET imaging facilities that will support translational and clinical research and help scientists to determine disease pathways and possible targets for drugs (see tissue disease and degeneration)
To improve the way clinical trials are conducted, we have invested £16m to establish seven Hubs for Trials Methodology Research. These regional hubs perform high quality methodology research and fulfil an important advisory role helping researchers conducting clinical trials to tackle methodological problems. The hubs are linked through an overarching network, which held a national conference to showcase and discuss clinical trials methodology in 2011.
Jointly with MRC Technology we have established the MRCT Centre for Therapeutics Discovery. This expands the remit of successful MRCT Drug Discovery Group, which works with intramural scientists, to provide a national drug discovery resource that can be used by scientists across the UK to support the development of small molecule or antibody based therapy. Examples of projects that have been advanced from basic research to clinical endpoints include antibodies for potential use against multiple sclerosis and cancer, and compounds that show promise against malaria.
2. Embed the ethos of translation in academic communities
We have firmly established two managed schemes, the Developmental Pathway Funding Scheme (DPFS), which focuses on preclinical development, and the Developmental Clinical Studies (DCS), which supports early stage clinical trials. Both are goal-orientated and milestone-driven, representing a new way for the MRC to specifically stimulate translational research. In 2012 we merged the schemes into a single funding stream to accelerate the development of promising discoveries towards preclinical research and studies in patients.
Since 2009 we have invested £72m to support 97 DPFS and DCS studies (figure 4) at various stages of development from the definition of products to early clinical assessment in patients (figure 5). The studies address a range of disease areas including infections, cancer, and neurological diseases (figure 6) through the development of drugs and diagnostics, including novel treatment strategies such as gene therapy and antibody approaches (figure 7). Many DCS studies
216 Effectiveness of thigh-length graduated compression stockings to reduce the risk of deep vein thrombosis after stroke (CLOTS trial 1): a multicentre, randomised controlled trial Lancet, Volume 373, Issue 9679, Pages 1958 - 1965, 6 June 2009
76 focus on the ‘repurposing’ of existing drugs for new disease indications, which will facilitate adoption into clinical practice.
Figure 4
DPFS/DCS Awards by Year
30
25
20
15 £m
10
5
0 09-10 10-11 11-12
Figure 5
Project Start Point Awards
Last 2 Rnds 60
50
40
30 %
20
10
0 Product Refinement - Early Clinical Other Definition Non Clinical Assessment
77 Figure 6
Figure 7
Modality Awards
Last 2 Rounds
30
25
20
% 15
10
5
0
Other
Vaccine
Physical
siRNA/ASO
Peptide
Radiotherapy
Gene therapy
modification
Medical Medical device
Drug - Protein/ Drug and Nutrition
Drug - AptamerDrug
Drug - AntibodyDrug Behavioural risk
chemoprevention
Drug - Drug -- Other Drug Drug
Diagnostic - Imaging Diagnostic
Drug - SmallDrug Molecule
Regenerative Medicine
Diagnostic - Non-Imaging Diagnostic Psychological/behavioural
In 2009, we have also piloted a programme of five DPFS Devolved Portfolios, where institutions were given block grants of £2m each to fund a portfolio of therapeutic/diagnostic development projects, with individual funding decisions delegated to the host institutions. All the institutes reported that possessing a devolved portfolio had a dramatic and positive effect on enhancing the translational activity across their universities.
78 Through the Efficacy, Mechanism and Evaluation (EME) scheme, a partnership between MRC and NIHR, we are supporting the science-driven evaluation (phase 2b and 3 trials) of novel healthcare treatments and tests. The scheme provides a route for further funding following a DPFS/DCS award. Since 2009, the scheme has supported 45 studies with over £40m of funding. Particular success has been seen in cardiovascular disease, cancer, mental health, metabolic and neurological disease. A recent highlight was the award of funding for a ground-breaking trial of gene therapy for cystic fibrosis. The EME programme has recently been augmented by a “commissioned mode”, which identifies priority topics in which to invite applications. This component is funded by NIHR, further strengthening the links between the MRC and NIHR.
3. Use expert input from partners and stakeholders to prioritise clinical, patient, scientific and industrial research needs
MRC manages the joint MRC-NIHR Methodology Research Programme, which supports high quality investigator led research to improve the design and evaluation of medical and health research. In 2011 the programme has focussed attention on developing a needs-led research stream through the establishment of a new Advisory Group. This new Group will work in partnership with NICE, the MHRA and UK Health Departments to define methodology research needs that underpin the delivery of healthcare
Working in close partnership with the ABPI and companies we have shaped and launched a £9.5m initiative in inflammation and immunology and have established two disease specific consortia in COPD and Rheumatoid Arthritis (see also natural protection). The consortia bring together the best science in the clinical community, well-characterised cohort studies and industry partners in a way that has not happened before to answer critical research questions.
Working closely with industry, we have established a further consortium tackling diabetes, obesity and metabolic medicine. This investigates why patients respond or do not respond to existing medicines and links up expertise in areas such as health informatics and genetics to develop novel diagnostic biomarkers. It is also well connected with the NIHR Clinical Research Networks in diabetes.
We have launched a novel compound sharing initiative with AstraZeneca representing a new way of working with an industrial partner. 22 AstraZeneca compounds will be made available to the UK academic research community to investigate disease mechanisms and study whether these drugs can be used for previously unknown indications.
In 2011 we announced in partnership with the Technology Strategy Board, the formation of the TSB/MRC Biomedical Catalyst, a £180m programme, which will support academic and industry scientists to move their research more quickly from discovery to commercialisation. It will particularly focus on taking initial research from Universities through to small and small and medium-sized businesses (SMEs). The Biomedical Catalyst was launched by the Prime Minister and David Willets, Minister of State for Universities and Science. In July 2012 we have made the first awards contributing to this joint initiative: £7.4m “Confidence in Concept” funding has been awarded to 14 UK Universities to support around 150 pilot projects targeted at the development of earliest stages of new therapeutic concepts. In a co-ordinated initiative the TSB has awarded close to £2.5m to 18 SMEs to carry out feasibility studies and explore the commercial potential of new scientific developments.
79
UK researchers and UK companies have been highly successful in attracting funding through the Innovative Medicines Initiative (IMI)217. Of the 30 IMI projects supported in the first 3 calls UK academic groups are involved in 28, and UK Small and Medium Enterprises (SMEs) are involved in 9 (see also partnerships shaping the agenda).
4. Exploit the emerging opportunities from enhanced genetic knowledge for more sophisticated approaches to early trials and use patient groups stratified according to their characteristics, imaging and biological indicators
Following a workshop and consultation with leading scientists, clinicians, and industry researchers we have launched a Stratified Medicine call for proposals in January 2012. The call will establish research consortia in disease areas where stratification – the identification of patient subgroups with different characteristics – is not yet well developed and has the potential of delivering real health benefits in the short term. These include being able to deliver the right drugs to the right patients at the right time thereby increasing positive outcomes, reducing side- effects, and ensuring the most effective use of NHS resources.
We have also worked closely with the TSB to develop the TSB Stratified Medicine Innovation Platform and subsequent calls. Jointly with the TSB we have invested £3.7m to support seven company-led research projects developing biomarkers for inflammatory disease.
To increase mechanistic insights into disease processes that can be applied to the development of new therapies, we have launched a new funding scheme in Experimental Challenge Grants. This will support innovative research proposals that are focussed on humans and address a clearly described and substantial gap in knowledge, which will often require collaborations across disciplines and institutions and the use of novel approaches such as imaging, and computation.
In progress
We will enhance our translational investments through support of experimental medicine challenge studies We will align our managed schemes with the TSB/MRC Biomedical Catalyst We will support collaborative studies with AstraZeneca and explore similar compound sharing collaborations with other companies We will strengthen our portfolio in stratified medicine research and establish consortia in a range of disease areas We will increase our investment in needs-led methodology research influenced by policy makers
217 The Innovative Medicines Initiative: A European Response to the Innovation Challenge Clinical Pharmacology & Therapeutics 91, 418-425 (2012) doi:10.1038/clpt.2011.321
80 Outcomes 2009-2012
Stage of development for products and interventions reported via MRC e- Val by the end of 2011 (518 reports)
“Valley of Death”
74 new products and interventions were reported as launched onto the market since 2006 (47 since 2009), with a further 13 currently undergoing the process of market authorisation.
125 reports of products in early or late stage clinical evaluation, and 257 reports of products in initial or refinement stages. These projects in early developmental stages have been significantly added to with the inclusion of Developmental Pathway Funding Scheme (DPFS) projects in 2011.
There is particular interest in developments that face the “valley of death” which commonly refers to difficulty in obtaining commercial partners to take products into late stage clinical evaluation and beyond (potentially between 125 - 234 projects in the figure above). Assistance to translate discoveries such as these is available under the Biomedical Catalyst Fund218 which aligns existing MRC translational research schemes with new funding for the Technology Strategy Board.
Products/interventions in use Wendy Atkin In 2010 trials were completed that demonstrated that bowel (Imperial College cancer can be prevented with a simple, once-in-a-lifetime, London) five-minute screening test. In October 2010 the Government announced £60m funding to incorporate the “flexi-scope” test into the National Screening Programme, and subject to approval by the UK National Screening Committee expects that a four-year roll out of the test will begin in early 2011219. Benlysta® Combinatorial library/phage display technology, discovered
218 £180 million government support programme for innovative life science businesses http://www.mrc.ac.uk/Newspublications/News/MRC008394 219 Flexible sigmoidoscopy to be introduced into the NHS Bowel Cancer Screening Programme http://www.cancerscreening.nhs.uk/bowel/news/006.html
81 (Belimumab) by researchers at the MRC Laboratory of Molecular Biology GlaxoSmithKline was used by Cambridge Antibody Technology and Human Genome Sciences to develop Benlysta® (Belimumab) a monoclonal antibody directed against BLyS. Clinical development of Benlysta® as a drug for autoimmune disease was taken forward in collaboration with GSK, and phase III trials successfully completed in 2010. The treatment received FDA approval in February 2011220, and was recommended for EU approval in May 2011221. Adnan Custovic and Research at the University Hospital of South Manchester Angela Simpson NHS Foundation Trusthas shown that the IgE response to (The University of peanut allergen Ara h 2 is much more predictive of clinical Manchester) peanut allergy than currently used skin or blood tests based on whole peanut extract222,223. The test has been developed by Phadia (now Thermo Scientific) and made available in clinical practice since 2010.
Commercialisation Heptares From being set up in 2009, Heptares224 has struck Therapeutics Ltd. agreements with Novartis, Takeda, Shire and AstraZeneca (MRC spin out for work potentially worth approx. £450m, and already met company) some early milestones. There is huge interest in designing drugs which act upon G protein coupled receptors (GPCRs), but until now these GPCRs have been impossible to study at the molecular level. Heptares is commercialising a transformational technology proven to address this problem. The company combines expertise from MRC LMB and NIMR on protein structure, with pharmacology of GPCRs, and now employs around 50 staff. Summit Plc. Summit’s programme in Duchenne Muscular Dystrophy (Oxford University (DMD)225 therapy is based on the work of Professor Kay spin out) Davies (honorary Director of the MRC Functional Genomics Unit) who has been funded by MRC for more than 20 years. In December 2011 Summit announced that it had obtained funding for a phase I study in DMD patients from a consortium of DMD charities. Phagenesis Ltd. Phagenesis226 is based on the MRC funded work of (University of Dr Shaheen Hamdy, a medical device company focussing on Manchester spin the development of technology for the assessment, out) treatment and management of dysphagia (swallowing problems) post stroke. In 2011 the company announced having closed a 7m euro series B funding round.
220 GSK and HGS announce FDA approval for Benlystahttp://www.hgsi.com/latest/human-genome- sciences-and-glaxosmithkline-announce-fda-approval-of-benlysta-belimumab-for-treatment-of- systemic-lupus-erythema.html 221 GSK and HGS announce positive opinion in Europe from the CHMP for Benlystahttp://www.hgsi.com/latest/glaxosmithkline-and-human-genome-sciences-receive-positive- opinion-in-europe-from-the-chmp-for-benlysta-belim.html 222 Allergy or tolerance in children sensitized to peanut: prevalence and differentiation using component resolved diagnostics. J Allergy ClinImmunol(2010); 125 (1): 191-7.el-133. 223 Allergen-specific IgG antibody levels modify the relationship between allergen-specific IgE and wheezing in childhood. J Allergy ClinImmunol (2011) 127(6):1480-5. 224 Heptares therapeutics Ltd. www.heptares.com/ 225 Summit Plc. DMD research programme http://www.summitplc.com/DMD-utrophin- upregulation.aspx 226 Phagenesis Ltd. http://www.phagenesis.com
82 James Sharpe Optical projection tomography (OPT) is a relatively new (formerly of the imaging technique, developed by the MRC, in 2002227. The MRC Human aim of OPT is to accurately image the development of 3D Genetics Unit) structures. It works by projecting light through a whole specimen. Since 2005 MRC Technology has provided 39 OPT microscope systems and training courses to laboratories around the world generating income of £2.6million228. The system has also been a feature at the EMBO Practical Course on 3D Developmental Imaging in 2009 and 2010, and in 2011 two out of 21 winners in the Wellcome Trust image awards229 were taken using OPT. In 2012 the technique was applied to studying the growth of breast cancer cell cultures230. MRC Human In 2012 AquaPHarm, the Scottish biotechnology firm, Nutrition Research announced a collaboration with the MRC HNU231 to evaluate Unit (HNU), the potential of a new approach to digestive health. Called Cambridge EndoSeaRch, the collaboration represents the first in-vivo application for a patented Aquapharm technology. Aquapharm is already developing a number of marine extracts as novel ingredients for food and skin-care products, and evaluating compounds derived from them as novel drugs. It is now applying its expertise to intestinal bacteria. The UK Abcodia Ltd.232 was established as the means by which Collaborative Trial diagnostic, pharmaceutical and technology companies as of Ovarian Cancer well as academic groups can access serum samples Screening collected in UKCTOCS (funded by the MRC) for the purpose (UKCTOCS) of ethical biomarker validation and discovery. In 2011 Abcodia and Oxford Gene Technology (OGT) begin collaborative work to improve the early detection of pancreatic cancer. In 2012 Abcodia announces a second collaboration with VolitionRX to discover blood based biomarkers for cancer. Edmund Kunji(MRC Dr Kunji discovered a way to shield measuring devices, such Mitochondrial as optical probes, from the interference of air bubbles. The Biology Unit) device is useful for monitoring fermentation processes. Further development of the device is being taken forward by a new company Cytoprom Ltd.233 Platelet Solutions Platelet Solutions Ltd.234 aims to use novel technology to Ltd. (University of measure platelet function simply and accurately in any Nottingham) clinical setting. In 2011 the company won the Start Up Award in Medilink East Midlands Business Competition, and the award of an MRC DPFS grant leads to formal incorporation.
