School of Clinical Medicine Research Directory 2012-2014

School of Clinical Medicine Research Directory 2012–2014

Contents

02 03 04 05 06 07 08 10 14 17 19 21 34 37 38

Aims of the School

Regius's Editorial

Cambridge Institute for Medical Research (CIMR) Cambridge Institute for Public Health (CIPH) Wellcome Trust Institute of Metabolic Science (IMS) Heads of Department

Clinical Biochemistry

Clinical Neuroscience

42 44 46 48 51 53 57 58

Haematology

Histopathology

Medical Genetics

Medicine

MRC Epidemiology Unit

Obstetrics and gynaecology

60 62 64 65 66

Medical Research Council Cancer Unit Paediatrics

Psychiatry

Public Health and Primary Care

Radiology

Surgery

Medical Education and Postgraduate Study Translational Research – The road to drug development – New molecular testing device for oesophageal cancer The School of Clinical Medicine – Administration – Research support Cambridge University Health Partners (CUHP) NIHR Cambridge Biomedical Research Centre (BRC) Strategic Partners

History of the Clinical School and Biomedical Campus

Cancer Research in Cambridge – Department of Oncology and Cancer Research UK Cambridge Institute CONTENTS

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Aims of the School The University of Cambridge School of Clinical Medicine aims to provide leadership in education, discovery and healthcare. The School will achieve this through: inspirational teaching and training, outstanding basic and clinical research and integration of these to improve medical practice for both individual patients and the population.

The School will

• through inspirational teaching and training, educate individuals who:

– will become exceptional doctors or biomedical scientists – combine a depth of scientific understanding with outstanding clinical and communication skills – demonstrate a caring, compassionate and professional approach to patients and the public and – are equipped to become future international leaders of their profession

• through its commitment to the pursuit of excellence, support scientists of international standing in basic and clinical research aiming to: – understand fundamental biology and thereby the mechanisms underlying disease – integrate basic and clinical research – apply a rigorous mechanism-based approach to clinical problems and – innovate to solve the health challenges of our society

The School’s core values are

• to uphold the rights of the individual to freedom of thought, freedom of expression, access to education and access to appropriate healthcare

• to respect the diversity of our students, academics, non-academic staff, patients and volunteers and value their different expertise and contributions to the life of the School

• to instill in our graduates, staff and alumni a life-long passion for the pursuit of excellence in the service of society and an understanding of their responsibility to engage with the public about their research

Remit statement The University of Cambridge School of Clinical Medicine aspires to change the practice of medicine and improve biological understanding in a wide range of clinical specialties and scientific disciplines.

Collaborative research, both within biomedicine and crossing the boundaries to the mathematical, physical and social sciences, is key to our approach. The School also supports key enabling technologies and facilities in imaging, bioinformatics and biological systems.

The main areas of research interest are: Cancer Research Cardio-Respiratory Medicine Cellular Mechanisms of Disease Diabetes, Endocrinology and Metabolism Epidemiology, Public Health and Primary Care Genetics and Genetic Medicine Haematological and Transplantation Medicine Infection and Immunity Neurosciences and Mental Health Stem Cells and Regenerative Medicine

• • • • • • • • • •

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AIMS OF THE SCHOOL

Regius's Editorial The School of Clinical Medicine at Cambridge is a very special place.

It is at the heart of the Cambridge Biomedical Campus which brings together outstanding research, education, patient care and a major industrial presence on a single site (see picture on page 68). I came here in 2012 as the 27th Regius Professor of Physic and Head of the Clinical School. Since its foundation in 1976 the School of Clinical Medicine has become a major force in biomedical research (see timeline on page 66). It benefits enormously from the unique environment here – especially extensive interactions with our NHS partners, the Medical Research Council’s Laboratory for Molecular Biology and the MRC units on the site and nearby, the wider University, the nearby Babraham Institute, European Bioinformatics Institute and the Wellcome Trust Sanger Institute.

Patrick Maxwell, Regius Professor of Physic

Alongside academic excellence, the School aims to be an outstanding organisation to work for. We were delighted that our commitment to this was recognised by an Athena SWAN Silver Award to the whole School in 2013.

The Directory provides a description, department by department, of the main areas of our research together with a small number of key publications.

