School of Clinical Medicine Review 2009 - 2011

School of Clinical MedicineReview 2009–2011

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IntroductionWelcome to the Clinical School Review

CUHPCambridge University Health Partners

NIHRNational Institute for Health Research Funding

CCTUCambridge Clinical Trials Unit

EASIHEastern Sequence & Informatics Hub

DILJuvenile Diabetes Research Foundation/ Wellcome Trust Diabetes & Inflammation Laboratory

Graduate School of Life Sciences

CUCRSCambridge University Clinical Research Society

The Raymond & Beverly Sackler Medical Research Centre

Medical EducationProviding good medical practice

MBPhD Programme at 21

BCNIThe Behavioural & Clinical Neuroscience Institute

CBUMRC Cognition & Brain Sciences Unit

CRICancer Research UK Cambridge Research Institute

CIMRCambridge Institute for Medical Research

CoNTENTS

Contents

IMSInstitute of Metabolic Science

IPHInstitute of Public Health

Appointments & ElectionsProfessors, Readers & University Lecturers

A model for advancing academic medicine

Teaching old cells new tricks

Expanding access to transplantation

Physical sciences illuminate neurodegenerative diseases

Changing behaviour to improve public health

Improving outcomes for autoimmune diseases

Delivering better ways of preventing stillbirth

Joining forces to tackle obesity

From blue sky to bedside

High risk hearts – a South Asian epidemic

Awards

Finance

020506080909101111 12 13 14 15 16 17

1819 20222426283032343638

4240

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Introduction

This mission is enshrined in the constitution of Cambridge University Health Partners which brings together the University and its three principal NHS partners – Cambridge University Hospitals NHS Foundation Trust, Papworth Hospital NHS Foundation Trust and Cambridgeshire and Peterborough NHS Foundation Trust – in a new legal entity from 2009. It is one of five such partnerships formally designated as Academic Health Science Centres by the Department of Health in England. As I write, this is a time both of opportunity and challenge for

all University/NHS partnerships. The opportunities lie in the translation of the outstanding research being pursued across the University and the partnership into advances in the treatment and management of disease. As this report shows, the vitality and success of our biomedical and translational research has never been greater. At the same time the challenge lies in the current major structural reorganisation within the NHS, and in the accompanying drive for efficiency savings across the whole service. This inevitably impacts on our NHS partners as it does throughout

Regius Professor of Physic, Sir Patrick Sissons

Aerial view of Cambridge Biomedical Campus

Welcome to the Clinical School Review for 2009–2011. It tells a story of continuing progress in the development of the University’s School of Clinical Medicine – progress, in all aspects of the 'tripartite mission' of education, research and clinical service.

Aerial view of campus

3INTRoDUCTIoN

the whole health service. As an Academic Health Science Centre we must look outwards to compare ourselves to the best equivalent centres across the world – in Europe, North America and increasingly in Asia – and here the achievements of Cambridge in biomedical and clinical research stand comparison with the very best centres internationally. However, at the same time as we measure ourselves against this global competition, it is crucial that we in the Clinical School also look to our regional healthcare system and ensure that our teaching and research lead to service innovation and benefit the healthcare economy we serve with our regional NHS partners. It is thus a key aspect of our mission as an Academic Health Science Centre to build educational, research and service partnerships with our surrounding NHS partner organisations which deliver healthcare in the region, and also provide undergraduate and postgraduate teaching and training for our medical students and faculty. My colleagues and I in Cambridge University Health Partners see our contribution to this wider 'Academic Health Science System' as a critical goal for the immediate future and, again as I write, it is encouraging to see there is a national recognition of the contribution that the Academic Health Science Centres can make to innovation across the health service.

The Cambridge Biomedical Campus is at an exciting stage of its development, reflecting the realisation of the plans the campus partners (Cambridge University Hospitals, the Clinical School, the MRC and Cancer Research UK) have pursued over the past decade. The new road and transport access for the expanded campus are in place and the splendid new building for the MRC Laboratory of Molecular Biology ('LMB2') is nearing completion. Plans for the relocation of Papworth Hospital to the expanded campus

are at an advanced stage, with building expected to start in a year’s time – realising a vision which goes back more than twenty years. The Government is rightly keen to position the UK so that it can build on its major contributions to the life sciences in an internationally competitive climate, by facilitating interactions with industry and translating research into advances in healthcare. The Cambridge Biomedical Campus with its close location to the Wellcome Trust Sanger Institute, the Babraham Institute and the surrounding science parks is part of the wider 'Cambridge cluster' but also forms one end of a corridor stretching from new developments in biomedical research in north London (with the Francis Crick Institute at St. Pancras), through the GlaxoSmithKline campus at Stevenage, to Cambridge – all of which gives the broader critical

mass so essential for international competitiveness.

The vitality of our research endeavour is captured in this report. of particular note is the success of our National Institute for Health Research (NIHR) Biomedical Research Centre which has just been successfully renewed (one of five nationally) in a competition judged by an international panel, and provides the infrastructural funding for translational clinical research – again our success is a reflection of the strength of the partnership between the University and Cambridge University Hospitals, through whom the NIHR funding flows. The NIHR CLAHRC (Collaboration for Leadership in Applied Health Research and Care), held through the University and Cambridgeshire and Peterborough

Aerial view of Cambridge Biomedical Campus

A student being examined in clinical skills

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NHS Foundation Trust partnership, is also proving a success in developing innovative new care pathways in mental health. The Clinical School’s annual research grant income from the principal funders of UK biomedical research (the Medical Research Council, Wellcome Trust and medical research charities) continues to follow an upward trajectory and now stands at some £86m annually. This reflects the excellence and creativity of my colleagues in the Clinical School, across its Departments and in our three principal Institutes: the Cambridge Institute for Medical Research, the Institute of Metabolic Science and the Institute of Public Health which, with the Cancer Research UK Cambridge Research Institute, provide so much of our cutting edge research. Here it is worth noting that we intend to build on our excellence in biomedical research with a strategic focus on research in population and public health, both at national and international level, and on the contribution public health can make to our regional healthcare system.

The strength of Cambridge biomedical research is further exemplified in the period under review by the awards of the Lasker Prize for Basic Biomedical Research in 2008 to David Baulcombe (for small regulatory RNAs); and in 2009 to John Gurdon (for nuclear re-programming); and of the 2010 Nobel Prize for Physiology or Medicine to Robert Edwards (for in vitro fertilisation) – all from our sister School of Biological Sciences – and by the international quality of the research on the Cambridge Biomedical Campus, with the award of the 2009 Nobel Prize for Chemistry to Venki Ramakrishnan from the MRC LMB (for the structure of the ribosome), and with the other prizes listed later in this report. These strengths in basic biological research underpin, and provide a fertile environment for, the highest quality clinical

research. In addition, clinical research draws increasingly on the strengths that can be harnessed across the wider University, as reflected in our collaborative research with the physical sciences, engineering and social sciences. This interdisciplinary approach across the University has been formalised in a number of strategic 'cross School' research initiatives approved by the University. These include the Cambridge Cancer Centre, Cambridge Neuroscience, the Cambridge Infectious Disease Initiative, the Cambridge Stem Cell Initiative and the Cambridge Immunology Network.

Finally, education and training remain at the heart of our mission. It is gratifying to see the success of our pioneering MBPhD programme (conceived by my predecessor Sir Keith Peters and led by my colleague Tim Cox) as reflected in the survey and analysis of the Programme described here on its 21st birthday, and in the growing number of its graduates who are now independent investigators.

We continue to attract the very best medical students to both our standard clinical course and our graduate entry course. The extended three year clinical course, and the associated new curriculum (led by my colleague Diana Wood), are aimed in particular at preparing our graduates for their transition to working as doctors in the health

service – and recent evidence suggests our graduates do indeed now feel much better prepared for this critical step. We look forward to the opening this year of the Deakin Centre (named after Tony Deakin, former Addenbrooke's NHS Trust Chairman) which includes new clinical skills training facilities for our students. It is becoming clear that the Clinical School needs to increase its intake of medical students so that it can offer more of the students who come to Cambridge to study Medicine the opportunity to complete their clinical training in Cambridge. This is an ambition we hope to realise in

the next few years, against a national background of continuing pressure for changes in medical education. Graduate student education is also a vital aspect of our educational activity – as evidenced by the growing number of PhD students and programmes, and new taught Masters courses.

Thus the story of medicine, and the journey of the School of Clinical Medicine in Cambridge, continue on an exciting and upward trajectory. This is only achieved by the contributions of the many people, students and staff, who study, teach and pursue research, in the School: I thank them all for what they do to make the School such a rewarding and stimulating place in which to work.

Deakin Centre

Introduction

TWo YEARS IN PRoFILE 5

In April 2009, following a competitive process judged by an international panel, the Department of Health formally designated five Academic Health Science Centres (AHSC) of which Cambridge University Health Partners (CUHP) was one.

Cambridge University Health Partners

Bringing together the University of Cambridge, Cambridge University Hospitals NHS Foundation Trust, Cambridgeshire and Peterborough NHS Foundation Trust and Papworth Hospital NHS Foundation Trust, CUHP exists to facilitate partnership working across a number of boundaries – between community and hospital-based medicine, between general and specialist services, and between the University and the NHS. CUHP enables the partners to work together in a structured fashion in order to pursue the tripartite mission of research, education and clinical service.

Since its formation, CUHP has enabled the partners to open formal discussions about shared infrastructure in a number of areas – including research support, where a clinical trials unit has already been launched under the leadership of Dr Ian Wilkinson; and fundraising, where the partners are discussing the possibility of a joint function to support philanthropy across all four partners. These are examples

of areas where the partners believe they can achieve added value through shared working, and it is an important part of CUHP’s mission to enable the partners not only to identify such areas, but also to facilitate implementation – often involving far-reaching culture change.

CUHP has been particularly active in the education realm through the Regional Innovation and Education Cluster. A number of workstreams have been formed to identify areas of clinical practice where new patient pathways require support in the form of innovative educational provision. These include diabetes, chronic obstructive pulmonary disease (CoPD), urology and palliative care. CUHP has also led for the partners on the policy agenda relating to the future of postgraduate education within the NHS.

Most recently, two new senior appointments have been made to CUHP. Dr Robert Winter, previously Medical Director at NHS East of

England, joins as Director of the Academic Health Sciences System. Dr Winter will work with the four CUHP partners and their regional associates to develop new clinical programmes and innovative healthcare pathways: to inform the commissioning of health services in the region and work with the emerging GP consortia to explore new opportunities for integrated services; to ensure that public health expertise is used to inform the work of CUHP; and to work with the University to identify programmes with potential for application to healthcare.

Dr Arun Gupta, Director of Postgraduate Education at Cambridge University Hospitals, joins as Director of Postgraduate Education: he comments "CUHP offers the opportunity to combine the strengths in healthcare education of each of the partners. It is vital that we maintain and develop the healthcare education sector to make sure we continue to produce excellent clinicians in the future."

Dr Robert Winter Mr Stephen Davis, Chief operating officerDr Arun Gupta

Two years in profile

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National Institute for Health Research (NIHR) fundingIn December 2006, Cambridge University Hospitals NHS Foundation Trust in partnership with the University of Cambridge, was designated one of the Government's new National Institutes for Health Research (NIHR) Comprehensive Biomedical Research Centres and as a consequence received substantial new research and development funding from the NIHR. In August 2011, the NIHR announced the second round of Biomedical Research Centres (BRCs) and Units (BRUs). Cambridge did exceptionally well in this competition, with its BRC (with Dr John Bradley as operational Director and Professor Steve o'Rahilly as Scientific Director) renewed for a further five years with a 48% increase in funding, and a new BRU in Dementia (directed by Professor Peter St George-Hyslop) awarded. our success in this competition builds not only on an our impressive track record of research achievement over the first five years of the BRC but also on our record of delivery through the Collaboration for Leadership in Applied Health Research and Care (CLAHRC) held by Cambridgeshire and Peterborough NHS Foundation Trust and the NIHR Research Networks. These investments underpin the research of the School of Clinical Medicine as a whole, and virtually every development reported in this Review has received support from the NIHR in some form or other.