227 Optical Projection Tomography - a better way to view tissues and genes http://www.mrc.ac.uk/Achievementsimpact/Storiesofimpact/OpticalProjectionTomography/index.htm 228 http://www.bioptonics.com/Home.htm 229 http://www.wellcomeimageawards.org 230 Determining tamoxifen sensitivity using primary breast cancer tissue in collagen-based three- dimensional cultureBiomaterials Volume 33, Issue 3, January 2012, Pages 907–915 231 Aquapharm & Medical Research Council evaluate EndoSeaRch™- a new approach to digestive health (May 2012) http://www.aquapharm.co.uk/biotechnology-news/aquapharm-medical-research- council-evaluate-endosearch%E2%84%A2-a-new-approach-to-digestive-health.aspx 232 http://www.abcodia.com/ 233 http://cytoprom.com/about-us/ 234 http://www.plateletsolutions.co.uk/
83 Research into policy Martin Dennis MRC research at Edinburgh University published in 2009 has (University of had significant impact on NICE and international clinical Edinburgh) guidelines for the treatment of stroke patients. It is estimated that the NHS may save £7m and 320,000 hours of nursing time a year by cutting the use of stockings for approximately 80,000 stroke victims a year in the UK235.
Products and interventions in development MRC Protein The largest UK academic/private sector collaboration, the Phosphorylation Division of Signal Transduction Therapy (DSTT) was Unit, Dundee renewed in 2012, bringing the total amount invested in DSTT since 1998 to £50m. The DSTT is funded by six of the world’s largest pharmaceutical companies236 and focusses on speeding up the development of drugs aimed at treating major diseases, including cancer, hypertension and lupus, by targeting proteins in the body’s ubiquitin system and types of enzymes called kinases. The new funding secures 50 posts in Dundee. Rebecca Fitzgerald Invention of an innovative new test – the cytosponge237, (MRC Cancer Cell which is essentially a sponge on a string- to diagnose the Unit) precursor of oesophageal cancer, catching it early and saving lives. A large multi-centre clinical trial partly funded by CRUK is now underway to investigate the findings238. Early clinical work was supported by MRC Technology via a development gap fund award. Graham Jackson MRC researchers have completed initial development for the (MRC Prion Unit) world’s first blood test for variant Creutzfeldt-Jakob disease (vCJD)239. Being able to detect the infectious agent via such a test is both vital to the epidemiological study of this disease, and to develop therapies. The test is currently in the early stages of clinical evaluation and has so far been used in the clinical care of around 30 patients. David Beeson A small study testing ephedrine as a treatment for DOK7 (University of congenital myasthenic syndrome, showed a dramatic Oxford) improvement in disability scores240. Some patients who were in wheel chairs were able to run and jump. Ephedrine and salbutamol (which acts in a similar way) are now therapies of choice for DOK7 CMS. This has led to further work to improve the management of this condition and better understand the disease mechanism. Angus Silver Development of a new type of optical element that can
235 Effectiveness of thigh-length graduated compression stockings to reduce the risk of deep vein thrombosis after stroke (CLOTS trial 1): a multicentre, randomised controlled trial Lancet, Volume 373, Issue 9679, Pages 1958 - 1965, 6 June 2009 236 The DSTT secures a further £14.4m from AstraZeneca, GlaxoSmithKline, Boehringer Ingelheim, Janssen Pharmaceutica, Merck-Serono and Pfizer (Scotsman 2012) http://www.scotsman.com/business/industry/pledges-to-drugs-discovery-centre-take-investment-to- 50m-level-1-2292598 . 237 Acceptability and accuracy of a non-endoscopic screening test for Barrett’s oesophagus in primary care: cohort study BMJ (2010);341:c4372 238 Barrett’s oEsophagus Screening Trial 2 (BEST2) http://www.mrc- ccu.cam.ac.uk/Our_Research/Rebecca_Fitzgerald/clinical_studies.html#BEST2 239 Detection of prion infection in variant Creutzfeldt-Jakob disease: a blood-based assay The Lancet, (2011) Volume 377, Issue 9764, Pages 487 - 493, doi:10.1016/S0140-6736(10)62308-2 240 Lashley D, et al. Ephedrine treatment in congenital myasthenic syndrome due to mutations in DOK7. Neurology. 2010 May 11;74(19):1517-23.
84 (University College focus and steer a laser beam high speed for use with 2- London) photon microscopy. This 3D imaging technology241 is well suited for measuring distributed neuronal signalling. It also has potential applications outside neuroscience and cell biology, including high capacity data storage, 3D lithography, laser tweezers and cold atom traps for quantum physics experiments. David Pritchard An enzyme from the greenbottle fly may improve the (Nottingham management of leg ulcers242. A prototype formulation University) outperforms the current treatment for removing necrotic tissue, and researchers are now scaling-up for clinical evaluation. This work is supported by an MRC DPFS Portfolio Award, and builds on previous support from Wellcome Trust, DSTL, EPSRC and TSB. David Rubinsztein In 2009 MRC-funded researchers discovered243 that an anti- (University of hypertensive drug, Rilmenidine, attenuates the severity and Cambridge) delays onset of disease in a mouse model of Huntington’s disease. This followed a search for drugs that can stimulate cellular processes to remove mutant huntingtin protein. A safety trial of the drug is planned in Huntington's disease patients. Aleksandra Development of equipment to give feedback on brain Vuckovic activity to spinal cord injury patients with neuropathic (University of pain244. This helps the patients to learn how to modulate it Glasgow) at will and results in an instantaneous decrease of pain. The equipment was developed with support from an MRC Discipline Hopping award, and the team has recently completed an MRC-supported clinical assessment of the approach in 30 patients. Pamela Ewan The definitive trial for a new treatment for peanut allergy (University of was initiated in 2010. Peanut allergy is the commonest Cambridge) cause of fatal food-allergic reactions, population studies show it affects 2% of children, meaning tens of thousands of UK children are at risk. The pilot study245 cured all 18 participants of their allergy and received significant media coverage. Peter White (Queen The largest trial246 of the effectiveness of therapies for Mary University chronic fatigue syndrome (CFS) found that cognitive London) behaviour therapy and graded exercise therapy are moderately effective outpatient treatments for CFS, when added to specialist medical care, as compared with adaptive pacing therapy or specialist medical care alone. CFS is estimated to affect 250,000 people in the UK.
241 A compact Acousto-Optic Lens for 2D and 3D femtosecond based 2-photon microscopy Opt Express. 2010 Jun 21;18(13):13721-45. doi: 10.1364/OE.18.013720. 242 Expression of a cGMP compatible Lucilia sericata insect serine proteinase debridement enzyme BiotechnolProg. (2012) Mar;28(2):567-72. doi: 10.1002/btpr.1516 243 Rilmenidine attenuates toxicity of polyglutamine expansions in a mouse model of Huntington's disease Hum Mol Genet. (2010); 19(11): 2144–2153. doi: 10.1093/hmg/ddq093 244 http://www.gla.ac.uk/research/researchfeatures/headline_228948_en.html 245 Efficacy and safety of high-dose peanut oral immunotherapy with factors predicting outcome (2011) Clinical & Experimental Allergy, 41: 1273–1281.doi: 10.1111/j.1365-2222.2011.03699.x 246 Comparison of adaptive pacing therapy, cognitive behaviour therapy, graded exercise therapy, and specialist medical care for chronic fatigue syndrome (PACE): a randomised trial (2011) Lancet, Volume 377, Issue 9768, Pages 823 - 836, 5 doi:10.1016/S0140-6736(11)60096-2
85 Martin Brown The International Carotid Stenting Study (ICSS)247 (University College concluded that carotid endarterectomy (CEA) is safer than London) carotid artery stenting (CAS) as a treatment for carotid blockages that can lead to stroke. The choice between surgical (CEA) and stenting (CAS) approaches is controversial and complex, and the initial findings of this trial have stimulated significant debate on the issue. The MRC has funded an extension to the study to continue follow up to collect a median of 5 years of data on all patients recruited to the ICSS. Joanna Wardlaw Stroke victims given a clot-busting drug within 6 hours of (University of the attack, recover better than those without the Edinburgh) treatment248. In the world’s largest trial of the approach (IST-3), more than 3,000 patients who had acute ischaemic stroke were given rt-PA intravenously. The trial found stroke survivors had better longer-term recovery with many more subsequently able to live independently. rt-PA confers a greater risk of death within seven days of treatment because the drug can cause a secondary bleed in the brain, but six months post stroke survival rates were similar in the treatment and control groups. The findings have been widely reported in the media249. David Lomas Research supported through programme grant funding has Cambridge resulted in a Discovery Partnerships with Academia (DPAc) agreement with GlaxoSmithKline to develop small molecules for antitrypsin deficiency.
247 Carotid artery stenting compared with endarterectomy in patients with symptomatic carotid stenosis (International Carotid Stenting Study): an interim analysis of a randomised controlled trial. Lancet. (2010);375(9719):985-97. Epub 2010 Feb 25. 248 The benefits and harms of intravenous thrombolysis with recombinant tissue plasminogen activator within 6 h of acute ischaemic stroke (the third international stroke trial [IST-3]): a randomised controlled trial Lancet, (2012) doi:10.1016/S0140-6736(12)60768-5 249 World's biggest stroke clot-buster trial reveals patient benefits (University of Edinburgh news) http://www.edinburghneuroscience.ed.ac.uk/edneuronews.html
86
Regulation, ethics, governance and working with decision- makers
“Benefitting research whilst maintaining highest ethical and practice standards”
The MRC is recognised by regulatory authorities as a key stakeholder and plays an important role in influencing UK and European policy-makers.
Objective
To uphold and guide ethical research practice and the highest standards of research governance; to enhance the regulatory process by providing innovative approaches.
Measuring up progress against commitments in Research Changes Lives
1 Engage with policy groups considering uses of health and √√√ Human Fertilisation and Embryology Authority data in research 2 Develop new guidance for stem cell researchers, in the light √√√ of the new Human Fertilisation and Embryology Bill, the review of the role of the Global Forum on Bioethics in Research and developments in international discussions in the area 3 Take a leading role in the development of policy and √√√ regulatory framework on the use of the electronic healthcare records in research 4 Work with other stakeholders to ensure that European √√√ legislation concerning the use of animals in research maintains appropriate standards of animal welfare, and balances the need for appropriate regulation with the resources needed for world class research 5 Continue to work with the Human Tissue Authority and √√√ other regulators with the aim that processes and guidance for researchers are as simple and efficient as possible 6 Continue to work through RCUK and other partners to √√√ develop policies and appropriate governance arrangements that foster UK research and maintain its integrity 7 Through RCUK, work with Universities UK and others to √√√ establish a common approach to good research conduct across the UK
Transformational developments MRC’s comprehensive input into the Academy of Medical Sciences review of the regulation and governance of health research has contributed to the establishment of a new Special Health Authority, the Health Research Authority, to streamline regulation and improving the cost effectiveness of clinical trials250
250 http://www.acmedsci.ac.uk/p47prid88.html
87
1. Engage with policy groups considering uses of health and Human Fertilisation and Embryology Authority data in research
We improved access to data held by the Human Fertilisation and Embryology Authority (HFEA) through discussions between the HFEA, Academy of Medical Sciences, researchers, and the Wellcome Trust. The data will facilitate the long-term follow up of women who have received IVF treatment to investigate potential health impacts for them, their partners and any children born following IVF and related procedures. We will continue to review this area following potential changes to arrangements for governance of these data.
2. Develop new guidance for stem cell researchers
To support the stem cell research community in developing safe and effective treatments, the MRC in partnership with the Department of Health has launched a web based ‘toolkit’ providing an interactive route map through the UK regulatory processes251 (see also Repair and Regeneration). The toolkit has been accessed by more than 13,000 users since 2009.
We have responded to the 2011 ruling of the European Court of Justice banning the patenting of interventions involving human embryonic stem cells (hESCs) by briefing Ministers and publishing opinion pieces. The aim was to reassure academic researchers and industry that the ruling will not affect MRC’s investment strategy in hESC research or the current UK regulatory framework and is unlikely to affect current private sector investment in trials.
The China-UK Research Ethics Committee, established by the MRC, has produced ethical guidance and a checklist for UK researchers wishing to conduct collaborative stem cell research with scientists in China.
3. Take a leading role in the development of policy and regulatory framework on the use of the electronic healthcare records in research
MRC has worked with the Wellcome Trust to provide input to the Ministry of Justice on the implications for research of the draft EU Regulation setting out a new general EU framework for data protection, which will replace the 1995 Data Protection Directive.
The MRC Regulatory Support Centre (RSC) has developed and launched a new e- learning module on Research Data and Confidentiality, focusing on the use of healthcare records in research.
In partnership with 9 other funding partners, MRC is leading the establishment of 4 Centres of Excellence, across the UK utilising and linking electronic health data for health research (see Use of Population-based Data). These Centres will build capacity and capability in utilising electronic health records and will address policy, ethical and regulatory issues relating to the use of such data for research. The centres will be working closely with the general public to engender support for the research proposed and to ensure that any concerns about the use of the data are appropriately addressed.
251 UK Stem Cell Toolkit http://www.sc-toolkit.ac.uk/home.cfm
88 MRC is participating in the Administrative Data Taskforce to review use for research of related administrative data across government.
4. Work with other stakeholders to ensure that European legislation concerning the use of animals balances the need for appropriate regulation with the resources needed for world class research
We have engaged with the Home Office directly and through the UK Bioscience Sector Coalition (which includes representatives from industry, academia, science funders and breeders) to influence the transposition into UK law of the EU Directive 2010/63/EU on the protection of animals used for scientific purposes. The Directive came into force in November 2010 and needs to be transposed into law by member states by November 2012. MRC’s activities ensure that the views of our scientific community are taken into consideration so that researchers can continue to conduct leading science and unnecessary bureaucracy can be reduced whilst maintaining the highest animal welfare standards.
In July 2011, the MRC, BBSRC, NC3Rs and the Wellcome Trust published a joint review of research using non-human primates. The Panel, chaired by Sir Patrick Bateson, reviewed the quality, outcomes and impact of research supported by the four funders and concluded that the research was generally of high quality, but there was a need to improve the speed of translation of research findings into scientific, medical or social benefits. The Panel acknowledged that the funders’ review mechanisms for research using primates had improved in the last decade, and made 15 recommendations for further improvements. We are now working with BBSRC, NC3Rs and the Wellcome Trust to implement these.
5. Continue to work with the Human Tissue Authority and other regulators with the aim that processes and guidance for researchers are as simple and efficient as possible
We have been working with the Department of Health, Government, the Academy of Medical Sciences and regulatory agencies to develop an optimal framework for funding, storing and using of tissues for research. On behalf of the UKCRC Experimental Medicine Funders Group, we have jointly with the National Cancer Research Institute produced a report outlining the vision for access to human tissue resources and the actions required to achieve this. The aim is to make human tissue, which is necessary to progress many research areas, more discoverable, accessible and usable by researchers within a robust ethical framework that respects the wishes of donors. MRC (through the MRC Regulatory Support Centre) and UKCRC partners are now working with STRATUM group, an AstraZeneca led group funded by the Technology Strategy Board, to deliver the vision for access to human tissue resources.
Two staff members of the MRC Regulatory Support Centre have been seconded part time to the Health Research Authority (HRA) and are working with HRA team on harmonising training and guidance relating to the regulatory environment to facilitate improved communications and to ensure better support for scientists through regulatory requirements.
6. Continue to work through RCUK and other partners to develop policies and appropriate governance arrangements that foster UK research and maintain its integrity, and
89 7. Through RCUK, work with Universities UK and others to establish a common approach to good research conduct across the UK
Together with the other Research Councils, Universities UK, and the Higher Education Funding Councils we have developed a new Research Integrity Concordat, which was published in summer 2012252.
We have also reviewed MRC guidance on good research conduct, and developed a new version published in summer 2012253.
We have worked with other Research Councils to develop a common approach to the open access model of publishing and have published a harmonised RCUK policy in July 2012254. There will be a continued requirement for all MRC funded research to be published in the open access repository UK PubMed Central within six months of publication in a journal.
Research Changes Lives objectives in progress
In the light of the Animal Research: Reporting of In Vivo Experiments (ARRIVE) guidelines recently published by the National Centre for the Replacement, Refinement and Reduction of Animals in Research (NC3Rs) we will review our guidance for applicants and reviewers to encourage the highest standards of experimental design and reporting of animal experiments
We will work with the STRATUM group to take forward the actions for improving access to human tissue resources, including the scoping of a web-based directory, mapping standards for collections, and collecting public views on consent
We will work with policy makers and funders to consider the clinical opportunities and influence regulatory requirements associated with mitochondrial donation
Outcomes 2009-2012
MRC Hubs for MRC researchers led discussions to outline a more flexible, Trials Methodology risk-based approach to clinical trials. The MRC HTMR Research (HTMR) Network collaborated with University of Oxford, Duke University, and The Public Health Research Institute to sponsor an international meeting on the issue in September 2009255. Peter Croft The former Arthritis Research Campaign was heavily (Keele University) orientated towards describing its mission in terms of specific rheumatic diseases. Consultation with researchers, including MRC funded groups, during their re-launch emphasised the importance of assessment of pain and disability as the core feature of musculoskeletal conditions.
252 http://www.universitiesuk.ac.uk/Publications/Pages/concordattosupportresearchintegrity.aspx 253 http://www.mrc.ac.uk/Ourresearch/Ethicsresearchguidance/Researchpractice/principles_guidelines/in dex.htm 254 www.rcuk.ac.uk/media/news/2012news/Pages/120716.aspx 255 Senior UK researchers campaign for sensible guidelines on regulating trials BMJ (2009);339doi: 10.1136/bmj.b3671
90 This has been directly incorporated into the key frontline messages of the re-launched Arthritis Research UK, the leading Charity for musculoskeletal conditions in the UK in terms of research, education and policy influence256. Max Parmar (MRC Arthritis Research UK approached the HTMR Network257 for Hubs for Trial guidance on evaluating biologic therapies. The economic Methodology models for these treatment comparisons are complex; Research, HTMR) direct, head-to-head comparisons in randomised trials are lacking; and the results from modelling can depend highly on the model used. Outputs of the subsequent workshop included a supplementary edition of the journal of Rheumatology258, and formation of a clinical studies group (including clinicians, NICE, and modellers). The process through which consensus was achieved will be documented, along with insights for the successful development of preferred decision models in other disease areas. Max Parmar (MRC The Methodology Advisory Service for Trials (MAST259) was Hubs for Trial launched to provide a main point of entry to access Methodology methodological advice from the HTMR Network. This service Research, HTMR) has been offered to clinical trials units, Research Design Services and trial funders such as ARUK, CRUK, and The Wellcome Trust. In addition, the eight Hubs have individually advised on many methodological queries and work is on-going to collate these queries into the central MAST database.
256 In 2010 Arthritis Research UK launched 10 goals. Goal 3 is to “ensure that people remain active and free from pain” http://www.arthritisresearchuk.org/about-us/our-goals/goal-3.aspx 257 Biologic Therapies in Inflammatory Joint Diseases: Models for Decision Makinghttp://www.methodologyhubs.mrc.ac.uk/news__events/workshop_summaries/biologic_therapi es.aspx 258 Biologic therapies in inflammatory joint diseases: models, evidence and decision making Rheumatology Volume 50 suppl 4 September 2011http://rheumatology.oxfordjournals.org/content/50/suppl_4.toc 259 http://www.methodologyhubs.mrc.ac.uk/methodology_advisory_service.aspx
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92 Communication
“Effective communication with key stakeholders and the public”
The MRC is funded by the UK taxpayer. We recognise our responsibility to inform and involve the public, policymakers and our partners about our work. Through our initiatives, many of which involve MRC-funded scientists, we develop effective relationships with a range of audiences.
Objective
To enhance communication with scientists, the public, policy-makers and partners.
Measuring up progress against commitments in research Changes Lives
1 Help the public understand our scientific findings by √√√ improving access to our scientists and research findings through more face-to-face interaction 2 Provide better information online and in the media √√
3 Continue to inform debate and help shape policy through √√√ the timely provision of accurate, up-to-date information on policy-relevant topics 4 Encourage our scientists to nurture relationships and share √√√ information with policymakers and parliamentarians, to guide policy and the regulation of research 5 Continue to stress the importance of animal models in √√√ certain areas of research 6 Embed a culture of public dialogue and stakeholder √√ engagement in our organisation by providing communication training as an integral part of the skills development programme for our scientists 7 Build a community of MRC ambassadors, drawn principally √√ from our own scientists, boards and Council members, to take an active role in disseminating MRC information
MRC media coverage in the national media (broadcast and print) and online has increased, from 248 articles and features in 2009 to 2,496 in 2011. Since 2009, evidence and information was provided to parliamentarians and policymakers on 58 separate occasions. MRC’s success in the commercialisation of products and interventions was highlighted by the Chancellor of Exchequer’s speech to open the Imperial Centre for Translational and Experimental Medicine in May 2012260.
260 http://www.hm-treasury.gov.uk/speech_chx_280512.htm
93 Transformational developments
67,000 members of the public signed up to take part in the BBC Lab UK Brain Test Britain experiment using online games licensed from MRC research. 11,430 completed the initial six-week brain training period, making this the largest ever study of computer-based training (see outcomes).
1. Help the public understand our scientific findings by improving access to our scientists and research findings through more face-to-face interaction
MRC regional communication managers support MRC-funded scientists to help them engage with non-specialist audiences. In 2009 and 2010 MRC e-Val recorded 4,270 separate engagement activities by MRC scientists.
We have taken events which showcase MRC science to all of the major UK science festivals where our scientists, in particular PhD students and post-docs, explain their science and its impact on health and society to a varied audience of school students and families.
To help ensure good quality public engagement, we have provided public engagement training for our researchers before they take part in public-facing events.
2. Provide better information online and in the media
Through the efforts of our press office, our media coverage in the national media (broadcast and print) and online has increased, from 248 articles and features in 2009 to 2,496 in 2011.
We have recruited and supported a broad range of MRC scientists as media spokespeople, either on specialist areas of science or on strategy. We have provided media training for all our spokespeople.
3. Continue to inform debate and help shape policy through the timely provision of accurate, up-to-date information on policy-relevant topics
Through our involvement in the All-Party Parliamentary Group on medical research, we have engaged parliamentarians and research bodies through a programme of briefings and discussion events on topics including the use of animals in research and how data saves lives: the power of information.
To help ensure that the transposition of the EU Animals Directive into UK law is supportive of the UK research base, we have worked as part of the UK BioScience Coalition to ensure that MPs have the information they need to make a informed decision. A programme of visits by MPs to MRC units is underway, and is expected to continue throughout 2012 and into 2013.
The MRC led the response from the UK research community following an European Court of Justice ruling on the patenting of stem cells. This helped parliamentarians understand the issues and the possible impact of the ruling on
94 regenerative medicine research. It also helped reassure researchers that the MRC remains committed to funding research in this area.
4. Encourage our scientists to nurture relationships and share information with policymakers and parliamentarians, to guide policy and the regulation of research
The MRC frequently submits evidence relating to biomedical research to inquiries and consultations by government departments, Select Committees of the House of Commons and the House of Lords, and to other organisations. Since 2009, we have provided evidence and information to parliamentarians and policymakers on 58 separate occasions.
We jointly led (with the Wellcome Trust) a media plan to ensure that the publication of the Bateson Report on the use of primates in research did not damage public confidence in and support for the use of animals in research. The subsequent media coverage was mostly supportive or neutral of the use of primates.
5. Continue to stress the importance of animal models in certain areas of research
We have representation on the communication advisory group of Understanding Animal Research, through which we support efforts to normalise the use of animals in research.
Wherever possible, we include reference to the animal models used in research in our press releases and news articles.
6. Embed a culture of public dialogue and stakeholder engagement in our organisation by providing communication training as an integral part of the skills development programme for our scientists
We have provided media training to 40 strategic and scientific spokespeople.
We have provided media training and coaching to 42 researchers ahead of publication of research which is being promoted through the media or may attract media interest.
We have provided science communication and public engagement training to 233 MRC scientists and others preparing to take part in events for the public, for example activities at science festivals.
We have piloted a writing training course, for scientists who wish to write for public audiences, and we are now rolling this out across the MRC. To date, 136 people have been trained.
We have also encouraged stakeholder engagement in research programmes. For instance we have sought input from public reviewers for the assessment of public engagement programmes and plans for public participation in research programmes funded through the MRC-led Lifelong Health and Wellbeing (LLHW) and e-health informatics research centre call for proposals (see Life course Perspective and Use of Population-based Data). The design and management of the rehabilitation project and subsequent clinical trials conducted by the LLHW
95 ENVISAGE consortium in Strathclyde have been influenced by users including patients and therapy professionals.
7. Build a community of MRC ambassadors, drawn principally from our own scientists, boards and Council members, to take an active role in disseminating MRC information
Since early 2010, the MRC press office has recruited the chairs of MRC funding boards to become spokespeople for the MRC in their area of science. Research Changes Lives objectives in progress
A new content management system for the MRC corporate website is currently being sourced (as part of a research council-wide project) which will support audio and video content, which will make the website more attractive and accessible to an interested lay audience as a source of information on medical research and its outcomes.
Outcomes 2009-2012
Dissemination activities captured via MRC e-Val
Researchers reported activities in which they talked about research to audiences other than their academic peers. This included groups of policymakers or parliamentarians, the public, media (as a channel to the public) etc. MRC e-Val captured details of almost 13,000 instances of this work between 2006 and 2011, reported by 1800 researchers.