Biomedical Research CentreThe Cambridge BRC is a collaboration between the University of Cambridge and Cambridge University Hospitals NHS Foundation Trust. As well as contributing to the direct costs of clinical research programmes in ten key thematic areas, including Cancer, Cardiovascular Disease and

Metabolism and Endocrinology, the BRC has provided investment in core infrastructure to support clinical research across the campus. This has included not only the development of physical facilities such as a molecular phenotyping hub, a bio-repository and associated sample storage area, and (together with the Medical Research Council) the Eastern Sequencing Hub (EASIH), but also the funding of a major programme of research training for clinicians, under the leadership of Professor David A Lomas.

The BRC has also formed important links with Industry. A PET-CT scanner acquired in partnership with Merck, underpins research across a number of themes, and serves a wide range of research organisations. In excess of 200 patients have been entered into studies using the PET scanner many of which are sponsored by Cambridge University Hospitals NHS Foundation Trust.

At the point of renewal, the BRC has been expanded to include not only Cambridge University Hospitals, but also to include research partners within Cambridgeshire and Peterborough NHS Foundation Trust. over the next five years, the BRC aims to use its expertise in genomics, population science, imaging, pathology, immunology, cell, molecular and developmental biology, and regenerative medicine to continue developing novel diagnostics and treatments for common and rare diseases.

Key objectives of the BRC from 2011 onwards, as shown in the table, include cancer, cardiovascular disease, dementia and neurodegeneration, brain injury, mental health, obesity and diabetes, infectious diseases, disorders of the immune system,

and those associated with women's health. To enable and accelerate these health benefits, the BRC will continue to work with other BRCs and BRUs, research councils, research charities and industry to embed infrastructure for translational research within the NHS to pull through our world-class experimental medicine into NHS clinical use.

The BRC aims to achieve effective integration and translation through sharing of research findings and methodologies, fostered by shared infrastructure including clinical informatics, ongoing review of scientific discoveries in the context of clinical needs and priorities, and the application of Health Service Research methodologies to experimental medicine. The BRC will develop capacity across professions, building on the success of the existing Capacity Development and our Training Theme. The NIHR Cambridge BRC will provide, within the Cambridge Biomedical Campus, opportunities for translational research that are offered by very few biomedical centres in the world.

John Bradley, Director of R&D Cambridge University Hospitals NHS Foundation Trust and the Cambridge Comprehensive BRC


Collaboration for Leadership in Applied Health Research and Care (CLAHRC)The CLAHRC is a collaboration between the University of Cambridge and Cambridgeshire and Peterborough NHS Foundation Trust. It forms a partnership between the University of Cambridge and a consortium of NHS and Social Service organisations, which as well as Cambridgeshire and Peterborough NHS Foundation Trust includes, NHS Cambridgeshire, NHS Peterborough, Cambridgeshire County Council and the local Strategic Health Authority.

The University component includes the Department of Psychiatry, the Institute of Public Health, the Judge Business School and the Engineering Design Centre. The CLAHRC focuses on the application of research to everyday practice in mental health care, and will align its activity with

the BRC. The investment of the NIHR Cambridge BRC in the Herchel Smith Building for Brain and Mind Sciences and the establishment of themes in Mental Health, Dementia and Neurodegeneration, and Evaluation and Implementation, within the BRC, will ensure effective transition between the early stages of translation supported by the BRC, and the later stages of implementation that form the focus of the CLAHRC.

NIHR Research NetworksA further source of NIHR support to clinical research is represented by the NIHR Research Networks, including the West Anglia Comprehensive Local Research Network, the West Anglia Cancer Research Network, and the Eastern England Diabetes Research Network.

By working closely with the BRC, the NIHR Research Networks, fostered

by the involvement of key Cambridge researchers, ensure an effective environment on campus for the transition of translational research activity into later stage clinical trials.

Effective translation is also supported via additional NIHR funding streams such as Research for Patient Benefit and Programme Grants where funding has been received by Cambridge University Hospitals researchers in areas such as Cancer; End of Life Care; Imaging; Medicines Management; Diabetes (reducing the burden of Type 2 diabetes by translating epidemiology and behavioural science into preventative action); Mental Health (causes & effective treatments for psychotic disorders) and Transplantation (access to transplantation and transplant outcome measures), which involves the transplant units across the UK, UK Transplant and the UK Renal Registry.

The NIHR Cambridge BRC is built around nine topic specific themes, with cross cutting themes in Population Science and Genomics, and cross-cutting resources for Imaging, Capacity Development, and Evaluation and Implementation.

PopulationScience Genomics Imaging

CapacityDevelopment

Evaluation andImplementation

Women's Health

Transplantation and Regenerative Medicine

Metabolism Endocrinology and Bone

Mental Health

Immunity Inflammation Infection

Dementia and Neurodegeneration

Cardiovascular

Cancer

Brain injury and repair

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2011 has seen the establishment of the Cambridge Clinical Trials Unit under the directorship of Dr Ian Wilkinson. Funded through the Cambridge Biomedical Research Centre, Cambridge University Hospitals NHS Foundation Trust and Cambridge and Peterborough NHS Foundation Trust, this is one of the first collaborations under Cambridge University Health Partners.

Cambridge Clinical Trials Unit

Working alongside Dr Ian Wilkinson, dealing with the day to day operations and set-up of the unit, is the Assistant Director, Dr Sabine Kläger. The Unit has grown considerably in the first year from three to 15 members of staff, working in three teams: Clinical Trial Management and Co-ordination; Quality Assurance and Safety; and Data Management and Statistics. The Unit also has close links with the Cambridge Cancer Trials Centre, and various University Departments including the Centre for Health Services Research, the Department of Public Health and Primary Care, and the MRC Biostatistics Unit.

The aim of the Unit is to work with investigators to develop and conduct the highest quality clinical research. This may range from simple advice through assistance with protocol development and trial design, to full-blown trial co-ordination, databasing and statistical analysis. The Unit has developed a suite of guidance notes, templates, forms and standard operating preocedure (SoPs) available to investigators for all key aspects of trial activities, which will ensure that researchers are working within the regulations that surround Clinical Trials of Investigational Medicinal Products (CTIMPs). In addition, the Unit can now provide a data management system called MACRo to build clinical trial data bases.

Trial data bases in MACRo meet all the Medicines Healthcare products Regulatory Agency (MHRA) validation and Good Clinical Practice (GCP) audit trail requirements. It enables electronic data capture (EDC), replacing paper case report forms (CRFs) with on-line electronic CRFs (eCRFs), which have inbuilt data cleaning checks and data audit trail. A library of eCRF templates for common data capture pages like vital patient statistics, blood results, or serious adverse event/serious adverse reaction (SAE/SAR) forms facilitates the set-up of such data bases.

Providing these resources, the Unit will enable researchers to take on more clinical trial work, knowing that the appropriate back-up for regulatory and GCP compliant systems and resources are in place.

The Unit has delegated oversight for all Cambridge University Hospitals or University sponsored CTIMPs. The majority of the currently active 33 CTIMPs are early phase I/II trials and multi-centre trials. The portfolio also includes phase III/VI trials and a number of small mechanistic studies, as well as some large observational studies. The Unit does not focus on specific disease areas, but supports investigators from all specialities and is currently involved in the set-up of around 24 new projects.

Dr Ian Wilkinson


Juvenile Diabetes Research Foundation/ Wellcome Trust Diabetes and Inflammation Laboratory (DIL)The DIL is supported by a five year Strategic Award from the Wellcome Trust, plus funding from the Juvenile Diabetes Research Foundation, National Institute for Health Research Biomedical Research Centre, the EU FP7 and the National Institute of Diabetes and Digestive and Kidney Diseases, to identify mechanisms and disease precursors in autoimmune diabetes (T1D) and related diseases.

In this third period of funding, we are exploiting our genetic findings to characterise immunophenotypes in human blood samples that are under the control of the T1D risk loci and genes. By using microarray gene expression, next generation

sequencing, immunoassays and polychromatic flow cytometry we have identified cellular and molecular phenotypes that could lead to informative biomarkers, and that could be used in future treatment and prevention trials in T1D. Most recently, the DIL is establishing a clinical team to begin studies and trials in patients and unaffected siblings towards stratified, mechanism-based prevention strategies.

The DIL has three principal investigators, John Todd (Director), Linda Wicker (co-Director) and David Clayton, who supervise immunology, genetic, clinical, bioinformatics and statistical studies in the Cambridge Institute for Medical Research and with their collaborators.

Eastern Sequence and Informatics Hub (EASIH)In the last few years next generation DNA sequencing has been developed, the first major advance since Sanger sequencing was invented over two decades ago.

The new sequencing methods allow DNA sequencing at a higher throughput and lower cost. These advances are literally revolutionising genomics in basic and medical research, from whole genome sequencing (including

hospital pathogen sequencing and identification), to the identification of the parts of the genome that control gene expression.

In 2009 the University of Cambridge won a national funding competition from the MRC to establish one of four next generation sequencing hubs. EASIH (www.easih.ac.uk) is now fully set up and operational in the heart of the Clinical School, with additional support from the NIHR Cambridge Biomedical Research Centre and the University of Cambridge.

our major projects are medical sequencing, exome sequencing, RNA-sequencing, ChIP-seq, HLA typing and hospital pathogen sequencing.

EASIH will become clinically accredited and, in collaboration with East Anglian Medical Genetics

Service, will play a major part in the introduction of medical genomics into the NHS for patient benefit. The facility is headed by Dr Anthony Rogers, and the Director is Professor John Todd.

Linda WickerProfessor of Immunogenetics

John Todd Professor of Medical Genetics

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The Graduate School of Life Sciences has been established to create a single vibrant postgraduate research community for approximately 1,500 graduate students and 1,500 postdoctoral early-career researchers spread across 21 University departments in the Faculties of Clinical Medicine, Veterinary Medicine and Biology, five University institutes and 12 local University Partner Institutes, such as the MRC Laboratory of Molecular Biology and the Wellcome Trust Sanger Institute.

A key element in the success of the Graduate School has been the co-ordination of the admission, monitoring and examination of students, creating a firm platform on which their research activities and skills training can take place.

This has been achieved through central academic and administrative collaborations and dissemination of best practice, but also through response to feedback from students.

This collaborative arrangement has also provided a suitable framework for the rapid and co-ordinated development of showcase doctoral research programmes, such as, our four-year doctoral training programmes funded by the Wellcome Trust, MRC and British Heart Foundation; a Translational Medicine and Therapeutics MPhil and PhD programme; three highly successful international scholarship programmes with the National Institutes of Health, Howard Hughes Medical Institute (Janelia Farm) and A* Singapore; and a new Clinical Academic Training programme for clinicians, set up in response to NIHR requirements.

In each case, the Graduate School provides the wider context in which such programmes can readily be integrated with training and research in basic biomedical sciences across the University. For example, some of the students admitted to a four-year doctoral training programme in Medicine may proceed to a PhD in Biological Sciences and vice-versa.

The Graduate School is now recognised in the University as a focus for graduate student training, providing induction and a wide range of research and transferable skills training. In recent Postgraduate Research Experience Surveys, the Graduate School consistently scored highly compared to other Cambridge Schools and UK universities in the level of satisfaction expressed by students with support offered for their research and skills training.

Graduate School of Life Sciences


The Raymond and Beverly Sackler Medical Research Centre

As highlighted in an article by Professor Edwin Chilvers further on in the review, there are concerns about academic medicine in the UK. The Cambridge University Clinical Research Society founded in December 2009 by Garth Funston and Adam Young whilst studying as undergraduate clinical medical students, has been a welcome addition to the work the University is doing to contribute to the national drive to 'rejuvenate' academic medicine.