Examples of these activities include:
Adrian Owen BBC Lab UK261 launched in September 2009 with the Brain (formerly MRC Test Britain experiment, which aimed to answer the question: Cognition and does brain training actually work? Of the 67,000 people who Brain Sciences signed up to take part in Brain Test Britain, 11,430 Unit, Cambridge) completed the initial six-week brain training period, making
261 What is BBC Lab UK? http://www.bbc.co.uk/labuk/articles/
96 this by far the largest ever study of computer-based brain training. The results were published in Nature262.The online games were licensed from work at the MRC Cognition and Brain Sciences Unit that had been supported by a MRC Technology development gap fund award. Brad Amos (MRC The Mesolens is the only microscope of its kind in the world Laboratory of that can show three-dimensional images within cells and Molecular Biology, tissues at the same time as showing the whole organism. The Cambridge) microscope can produce results in seconds rather than hours, potentially speeding up the process of drug development. It is being developed at the University of Strathclyde based on the work of Dr Amos at the MRC LMB263. In 2010 The Mesolens prototype was exhibited at the Royal Society achieving significant media coverage, and in 2012 the Mesolens was the subject of the Leewenhoek Lecture, a prestigious triennial public engagement lecture. Terrie Moffitt TV program featuring Dunedin cohort and E-Risk study on (MRC Social the American Public Broadcasting System news hour 3rd June Genetic and 2011. It included footage from the Real Science of Us (a Developmental forthcoming TVNZ documentary on the Dunedin Study). Psychiatry Centre, Coverage of results on self-control research was in the Kings College economic and finance news section of the program, not the London) medical news section. The program shows how Dunedin and E-risk findings on childhood self-control and adult financial health have now been taken up by Sesame Street to teach children about sound financial planning and policy264. Susan Jebb (MRC Filmed in regards to the use of supplements and dietary Human Nutrition sufficiency. Aired on BBC's The One Show to an audience of Research Group, 4.85million. Cambridge) Julie Williams In 2011 MRC funded researchers announced five new genes (MRC Centre for with a role in Alzheimer’s disease, bringing the total number Neuropsychiatric of genes known to increase the risk of developing the disease Genetics and to ten. The discovery was widely reported in all national Genomics, newspapers and by the BBC265. University of Cardiff) Ian Deary The Centre's Deary-Liewald Reaction time task and (MRC/University Interactive 3D brain were exhibited at “Measuring the Brain”, of Edinburgh part of the Edinburgh International Science Festival's Medical Centre for Detectives theme. The 3D brain is an interactive exhibit of Cognitive Ageing the brain, allowing people to view and manoeuvre MRI scans and Cognitive of young and old brains in 3D. Several CCACE staff and Epidemiology, members were there to speak to the visitors and CCACE) demonstrate a variety of cognitive assessments and displays. 300 members of the public visited the stand, participated in activities, asked questions, and took away information about how CCACE measures the brain both physically through brain imaging and through psychological/cognitive tests.
262 Putting brain training to the test Nature 465,775–778(2010) doi:10.1038/nature09042
263 "MRC scientists develop new giant lens" http://www.mrc.ac.uk/Newspublications/News/MRC006930 264 'Sesame Street' Tells You How to Get to Sunnier Days Financiallyhttp://www.pbs.org/newshour/bb/business/jan-june11/makingsense_06-03.html 265 Five more Alzheimer's genes discovered, scientists say (BBC, April 2011) http://www.bbc.co.uk/news/health-12937131
97 MRC Clinical The CSC published a book, Suffrage Science, to celebrate the Sciences Centre achievements of women scientists and mark the centenary of (CSC), Imperial the International Women's Day. The book was launched in College May 2011 with a debate moderated by BBC4 broadcaster Vivienne Parry and involving leading women scientists and artists266.
266 http://www.csc.mrc.ac.uk/PublicScience/FabricsOfLife/SuffrageScience/
98 STRATEGIC AIM THREE: Going global
Partnerships and shaping the agenda
“Delivering MRC strategy through international partnerships”
The landscape for research across the world is changing due to large investments in science and innovation in emerging economies, particularly Asia, and increased opportunities for international cooperation. Governments recognise that investment in research and development is a key factor for economic growth, and are creating centres of excellence in rapidly developing areas of research such as stem cells or neuroscience.
The MRC has opportunities to develop strategic partnerships to develop world- leading collaborative research and to enable UK scientists to engage with the best minds, ideas and resources wherever they are located.
Objective
To provide international leadership in partnerships which enhance the competitiveness of the UK knowledge and health base.
Measuring up progress against commitments in Research Changes Lives
1 Develop large international projects and partnership √√√ schemes to help stimulate interactions between MRC scientists and scientists in other countries which offer a particular competitive benefit and where links are not strong or need to be shaped 2 Influence European research agendas, including the next √√√ Framework Programme and strengthen the European Research Area 3 Develop strategic alliances with the major European √√√ national funding agencies, including a new European Union initiative on joint programming in areas such as neurodegeneration or ageing.
Since 2009 over £9 million has been invested in international partnerships funding.
Transformational developments
We have significantly increased joint funding opportunities with other countries adding value to UK research
99 1. Develop large international projects and partnership schemes to help stimulate interactions between MRC scientists and scientists in other countries
On behalf of Research Councils UK, MRC has taken over the management of Research Offices in China, India, and the USA. The overseas teams work with research funding organisations in these countries to facilitate collaborations with UK scientists.
We are working with partners around the world to combine research strengths to address health problems:
In partnership with Singapore’s Agency for Science Technology and Research (A*STAR) we jointly invested £2m to support six projects led by UK and Singapore researchers to tackle infectious diseases. The projects address a range of infections, including tuberculosis, HIV, and hepatitis.
MRC has provided close to £5m to fund two UK-US collaborative stem cell research programmes in partnership with the Californian Institute of Regenerative Medicine (CIRM). The awards test stem cell therapies for age- related macular degeneration, a leading cause of blindness in the elderly, and targeting cancer stem cells in acute myeloid leukaemia (see repair and replacement).
Jointly with the Canadian Institute of Health Research (CIHR) we have invested £2m each to support two joint Canada-UK collaborative research programmes addressing the escalating problem of antibiotic resistance (see Natural protection).
Together with six other international funders we are supporting the International Severe Acute Respiratory Infection Consortium (ISARIC). This brings together researchers working in 20 existing clinical research networks to prevent the transmission and improve treatment of new and re-emerging severe respiratory infection.
We have launched two initiatives to stimulate interactions with China, a rapidly developing economic and scientific power. Following an MRC hosted workshop in partnership with the Natural Science Foundation of China we have supported 9 applications at a level of £400k to support small collaborative research projects between UK and Chinese researchers in the area of stem cells. Jointly with Research Councils UK and the Chinese Ministry of Science and Technology (MoST) we have also launched a joint call to strengthen UK-China research links in a number of areas, including healthy ageing populations.
MRC is establishing a fellowship exchange scheme in the area of regenerative medicine with Israel. The MRC and the Israeli Ministry of Science and Technology are both providing up to 50k for the new scheme under the umbrella of BIRAX, the Britain Israel Research and Academic Exchange Partnership in Regenerative Medicine.
2. Influence European research agendas, including the next Framework Programme and strengthen the European Research Area.
MRC’s Chief Executive John Savill has participated on the High Level Advisory Group for Framework Programme 8, now called ‘Horizon 2020’. The programme will run from 2014 – 2020, with an estimated budget of €80b for Research and
100 Innovation. Health research features strongly and MRC has shaped the health agenda to ensure that this is aligned with UK priorities and focuses on research that cannot be achieved by individual countries on their own.
MRC also represents the UK on the European Innovative Medicines Initiative (IMI) States Representative Group and acts as the national contact point for the initiative promoting the opportunities to the UK community. IMI supports collaborative research projects and builds networks of industrial and academic experts in order to boost pharmaceutical innovation in Europe. In three IMI calls for proposals supported since 2009, UK scientists have been involved in 29 projects attracting €55M from the European Commission, the highest level of funding received by any member state.
To deliver the bioinformatics infrastructure necessary to manage and interrogate large datasets across Europe we are working jointly with other UK Research Councils and European partners on the ELIXIR (European Life Science Infrastructure for Biological Information) project. This initiative aims to connect national databases in a distributed network. It will develop existing infrastructure at the European Bioinformatics Institute in Cambridge as its central ‘hub’, and has secured £85m from the UK’s Large Facilities Capital Fund to develop a new data centre and technical hub placing the UK at the forefront of the multinational project. MRC and BBSRC are currently discussing the priorities for developing UK nodes to capitalise on this investment.
The UK is playing a leading role in the INSTRUCT consortium, which co-ordinates access to state of the art structural biology facilities for European academic and commercial researchers. Through the consortium researchers capitalise on the major technological advances in structural biology instruments to better understand diseases and inform the development of treatments. Following the development of the INSTRUCT consortium the UK Biological Nuclear Magnetic Resonance (NMR) community have developed a draft proposal for a National NMR infrastructure for the UK which has been submitted for potential inclusion in the RCUK Capital Roadmap which is currently under development.
MRC is promoting the open access agenda and we been involved in a task force set up by the European Medical Research Council to facilitate better access to research results published in the biomedical literature. This is working towards a common repository for all European biomedical literature and will recommend that the current UKPubMedCentral (UKPMC) platform will be extended to become a European open access repository (EuropePMC).
3. Develop strategic alliances with the major European national funding agencies, including a new European Union initiative on joint programming
In order to tackle the burden of debilitating neurodegenerative disorders, such as Parkinson’s and Alzheimer’s disease, we are teaming up with Government departments and funding agencies from 25 European countries through the Joint Programming in Neurodegenerative Disease (JPND) Initiative. MRC has led the development of a 10 year research strategy for co-ordinated investment in neurodegeneration research on behalf of all countries. We have completed the first funding call with the aim of harmonising biomarkers for use in future clinical trials across European centres. (see tissue repair and degeneration).
101 Together with Canadian Institutes of Health Research (CIHR) and the Deutsche Zentrum für Neurodegenerative Erkrankungen (DZNE, Germany) we have established the Centres of Excellence in Neurodegeneration (COEN) initiative. This promotes innovation and the co-operative use of cutting edge technologies across countries to speed up progress in neurodegeneration research. MRC chairs the oversight group of COEN, which has now six international partners, and we have administered its first funding call (see tissue disease and degeneration).
We are partners in the management programme to develop a strategic research agenda for joint programming in the area of ‘a healthy diet for a healthy life’. We have consulted the UK research community on priorities in this area to shape the European research agenda.
Research Changes Lives objectives in progress
We will work with RCUK and European partners to enhance bioinformatics infrastructure and capacity for UK researchers Building on the successful interactions with A*STAR we will stimulate further research partnerships between UK and Singapore researchers We will encourage joint working between UK and Japanese researchers in neuroscience research
Outcomes 2009-2012
Research Partnerships reported via MRC e-Val MRC funded groups reported research partnerships with organisations based in 96 different countries, a view of the frequency of collaboration by country is given below. The data includes 11,000 reports of partnerships initiated since 2006, 80% of which are still active now. 50% of these partnerships are outside of the UK, 10% are with organisations in the US, and 17% with organisations based in Europe.
102
European Union MRC funded groups enjoy substantial success in obtaining funding funding from the EU. MRC researchers have reported involvement in more than 450 programmes funded through FP6 and FP7, totalling more than £130m in value. In addition 100 awards via Marie Curie Actions totalling £34m, 40 awards via the HFSP totalling £7m, and 50 awards from the ERC totalling £88m. NIH launches new In May 2012 the U.S. government267 said it will work with initiative modelled large pharmaceutical companies to try to find new uses for on the once-promising drugs that have been cast aside by the MRC/AstraZeneca: industry. The collaboration between the National Institutes Mechanisms of of Health, Pfizer Inc., Eli Lilly & Co. and AstraZeneca Plc. Disease call aims to match abandoned drugs with researchers from universities, hospitals and the NIH. The arrangement is modelled on the scheme launched in 2011 involving AstraZeneca and the MRC. The MRC scheme has already received 100 research proposals from 37 institutions. Establishing Discussions are underway with the European Commission partnerships in the and the US National Institutes of Health to pilot MRC e-Val US and Europe to to capture output information in the US and Europe. The collect and analyse interest shown recognises the success that the MRC has output information had in compiling high quality output information. European Medical The MRC chaired an expert group, convened by the EMRC, Research Council to develop a special policy brief on the classification of (EMRC) special research portfolios268. The work recognised the importance policy brief on of consistently categorising research inputs, in a way that
267 “NIH Industry to seek uses for abandoned drugs” (Wall Street Journal, 2012) http://online.wsj.com/article/SB10001424052702303877604577382392599422600.html?KEYWORDS =%22medical+research+council%22 268 Health Research Classification Systems - Current Approaches and Future Recommendations http://www.esf.org/research-areas/medical-sciences/activities/science-policy/health-research- classification-systems-current-approaches-and-future-recommendations.html
103 research would allow comparison across research organisations. classification The resulting paper called for the UK Health Research Classification System to be used more widely, for greater co-ordination, and for efforts to be made to automate classification. Around 20 EMRC members have endorsed the recommendations.
104 Global Health
“From major infectious diseases to non-communicable diseases and emerging infections”
The Government’s strategic document, Health is Global269 identified the challenge of bringing the benefits of biomedical research to all people across the world. The MRC’s support for global health research brings a distinctive and effective contribution to health problems, including excellent African scientists as part of the solution.
Objective
To support global health research that addresses the inequalities in health which arise particularly in developing countries.
Measuring up progress against commitments in Research Changes Lives
1 Continued commitment to supporting and developing √√√ existing centres of excellence in Africa and creating opportunities for such centres to build on key methodological and technological UK strength 2 Support African leadership √√√
3 Leverage funding and working in partnership to accelerate √√√ progress with major diseases
4 Work with partners to identify best ways to take forward √√ research on health care infrastructure
5 Addressing the grand challenge of non-communicable √√√ diseases
MRC’s portfolio in global health research has increased from an investment of £38m per annum in 2008/09 to £48m in the 2011/12 financial year. In both cases this figure includes concordat funding from the Department for International Development (DfID) at £9m per year.
MRC funding in global health research has traditionally focussed on infectious diseases in Sub-Saharan Africa with a particular emphasis on Malaria, HIV/AIDS, and tuberculosis. While maintaining investment into these diseases, which contribute significantly to the mortality in low and middle income countries, MRC has increased funding for non-communicable diseases, such as diabetes, heart and lung disease, and cancer, thus reflecting the changing burden of disease in the developing world.
269http://www.dh.gov.uk/en/Publicationsandstatistics/Publications/PublicationsPolicyAndGuidance/DH_ 088702
105
Transformational developments
MRC investments have made considerable contributions towards improving health in developing countries.
The DART clinical trial270 found that regular laboratory tests to monitor the effects of ART offered little additional benefits compared to careful clinical monitoring, which means that many more people with HIV can be treated for the same money.
The Jinja trial271, involving MRC’s Unit in Uganda demonstrated that ART delivery for the treatment of HIV through a home-based care model is as effective as clinic-based delivery, again helping more people to receive effective treatment
The FEAST trial272 showed that intravenous fluid resuscitation for African children in shock with severe infections does not save lives, which will help to improve clinical practice.
1. Supporting and developing existing centres of excellence in Africa
A significant proportion of MRC’s global health portfolio, approx. £10m per year, is delivered through the two African Units in The Gambia and Uganda. The funding for these MRC Units has been successfully renewed, with new respective strategic and business models increasing coherence across the Unit programmes and leveraging additional funding. Both Units are now headed by local Directors strengthening African leadership. These centres are now attracting additional funding available from major players such as the Bill and Melinda Gates Foundation, to deliver significant impact and expand their reach across Africa. An early success has been an award of £6m to The Gambia Unit from the Gates Foundation for the study of pneumococcal disease.
2. Support African Leadership
Together with DfID, MRC has awarded £4.9m in a pilot scheme to support African Research Leaders. Two awards were made to outstanding leaders in South Africa and Ghana, and a third project was awarded to an emerging leader who had recently returned to Burkina Faso. The successful pilot scheme has been followed up with a second phase, this time focusing on rising star investigators to develop African leaders of the future. Two awards were made supporting researchers in Ghana and South Africa.
3. Leverage funding and working in partnership to address major disease
270 DART study website http://www.ctu.mrc.ac.uk/dart/ 271 Rates of virological failure in patients treated in a home-based versus a facility-based HIV-care model in Jinja, southeast Uganda: a cluster-randomised equivalence trial; Jaffar, S et al. Lancet (2009), Volume 374, Issue 9707, Pages 2080 - 2089, doi:10.1016/S0140-6736(09)61674 http://www.mrc.ac.uk/Newspublications/News/MRC006233 272 FEAST trial shows fluid resuscitation for African children in shock with severe infections does not save lives (2011) http://www.feast-trial.org/node/342
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The European and Developing Countries Clinical Trials Partnership (EDCTP), which brings together 18 European countries and most countries sub- Saharan Africa, has now awarded 77 clinical trials addressing the development of drugs and vaccines for HIV, TB and malaria. The MRC chaired the working group that has developed a business case for EDCTP II, which proposes a €1bn programme with €500m contributions by members states to be matched by €500m from the European Commission. MRC leadership has ensured that the increased funding available will contribute to expanding the remit of the partnership to include Neglected Tropical Diseases (NTD) as well as health systems optimisation for the implementation of the outcomes of EDCTP funded trials.
MRC increased investment into global health clinical trials by leading a joint initiative with DFID and the Wellcome Trust focussing on late stage clinical and health intervention trials. The pooling of resources means that implementable results can be achieved faster. So far £19m has been invested by the funders in the first of three annual calls with the second call due to make awards in the summer of 2012.
Increasing preparedness for new and emerging infections MRC has invested £6.5m, jointly with the Wellcome Trust and BBSRC, on understanding the development and spread of pandemic influenza H1N1 (see Natural Protection). MRC has partnered in the International Severe Acute Respiratory Infections Consortium which provides access to international consortia and infrastructure for research increasing the ability to respond rapidly to emergent threats (see Partnerships and shaping the agenda). The MRC has also led a £10.7m Cross- Council initiative to investigate the ecology of infectious diseases, including how animal pathogens spill over and spread in human populations (see Environment and Health).
4. Identify best ways to take forward research on health care infrastructure
MRC, DFID, the Wellcome Trust and ESRC held a workshop to discuss the opportunities to work jointly on implementation and health systems research. The four funders are working together to define the scope of a call tackling this area.
5. Addressing the grand challenge in non-communicable disease
Affordable strategies for the prevention and treatment of non-communicable diseases in developing countries are badly needed. MRC is a founding member of the Global Alliance for Chronic Diseases (GACD) under whose auspices MRC and the Indian Council for Medicine Research had a joint call for research on how to implement new interventions for chronic diseases in real world settings. Three awards were made in 2011 addressing diabetes and lung disease and a further award is expected in 2012. The total MRC investment will be just under £3.2m. The alliance has also recently completed a joint call on hypertension research. MRC has invested £1.5m to support two proposals, including a school-based education programme to reduce salt intake.
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Research Changes Lives objectives in progress
We will increase our investment in Health Policy and Systems Research in partnership with other funders, to ensure that the outcomes of our research can be better translated into practice.
Further capitalising on the recently published highlight notice in Neglected Tropical Diseases, we will increase investment into these diseases, which so heavily impact on the health in impoverished countries. To date the highlight notice has resulted in the support of two studies addressing Leishmaniasis, a potentially fatal parasitic infection; and podoconiosis, which disfigures patients through severe swelling of the lower legs.
Outcomes 2009 – 2012
Products and interventions in development DART Trial (MRC The DART clinical trial found that regular laboratory tests to Clinical Trials Unit monitor the effects of ART offered little additional benefits and Imperial compared to careful clinical monitoring, which means that College) many more people with HIV can be treated for the same money.
A follow up analysis of DART data273 has shown that addition of an antibiotic treatment (co-trimoxazole) cuts the risk of death on ART by 50%. ARROW Trial (MRC The 5 year ARROW study started in 2007 and is the largest Clinical Trials Unit) paediatric ART trial in Africa. Evidence generated by the study so far has shown how to improve children’s access to research participation and the acceptability and benefits of using scored tablets (rather than syrups) in resource limited settings274. ARROW has also strengthened African research capacity with staff from the successful CHAPAS1 trial remaining in country. Jinja Trial team The Jinja trial275, demonstrated ART delivery for the (MRC/UVRI treatment of HIV through a home-based care model is as Uganda Research effective as clinic-based delivery, again helping more people Unit on AIDS) to receive effective treatment Kathryn Maitland The FEAST trial276 showed that fluid resuscitation for African (Imperial College children in shock with severe infections does not save lives, and KEMRI- which will help to improve clinical practice. Wellcome Trust Programme) Dr Kalifa Bojang AQUAMAT277 the biggest ever trial in severe malaria has MRC Laboratories, shown that the drug artesunate should now be the preferred
273 Daily co-trimoxazole prophylaxis in severely immunosuppressed HIV-infected adults in Africa started on combination antiretroviral therapy: an observational analysis of the DART cohort. Lancet. 2010 Apr 10;375(9722):1278-86 274 Three case studies from the ARROW trial published by Evidence for Action in November 2010: http://www.arrowtrial.org/content_pages/documents/improving_childrens_access.pdf, http://www.arrowtrial.org/content_pages/documents/use_of_scored_tablets.pdf, http://www.arrowtrial.org/content_pages/documents/tablets_are_more_acceptable.pdf 275 Rates of virological failure in patients treated in a home-based versus a facility-based HIV-care model in Jinja, southeast Uganda: a cluster-randomised equivalence trial. Lancet.(2009);374(9707):2080-9 276 Mortality after fluid bolus in African children with severe infection N Engl J Med. (2011);364(26):2483-95
108 The Gambia treatment for the disease in both children and adults. By treating patients with artesunate rather than quinine, the number of deaths from severe malaria could be reduced by 22.5 per cent. The trial involves an international consortium, led by Professor Nick White of the Wellcome Trust-Mahidol University-Oxford Tropical Medicine Research Programme Adrian Hill and Researchers have developed adenovirus-based vaccine Simon Draper vectors, produced these to GMP grade suitable for (University of immunisation against malaria, and carried out Phase I Oxford) safety and immunogenicity studies. The results show improvements over previous approaches278, and may provide a route to an effective malaria vaccine. Adam Cunningham Researchers at the MRC/University of Birmingham Centre for (University of Immune Regulation have discovered a promising candidate Birmingham) for vaccination against non-typhoid Salmonella infection279, a major cause of child death in sub-Saharan Africa. The product is being developed by Novartis Vaccines for Global Health. Microbicides A major multicentre clinical trial across 5 countries on the Development efficacy of 1% Pro200 gel as microbicide found that, Programme although safe, there was no evidence that the product reduces the risk of HIV infection in women280. A crucial finding from the study showed that women enrolled on the trial were willing to use the gel as part of their regular sexual routine.
Scientific Advances Dr Paul Hunt A novel genomics technique to identify drug resistance (University of genes in the malaria parasite a rat model. In 2010 a new Edinburgh) in mutation conferring resistance to artemisinin was published collaboration with using this method281. The approach is now being proactively the New University deployed to generate candidate mutations before these of Lisbon develop in the field. Steve Lindsay, Mosquito screens were found to significantly reduce the MRC researcher number of mosquitoes inside homes in The Gambia, Africa, and Chair in and contribute to the prevention of anaemia in children282 Disease Ecology at Durham University Kinyanda, E A study283 of HIV positive Ugandan teenagers has shown that MRC/UVRI Uganda HIV/AIDS infection in adolescence is associated with
277 Artesunate versus quinine in the treatment of severe falciparum malaria in African children (AQUAMAT): an open-label, randomised trial Lancet, Volume 376, Issue 9753, Pages 1647 - 1657 278 Clinical Assessment of a Recombinant Simian Adenovirus ChAd63: A Potent New Vaccine Vector J Infect Dis. (2012); 205(5): 772–781. doi: 10.1093/infdis/jir850 279 The porinOmpD from nontyphoidal Salmonella is a key target for a protective B1b cell antibody response PNAS (2009)vol. 106 no. 24 9803-9808 280 PRO2000 vaginal gel for prevention of HIV-1 infection (Microbicides Development Programme 301): a phase 3, randomised, double-blind, parallel-group trial: The Lancet, Volume 376, Issue 9749, Pages 1329 - 1337, 16 October 2010. doi:10.1016/S0140- 6736(10)61086-0 281 Paul Hunt et al. Experimental evolution, genetic analysis and genome re-sequencing reveal the mutation conferring artemisinin resistance in an isogenic lineage of malaria parasites BMC Genomics (2010), 11:499 doi:10.1186/1471-2164-11-499 282 Effect of two different house screening interventions on exposure to malaria vectors and on anaemia in children in The Gambia: a randomised controlled trial (2009) Lancet. Volume 374, Issue 9694, Pages 998 - 1009, doi:10.1016/S0140-6736(09)60871-0 283 http://www.ncbi.nlm.nih.gov/pubmed/19530544
109 Research Unit on considerable psychological problems and the presence of AIDS major psychiatric disorders. ART is now more available so many HIV + children are surviving into adolescence, thus calling for the development of adolescent friendly HIV medical and psychological support and treatment services in developing countries such as Uganda.
Research into policy CHAPAS 1 trial Development of an antiretroviral formulation specifically (MRC Clinical Trials designed for children with HIV. “Triomune” combines three Unit) existing therapies and is administered according to a child’s weight, allowing each child to safely receive the correct dose. The formulation is approved in Zambia and has been added to the WHO’s list of prequalified medicines. MRC Laboratories, Results from the MRC Gambia Unit had a significant the Gambia influence on WHO recommendations for global immunisation against Haemophilus influenzae type b (Hib) disease. In 2005 MRC surveillance of the first large-scale immunisation programme in Africa for Hib, showed that the disease could be eliminated. WHO issued recommendations in 2006, and in 2009 was joined in its work by the Global Alliance for Vaccine Immunisations (GAVI). This has led to vaccination programmes across more than 160 countries, 120 million children immunised and estimates that 700,000 lives will be saved284. MRC Laboratories, Similar to the situation with Hib disease, WHO had available the Gambia high quality evidence from an MRC-funded trial of pneumococcal vaccine in the Gambia in 2005. A recommendation for global vaccination was made by WHO in 2007, and GAVI began rolling out vaccination programmes in 2010. The aim is to reach 58 countries and 90 million children by 2015285. CHIPS (a multi- Recommendations in WHO (2010) and PENTA (2009) centre cohort guidelines concerning when to start treatment according to study of HIV age-related CD4 counts and percentages are based in part infected children in on data from CHIPS. the UK and Ireland)286 Conway, David Intermittent preventative treatment in infants (IPTi) is MRC Laboratories recommended by WHO as part of the global strategy for the Gambia malaria control. Research in the Gambia has shown that IPTi can be effectively delivered to children as part of the expanded programme on immunisation, and that the drugs used do not impair serological responses to vaccines287. Professor Brian In 2012 Professor Greenwood was knighted for services to Greenwood Malaria Research in Africa288.