The CUCRS had a very successful first year, holding a number of events including, among other things, talks by leading scientists and a large national student conference where 65 medical students, from 11 UK universities presented their submissions.

Keen to build on this success Garth and Adam have secured additional funding from the Wellcome Trust to expand their initiative and establish a National Student Association of Medical Research. Sir Mark Walport, Director of the Wellcome Trust, is Honorary President of the Association which was launched in November 2011 (see http://ftp5.dns-systems.net/~nsamr/ for more details). The Association envisages individual university societies working together to promote the cause of academic medicine on the national stage.

'Garth and Adam have demonstrated the very real appetite that exists amongst medical undergraduates to engage with research. Their leadership, in driving forward the establishment of a student led research society, not just in Cambridge but also in other schools, demonstrates the appeal of their vision. They have thrown out a powerful challenge to those in leadership roles in our medical schools to ensure that the training that they offer meets the needs and expectations of the fee paying student generation. The future health of academic medicine demands a creative response.’

John Williams PhD FRCPE Head of Clinical Activities Head of Neuroscience & Mental Health Wellcome Trust

Cambridge University Clinical Research Society (CUCRS)

Garth Funston

Adam Young

The Clinical School remains grateful to the Raymond and Beverly Sackler Foundation for their generous and consistent support for medical education and research through the Sackler Scholars and the Sir Keith Peters Scholarships programme, and for enabling academics and students from across Cambridge to hear distinguished scholars and scientists on subjects within the field of medical sciences through the Sackler Distinguished Lectures programme.

Raymond and Beverly Sackler StudentshipsA growing number of highly qualified postgraduates are applying for the Raymond and Beverly Sackler Studentships. In october 2009 the School was able to offer a total of 28 awards. In october 2010 we offered 29 and for the academic year beginning october 2011 we have just awarded 24 awards. We have also been able to provide funding for Clinical School MBPhD students during their three year research phase.

Sackler Distinguished LecturesThe Sackler Distinguished Lectures Fund provides lectures by distinguished scholars and scientists on subjects within the field of the medical sciences. During the period under review there have been two lectures:

20 June 2011, 'How antibiotics illuminate ribosome function and vice versa', Professor Venki Ramakrishnan FRS.

14 June 2010, 'Small RNA and epigenetics: lessons from plants for studies of heritability and disease', Professor Sir David Baulcombe FRS.

Professor Sir Venki Ramakrishnan FRS and the Regius Professor of Physic

The Regius Professor of Physic and Professor Sir David Baulcombe FRS

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Titlebody

Medical education in the Clinical School aims to produce graduates who combine high academic achievement with excellence in the clinical, communication, practical and interpersonal skills required for good medical practice.

The School attracts applications from outstanding students and is greatly over-subscribed by Cambridge pre-clinical medics wishing to continue their clinical studies here. This complete change from the historic situation reflects the introduction of the new clinical curriculum in 2005 and the huge amount of work put in by both academic and NHS staff in Cambridge and throughout the Eastern region. This has been led by a dedicated group of staff who have become enthused by the challenges and rewards of student teaching and learning, many of whom have undertaken higher academic qualifications in medical education to further their educational expertise. Staff development for education is expanding within the School and we work closely with NHS colleagues in postgraduate education to ensure that skilled and dedicated clinical teachers are available in all the Trusts and general practices where Cambridge students are taught. In this way we offer clinical education

of a very high standard across a wide range of socio-economic settings and clinical environments which is much appreciated by the students and which provides them with a sound basis for making the transition from medical student to doctor.

Looking to the future, in the light of recent success, the changes in Higher Education funding and the structural changes in the wider NHS educational environment, the School aims to continue to increase the number of places available for students to study clinical medicine in Cambridge, with the overall aim of providing a complete medical education programme for all our Cambridge students.

The period under review has seen two important anniversaries. Events to mark the 21st anniversary of the MBPhD programme are described over the next page. Taken together with the structured approach to clinical academic training developed through the CATo office (see p22),

we are now able to offer a more integrated career pathway to our students with academic ability and ambition. 2011 also marked the 10th anniversary of the Cambridge Graduate Course in Medicine (CGCM) which admitted its first students in 2001 and which now shares its final year with MBPhD students completing their clinical studies. CGCM students tend to be over-represented at the top of the academic rankings and we have been particularly pleased that recent analysis shows the performance of our students whose first degree is in a non-biomedical science is equal to that of the science graduates. These students add diversity to the student body and their breadth of experience bodes well for them and the profession as they move on into their future careers.

Nationally, medical schools are keen to preserve the diversity of undergraduate medical education programmes, whilst providing evidence of equal achievement of the graduate outcomes established by the General Medical Council. We do not seek to educate our students to minimum standards. Rather, working together with the School of Biological Sciences and our NHS partners, we aim to enthuse our students to take all the educational opportunities available and move on to excel in their subsequent medical careers. There is always work to be done, but current evidence suggests that our education programmes are thriving!

Medical Education

Dr Diana Wood, Clinical Dean

A student in a simulated patient/doctor environment


MBPhD Programme at 212010 saw the Clinical School celebrate 21 years of the first UK MBPhD Programme with an all-day symposium in November. Professor Cox, Director of the Programme since its inception, reviewed the Programme’s development and progress to a large and diverse audience of numerous programme alumni and other distinguished speakers, including the Vice-Chancellor, Sir Mark Walport (Director of the Wellcome Trust), and Professor Sir Keith Peters.

Sir Keith had conceived this educational initiative on his appointment as Regius Professor of Physic in 1987 with the Programme actually starting in 1989.

The six-year Programme includes a three-year full-time research period integrated within the standard clinical course and has an overall duration from matriculation of nine years. Since 1989, 162 graduates have been enrolled of which a quarter have transferred as graduates from other universities in both the UK

and overseas. of the 107 members who had graduated by 2010, almost one third were women.

Not only has the performance of the Programme been striking in its achievements in the clinical examinations, but alumni have also gone on to excel in the research field. In an anonymous electronic survey carried out in 2010, 90% of alumni contacted responded. of those nearly 80% were still engaged in research, 90% have continued research after graduating, and 85% were planning further academic work – including a majority with research fellowships in mind.

Perhaps the most telling statistics of the survey were the career placements of the alumni. of the respondents, 30 were full-time academic staff. Just after the symposium, Dr Jeremy Hall was appointed Professor of Psychiatry in the University of Edinburgh – the second Full Professor in the cohort. Dr Moeen Panni had earlier

been appointed as Full Professor and Chairman, Department of Anaesthesiology, Duke University Medical Centre, NC, USA. of the 35 alumni still in clinical training, 11 were Specialty Registrars, six Academic Clinical Fellows, three Academic FY2s. Many former Programme members were full-time Clinical Consultants. There were many other notable achievements: Dr Barakat, a Reader in Metabolic Medicine and Medical Director of the Department of Medicine at Imperial College was awarded the oBE for establishing the Imperial College London Diabetes Centre in Abu Dhabi. other achievements included a Wellcome Trust Senior Research Fellowship to Dr Floto and an MRC Senior Clinical Fellowship to Dr Marciniak (both pictured above) both of whom are based in Cambridge.

Professor Tim Cox Dr Stefan Marciniak Dr Andres Floto

Professor Roger Barker with MBPhD students

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The Behavioural and Clinical Neuroscience Institute (BCNI)

Funding was recently renewed (2010) for a second five-year period. The BCNI Director, Professor Trevor Robbins, is Head of the Department of Experimental Psychology and based at the Downing site in central Cambridge; the Clinical Director, Professor Ed Bullmore, is in the Department of Psychiatry and based on the Cambridge Biomedical Campus. The BCNI is thus organised to bring together Cambridge's geographically distributed strengths in basic and clinical neuroscience to optimise translational impact on a wide range of neurological and psychiatric disorders. The BCNI is partly accomodated in refurbished space in the Herchel Smith Building for Brain & Mind Sciences and has a strong collaborative partnership with the neuroimaging facilities managed by the Wolfson Brain Imaging Centre.

one of the four principal programmes of the BCNI includes several projects

thematically related to aspects of compulsive and impulsive behaviour. This behavioural trait has been explored in animal models and linked to the function of frontal cortical and striatal circuits in the brain. Compulsivity and associated abnormalities of fronto-striatal network function have also been linked to a range of disorders such as drug addiction, obsessive-Compulsive Disorder (oCD) and attention deficit/hyperactivity disorder. This work provides a rational mechanistic basis to 'repurpose' existing drugs for

new therapeutic indications in the treatment of addiction and oCD – two disorders which currently lack specific pharmacotherapies. The cross-cutting dimension of reward-driven compulsivity is also relevant to understanding some of the behavioural factors that drive over-eating and obesity. This provides a focus for inter-disciplinary interactions between neuroscience and metabolic science in the University and has also been central to the successful partnership between BCNI investigators and GlaxoSmithKline to develop the therapeutic potential of a new opioid receptor antagonist for binge eating and substance dependence disorders.

other programmes are concerned with identifying the psychological mechanisms underlying such disorders as schizophrenia and depression, relating these to changes in brain circuitry, and testing possible therapeutic effects of drugs on cognitive functioning. The BCNI also has a keen interest in cognitive disorders in neurodegenerative diseases such as Parkinson’s and Alzheimer’s diseases, in collaboration with the Department of Clinical Neurosciences. Specific achievements include the design of a neuropsychological test of visuospatial learning and memory that can be used to predict a diagnosis of Alzheimer’s disease 32 months earlier in patients with mild cognitive impairment and is now available on iPad for use in GP surgeries.

These and other aspects of the BCNI’s translational agenda will be greatly strengthened by infrastructural support through the Mental Health theme of the NIHR Cambridge Biomedical Research Centre.

Professor Ed Bullmore

Professor Trevor Robbins

The Behavioural and Clinical Neuroscience Institute (BCNI) is a centre for translational neuroscience, jointly funded by the Medical Research Council and the Wellcome Trust.

Working hypothesis: impulsivity arises from a reduced density of spines on GABA-ergic neurons in the Nacb core


The MRC Cognition and Brain Sciences Unit is a leading centre for cognitive science and neuroscience and its translation into benefits for health and well-being. Established in 1944 as the Applied Psychology Unit, it has an illustrious history as one of the largest and most long-lasting contributors to the development of psychological theory and practice.

In April 2011 Professor Susan Gathercole was awarded a MRC Research Chair at the University, and took up the role of Honorary Director of the Unit. Sue is a cognitive psychologist whose research focuses on the processes of memory, attention, language, and learning. Much of her work involves children with developmental disorders in these areas of cognition, investigating both the fundamental mechanisms underpinning these disorders and the development of cognitive and educational interventions.

Sue says “It’s a privilege to take on the stewardship of the CBU at this exciting time at which cognitive neuroscience has come of age, and is now delivering real benefits for health”. The mission of the CBU is to improve human health by understanding and enhancing cognition and behavior in health, disease, and disorder. It will maintain its long-standing commitment to cognitive science and cognitive

neuroscience of the highest quality, particularly in the fields of memory, attention, language, and emotion in which important advances are being made in understanding both the cognitive processes and their brain mechanisms.

The Unit is also strongly committed to translating its discoveries in these fields into preventative, therapeutic and educational interventions. Recent advances include the development of new techniques to treat emotional disorders such as anxiety, depression and Post Traumatic Stress Disorder (PTSD), to address cognitive problems resulting from brain damage, and to enhance prosthetic devices in hearing-impaired populations.

With several new teams joining the CBU, there will be an increased emphasis on understanding typical and disordered development spanning childhood through to older age, enhanced by partnerships with clinical and non-clinical teams within and beyond the University.