284 GAVI Haemophilus influenzae type b vaccine supporthttp://www.gavialliance.org/support/nvs/hib/ 285 GAVI pneumococcal vaccine support http://www.gavialliance.org/support/nvs/pneumococcal/ 286 CHIPS is a collaboration between clinical centres that care for HIV infected children, the National Study of HIV in Pregnancy and Childhood (NSHPC) at the Institute of Child Health, and the Medical Research Council (MRC) Clinical Trials Unit. CHIPS includes data on almost all UK children infected with HIV since 2006 and its data has underpinned studies to assess the general nature of problems in clinical management of HIV in paediatrics, as well as recently specifically contributing evidence to inform guidance on the use of tenofovir in paediatric patients. 287 Two Strategies for the Delivery of IPTc in an Area of Seasonal Malaria Transmission in The Gambia: A Randomised Controlled Trial PLoS Med. 2011 February; 8(2): e1000409. 288 Knighthood for Brian Greenwood http://www.lshtm.ac.uk/newsevents/news/2012/item19326.html
110 (Former Director of the MRC Laboratories, Gambia)
Public engagement DART Trial (MRC A film describing the DART trial, narrated by a trial Clinical Trials Unit) participant, was produced and shown on BBC World in late 2009, in the USA in 2010, and has also been broadcast across several African countries. The film-maker was nominated and shortlisted for the British Medical Journal Health Communicator of the Year Award for this work. Executive A consortium of researchers, advocates and clinicians Committee of the announced research priorities for improving the lives of Grand Challenges people with mental illness around the world, and called for in Global Mental urgent action and investment289. The Grand Challenges in Health Global Mental Health is led by the US NIH and the Global Alliance for Chronic Disease. The MRC is represented on the Executive committee and several UK, MRC-supported researchers are members of the international scientific advisory board. FEAST Trial The FEAST trial (Mortality after fluid bolus in African children with severe infection) has won Research Paper of the Year at the 2012 BMJ Group Improving Health Awards290.The trial confirmed the detrimental effect of fluid in children with the most severe shock and demonstrates the importance of testing interventions for effectiveness in different settings. It serves as a model for future trials in resource poor settings and it is hoped that the trial will avert thousands of deaths a year from the inappropriate use of fluid.
289 Grand challenges in global mental health Nature (2011) http://grandchallengesgmh.nimh.nih.gov/Grand%20Challenges%20in%20Global%20Mental%20Healt h.pdf 290 BMJ Group Improving Health Awards (2012) http://groupawards.bmj.com/2012%20Shortlist/and- the-winners-are..#research-paper-of-the
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STRATEGIC AIM FOUR: Supporting scientists
Capacity
“Training the next generation of leading researchers aligned with MRC strategy”
The MRC has an important national role in training future research leaders across a range of basic science and clinical disciplines. We will continue to work with a range of partners to identify and respond to national gaps in strategic biomedical research skills, to continue our tradition of supporting the UK’s most talented individuals at critical stages of their research careers and to seek novel ways of enabling career research scientists to flourish. Interdisciplinary research and training lead to new research opportunities and drive innovation. Maintaining a cadre of highly-skilled researchers in the UK is essential for the innovative research that increases our understanding of health, disease and treatments. A skilled research workforce is also essential if the UK is to be the preferred country for the pharmaceutical, biotechnology and devices industries to undertake pre-clinical and clinical research.
Objective
To strengthen and sustain a skilled research workforce through targeted support for excellent training and the development of world-class research leaders.
Measuring up progress against commitments in Research Changes Lives
1 Respond to needs identified by the MRC’s research boards √√√ by prioritising strategic areas as part of a refreshed skills and careers strategy
2 Promote the development of high-quality training √√√ environments through our doctoral training schemes
3 Monitor the quality and uptake of our enhanced capacity- √√√ building schemes, further shaping and balancing priorities in response to evidence of gaps in provision 4 Provide skills training and information about career tracks √√ for technologists in instrumentation, bioinformatics and data management
5 Invest in clinical research training √√√
6 Strengthen networking among our students and junior √√ fellows
7 Invest in the development of global health research √√ capacity among UK health researchers, to ensure that there are opportunities to train future leading scientists for work in this field
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In 2011/12 MRC committed £71m through Research Careers Award funding to support studentships and fellows, representing ~ 10% of the total MRC expenditure. A further £10m per annum was invested in training through MRC Units and Institutes. Numbers of extramural studentships have been slightly reduced from 350 to 320 students per annum reflecting the increased priority given to post-doctoral awards. At the same time funding for Industrial CASE PhD studentships has increased from 10 studentships in 2007/8 to ~35 per annum in 2010/11. In 2010/11, 95 personal fellowships were awarded, of which 49 were post-doctoral and the remainder were pre-doctoral Clinical Research Training Fellowships. We have sustained a suite of post-doctoral Strategic Skills Fellowships to build up UK expertise in statistics, bioinformatics, health economics, population health sciences and methodology development. £15m has been invested in the 2010/11 and 2011/12 financial years to support fellows in these areas. In 2011/12 MRC committed £5m to support a total of 206 new Masters studentships on 20 advanced masters research courses to start in 2011, 2012 and 2013. Priorities were (i) mathematics, statistics, and computational science for biomedicine and health; (ii) imaging sciences, and (iii) in vivo sciences (non- human).
Transformational developments The establishment of Doctoral Training Partnerships with Universities to strengthen accountability for the use of block Doctoral Training Grants allocated on the basis of University grant income and to optimise the alignment of training strategies with MRC’s priorities and each University’s research strengths. Strengthened engagement with industry through broadening the range of companies involved in the Industrial CASE studentship scheme, the creation of two Clinical Pharmacology and Pathology Programmes (recruiting up to 20 clinician PhDs over three years), and the launch of new MRC partnership awards to stimulate industry collaborations of existing fellows
1. Respond to needs identified by the MRC’s research boards by prioritising strategic areas as part of a refreshed skills and careers strategy
During 2010/11 the MRC’s Research Boards were consulted on capacity building and skills priorities. Three previous cross-cutting skills priorities – also identified by industry as key skills - were confirmed: (1) in vivo science; (2) biological and medical imaging; and (3) mathematical and statistical research. We subsequently awarded 20 block Advanced Research Masters awards in these areas though open competition, equivalent to 206 students over three years from 2011/12. In addition, we continue to work through our Doctoral Training Partnerships to promote these skills at PhD level.
The MRC Boards respond to capacity-development needs in a number of ways, including Centre grants. The Infections and Immunity Board identified a significant long standing gap in attracting young scientists into ‘modern’
114 microbiology and funded a new MRC Centre for Molecular Bacteriology and Infection at Imperial College to enhance training in this area (see Natural Protection).
2. Promote the development of high-quality training environments through our doctoral training schemes
MRC is promoting dialogue and agreement with Universities and other research organisations (ROs) awarded a Doctoral Training Grant (i) automatically, on the basis of significant MRC grant income; or (ii) by competition. Portfolios have been agreed with the 16 ROs that receive automatic allocations. The Training & Careers Group reviewed the portfolio agreements and data on training performance in October 2011 and concluded that most ROs’ portfolios were well aligned to MRC priorities and built on leading science. Performance data, including PhD submission time and next destinations were mostly reassuring. Feedback was provided to all 16 Studentship Partner ROs. The Doctoral Training Partnership Agreements will form the basis for ongoing engagement with the ROs and with MRC-funded students.
3. Monitor the quality and uptake of our enhanced capacity-building schemes, further shaping and balancing priorities in response to evidence of gaps in provision
Following a progress review of the suite of Strategic Skills Fellowships by the Training and Careers Group in June 2010, we have consolidated the capacity building fellowship schemes and fine-tuned the descriptions of the individual schemes. The aim was to improve communication about the opportunities these fellowships offer to a wide range of potential fellows including those from mathematical, physical, social and economic sciences – applying their expertise to important biomedical and health research questions. Ongoing monitoring indicates that more needs to be done to promote interdisciplinary fellowships (e.g. economics of health) through the mainstream disciplinary organisations, following the example of our work with the Young Statisticians section of the Royal Statistical Society.
4. Provide skills training and information about career tracks for technologists in instrumentation, bioinformatics and data management
Responding to topics identified by senior MRC-funded data managers, MRC supported a series of workshops on research data standards in population health sciences (PHS), introducing the wider PHS community to the Data Documentation Initiative (DDI) standards in particular. This is likely to be adopted as a standard for the kinds of information about research data that enables data to be shared widely – for instance through data harmonisation and data linkage.
5. Invest in clinical research training
MRC supports 45-50 clinician-PhD candidates per year through the Clinical Research Training Fellowship (CRTF) scheme. In addition, a further 20 clinician-PhD places (over 2-3 years) are being awarded through two Clinical
115 Pharmacology and Pathology Programmes in Scotland and Manchester- Liverpool.
One indicator of the strength of the MRC fellowship brand is the growth in charity partnering with MRC to co-fund CRTFs. Over £3.5m has been contributed since 2007 by 21 partners to 36 CRTFs and one Clinician Scientist award. In 2010/11 the partnership contribution to £2.2m of CRTF spend was £0.9m.
We are working with partners to strengthen clinical academic training to address the shortage of candidates for intermediate research fellowships (Clinician Scientists)291. From 2013 we shall become a co-funder of the Academy of Medical Sciences developed Starter Grants for Clinical Lecturers scheme, alongside the Wellcome Trust, the British Heart Foundation and Arthritis Research UK.
Tracing the current careers of various groups of past MRC fellows demonstrated strong outcomes292. For instance, we found that 65% of the Clinical Research Training Fellows who had completed their PhD awards in the 1993-2003 period currently held senior academic positions - and 88% of these were clinically active. The 27% of CRTFs who listed ‘NHS Consultant’ as their current post were mostly research active (80%). Of the CRTFs completing their fellowship in 1991/92, close to 20% had been elected members of the Academy of Medical Sciences, a significant mark of esteem. In general, the success-rate of past MRC research fellows in attracting further MRC grant funding has been twice the MRC average for all applicants.
6. Strengthen networking among our students and junior fellows
Responding to feedback from MRC Fellows, MRC instituted in 2010 an annual Postdoctoral Fellows’ Symposium, focused principally on enabling fellows to extend their networks. Evaluation after the 2011 and 2012 events indicated that for more than 95% of respondents the meeting met their expectations and made them feel more part of the MRC. To ensure that the programme stays fresh and meets fellows’ needs, the 2013 programme committee includes four fellows.
A survey of students in 2010 indicated that an appetite for increased interaction with the MRC was limited and focussed on improved connection with MRC researchers in their field, especially with those willing to share resources, rather than MRC as an organisation.
An example that this is happening is the networking of early career researchers in ageing research: The Newcastle Lifelong Health and Wellbeing (LLHW) Centre for Brain Ageing and Vitality hosts an annual retreat for all students and post- doctoral researchers funded through the programme. In 2012 the Centre is holding a two day conference for over 80 early career researchers in ageing research on behalf of the MRC-led LLHW programme.
291 Office of Strategic Coordination of Health Research UK-wide survey of health research fellowships, November 2009 http://www.mrc.ac.uk/Utilities/Documentrecord/index.htm?d=MRC006501 292 What happens to clinical training fellows? A retrospective study of the 20 years outcome of a Medical Research Council UK cohort http://bmjopen.bmj.com/content/2/4/e001792.full
116 7. Invest in the development of global health research capacity among UK health researchers, to ensure that there are opportunities to train future leading scientists for work in this field
The Tropical Epidemiology Group (London School of Hygiene and Tropical Medicine), which focuses on the design and evaluation of interventions against major diseases in developing countries, provides strong capacity building in epidemiology and related methodologies including training in medical statistics at Master’s level through five competitively-awarded fellowships.
The MRC Centre in Genomics and Global Health (Oxford), which aims to translate research on human and pathogen genome variation into large-scale clinical and epidemiological investigations of practical relevance for global health, trains bioinformaticians in the MRC Laboratories in The Gambia and other Units in Africa and Asia with UK mentorship and a supporting network approach.
Research Changes Lives objectives in progress
Embed further opportunities for MRC students and research fellows to engage with industry (and also the NHS), particularly in academic environments with a coherent range of collaborative activities based on strong discovery science and translational capabilities Strengthening MRC intelligence about - and responsiveness to - specific skills and capacity needs of UK biomedical science, by working with our Studentship Portfolio partners in universities, with MRC Institutes and Units, our Research Boards and with other funders Ensure that human capital critical to UK successes, including that represented by highly productive scientists and technologists who are not destined to be ‘programme leaders,’ is effectively nurtured and sustained We are working jointly with the Academy of Medical Sciences to determine career support currently available and the needs for additional support
Outcomes 2009-2012
Destinations for staff leaving MRC support Since 2006 there have been approximately 6000 staff reported as leaving MRC support (either during, or at the termination of grant/fellowship/programme funding). 72% stay in the UK, with approximately 6% moving to take up project leader positions. 5% move to the USA, but 10% of these take up project leader positions. Just 1% move/return to China, but more than 30% of these take up project leader posts.
These figures illustrate MRC’s contribution to the ‘Brain Circulation’ outlined in the report on International Comparative Performance of the UK Research Base (2011)293 prepared for the Department of Business, Innovation and Skills. The movement of researchers between countries, with return rates, network building and diaspora effects is seen as beneficial to all parties.
293 http://www.bis.gov.uk/assets/biscore/science/docs/i/11-p123-international-comparative- performance-uk-research-base-2011
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Sector of next destination for staff leaving MRC support 60% of staff stay in the academic sector, 10% of staff leaving MRC support move into the private sector (almost 600 staff). 10% of those that move into the private sector do so to take up project leader posts (57 staff).
118 Use of population-based data
“Maximising the value of cohort resources and existing data”
Data are at the heart of the MRC’s ability to improve the understanding of human health. To maximise the exploitation of MRC data sets, it is important to ensure that the MRC plays a strong leadership role in the development of informatics and infrastructure that enables the effective use and analysis of MRC data. We must recognise that the maintenance and development of population cohorts and the data sets that flow from them need active and effective management across discipline boundaries.
Objective
To exploit fully the complexity and benefits of population-based data; to maximise sharing and linkage of data, and to develop data collection and storage.