Professor Susan Gathercole

MRC Cognition and Brain Sciences Unit (CBU)


Cancer Research UK Cambridge Research Institute (CRI)

of particular note was the official launch of the Cambridge Cancer Centre on 3 February 2010. The centre is a collaboration between Cancer Research UK, the University of Cambridge, Cambridge University Hospitals NHS Foundation Trust and the Medical Research Council, and has a vision to build strong links across disciplines from the laboratory to the clinic. The CCC builds on the previous centre that has been active since 2006, and its new formal identity will further strengthen our mechanisms for joint planning between the partners. The CCC annual symposia continue to be extremely popular,

the 2011 plenary speaker was Robert Weinberg from the Whitehead Institute. We also hosted a popular Experimental Cancer Medicine Centre open day for the public, and CRI staff ran interactive displays at the Cambridge Science Festival with their CUH colleagues.

We were very pleased with the outcome of the CRI's first five-year review on 14 April: the review panel were extremely positive and praised our approach to translational research. For example, pancreatic cancer research and clinical trials continue to be a core focus for the CRI, and our work in this area was

strengthened by the launch of the Cambridge Pancreatic Cancer Centre in March 2011, which aims to bring treatments into first-in-man clinical trials as quickly as possible. In addition, CRI group leader David Tuveson was awarded an honorary professorship, with the title of 'Professor of Pancreatic Cancer Medicine'. The translation from the laboratory to the clinic is a core thread to the CRI's work, which has been supported by the launch of a biomarkers initiative to support this work.

The number of research groups at the CRI now stands at 22. We have been joined by Shankar Balasubramanian, who holds the Herchel Smith Professorship of Medicinal Chemistry (in a joint appointment with the Department of Chemistry) and Douglas Fearon. Junior group leaders Jason Carroll and Duncan odom were awarded tenure and promoted to senior group leaders. other group leaders who have been honoured include: Simon Tavaré (Fellow of the Royal Society), Carlos Caldas (Fellow of the European Academy of Cancer Sciences), Shankar Balasubramanian (Fellow of the Academy of Medical Sciences) and John Griffiths (Gold Medal of the International Society for Magnetic Resonance in Medicine).

2010 and 2011, our fourth and fifth years of operation, have marked a period of consolidation of our important interactions with the wider Cambridge scientific community and the public, and the launch of some new collaborative initiatives.

Scientists in the Caldas lab at the Cambridge Research Institute discuss data.

Image provided by Charles DN Thomson, Cancer Research UK

Professor Sir Bruce Ponder; Li Ka Shing Professor of oncology and Director of Cancer Research UK Cambridge Research Institute


Its outstanding feature is the interweaving of clinical medicine with molecular and cell biology and it provides a unique interface between basic and clinical science that is supported by a Strategic Award from the Wellcome Trust. The CIMR has as its major goal the determination and understanding of the molecular and cellular mechanisms of disease. Presently, the major research themes are misfolded proteins and disease, intracellular membrane traffic, autoimmune disease and haematopoietic stem cell biology.

The CIMR provides a state of the art research environment for over 250 researchers and accounts for almost a third of the research grant expenditure in the Clinical School. over 40% of its Principal Investigators are medically qualified and clinically active, a percentage that has remained constant since the CIMR opened ten years ago. Eight of the CIMR Principal Investigators are Wellcome Trust Principal Research Fellows, a quarter of the national total and the most at a single location in the UK. All of the clinical and non-clinical scientists in the CIMR belong to home departments and currently there are six with some staff who are primarily housed in the CIMR. These are the Departments of Medicine, Medical Genetics, Clinical Biochemistry, Clinical Neurosciences, Haematology and Pathology.

Principal Investigators in CIMR make an important contribution to the translational agenda of the Clinical School. Examples of activities that have progressed along the translational path towards patient benefit include (i) the introduction by Professor Tony Green (Department of Haematology) of the diagnostic use of mutations in JAK2 and other genes for frontline investigation of myeloproliferative disorders (also now a central part of national and

international guidelines), (ii) the identification and use of novel transcription signatures by Professor Ken Smith’s group (Department of Medicine) to predict prognosis in autoimmune disease, (iii) the clinical safety trial of an autophagy-inducing drug for Huntington’s disease following Professor David Rubinsztein’s pioneering studies of the activation of autophagy to clear mutant huntington in cell and animal models of Huntington’s disease and (iv) high through-put screens carried out by Professor David Lomas’ group (Department of Medicine) to identify small molecules to block serpin aggregation and so treat the group of diseases known as serpinopathies.

Cambridge Institute for Medical Research (CIMR)

The Cambridge Institute for Medical Research (CIMR) is a cross-departmental, multidisciplinary research centre within the Clinical School and is housed in the Wellcome Trust/MRC Building.

Professor Paul Luzio, Director of CIMR

Crystal structure of a serpin dimer revealed a large scale domain swap Yamasaki M, Li W, Johnson DJ, Huntington, JA. (2008). Crystal structure of a stable dimer reveals the molecular basis of serpin polymerization. Nature 455, 1255–8

18


Institute of Metabolic Science (IMS)

obesity and related health problems are some of the most pressing public health issues of our time. Nearly a quarter of all adults and one in five children in England are classed as obese, and these numbers continue to increase (www.ic.nhs.uk). The IMS is a joint venture of the University of Cambridge, the Medical Research Council and Cambridge University Hospitals NHS Foundation Trust. Led by Co-Directors Professors Stephen o’Rahilly and Nick Wareham, it is unique in the UK, providing an interface between experimental and clinical research to further fundamental understanding of obesity, diabetes and related metabolic diseases, and linking these advances directly to patient care and disease prevention.

The IMS provides facilities for laboratory and clinical research at the University of Cambridge Metabolic Research Laboratories (MRL), allied closely with epidemiological and public health research at the MRC Epidemiology Unit, and clinical areas (the Wolfson Diabetes and Endocrine Clinic and the Weston Centre for Childhood and Adolescent Diabetes and Endocrinology) that provide state-of-the-art treatment facilities.

The MRL currently hosts 20 Principal Investigators. It leads the MRC Centre for obesity and Related Metabolic Diseases, which also involves scientists in the School of Biological Sciences, local MRC Units, the Wellcome Trust Sanger Institute and the University of oxford, and hosts the Wellcome Trust 4-year PhD Programme in Metabolic and Cardiovascular Disease.

The most exciting scientific discoveries at the MRL during the last two years include: identification of the first rare copy number variants associated with severe early-onset obesity; novel insights into epigenetic changes that link poor diet during pregnancy with an increased risk of the offspring developing Type 2 diabetes in later life; that the effects of thyroid hormones on brown fat are mediated via the hypothalamus, a region of the brain that also controls food intake; and paradigm shifting observations of circadian regulation in red blood cells that overturn the long held belief that circadian rhythms require changes in gene expression. In 2009, Professor David Ron, an international authority on endoplasmic reticulum stress and metabolic disease, moved from

New York to take up a Wellcome Trust Principal Research Fellowship at the MRL.

The main research areas of the MRC Epidemiology Unit are the genetic, environmental and developmental aetiology of diabetes and obesity, nutritional and physical activity epidemiology and the translation of that understanding into prevention strategies at both individual and population levels.

In the last two years the MRC Epidemiology Unit has been instrumental in major international collaborative studies identifying genetic variants associated with common obesity in adults and children, timing of puberty, type 2 diabetes and multiple other metabolic traits. other significant discoveries include that physical activity attenuates the genetic predisposition to obesity. We have also established evidence on the benefits and harms of screening and hence early detection of Type 2 diabetes that are directly informing the design of UK preventative strategies.

The Institute of Metabolic Science (IMS) is a purpose-built institute on the Cambridge Biomedical Campus. It addresses the growing health threat posed by obesity, diabetes and related metabolic and endocrine diseases.

Professor Steve o'Rahilly FRS Professor Nick Wareham


The Institute of Public Health (Director Professor Brayne) was formed nearly twenty years ago as a strategic partnership between the NHS, MRC and the University. It is one of the three Institutes within the School of Clinical Medicine.

The Department of Public Health and Primary Care is a core member of the Institute. It also includes three MRC units, the MRC Biostatistics Unit, the MRC Epidemiology Unit (also in the Institute of Metabolic Science) and the Human Nutrition Unit. The NHS members are the Eastern Region Public Health observatory including Quality Intelligence East, the Regional Epidemiology Unit of the Health Protection Agency and the Eastern Region Cancer Intelligence Centre whose core function is to provide population health intelligence for commissioning and surveillance. The Foundation for Genomics and Population Health (PHG Foundation) is the first charitable status member.

The Institute’s purpose is to foster research, training and service to improve population health. The research programmes within IPH focus on major chronic disorders from biology to policy, integrating different approaches for maximum benefit. These thrive on the IPH partnership and are illustrated by the programme on cardiovascular epidemiology on p40 (Professor Danesh). There are four major initiatives, Professor Marteau’s is profiled on p30, all focus on cross IPH linked translational research.

CEDAR (Centre for Diet and Activity Research, Director Professor Wareham) is one of five Centres of Excellence in Public Health Research. Its purpose is to develop the evidence required for changing dietary and physical activity behaviours in populations including research capacity building.

Successes include 19 grant funded appointments made in 2010–2011 including studentships, fellowships, and lectureships. Research includes tracking active travel in relation to the Cambridge Guided Bus-way and evaluating the Activ8 programme, an afterschool physical exercise club in primary schools.

The new Cambridge Centre for Health Services Research (CCHSR) was established in 2010 (Director Professor Roland). It is a collaboration between the university and RAND Europe, an independent not-for- profit policy research centre based in Cambridge. CCHSR will develop new methods of measuring quality of care, evaluate initiatives to improve the quality of health care and inform health policy in the UK and abroad.

The IPH hosts the Public Health and the End of Life themes of the NIHR Cambridge Collaborative Leadership

in Applied Health and Care (CLAHRC, Director Professor Jones). This CLAHRC aims to improve translation of research relevant to mental health into practice at points of transition across the lifespan. These have increased capacity in health services research, health economics, policy analysis and implementation. Key areas of work include systematic reviewing for policy development in dementia, evaluation of service reconfiguration and innovation, particularly in old age and at the end of life.

IPH members provide a range of teaching, from training health intelligence staff from Primary Care Trusts to doctoral programmes. The IPH has three Masters programmes: the longstanding MPhil in Epidemiology, the MPhil in Public Health and a new Masters in Primary Care (MPhil in Clinical Sciences (Primary Care Research)).

Institute of Public Health (IPH)

Professor Carol Brayne

20

Appointments & Elections

Professorial appointments during period under review

Appointments & elections

Ken Smith

Professor of Medicine

Geoff Woods

Professor of Human Genetics

Christopher Watson

Professor of Transplantation

James Huntington

Professor of Molecular Haemostasis

Ziad Mallet

BHF Professor of Cardiovascular Science

Arthur Kaser

Professor of Gastoenterology

David Ron

Professor of Cellular Pathophysiology and Clinical Biochemistry

Keith Martin

Professor of Ophthalmology

RogerBarker

Professor of Clinical Neuroscience

Sadaf Farooqi

Professor of Metabolism and Medicine

Susan Gathercole

MRC Research Professor of Cognitive Psychology

Berthold Göttgens

Professor of Molecular Haematology

Willem ouwehand

Professor of Experimental Haematology

APPoINTMENTS AND ELECTIoNS 21

University LecturersUniversity Senior Lecturers

Dr Cedric Ghevaert, Haematology

Mr Paul Gibbs, Surgery

Dr Pablos Monsivais, Public Health and Primary Care (PHPC)

University Lecturers

Dr Stephen Barclay, Public Health and Primary Care (PHPC)

Dr Kathy Beardsall, Paediatrics

Dr Menna Clatworthy, Medicine

Dr Emanuele Di Angelantonio, Public Health and Primary Care (PHPC)

Dr Thomas Krieg, Medicine

Dr Belinda Lennox, Psychiatry

Dr Stefano Pluchino, Clinical Neuroscience

Dr Ken Poole, Medicine

Dr Marc Tischkowitz, Medical Genetics

ReadersDr Francesco ColucciReader in Immunology

Dr Fiona GribbleReader in Endocrine Physiology

Dr Susan ozanneReader in Developmental Endocrinology

Dr James RoweReader in Cognitive Neurology

Dr Ian WilkinsonReader in Clinical Pharmacology and Therapeutics

22

Professor Edwin Chilvers

Clinical academic staff play a crucial role in advancing the treatment and care patients receive in the NHS. Professor Edwin Chilvers, Director of the Clinical Academic Training Office explains how Cambridge is helping lead the way in rejuvenating academic medicine nationally.

Katy Teo, Academic Clinical Fellow in Surgery

A model for advancing academic medicine

23A MoDEL FoR ADVANCING ACADEMIC MEDICINE

In 2005, the Walport Report on Modernising Medical Careers sounded the alarm about the state of health of clinical academic training in the UK. 'Warning bells have been ringing for some time over the perilous state of academic medicine and dentistry,' the report said.

Research, it pointed out, is an essential part of a healthy NHS, but too many barriers face those seeking a clinical academic career: routes of entry and career paths were unclear; there was a shortage of properly structured and supported posts; and greater flexibility was required in the balance between clinical and academic training.

on the back of the report, and determined to rejuvenate academic training in the field, Cambridge set up the Clinical Academic Training office (CATo) in 2009. Two years on, CATo's director Professor Edwin Chilvers is upbeat about its impact.

“Research training is a vital part of postgraduate training for people in all specialities, both hospital- and community-based,” he explains. “We regard research training as an integral part of clinical training. It's not just about generating clinical academics – the professors and senior lecturers of the future – but also enriching the clinical practice of those who go on to become full-time NHS doctors.”

Facilitating this training is where CATo comes in. By delivering high-level administrative and mentoring support for academic training programmes across the Clinical School, CATo shoulders the burden previously borne by individual departments and programme leads.

A key part of CATo's work is acting as the interface between the NHS (which in many cases is the employer), national and international, funding bodies such as the National Institutes of Health (NIH), Wellcome Trust and National Institute for Health Research (NIHR), the postgraduate deanery, (which is responsible for ensuring doctors are properly trained,) and the Clinical School, which is responsible for the academic component.

We hope, says Professor Chilvers, that “CATo brings the structure and support needed to enable clinicians to train as world class scientists with access to research and academic mentorship right the way through from undergratuate medical student level to postgraduate Foundation, Core and Specialist Training posts. Many of the programmes that offer this opportunity are now administered by CATo."

Responsible for more than half a dozen different programmes – funded by organisations from the NIHR and the Foundation Programme to the NIH, MRC and the Wellcome Trust – worth some £15 million a year, CATo has catalysed major changes in academic clinical training at Cambridge.

“A significant proportion of trainees working in the Cambridge University Health Partnership hospitals are academic trainees in one of these programmes,” he says. "one example of this is the doubling in the number of Clinical Lectureships in the School over the past five years; these posts have been funded in part by the NIHR and CATo has played a key role in their establishment. So CATo provides the local hub for a very exciting uplift in clinical academic training occurring countrywide."

Another measure of its success is the fact that 70% of NIHR-funded Academic Clinical Fellows now go on to get nationally competitive Research Training Fellowship support, and a similar proportion of academic clinical lecturers go on to more senior fellowships. Crucially, those who are appointed from these schemes to NHS posts continue to have very research-active careers.

CATo has also been instrumental in delivering a raft of postgraduate qualifications for these trainees, including masters-level qualifications, and its ability to demonstrate the value of its work is helping secure further funding.

According to Professor Chilvers: “Having a strong administrative core in CATo acts as a sound springboard for Cambridge to compete nationally and internationally for further

academic programmes. When these bids go in we need to show how they will be administered, and through CATo we can demonstrate we have all the necessary facilities, structures and know-how.”

With many more programmes than most other medical schools in the UK, Cambridge ranks highly, thanks to CATo. “It's a model of how to do interface working in a modern academic health sciences centre,” he concludes.

For more information on the Cambridge Academic Training office, visit cato.medschl.cam.ac.uk

I was a product of the Cambridge MBPhD Programme and began an NIHR-funded academic clinical fellowship in psychiatry in 2007; CATo was created two years later. Its energetic team have taken a lead in organising clinical academic training across specialities and grades, improving access to research training opportunities and making it significantly easier to organise academic training when multiple agencies (e.g. funding bodies, postgraduate deanery, university, NHS trusts) are involved. Following my ACF post I was awarded a Wellcome Trust postdoctoral fellowship for MBPhD graduates, to develop computational models of unsupervised attentional selection and competitive learning in the brain; I hope to pursue a career in clinical academic psychiatry.

Rudolf Cardinal

Dr Ludovic Vallier

Much hyped by the media, stem cells have tremendous power to improve human health. As part of the Cambridge Stem Cell Initiative, Dr Ludovic Vallier's research in the Anne McLaren Laboratory for Regenerative Medicine shows how stem cells can further our understanding of disease and help deliver much-needed new treatments.

Teaching old cells new tricks

24

25TEACHING oLD CELLS NEW TRICKS

How do you study a human disease that has no equivalent in animals and where the human cells in question are so hard to grow outside the body they cannot be tested in the laboratory? The answer, until now, was with great difficulty. But by using a new stem cell technique, that is set to change.

Dr Ludovic Vallier, who holds an MRC Senior Fellowship in the Anne McLaren Laboratory for Regenerative Medicine, Department of Surgery at Cambridge in collaboration with Professor David Lomas (CIMR and Department of Medicine), works on a group of devastating genetic diseases affecting the liver.

“We target metabolic diseases of the liver, diseases such as alpha 1 antitrypsin deficiency. It's one of the most common single genetic disorders and the protein it affects – which is only produced by the liver – is really important because it controls activity of elastase in the lung. Without this control, people develop serious lung problems and the disease also affects the liver, so these patients develop liver failure,” he explains.

The problem is that these diseases cannot be studied in vitro – in a dish –in the laboratory, he says: “You can't take cells from the liver of these very sick patients, and if you could they wouldn't grow, which means you don't have any way of screening drugs that could help treat these diseases.”

Without effective drugs, the only current treatment is a liver transplant. “There is a huge shortage of organs and transplantation involves taking immunosuppressive drugs, which is heavy treatment especially in already fragile patients,” Dr Vallier says. “And the disease is progressive so it's very complicated to manage.”

Understandably, Dr Vallier is excited that a new method of producing stem cells developed in Japan has given him and other researchers a way of studying these diseases and screening potential drugs to treat them.

“The new technology consists of taking cells from skin and reprogramming them so that they become stem cells – cells that are capable of proliferating and differentiating into almost all tissue types,” he says.

This reprogramming means a cell with a previously fixed identity can be taught a new one – in this case taking skin cells and reprogramming them to become liver cells. When the skin cells come from a patient with liver disease, these skin-turned-liver cells also have the disease, making them ideal for studying the disease and screening potential drugs to treat it.

According to Dr Vallier: “Because we can generate liver cells that mimic the disease of the original patient in vitro, that allows us to do basic studies that were impossible by biopsy or primary culture and also to do drug screening.”

And because the skin cells can come from a whole range of people, it gives researchers access to a broad diversity of patients as well as overcoming some of the ethical concerns associated with embryonic stem cells.

“That's a very important step because it solves the problems associated with a limited stock of stem cells,” he says, “and because it's a simple method, it is easily accessible to a wide number of laboratories .”

Showing this can be done in a small number of liver patients in Cambridge is an important proof of concept, that supports the possibility that a similar approach might be applicable to a wide range of other serious diseases that still lack effective treatments, including neurodegenerative diseases such as Parkinson's and Alzheimer's Disease as well as heart diseases.

And Cambridge – which now has almost 30 groups doing stem cell research and strong links between academic researchers and clinicians – is perfectly positioned to make the most of this new technique.

“The Laboratory for Regenerative Medicine is starting to become an expert in this disease modelling and we are all part of a larger

consortium, the Cambridge Stem Cell Initiative (SCI)” says Dr Vallier. “Together, we are putting together resources and scientific interest to really develop stem cells and their clinical application. The SCI is a unique consortium because it brings together a wealth of complementary expertise.”

While this first revolution involves in vitro disease modelling and drug screening, Dr Vallier hopes this work will ultimately lead to personalised cell-based therapies where liver cells reprogrammed from a patient’s own skin cells could be used in place of a liver transplant. “It will take time for us to assess this clinical use and show that it is safe as well as effective,” he says, “but if you ask me again in five years I should be able to tell you whether we are going to do it.”

For more information on the Cambridge Stem Cell Initiative, visit www.stemcells.cam.ac.uk

Professor Andrew Bradley

In the UK, one in 20 people who need a kidney transplant will die waiting. With waiting lists expanding while the number of donors remains static, research in Cambridge is helping change policy and practice on kidney transplantation, giving more patients the chance of a new organ – and a new life.

Mr Gavin Pettigrew, Professor Bradley and Professor Chris Watsonleading research to increase access to transplantation


26

27ExPANDING ACCESS To TRANSPLANTATIoN

“Transplants are a miracle of modern medicine,” says Professor Andrew Bradley, Clinical Director of Transplant Surgery at the Cambridge Transplant Unit. More and more people need access to this miracle. Today, over 7,000 people in the UK are waiting for a new kidney – twice as many as ten years ago – yet only 800 kidneys become available each year, a number that is flat-lining.

“There is an increasing discrepancy between the huge number of patients waiting for a kidney transplant and the number of available organs,” Professor Bradley says. “Waiting lists are going up but the number of organs is static.”

Studies at Cambridge are improving access to kidney transplants – research that is changing national and international policy, as well as patients' lives.

Since the 1970s, most organs for transplant have come from so-called brain-death donors – people whose brains die before their hearts stop beating. But over the past decade the number of brain-death donors has declined because fewer people die due to traffic accidents and the way patients with head injuries are cared for has changed.

Another group of potential donors exists – people who have recently died from cardiac arrest – yet many surgeons believe kidneys from these cardiac-death donors are somehow inferior. A Cambridge-led study, however, has shown this is not the case.

Comparing hundreds of patients who received kidneys from either brain-death or cardiac-death donors, they found no difference in long-term kidney function or survival rates.

Unlike kidneys from brain-death donors, which are allocated nationally according to a points-based system, use of kidneys from cardiac-death donors still depends on local policy. In Cambridge, as result of the transplant team's research, over half of all transplanted kidneys now come from cardiac-death donors.

“Cardiac-death donors represent an extremely important and widely overlooked source of high-quality donor kidneys and have the potential to make a big difference to the number of kidney transplants done in the UK,” Professor Bradley says.

“Using these kidneys has allowed us to double our transplant rates. If what we have achieved in our region was reproduced across the UK, we could increase the number of kidney transplants by between 50 and 100%.”

The study could change the number of kidneys available and how they are shared throughout the UK. As a result of the findings, NHS Blood and Transplant (which manages and optimises the supply of blood, organs and tissues and raises the quality, effectiveness and efficiency of blood and transplant services) has set up a working group to decide whether these kidneys should be shared in the same – or similar – way to organs from brain-death donors.

And other studies done at Cambridge indicate the number of available organs could be expanded even further.

Transplant policies in the UK mean that many kidneys from potential donors who have died from primary brain tumours go unused because of cases where some recipients have developed cancer from the donated organ.

But research in Cambridge, which tracked thousands of patients using both the UK transplant registry and cancer registries in England, Wales and Northern Ireland, found that none of the 448 recipients who received organs from donors with brain cancer developed the disease.

A kidney patient developing cancer from a donor is, Professor Bradley admits, catastrophic, but his research shows it's a rare occurrence that must be balanced against the risk of not getting a transplant. “We talk about patient and graft outcomes and survival, but if you don't get a transplant and get left on the waiting list, then for kidney transplants

5% of those on the waiting list die every year,” he explains.