Measuring up against commitments in Research Changes Lives
1 Address scientific priorities and stimulate cross-disciplinary √√√ working through strategic investment in the most appropriate data sets
2 Achieve cultural change so that data-sharing and better √√√ data access become common practice
3 Proactively manage existing and new population-based √√√ cohort investments in partnership with other funders.
4 To understand and address methodological issues that arise √√ from linking and combining data sets, including those that arise from cross-disciplinary collaboration
5 Implement the recommendations of the Academy of Medical √√√ Science’s January 2006 report on the use of health records in research.
MRC’s annual investment in population health sciences is £100m per year of which £10.5m is invested into large scale population cohort resources.
Transformational developments
UK Biobank, an internationally unique cohort resource combining breadth and depth of measurements has opened for use by researchers in 2012294. The £93m UK Biobank project follows half a million UK adults, which were recruited between the ages of 40 and 69. They have undergone detailed
294 What makes UK Biobank special? http://www.thelancet.com/journals/lancet/article/PIIS0140- 6736(12)60404-8/fulltext
119 body measures (such as lung and eye function), provided blood, urine and saliva samples and comprehensive lifestyle information.
An MRC supported Aneurysm Screening Study showing that around half of all aneurysm-related deaths could be prevented by a nationwide screening programme has led to the launch of a national programme to detect AAAs early in 2009 (see outcomes).
Four UK e-health research centres of excellence have been awarded through a 10 partner £19m MRC-led initiative. By combining clinical, research and social information they will enable transformational change in the development of treatments, improvement of drug safety and assessment of risk to public health.
1. Address scientific priorities and stimulate cross-disciplinary working through strategic investment in the most appropriate data sets
MRC’s investment into large scale population cohort resources is £10.5m per annum. We have renewed our investment into three population cohorts that are used by researchers across disciplines to answer health related questions: the Avon Longitudinal Study of Parents and Children (ALSPAC), which has followed 14,000 pregnant woman and their children since 1991 (£3m over 6 years); the European Prospective Investigation of Cancer (EPIC) – Norfolk, which focuses on dietary exposure in older age groups (£2m over 5 years). Both of these studies have delivered important insights into the influence of environmental factors and genetics on health and disease (see section on Environment and Health). We also renewed the Whitehall II study (£2m for 3 years), which places an emphasis on the social factors affecting health; and have extended and enhanced the measurements taken for UK Biobank, which has opened for use of researchers in 2012 (see below).
Jointly with ESRC we have scoped the requirements and recruited the leadership team for a Cohort Resources Facility, which will provide infrastructure to increase collaborations across major UK population cohorts by promoting access, harmonisation of cohort data and linkage to other data sources. This activity will be co-ordinated with the MRC Research Gateway (see below).
We have established a Cross-Board Cohort Advisory Group, which reviews all major population cohorts requesting new or further funding to ensure that the cohort addresses a unique and important scientific and strategic niche. The Panel will also review the implementation of Data Management Plans, the requirements for which were updated in 2012 (see below).
2. Achieve cultural change so that data-sharing and better data access become common practice
In step with Government and Research Council UK efforts to promote greater use and responsible management of high quality data, MRC has updated its requirements for all research proposals to be accompanied by a short and informative Data Management Plan. In addition, we published more detailed guidance on data sharing for population health sciences and cohort researchers295, focussing on greater transparency and good governance. We will
295 MRC policy on sharing of research data from population and patient studies http://www.mrc.ac.uk/Ourresearch/Ethicsresearchguidance/datasharing/Policy/PHSPolicy/index.htm
120 review progress made by MRC’s principal cohorts towards meeting our policy requirements early in 2013.
To support cross-cohort collaboration we held a series of workshops with MRC research data managers to evaluate and promote common standards for describing research studies and their variables, so that this information can be searched for and discovered by other researchers. We plan to continue supporting development and sharing of good practice, standards and tools by MRC research data managers, extending and broadening participation according to need.
We have launched a prototype MRC Research Data Gateway, a web-based directory of MRC cohorts that enables researchers to discover studies and variables of interest to enable new research. The Gateway also promotes the development and implementation of data standards that support data harmonisation, linkage, new analyses and other forms of data sharing. Moving forward, the focus will be on improving and documenting the way Gateway supports researchers’ needs.
To stimulate research collaboration on the causes of mental illness, we have awarded £1.1m for 7 projects that use existing data sets from cohorts and other data sources such as administrative data or patient records to conduct research in this area.
3. Proactively manage existing and new population-based cohort investments in partnership with other funders
MRC manages jointly with ESRC the Birth Cohort Study and Cohort Resources Facility, which are supported by both funders and the Large Facilities Capital Fund at a total level of £33m. The Birth Cohort Study is a new population cohort, which is currently in its development phase. It will recruit at least 90,000 pregnant mothers and partners to collect data and samples that can be used by researchers to understand how factors in early life influence health and wellbeing as people age. The development phase for the study began in July 2011 and the recruitment of mothers is due to start in 2013.
Together with the Wellcome Trust and the Department of Health we support UK Biobank, a £93m project that has received funding until 2015. UK Biobank follows 500,000 UK adults between the ages of 40 and 69. It has opened for use in March 2012 and data and samples can now be accessed by researchers world- wide to investigate why some people develop common life-threatening illnesses such as cancer, heart disease, stroke, diabetes and dementia whilst others do not. In order to further enhance the resource we have committed funding for the measurement of key biomarkers of health in the blood samples of the whole cohort.
4. To understand and address methodological issues that arise from linking and combining data sets, including those that arise from cross- disciplinary collaboration, and 5. Implement the recommendations of the Academy of Medical Science’s January 2006 report on the use of health records in research
MRC has led a mapping exercise296 on behalf of the major funders and industry to determine what is needed for UK researchers to be in the best position to make
296 http://www.mrc.ac.uk/consumption/groups/public/documents/content/mrc007896.pdf
121 use of electronic health records for research. In response to the findings we have brought together 10 funding partners, including Research Councils, Government and charities in a £19m initiative, which has established four major e-Health Informatics Research Centres across the UK (London, Manchester, Dundee, and Swansea). These Centres will carry out leading research linking e-health NHS records with other forms of research and routinely collected data. They will play an important role in capacity building, methodology development, and public engagement. The Centre funding was announced by the Minister of State for Universities and Science David Willets in August 2012.
Research Changes Lives objectives in progress
We are currently developing an MRC cohort strategy to identify scientific opportunities, taking into account the existing MRC cohort portfolio , how this will change over time and major investments by other funders
We will expand the MRC Research Gateway to include further cohort studies
We are establishing an e-health informatics centre network to work collaboratively with the wider research community, the NHS, industry and the public to ensure that the wealth of patient information within the NHS is used effectively to improve treatments, public health, and the provision of health services
Outcomes 2009-2012
Scientific advances Twins Early TEDS297 is the largest study by far on learning abilities and Development Study disabilities, extensive data have been obtained for more (TEDS), (MRC than 5000 pairs of UK twins born 1994-96. Much effort has SDGP, Kings gone into developing a user-friendly database which has College) been used by dozens of collaborators. UK Biobank To maximise the use of the knowledge and infrastructure developed for UK Biobank by other biomedical studies involving human volunteers, UK Biobank has set up a trading subsidiary (UK Biocentre298). MRC Clinical Trials Middle-aged men who smoke, have high blood pressure and Services Unit, high cholesterol can expect to live 10 to 15 years less than Oxford and men who don’t have these heart disease risk factors. The Department of finding is the conclusion of research299 based on data Epidemiology and gathered over 40 years from 19,000 male civil servants in Public Health, UCL the Whitehall II study. Ruth Loos (MRC Research has shown300 that predisposition to obesity can be Epidemiology Unit) offset by around 40 per cent with regular physical activity. The findings challenge the popular myth that obesity is unavoidable if it runs in the family and could guide future treatments to combat the obesity crisis. From a study of over 20,000 men and women aged 39-79, who had taken
297 http://www.teds.ac.uk/about.html 298 UK Biocentrehttp://www.ukbiobank.ac.uk/uk-biocentre-2/ 299 Life expectancy in relation to cardiovascular risk factors: 38 year follow-up of 19 000 men in the Whitehall study BMJ 2009;339:b3513 300 Physical Activity Attenuates the Genetic Predisposition to Obesity in 20,000 Men and Women from EPIC-Norfolk Prospective Population Study. (2010) PLoS Med 7(8): e1000332. doi:10.1371/journal.pmed.1000332
122 part in the EPIC-Norfolk study. Alastair Leyland Scotsmen under the age of 65, living in deprived (MRC SPHSRU) neighbourhoods are 32 times more likely to die from assault than their richer countrymen. Research examined the social patterning of deaths due to assault in Scotland between 1980 to 2005301. Carol Brayne Results from CFAS302 shows that education appears to stave (Cognitive Function off the clinical expression of dementia. More education did and Ageing Study not protect people studied from developing CFAS) neurodegenerative and vascular neuropathology by the time they died but it did appear to mitigate the impact of pathology on the clinical expression of dementia before death. Further research to understand why education is protective even when there is disease may be of considerable value to society. Simon Griffin (MRC A risk score to identify people at high risk of having or Epidemiology Unit) developing type 2 diabetes which utilises data routinely held in general practice electronic records303. The risk score was used to identify ~33,000 individuals at high risk (from a population of ~150,000 aged 40-69 years) who were then invited for screening for diabetes as the first stage of the ADDITION trial. Details of the risk score have been requested by clinicians and policy-makers internationally. 1958 birth cohort The MRC has funded the banking of DNA samples from the (Institute of Child 1958 birth cohort. This has become a very widely used Health, UCL)304 resource underpinning a significant number of whole genome studies. Since 2006 the 1958 cohort has been an essential component of studies that have generated 13 papers with an exceptional citation impact of more than 8 times the world average. Terrie Moffitt (MRC Following a cohort of 1000 New Zealand children from their SGDP, Kings birth to age 38 in 2011, researchers at the MRC Social, College London) Genetic and Developmental Psychiatry Centre have shown that childhood self-control predicts criminal offending, addiction, personal finances, savings for retirement, and physical health and illness diagnosed via biomarkers305,306,307. Early interventions enhancing the population's self-control skills might reduce taxpayer costs of crime control, health care, and old-age dependency. Emerging Risk The ERFC has established a central database on over 2 Factors million participants from >125 prospective population-based Collaboration studies, in which subsets have information on lipid and (ERFC) inflammatory markers, other established risk factors and characteristics, as well as major cardiovascular morbidity
301 The social patterning of deaths due to assault in Scotland, 1980-2005: population-based study J Epidemiol Community Health. 2010 May;64(5):432-9. 302 Education, the brain and dementia: neuroprotection or compensation? Brain (2010) 133 (8): 2210-2216. doi: 10.1093/brain/awq185 http://brain.oxfordjournals.org/content/133/8/2210.full 303 Who attends a UK diabetes screening programme? Findings from the ADDITION-Cambridge study. Diabet Med. (2010) Sep;27(9):995-1003. PMID: 20722672 304 http://www.ucl.ac.uk/ich/research-ich/mrc-cech/cohort-studies/1958 305 Undercontrolled Temperament at Age 3 Predicts Disordered Gambling at Age 32 : A Longitudinal Study of a Complete Birth Cohort Psychological Science published online 28 March 2012 DOI: 10.1177/0956797611429708 306 Family history and oral health: findings from the Dunedin Study Community Dent Oral Epidemiol. 2012 Apr;40(2):105-15. doi: 10.1111/j.1600-0528.2011.00641.x. 307 A gradient of childhood self-control predicts health, wealth, and public safety (2011) Proceedings of the National Academy of Sciences 108:2693-2698 PMID: 21262822
123 and cause-specific mortality. The collaboration has resulted in a series of high impact papers on cardiovascular disease308 and diabetes309 Keith Godfrey (MRC Studies on the Southampton Women’s Survey have shown Lifecourse that epigenetic changes caused by maternal diet strongly Epidemiology Unit, influence a child’s adiposity up to 9 years of age and this University of effect is independent of mother’s weight or weight of the Southampton) baby at birth310.
Research into policy Multicentre The study311 showed that around half of all aneurysm- Aneurysm related deaths could be prevented by a nationwide Screening Study screening programme. A national programme to detect (MRC Biostatistics AAAs early was launched in 2009. AAAs affect 4 per cent of Unit, Cambridge) men aged 65-74 (approximately 80,000), and result in 6,000 deaths a year312.
Public Engagement National Survey of In 2011 the NSHD participants celebrated their 65th Health and birthday, an event which gained a lot of interest in the Development media313 including an editorial in the journal Nature. (NSHD) MRC Lifelong Health and Ageing Unit
308 C-reactive protein concentration and risk of coronary heart disease, stroke, and mortality: an individual participant meta-analysis Lancet. (2010); 375(9709): 132–140. doi: 10.1016/S0140- 6736(09)61717-7 309 Diabetes mellitus, fasting blood glucose concentration, and risk of vascular disease: a collaborative meta-analysis of 102 prospective studies Lancet, (2010) Volume 375, Issue 9733, Pages 2215 - 2222, 26 doi:10.1016/S0140-6736(10)60484-9 310 Epigenetic gene promoter methylation at birth is associated with child's later adiposity Diabetes. (2011);60(5):1528-34. 311 Screening men for abdominal aortic aneurysm: 10 year mortality and cost effectiveness results from the randomised Multicentre Aneurysm Screening Study BMJ (2009);338:b2307 312 NHS Abdominal Aortic Aneurysm Screening Programmehttp://aaa.screening.nhs.uk/ 313 http://www.nshd.mrc.ac.uk/nshd__65/65th_publications.aspx
124 Research environment
“Providing world-class facilities for world-class research”
Working across disciplines is key to achieving the best results with new and emerging technologies. We will support top research centres and technology facilities to accelerate progress in research, and attract and retain world-leading scientists in the UK.