Similarly, work at Cambridge has shown that lengthening the time window within which kidneys can be removed after life support has been discontinued from one to four hours makes 30% more kidneys available without affecting the success of the transplant.

Through robust research, these studies are providing the evidence needed to change policies and practice, increasing access to transplantation and making a real difference to patients.

And making a difference is, Professor Bradley and his team point out, what their research at Cambridge is all about: “There are 23 kidney transplant centres in the UK. We're a close community. It's essentially a national service with common protocols, sharing schemes, and there are guidelines for many aspects of practice. What we hope is that our work informs those guidelines and gets taken up nationally and ideally internationally.”

“It's very rewarding when you see things actually change,” he concludes, “Moving from a situation of never sharing cardiac-death donor kidneys in the UK towards a sharing scheme where they can move around the country would be very satisfying.”


Professor Peter St George-Hyslop, FRS

What do physicists, chemists, mathematicians and biologists have in common? One of the answers at Cambridge is a shared interest in unravelling the processes behind neurodegenerative diseases such as Alzheimer's, Parkinson's and Motor Neurone Disease.

Physical sciences illuminate neurodegenerative diseases

28

Accumulation of protein called tau in neurons as Neurofibrillary tangles

Accumulation of protein called Amyloid beta-peptide (Abeta) in brain as Amyloid or Senile plaques

Loss of nerve cells in brain

29PHYSICAL SCIENCES ILLUMINATE NEURoDEGENERATIVE DISEASES

As more people live to a ripe old age, an increasing number of us will develop neurodegenerative diseases such as Alzheimer's. Despite the escalating economic costs and human misery associated with these diseases, we still know relatively little about how they develop or how best to tackle them.

Alzheimer's is the most common neurodegenerative disease. “It's an enormous problem and we're not doing very well at the moment in slowing the disease or treating its symptoms effectively,” says Professor Peter St George-Hyslop.

Neurodegenerative diseases such as Alzheimer's are difficult to study for several reasons. “one is that it's not easy to get pieces of living brain,” he explains. “It's also a disease where patients become unable to speak for themselves, so unlike people with AIDS or breast cancer they aren't demonstrating outside the houses of Parliament demanding funding.”

Although charities and campaigners are doing sterling work raising the profile of Alzheimer's, until recently attitudes to neurodegenerative disease had much in common with the way we viewed cancer 50 years ago.

“We are, for Alzheimer's, like where we were for cancer in the 1950s, when people didn't like to talk about it, were frightened or ashamed of it. And therapeutically we are in the same place; although we are beginning to learn about these diseases we don't yet have much in the way of effective therapies,” Professor St George-Hyslop says.

one crucial discovery is that proteins misfolding in the brain form clumps or aggregates and these play a major role in causing neurodegenerative diseases. When these proteins misfold they take on certain characteristics that become noxious to cells, but what we need to know now is why these proteins misfold, which aggregates do the damage, and how that damage occurs.

Which is where physics, chemistry and mathematics enter the biological picture.

Professor St George-Hyslop leads a group of experts from disparate disciplines, each bringing different tools and different ways of working to the study of neurodegenerative diseases.

What began in late 2008 as a series of meetings has now developed into a 12-strong group funded by a £5.3 million Strategic Award from the Wellcome Trust and Medical Research Council. “It's a very interesting group of people who came together because they wanted to come together. They each knew they had something to contribute but also that they needed something else – some skills, some knowledge, some point of view – from another member of the group,” he says.

“The biologists among us knew there were techniques that the physicists and chemists had that could help us. They in turn knew we had some biological knowledge that would help them apply, in a sensible way, their very good and insightful physical and chemical tools.”

Among the group is Professor David Klenerman from the Department of Chemistry. one of the inventors of rapid, high-throughput DNA sequencing, he is now applying this knowledge to protein misfolding. From the same department comes Professor Michele Vendruscolo, a theoretical physicist working on the mechanics and thermodynamics of protein misfolding. Professor Chris Dobson, who is also from the Department of Chemistry works on protein misfolding in neurodegenerative diseases, while from the Department of Chemical Engineering and Biotechnology Dr Clemens Kaminski brings modern laser spectroscopy tools that allow you to watch these proteins misfold inside living cells in real time.

The group has applied these physical tools to study nematode worms in which a mutation produces the

same protein misfolding that causes disease in humans. “That ability to see these things as they happen in a living model give us a much greater understanding compared with previous techniques, which essentially involved grinding up biological samples and examining them after these processes had occurred,” Professor St George-Hyslop explains.

“What's important is the marriage of the physical tool with the biological question,” he says. And he hopes that by revealing where these misfolded proteins act, these new tools could help researchers develop ways of blocking the damage they cause in both Alzheimer's and other neurodegenerative diseases.

“The primary goal is to understand what the beginning and the middle parts of the process are. We know what the end is – the cell dies and you get a disease – but if you know why the cells get sick and what the mechanisms are then you have a better chance of preventing or halting it,” says Professor St George-Hyslop. “our goal is to provide that fundamental knowledge of cause and mechanism. Hopefully from that will come some idea of which parts of those pathways you can monitor as a diagnostic and which parts you can block or change as a treatment.”

More recently, the group has been enlarged by a £4.5 million grant from the National Institute of Health Research to support an extension of the Cambridge Biomedical Research Centre via the creation of a Biomedical Research Unit in Dementia for translational research. This has allowed the inclusion of researchers in immunology and in brain imaging from the department of Medicine and the Wolfson Brain Imaging Centre.

Professor Theresa Marteau

Bringing together experts from a broad range of disciplines, Cambridge's new Behaviour and Health Research Unit (BHRU)will provide policy makers with new evidence on ways of changing behaviour to improve health across the population.

It seems at once the simplest and most complex of health problems: by eating healthily, not smoking, being more active and cutting down on alcohol, we can live longer, healthier lives. Why, then, do so many of us ignore this advice?

New unit boosts research on changing behaviour to improve public health

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31IMPRoVING PUBLIC HEALTH

April 2011 saw the launch of Cambridge's new Behaviour and Health Research Unit (BHRU). Funded by the Department of Health's Policy Research Programme, the Unit's remit is to develop and evaluate ways of changing behaviour at a population level to improve health and reduce health inequalities. Something that, so far, many countries have tried to do, with limited success.

The Unit brings together a team of experts from the University of Cambridge, two MRC units in Cambridge (Epidemiology and Human Nutrition Research), RAND Europe and the University of East Anglia. As well as researchers from the Clinical School, the Unit includes David Spiegelhalter, Winton Professor of Public Understanding of Risk at the Centre for Mathematical Sciences. The range of disciplines covered includes behavioural science, neuroscience, anthropology, economics and epidemiology.

This mix is what marks out the new Unit, says its Director and Honorary Professor of Behaviour and Health, Theresa Marteau. “It's a range of disciplines, some of which have been addressing similar problems but from different perspectives, for example bringing in neuroscience as well as epidemiology and behavioural science to understand the behaviour that contributes to population health and ill-health.”

Insights from behavioural and neurosciences into the basis of everyday behaviour will be particularly important. “We will focus on two key systems. The first is the reflective, goal-directed system driven by our values and intentions. We want to lose weight, we intend to eat less. The second system is the more automatic system that is driven by immediate feelings and habits. These two systems operate sometimes synergistically as well as antagonistically in shaping our behaviour,” she says.

So, despite intending to eat less, we find we have bought the chocolate bar at the checkout. “As neuroscience increasingly reveals how our behaviour is governed by unconscious processes, we understand better how advertisers and retailers shape our behaviour, unfortunately often to the detriment of our health. The trick is to see how we can capitalise on this understanding to develop more effective interventions that cue healthier behaviours.”

Focusing on four key behaviours – diet, physical activity, smoking and alcohol consumption – the Unit's research programme has two overlapping strands, primary research and synthesis of existing evidence.

According to Professor Marteau: “It's good science to start with what we know, based on rigorous evidence synthesis, and design new studies that contribute to the existing evidence.”

one of the Unit's new primary research studies involves studying on-line food purchasing using a virtual, online supermarket. Using this, researchers will be able to vary the way purchasing decisions are presented to thousands of 'shoppers', as well as altering how foods are presented.

“The virtual online supermarket provides the opportunity to run a large number of experiments in which we can change different features in a systematic way to identify the most promising interventions to take forward in real-life experiments,” she explains.

How, for example, do our brains deal with a chocolate bar that looks very inviting but carries a nutritional label warning us about its calorie count? And does a web site adorned with fruit and vegetables prime people to buy more of this type of food?

The virtual online supermarket goes to the heart of what researchers in the field call 'choice architecture'

and how consumers might be 'nudged' into making healthier choices.

To be useful to policy makers, interventions need to be acceptable as well as effective, so another strand of research at BHRU is examining the public and political acceptability of interventions, something particularly relevant to alcohol.

According to Professor Marteau: “The majority of smokers want to quit and the majority of those who are overweight want not to be so. By contrast, most people in the UK don't want to reduce how much alcohol they consume. In part reflecting this, only half the population favours any kind of pricing policy to reduce alcohol consumption. This raises questions about the basis upon which such judgments are based. What happens if the evidence about the effectiveness of alcohol policies is presented not in terms of health but, for example, in terms of road accidents or violence? Does this alter how acceptable people find policies that at first glance they reject? How sensitive are people’s judgments to the weight of evidence including its uncertainty? Exploring these questions using experiments grounded in qualitative work could shed light on the complex relationship between science and policy in health and other areas of public policy.

For more information on the Behaviour and Health Research Unit, visit www.bhru.iph.cam.ac.ukNew unit boosts research on changing

behaviour to improve public health

Professor Ken Smith

They are chronic, debilitating but highly variable conditions. Now, researchers are discovering that different autoimmune diseases seem to be underpinned by common genetic signatures, and that these signatures could change the way doctors treat patients with these common and often life-threatening diseases.

Improving outcomes for autoimmune diseases

The autoimmune transcriptome – fluorescent spots whose intensity reflects the level of all genes

expressed in CD8+ T lymphocytes from a patient with active systemic vasculitis.

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33IMPRoVING oUTCoMES FoR AUToIMMUNE DISEASES

We all rely on our immune system for protection against infection and disease. But for a significant proportion of us, that immune system mistakenly attacks our body's own, healthy cells.

Known collectively as autoimmune diseases, the term encompasses some 80 different conditions from type-1 diabetes and rheumatoid arthritis to lupus and vasculitis, and around one in ten of us will suffer from an autoimmune disease at some stage during our life.

Although therapies exist, treating patients with certain autoimmune diseases is not straightforward. Within the same condition the disease can be much more aggressive in some patients, which, combined with the fact that current treatments often have significant side effects, presents clinicians with a dilemma.

According to Professor Ken Smith of the Cambridge Institute for Medical Research and Department of Medicine: “When people present with these conditions, treatment is pretty standardised, so everybody with the same diagnosis gets much the same approach to treatment. That's because at the moment we can't tell which patient will have the more aggressive disease.”

Being able to accurately predict this however, would make a major difference to patients. “In Crohn's Disease, for example, there is a very effective treatment called anti-TNF therapy, but the trouble is it has side-effects,” Professor Smith explains. “Currently, we minimise that toxicity by taking a conservative approach to treatment, only giving anti-TNF therapy to those whose disease flares up repeatedly.”

“That means that if you don't have aggressive disease, you don't get

unnecessary treatment, which is good. The problem is that if you have aggressive disease your therapy is delayed and it's very clear that this delay reduces the effectiveness of treatment.”

Working with patients at Cambridge University Hospitals and using the latest microarray technology at the Cambridge Institute for Medical Research, Professor Smith and his team have discovered a way of identifying which patients are destined to have an aggressive form of these diseases.

By taking blood samples from patients with lupus or vasculitis, measuring gene expression – the process by which information encoded in our genes is converted into proteins and other large molecules that perform specific functions in our bodies – and then tracking the course of these patients' disease, the team found a key difference between those whose lupus or vasculitis proved aggressive and those with less aggressive disease.

“We found in one specific white cell, the so-called killer T cell, people had one of two different gene expression patterns. The difference was very distinct. And after three years it became very clear that the people in the smaller group – around one third of the patients – had a 90% chance of relapsing disease while the other two-thirds had only a 10% chance,” he says.

Repeating the blood tests with Crohn's Disease and ulcerative colitis they found the same split emerged. “If anything, it was even more striking,” says Professor Smith. “Gene expression patterns in these white cells divides patients into two groups when they present, and these predict long-term

outcome over three years so we can tell which will have more aggressive disease even though at the outset they look indistinguishable from each other clinically.”

of the four diseases so far studied – lupus, vasculitis, Crohn's Disease and ulcerative colitis – the same pattern holds. “Even though they are different diseases there is a common pattern that is determining outcome which is very interesting scientifically,” he reflects.

With the test now patented, the team is setting up further research in Crohn's patients that will use the test to guide therapy. “We would hope that by treating some patients earlier, treatment would be more effective and that long-term disease-related damage in these patients – which often requires surgery – would be reduced.”

The research shows what can be achieved by combining well-defined patient populations with advanced genomic technology, and by forging strong links between lab and clinic. “That's been critical, and it's why Cambridge is a good place to do this work: it's our laboratory excellence integrated with the clinic that enables this to happen,” says Professor Smith.

The implications for patients with these and other diseases could be far-reaching, he believes: “We can begin to define prognostic biomarkers – in other words tests that should allow us to predict long-term disease behaviour – and that is the first step on the road to ‘personalised medicine’. If that’s successful, we'll roll out the test in Crohn's and do similar studies in other diseases,” he says. “The fact that this works in four conditions suggests it might work in many others.”

Despite recent dramatic reductions in cot death rates in the UK, and the development of sophisticated screening for Down's syndrome, preventing stillbirth is proving tougher to tackle. Now, a major study under way at Cambridge could change all that.

Professor Gordon Smith

Delivering better ways of preventing stillbirth

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35DELIVERING BETTER WAYS oF PREVENTING STILLBIRTH

In the UK, one in every 200 women reaching their 24th week of pregnancy will have a stillborn baby. That means stillbirth is ten times more common than cot death and three times more common than Down's syndrome.

Yet compared with cot death, rates of stillbirth have fallen little over the past decade. And whereas women now have access to sophisticated screening for Down's syndrome, the way we screen for stillbirth still relies on little more than a tape measure.

According to Professor Gordon Smith of the Department of obstetrics and Gynaecology: “When we think of serious complications of pregnancy one of the most common is stillbirth. But if you look at how we screen for stillbirth, for the general low-risk population – which is the population that has most stillbirths because there are more of them – the only currently recommended way of screening is measuring the size of the uterus with a tape measure.”

For parents, a stillborn baby is tragedy. Many of these tragedies could be prevented given better ways of predicting which women are at most risk. Which is why in 2008 Professor Smith set up the Pregnancy outcome Prediction Study (PoPS).

one the largest and most robust studies of its kind, the four-year, National Institute for Health Research-funded study involves more than 4,000 volunteers – women in their first pregnancies who agree to take part in the research when they book their first scan at the Rosie Maternity Hospital in Cambridge.

As well as their routine ultrasound scans at 12 and 20 weeks, the women have blood tests, and additional research scans at 28 and 36 weeks, and when they give birth a sample of the placenta is kept and stored. Combining all this information will, Professor Smith believes, provide a clearer picture of how best to identify women at increased risk of stillbirth.

“The aim of PoPS is to try and identify whether there's a combination of ultrasound and biochemical markers that better predict high-risk pregnancy, and which when applied in a screening programme would reduce the number of stillbirths,” he says.

“The basic premise is that by studying the placenta and comparing it with controls, we can identify the things which are different in the placenta of a complicated pregnancy. And the rationale for studying the placenta is that there's a great deal of evidence to indicate that many stillbirths are related to an abnormal placenta.”

Knowing which women are at higher risk of stillbirth would allow clinicians to decide how best to intervene to reduce that risk. “Initially, we would see this information being used to predict complications at term, 37 weeks and beyond, which is when one third of stillbirths occur,” Professor Smith explains.

“one of the key things for me is the prospect of intervention, and the most obvious intervention is to deliver the baby early. Stillbirth often results from a diseased placenta so it’s hard to treat, but once a woman reaches the 37th or 38th week of pregnancy you have the option of inducing labour,” he says.

“or it might be that we simply monitor the baby continuously during labour, or advise against certain women giving birth at home or in a midwife-led unit.”

Cambridge is ideally placed to conduct a study like PoPS. As well as having hundreds of willing volunteers, “Cambridge is probably the strongest centre in the world for people with an interest in the biology of the placenta,” says Professor Smith. “We also have the Centre for Trophoblast Research, which brings together clinical and non-clinical researchers working on the placenta, and we have close links with the School of Biological Sciences, the Gurdon Institute and the Babraham Institute.”

Coupled with great researchers, Cambridge excels in clinical research design, without which developing screening to reduce stillbirth would be impossible, he says: “Good scientists need well-defined material to study, and what we have in PoPS is real excellence in clinical research design coupled with excellent basic science.”

If the results from PoPS do identify ultrasound and biochemical markers that predict risk of stillbirth, the next stage would be a trial to test the effectiveness of the screening and intervention. “The ultimate aim would be for our work to become part of a NICE guideline, changing the ante-natal care women receive,” he says. “It's early days but our initial analysis looks very promising.”

Professor Sadaf Farooqi

It's a complex and growing problem, and one that costs the NHS over £1 billion a year. Now, Cambridge scientists are joining forces with pharmaceutical firm GSK in the search for urgently needed new drugs to treat obesity.

People tend to view obesity as a simple matter of what you eat and how much exercise you do but, like many health problems, the truth is rather more complicated.

Joining forces to tackle obesityIm

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37JoINING FoRCES To TACKLE oBESITY

“Our thinking has shifted,” says obesity expert Professor Sadaf Farooqi of the Institute of Metabolic Science. “People have realised the simple response of 'go on a diet and do some exercise' is a bit prehistoric. We're not saying these things aren't important, but they don't help people who are already severely obese and it is those patients for whom we need to find treatments because of the problems they face.”

And those problems are serious. As well as being more likely to suffer from depression, people with a body mass index of more than 30 are at significantly greater risk of developing type 2 diabetes, heart disease, stroke and certain types of cancer.

Researchers at Cambridge have made important discoveries about obesity in recent years. By studying people with rarer, genetic forms of obesity Professor Farooqi has found that there are strong genetic and biological determinants of weight, which are disrupted to cause obesity. “This shows us there are circuits for regulating our appetite and our weight, and understanding these are crucial if we are to find new treatments,” she explains.

To do this metabolic scientists like Professor Farooqi are working with neuroscientists like Professor Paul Fletcher from the Department of Psychiatry. Until recently, he says, studies examining how people control their food intake have often stopped below or in the 'foothills' of the brain. The developing programme of research however, draws together neuroscientists working within the Behavioural and Clinical Neuroscience Institute and the Institute of Metabolic Science.

“There's an increasing acceptance that if we are going to understand how the incredible pandemic of obesity has come about, we have to think about the higher-order functions of the brain,” he says. “You can think of the brain as one big organ that's very finely tuned to avoid punishments and look for rewards in the environment, and food is one of our favourite rewards. So as well

as the metabolic level, we need to understand how this translates into day-to-day human behaviours.”

Inspiration and funding for this work comes from the Bernard Wolfe Heath Neuroscience Fund. In 2009, Professor Fletcher and Professor Farooqi also joined forces with the pharmaceutical company GSK in a new academic/industry incubator. By allowing the academics access to GSK's Clinical Unit in Cambridge, the incubator provides the support and resources that have enabled them to conduct an ambitious study evaluating a new obesity drug being developed by GSK.

According to Professor Fletcher: “The incubator draws together scientists to work on a project that has a real translational clinical meaning, and offers them resources and opportunities to collaborate and do ambitious studies on new compounds.”

Working with a group of 60 volunteers recruited by GSK, the study's focus is a drug that targets so-called mu opioid receptors in the brain. “We think these receptors affect craving or desire to eat food, particularly high-fat foods, so if you can suppress these cravings with this drug you might have an effective treatment for obesity,” Professor Farooqi explains.

Among the questions the study is seeking to answer are: does the drug affect metabolism; what impact does it have on food choices and weight loss, and how does it affect the way people's brains respond when they

are exposed to food or food-related stimuli?

Answering the latter involves investigating brain responses using brain scanning or functional Magnetic Resonance Imaging. “With the brain scanner we show people pictures of delicious and less appetising foods, ask them to make food choices, and observe the activity of different regions of the brain both on and off the drug,” says Professor Fletcher.

Both Fletcher and Farooqi are convinced that working together is the only way to tackle as complex problem as obesity. “The challenge is to harness findings from genetic, metabolic and neuroscience observations in order to help develop new treatments,” he says, “and then make sure that as academics we continue to collaborate well with industry to work out how best to investigate where those should be used. But it really is about joining forces and bringing combined expertise to a complex problem.”

“The incubator development of this new drug to control over-eating behaviour has been a great example of the University of Cambridge working innovatively and effectively with GSK to deliver a project in which the two organisations have worked closely together to achieve an outcome that might have been beyond the reach of either of them alone, said Ed Bullmore, who has played a leading role working half-time for GSK as Head of the Clinical Unit Cambridge and half-time for the University as a Professor of Psychiatry.

Professor Ed Bullmore Professor Paul Fletcher, Bernard Wolfe Professor of Health Neuroscience

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BIC

Doing clinical research is a huge challenge. Understanding complex diseases and developing new ways of treating them requires an enormous amount of brain power. But the strict regulations governing research mean running the trials is equally taxing. Which is where the Cambridge Cancer Trials Unit makes all the difference.

From blue sky to bedside in cancer research

Professor Tim Eisen Professor Dave TuvesonProfessor Duncan Jodrell

38

39FRoM BLUE SKY To BEDSIDE IN CANCER RESEARCH

From blue sky to bedside in cancer research

Set up a decade ago by Dr Pippa Corrie, the Cambridge Cancer Trials Centre (CCTC) now has 92 staff and with 109 studies open to recruitment and 96 in follow-up. Such a large number of trials are needed because cancer is not one disease but an umbrella term for over 200 different diseases, each of which requires different treatment. The CCTC also hosts the West Anglia Cancer Research Network (WACRN), which is crucial to make cancer trials available to people across our region. This has worked very well and WACRN has consistently been one of the best performing networks in the country over many years.

But what does the CCTC do, and what makes it so successful? “It's very much a collaboration between Cambridge University Hospitals NHS Foundation Trust, Cancer Research UK and the University,” says Professor Tim Eisen, who took over as director of the CCTC in 2006. “With an NHS department offering treatment to patients throughout our region and a highly successful oncology science base in Cambridge, we're linking the very pragmatic with the very blue sky, which will allow us to ask highly scientific questions on a population basis.”

Under Professor Eisen's leadership, the CCTC has changed its focus over the past four years, particularly in terms of the kinds of studies it majors on.

“Whilst continuing to offer entry to high quality trials as widely as possible, we are gradually focusing our own academic effort on translational work in clinical research. These are sophisticated studies which link the the laboratory to the patient. It's often called 'bench to bedside' but the reverse is also true. The work is focused in certain tumour types – breast, prostate, oesophageal, pancreatic, ovary, and lung cancer,” he says. “And we've put a lot of academic firepower behind early-phase trials and translational work, led by Professor Duncan Jodrell.”

Compared with late-phase studies, which test a new treatment on large numbers of patients to discover whether or not it's better than the current standard, early-phase trials are investigations into new treatments for which no large-scale data exist.

“It might be the first time you've used a particular drug in humans, or you may want to get an early indication of how effective it might be,” Professor Eisen explains.