Objective
To provide a world-class research environment.
Measuring up progress against commitments in Research Changes Lives
1 Develop new, larger facilities and new partnerships, such as √√√ links with universities, to strengthen centres of excellence 2 To create a new UK Medical Research Institute √√√ 3 Continue to provide opportunities to develop new centres of √√√ excellence in partnership with Universities 4 Work with MRC unit directors and universities to achieve √√√ close integration of units and universities, and stimulate interdisciplinary collaboration between biological and physical sciences
Transformational developments In a unique partnership between the MRC, major charitable funders, and London Universities we are on track to establishing the £540m Francis Crick Institute, a major new national biomedical research institute for the 21st century We are in the process of transforming the way in which we support research by fully integrating a large proportion of our MRC Units within UK Universities (3 transfers have been completed and 12 are ongoing)
1. Develop new, larger facilities and new partnerships, such as links with universities, to strengthen centres of excellence
To provide a new home for the internationally renowned Laboratory for Molecular Biology (LMB) we are nearing the completion of a state-of-the-art, £212m building. The construction is on schedule and within budget and LMB researchers are due to move into the new accommodation in early 2013. The new environment will provide world-class facilities for LMB researchers, including adaptable space for cutting edge equipment. It is designed to enhance networking and collaborations, to strengthen interactions with Cambridge University and the Clinical School and facilitate translational interactions with industry.
In order to increase the available space and improve facilities for researchers at the Clinical Sciences Centre (CSC) we have contributed £10m towards a new £73m Imperial Centre for Translational and Experimental Medicine. The Centre focusses on accelerating the translation of scientific discoveries into new ways of
125 preventing, diagnosing and treating diseases and brings together translational and clinical researchers funded by the MRC and research charities. Construction started in September 2009 and the building was opened by the Chancellor of Exchequer in May 2012.
MRC has contributed £2.5m capital funding towards the £54m Scottish Centre for Regenerative Medicine which brings together 250 clinicians and scientists, including those at the MRC Centre for Regenerative Medicine, to carry out cutting edge stem cell research into conditions such as multiple sclerosis, Parkinson’s Disease, and heart and liver diseases. The new Centre was opened by the Princess Royal in May 2012. We have also provided to £2m towards a new building to house the UK Stem Cell Bank, which was opened in 2010.
The new Research Complex at Harwell opened in 2010 to support research determining the structure of biological macromolecules to understand their function and facilitate the development of new therapeutics through structure- based drug design. It is located to take advantage of the Diamond Light Source and provides laboratories for scientists in the life and physical sciences to undertake research across disciplines. The MRC Protein Production Facility, a £6m investment, has moved into the Research Complex and close to 50 MRC funded groups have accessed the Research Complex facilities since 2010, mostly through the MRC Protein Production Facility.
MRC is contributing £6m to a new building for the Centre for Virus Research (CVR), a joint venture between the MRC and the University of Glasgow. The new CVR building will contain cutting edge research facilities needed to conduct research into viral diseases and will create an environment that supports the very best research and collaborations.
2. To create a new UK Medical Research Institute
To provide world class facilities and training environments to our scientists we are in the process of establishing the Francis Crick Institute (the Crick), at which research currently carried out at the National Institute for Medical Research will be housed after 2015. The Crick is a partnership between MRC, the Wellcome Trust, Cancer Research UK, University College London, Imperial College, and King’s College London, with MRC contributing almost half of the £540m construction budget, including a £220 million contribution to the build from the Department of Health. The business case for the institute was approved and Sir Paul Nurse took up the post of Chief Executive and Director in early 2011. Planning permission was granted and construction started in June 2011 and is on schedule to be completed in 2015.
3. Continue to provide opportunities to develop new centres of excellence in partnership with Universities
Since 2009 three new MRC-University Centres have opened and three further Centres have been awarded and are due to open in 2012. The Centres bring together expertise and build up capacity in strategic priority areas for the MRC. Half of the new centre investments are partnerships with policy makers or charities.
New Centres opened include the MRC-HPA Centre for Environment and Health (see Environment and Health) and the MRC Centre for Neuropsychiatric Genetics and Genomics (see Genes and Disease). In
126 addition, the MRC Centre for Reproductive Health has opened in Edinburgh following the decision to close MRC Human Reproductive Sciences Unit (HRSU). The Centre will build on the legacy of nearly four decades of research at the HRSU and continue some of the excellent work initiated at the Unit in a more flexible funding model that will encourage researchers to foster collaborations across the University and with external partners.
New Centres due to open in 2012 include two MRC-Arthritis UK Centres for Musculoskeletal Ageing (see Lifecourse perspective), and an MRC Centre for Molecular Bacteriology and Infection (see Natural Protection). We have also awarded funding for a new Wellcome Trust-MRC Stem Cell Institute in Cambridge, which brings together existing investments to form a new world leading institute investigating the properties of stem cells and how these can be exploited for health benefits.
4. Work with MRC unit directors and universities to achieve close integration of units and universities, and stimulate interdisciplinary collaboration between biological and physical sciences
In partnership with MRC Unit Directors and UK Universities we are progressing the University Units programme. Through this programme we are transferring MRC Units into University Units where both parties agree that there are mutual benefits and shared objectives. The aim is to increase strategic alignment between MRC and University investments, enhance interactions and improve efficiency and flexibility, thereby maximising the resources available for science. In practice this means that the University will become the employer of staff and the MRC will remain the main research funder. Since 2009 three MRC Units have successfully transferred to University Units. 12 further MRC Units, out of a total of 21 intramural MRC Units, are currently at various stages of the transfer process, including five which are currently in advanced transfer negotiations.
In 2010, the MRC Human Immunology Unit and MRC Molecular Haematology Unit have successfully transferred to form part of the MRC Weatherall Institute for Molecular Medicine in Oxford, a leading institute in translational medicine. This was followed in 2011 by the MRC Human Genetics Unit: 200 MRC staff and students joined the University of Edinburgh to form the Institute of Genetics and Molecular Medicine, one of the largest centres for human genetics research in Europe. In addition to supporting the new institute at a level of £60m over 5 years, MRC has contributed £3.5m to a new building improving integration between the MRC, Cancer Research UK and University activities at the institute and the linkages of research programmes with computational science.
Research Changes Lives objectives in progress
Working with our partners, we will ensure that the Francis Crick Institute will provide a world leading environment for UK research and contribute to the delivery of MRC strategic priorities
We will enhance strategic partnerships with Universities and continue the transfer of MRC Units into University Units through the University Units programme
We will build on our investments into leading MRC Centres to establish de novo University Units in key strategic areas
127 We will invest in new, cutting edge equipment to support research in structural therapeutics
We will continue to invest in the existing portfolio of property to improve facilities for researchers. We ill also participate in environmental programmes to reduce our carbon footprint and operating costs
Outcomes 2009-2012 MRC Mary Lyon A wide variety of mouse models of human disease are Centre, Harwell regularly disseminated from the Mary Lyon Centre in the form of frozen embryos/sperm or live mice. Between Nov 2009 and Oct 2010 a total of 178 stocks were sent to 108 different research groups from 13 countries. During the same period 75 stocks were imported for archiving and subsequent distribution to the scientific community via the MRC-Harwell's frozen embryo and sperm archive314. Since 2006 the Transgenics service has created 88 new mouse models, supporting 8 research groups at MRC Harwell and 20 additional programmes throughout the UK in 16 different universities and research institutes. MRC Institute of Scientists have discovered an enzyme that corrects the most Genetics and common mistake made during DNA replication315; the Molecular incorporation of RNA into the DNA sequence. RNA is much Medicine (IGMM) less stable than DNA, and accidental incorporation into the at the University genome can cause breaks in the double helix, a feature which of Edinburgh is common in cancer cells. Professor Nick Hastie, director of the MRC IGMM, said: “This study is a fantastic example of clinicians working alongside laboratory scientists towards a shared goal of improving our understanding of human health and disease. Such progress would not be possible without the critical mass of scientists at the IGMM, with capabilities in many key areas coupled with access to patient data and clinical expertise.” MRC Technology MRC’s additional investment in the CTD is aimed at opening Centre for up the unique expertise of MRC Technology’s collaborative Therapeutics centre to a wider group of UK researchers. More than 13 Discovery research groups have been provided with compound libraries (CTD)316 to carry out small scale screens to test assay robustness, identify tool compounds or useful chemistry starting points. The CTD has performed least six large-scale in silico screens of up to 800,000 compounds for researchers under the current grant. This has enabled research teams to identify potential hits and tool compounds or starting points for chemical optimisation within their research programmes. Over 20 tool compounds have been provided to support further research, and the first agreement with a commercial partner was announced in 2010317. The therapeutic antibody group within the CTD has had an involvement in developing 10% of the world’s pipeline of therapeutic antibodies
314 http://har.mrc.ac.uk/services/fesa/ 315 Enzymatic Removal of Ribonucleotides from DNA Is Essential for Mammalian Genome Integrity and Development Cell (2012) http://dx.doi.org/10.1016/j.cell.2012.04.011 316 http://www.mrctechnology.org/about/our-structure/centre-for-therapeutics-discovery 317 MRC Technology enters into an exclusive license agreement With Genentech http://www.mrctechnology.org/news/press-centre/mrc-technology-enters-into-an-exclusive-license- agreement-with-genentech
128 including the world’s first antibody to be used in a clinical trial for Alzheimer’s disease318. Kevin Park (MRC The MRC-funded Centre for Drug Safety Science was Centre for Drug established as a joint venture between the Universities of Safety Science319) Liverpool and Manchester to bring together a critical mass of knowledge and technologies in order to advance our understanding of Adverse Drug Reactions. Among projects at the centre which are adding value to the research environment is a HLA-typed biobank of peripheral blood mononuclear cells for 400 healthy volunteers. This biobank allows a better mechanistic understanding of drug-induced hypersensitivity reactions320, and has been used to define a new paradigm for analysing the impact of the immune system on drug-induced organ injury. In 2012 the centre has attracted funding from the Innovative Medicine Initiative to lead a £29m initiative to develop new tests for predicting drug-induced liver toxicity in partnership with 9 academic institutions, 6 small and medium enterprises and 11 pharmaceutical companies across Europe. Simon Philips RCAH is funded by the MRC and BBSRC to create a leading (Research multi-disciplinary centre of scientific excellence alongside the Complex at Diamond synchrotron. The aim was to ensure the Harwell, RCAH321) opportunities provided by Diamond, ISIS and the Central Laser Facility were maximised. Within the RCAH the highly successful Oxford Protein Production Facility aims to promote and facilitate high throughput structural biology for the UK academic community. A recent highlight was publication of the structure of an enzyme that confers antibiotic resistance322. Bacteria with this resistance had only been isolated from patients in 2010, and quickly obtaining structural information on the protein responsible has informed research searching for new anti-bacterial treatments. David Stuart The BM14 project ran from 2001 – 2009 to provide a state of (BM14) the art facility for macromolecular structure, build up the expertise of the community, keep the UK at the cutting edge of synchrotron structural biology beamline developments, and enable the transfer of knowledge and experience to Diamond. Use of BM14 has produced more than 600 publications, resulted in 535 deposited structures in the Protein Data Bank, and made significant contributions to the automation of sample handling, sample management and automation of data collection. A major achievement has been the development of an information management system for synchrotron beamlines, ISPyB which is now deployed at the ESRF and Diamond. The concerted international collaboration focussed on BM14 has changed the way MX data collection is executed and has impacted on other scientific disciplines who exploit synchrotron radiation. Finally, the BM14 project has benefited operations at Diamond, and also other synchrotron
318 1st patient treated with BAN2401 http://www.mrctechnology.org/news/press-centre/1st-patient- treated-with-ban2401 319 http://www.liv.ac.uk/drug-safety/index.htm 320 The Development of In Vitro Culture Methods to Characterize Primary T-Cell Responses to Drugs Toxicol. Sci. (2012) 127 (1): 150-158. doi: 10.1093/toxsci/kfs080 321 http://www.rc-harwell.ac.uk/home.html 322 Structure of New Delhi metallo-β-lactamase 1 (NDM-1) ActaCryst. (2011). F67, 1160- 1164 doi:10.1107/S1744309111029654
129 sources. The leader of the BM14 team was recruited as Life Science Coordinator at Diamond.
Under an agreement with the ESRF, the EMBL-Grenoble in collaboration with the Indian government now manages the BM14 beamline for the 19 EMBL member states and associated scientific communities, as well as the Indian crystallographic community. Peter Jezzard, In 2011, a new Acute Vascular Imaging Centre (OxAVIC323) Peter Rothwell, was opened to patients next to the John Radcliffe Hospital’s Alistair Buchan emergency department, providing patients with a fast and others assessment of the brain damage caused by stroke, as well as (University of research into new techniques of image capture and analysis. Oxford) Several of the teams are MRC-funded and will build on substantial existing clinical research infrastructure and strong NHS-University links fostered by the NIHR funded Oxford Comprehensive Biomedical Research Centre and Comprehensive Stroke Centre.
323 OxAVIC is funded through grants from the MRC, British Heart Foundation, Wellcome Trust, Department of Health, NIHR, Wolfson Institute, Dunhill Medical Trust, Foundation Leducq, University of Oxford and Oxford Radcliffe Hospitals Charitable Funds http://www.avic.ox.ac.uk/Welcome
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Glossary of terms
ABPI - Association of the British Pharmaceutical Industry
AHRC – Arts and Humanities Research Council
BBSRC – Biotechnology and Biological Sciences Research Council
EPSRC – Engineering and Physical Sciences Research Council
ESRC – Economic and Social Research Council
NIMR – National Institute of Medical Research
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