As far as researchers are concerned, however, it's the day-to-day business of running trials that makes CCTC so valuable. Setting up a clinical trial involves a series of legal, ethical, financial, administrative and data management hurdles that researchers need help clearing. “The CCTC is a central facility that enables researchers to do their best work,” he says.

A case in point is Professor David Tuveson, who works on pancreatic cancer. The number six cause of death due to cancer in the UK, where it kills 7,500 people a year, pancreas cancer is common but little discussed.

“It's thought to be a rare cancer but that's not so,” says Professor Tuveson of Cancer Research UK's Cambridge Research Institute. “It's just a cancer people don't talk about very often because patients don't live very long after they are diagnosed. Pancreatic cancer is a quiet killer that doesn't have the public recognition of the more common cancers.”

Until recently, researchers were puzzled by what made the disease so resistant to chemotherapy. Now, Professor Tuveson and his laboratory may have part of the answer.

“Pancreas cancer is a lethal disease. We understand the basic genetic problems underlying pancreatic cancer, but we don't understand why these genetics changes lead to such an intractable illness. What my laboratory concentrates on is providing an answer to this mystery,” he explains.

By developing a mouse model of the disease, they have begun to solve the mystery. According to Professor Tuveson: “Pancreas tumours are a big scar sprinkled with little nests of cancer cells. In this respect they are very different from other types of carcinoma. And because of this structure, they're just aren't enough blood vessels to get drugs into the tumour.”

Using this discovery, they are working on ways to disrupt the scar tissue so that they can deliver drugs into the tumour. “We have devised a method that increases the number of blood vessels in the tumour, and at the same time decreases the amount of scar tissue, by using a hedgehog pathway inhibitor (HPI). It's a developmental pathway that is very important for scar tissue formation, so the HPI shrinks the scar tissue and allows blood vessels to increase in number. Then,” he says, “you can deliver various drugs more effectively.”

A clinical trial is now under way to find out how giving patients the HPI affects the structure of their tumour. If the hypothesis is correct – and the HPI boosts the blood supply to the tumour – the team will go on to test it in combination with chemotherapy. To support this work, Professor Jodrell’s team has recently developed a method to measure chemotherapy concentrations in pancreatic tumours.

The CCTC, with the support of Professor Eisen and Professor Jodrell, has made all the difference. According to Professor Tuveson: “It's helped coordinate all the legal, ethical, medical and financial aspects of doing an investigational trial. So without the CCTC, there would be no trial.”

For more information on the Cambridge Cancer Trials Centre, visit www.oncology.cam.ac.uk/research/themes/cctc.html

40 RUNNING FooTER

From left: Dr Emanuele Di Angelantonio, Dr Danish Saleheen, Dr Rajiv Chowdhury and Professor John Danesh

Photo: Mark Mniszko

Why is heart disease increasing at a greater rate in South Asia than in any other region globally? Large-scale population studies in Pakistan and Bangladesh aim to discover the basis of a little-studied public health problem of epidemic proportions.

High-risk hearts: a South Asian epidemic

HIGH-RISK HEARTS: A SoUTH ASIAN EPIDEMIC 41

“The study of vascular disease among people living in South Asia has been comparatively neglected,” said Professor John Danesh, Head of the Department of Public Health and Primary Care. “South Asians number 1.5 billion people worldwide, yet until recently there have been few powerful studies tailored to evaluate the distinctive genetic, biochemical and lifestyle risk factors affecting this group.”

Now, two population studies jointly led by Professor Danesh and other researchers at the Department of Public Health and Primary Care hope to find some answers. With 35,000 participants, the Pakistan Risk of Myocardial Infarction Study (PRoMIS) is the most powerful study so far to search for biological and other risk factors for Cardiovascular Disease (CVD) among Pakistanis. And, despite commencing only in January 2011, the Bangladesh Risk of Acute Vascular Events (BRAVE) study already exceeds any previous Bangladeshi study in scale.

PROMIS“Pakistan is a country of 187 million people, yet fewer than 1,000 patients have been assessed in previous epidemiological studies of heart disease,” said Dr Danish Saleheen, who jointly leads PRoMIS. “When I was a medical student in Pakistan, infrastructure was lacking to conduct large-scale genetic investigations in that region. Moreover, there were not any instruments or studies that could specifically investigate lifestyle and dietary exposures which are very specific to South Asia in relation to conditions like heart attacks and stroke.”

He began a project with colleagues in Pakistan to investigate what it might be about South Asians that makes them more vulnerable to the development of heart diseases.

Were local dietary practices, such as the use of ghee as cooking fat, to blame? or the many non-cigarette-based ways of consuming tobacco, including chewing, sniffing and ingesting? or cultural habits such as marriage between first cousins? or environmental influences such as contaminants in food and water?

After Dr Saleheen moved to Cambridge in 2006 as a Cambridge Commonwealth Trust scholar, the study design was optimised, long-term funding was secured, and full-scale recruitment commenced under the joint leadership of Professor Danesh. It now recruits patients with heart disease, stroke or diabetes at a rate of 10,000 per year from 13 institutes across Pakistan through the Centre for Non-Communicable Diseases in Karachi, whose current Director is Dr Saleheen.

The study is poised to yield a harvest of novel findings. For example, it has recently contributed to the discovery of nine genes for coronary artery disease and six separate genes for type 2 diabetes, with the findings published in Nature Genetics. other detailed analyses are in progress with the support of more than £10 million in research funding from the US National Institutes of Health, Wellcome Trust and British Heart Foundation.

Perhaps where PRoMIS will have its greatest potential impact will be the evaluation of local risk factors that can be modified. “We are beginning to identify distinctive factors which increase the risk of, or protect against, heart diseases,” said Dr Saleheen. “For instance, consumption of ghee and indigenous types of tobacco, including ‘naswar’, increases the risk of heart attack. Through PRoMIS, we are now able to pinpoint the contribution of these factors in a more precise manner than ever before.”

BRAVEof all South Asian countries, Bangladesh probably has the highest rates of CVD and yet is the least studied. Dr Rajiv Chowdhury, who is himself from Bangladesh, explained the severity of the situation: “In the late 1990s it was estimated that there would be a 100% increase in CVD across South Asia by 2020. But, when you look at Bangladesh, there has already been a 3,500% increase. In the global combat against CVD, Bangladesh is a country ‘missing in action’.”

Gates Scholar Dr Chowdhury jointly leads the BRAVE study, which began seven months ago in pilot form in readiness for a subsequent large-scale study. “one important objective is to build an epidemiological resource – the first in Bangladesh – to be shared between the Bangladeshi and UK collaborators with equal intellectual partnership,” said Dr Chowdhury, who jointly leads the study with Dr Emanuele Di Angelantonio and Professor Danesh. “The biorepository will be used to test current and future hypotheses relating to potential risk factors to help shape local and global cardiopreventive policies.”

Dr Chowdhury is certain that, as in Pakistan, crucial risk factors will be discovered: “Bangladesh has the highest rate of urbanisation and population density in South Asia, and is facing the worst threats of climate change globally. Factors associated with such extraordinary circumstances may have influenced the population’s massive shift in epidemiology towards increased CVD. Equally, it could be linked to suboptimal nutrition, widespread environmental contaminants such as arsenic in ground water and plants, or specific vulnerabilities in the genetic or metabolic make-up that have yet to be discovered.”

42

Fellow of the Academy of Medical Sciences

Professor Gordon Smith Professor Maria Spillantini

Wellcome Trust Principal Research Fellowship

Professor David OwenProfessor David Ron (2009)

Wellcome Trust Senior Research Fellowship in Clinical Science

Dr James RoweDr David Savage

Pilkington Teaching Prize 2010

Dr John FirthDr Mark Lillicrap

Inbev-Baillet Latour Healh Prize 2010

Professor Stephen O’Rahilly

Dale Medal of the Society of Endocrinology


Donald Ware Waddell Award Arizona Cancer Centre, USA

Professor Sir Bruce Ponder

2010 Zulch Prize by Max Planck Society on behalf of the Gertrud-Reemtsma Foundation

Professor Alastair Compston

2010 McCulloch and Till Award from International Society for Haematology

Professor Berthold Göttgens

International Still birth Alliance Distinguished Researcher award

Professor Gordon Smith

Carl Camras Translational Research Award

Professor Keith Martin

British Society for Matrix Biology Fell Muir Award 2010

Professor Gill Murphy

Minkowski Prize (European Association for the Study of Diabetes 2010)

Dr Fiona Gribble

Awards

2010

43AWARDS

Fellow of the Academy of Medical Sciences

Professor Nick Morrell Professor Simon Thompson

Foreign Associate of the National Academy of Sciences of the United States of America


Fellow of the Royal Society

Professor Simon Tavare

Wellcome Trust Principal Research Fellowship

Professor David G ClaytonProfessor David Rubinsztein

Wellcome Trust Senior Research Fellowship

Dr Sergey Nejentsev

MRC Senior Clinical Research Fellowship

Dr Stefan Marciniak (March 2012)

Pilkington Teaching Prize 2011

Dr Mark GurnellDr David Perry

2011 Medical Research Society Young Investigator award

Dr Ferdinandos Skoulidis

Juvenile Diabetes Research Foundation’s David Rumbough Award for Scientific Excellence

Professor John Todd

Ian McDonald Award of the MS Society of Great Britain and Northern Ireland

Professor Alastair Compston

Robert H Pudenz Award for Excellence in CSF Physiology

Dr Marek Czosnyka

Colworth medal of the Biochemical Society

Dr Akhilesh Reddy

Membership of the European Molecular Biology organisation

Professor David OwenProfessor David RonProfessor David Rubinsztein

2011

44

Finance report

Growth in research grant incomeDespite the economic downturn experienced since the last report, the School has continued to benefit from growth in research funding from all major sponsors, noticeably the Medical Research Council and UK charities, which have perhaps been less affected than other areas by funding reductions over that period. Research funded by the European Commission represents a potential area for future growth, although UK charities still provide the majority – 47% – of the School’s research income.

Building developmentsDuring the last two years, the West Forvie Building has been occupied by researchers from different departments across the School – particularly those working in stem cells and cardiovascular medicine. The refurbishment work to the University’s Herchel Smith Building has been completed and the building is now in full operation, providing collaborative research space for the University, Medical Research Council and the NHS. Further expansion plans are currently being finalised for space in the MRC’s new Laboratory of Molecular Biology and in the NHS Blood and Transplant Centre, whilst planning continues for the Cambridge Cardio-Respiratory Institute associated with the move of Papworth Hospital to the Campus.

2009–2011 under review

Research grant expenditure increased by 10% from £71m in 2009 to £77m in 2010. A significant proportion of this was due to increased activity with the Medical Research Council, as well as continued expansion in the charities sector. Both the Comprehensive Biomedical Research Centre partnership with Cambridge University NHS Foundation Trust and the Collaboration for Leadership in Applied Health Research and Care (CLAHRC) with Cambridgeshire and Peterborough NHS Foundation Trust underpin the growth

in UK Government research income. Research expenditure accounted for 59% of School activity, compared to 23% for the University as a whole.

The School continues to receive support from local NHS organisations, particularly those associated with Cambridge University Health Partners. The School has commenced discussions about the future of the Anglia Clinical Academic Reserve which is funded until March 2013 and underpins a significant number of the School’s academic positions.

The Clinical School at a glanceTotal income increased to £131m in the last financial year (2009 – 10), compared to £117m in 2009. Expenditure is generally incurred to match the level of income, although new permanent endowments received during the year increased the School’s total funds to £107m – the vast majority of which are held in specific trust funds which are invested in the Cambridge University Endowment Fund.

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Design and production: Media Studio, Cambridge University Hospitals NHS Foundation Trust Front cover photograph: Media Studio, Cambridge University Hospitals NHS Foundation Trust

© University of Cambridge School of Clinical Medicine 2012 • MS111101 • 02/2012

Documents

School of Clinical Medicine Review 2009 - 2011