As a document of record it is organised on a departmental basis but of course modern medical research requires teams that work across departments.

In my view the Cambridge Biomedical Campus represents an extraordinary environment for these cross disciplinary interactions to occur.

Clinical School

REGIUS' EDITORIAL

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Cambridge Institute for Medical Research (CIMR)

Professor Gillian Griffiths FRS Director of the Cambridge Institute for Medical Research Tel 01223 763227 Email gg305@cam.ac.uk

Research at the Cambridge Institute for Medical Research (CIMR) utilises a unique partnership between basic and clinical research, aiming to understand the cellular basis of disease. 40% of our researchers are clinically active, and we have a demonstrated record of translating our basic research into successful clinical application. Our researchers use cell biology to understand molecular mechanisms of disease and conversely use genetic disease to reveal crucial mechanisms of cell biology. Although CIMR research has particular strength in key cell processes (membrane trafficking and protein folding) as well as biological areas (immune system and neuronal function), an important asset at CIMR is the breadth of disease areas that our research impinges on, and it is this that allows us to reveal fundamental principles of disease and infection.

Crucial to this is the use of multiple approaches, including genetics, and cellular and structural biology.

CIMR

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CAMBRIDGE INSTITUTE FOR MEDICAL RESEARCH

Cell biological themes • protein homeostasis and folding; • intracellular membrane traffic; • cellular mechanisms of infection and immune cell function;

• stem cell biology

Disease themes • neurodegenerative diseases; • haematological disorders; • immunological and infectious diseases;

• inherited neurological disorders As a cross-departmental institute of the University of Cambridge Clinical School, our researchers are widely integrated into the local research community and we encourage collaboration with other departments and institutes.

Cambridge Institute of Public Health (CIPH)

The Cambridge Institute of Public Health (CIPH) carries out research into the most important public health problems that affect the health of the nation, such as diabetes, vascular disease, cancer, musculoskeletal disorders and dementia. It does this so that we can better understand the causes of diseases, the risks to people of getting diseases, and how best to prevent disease.

Professor Carol Brayne Director of the Cambridge Institute of Public Health Tel 01223 330321 Fax 01223 762515 Email carol.brayne@medschl.cam.ac.uk

The Institute is made up of groups of researchers who provide the complementary range of skills necessary to generate new scientific advances that will provide the basis for helping people to live longer and healthier lives.

The CIPH is currently a partnership of ten member organisations which include the Department of Public Health and Primary Care (page 48) and the MRC Epidemiology Unit (page 34) at the University

of Cambridge; the MRC Biostatistics Unit and the MRC Human Nutrition Research Unit; Public Health England Knowledge and Intelligence Team (KIT East), the National Cancer Registry and Health Protection Epidemiology Unit); Public Health Genomics Foundation; UKCRC Centre of Excellence in Public Health Research; the Centre for Diet and Activity Research (CEDAR), with the University of East Anglia; the Department of Health Policy Research Unit on Behaviour and Health (BHRU), with the University of East Anglia; the Cambridge Centre for Health Services Research with RAND Europe; NIHR CLAHRC East of England.

The Institute is a member of the NIHR National School for Public Health Research, a partnership between eight leading academic centres in applied public health research in England.

CIPH

CAMBRIDGE INSTITUTE OF PUBLIC HEALTH

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Wellcome Trust-MRC Institute of Metabolic Science

The Wellcome Trust-MRC Institute of Metabolic Science (IMS) is a modern, purpose-built institute on the Cambridge Biomedical Campus.

Its fundamental aim is to further understanding of the causes and consequences of obesity, diabetes and related metabolic diseases, and to link these advances directly to patient care and disease prevention.

Co-Directors Professor Nick Wareham Tel 01223 330315 Email nick.wareham@mrc-epid.cam.ac.uk Professor Sir Stephen O’Rahilly, FRS Tel 01223 336855 Email so104@medschl.cam.ac.uk

Obesity and its related health problems are some of the most pressing public health issues of our time. Around a quarter of all adults and one in five children in England are currently classed as obese, and these numbers continue to increase. (www.hscic.gov.uk/catalogue/ PUB13648/Obes-phys-acti-dieteng-2014-rep.pdf )

IMS

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WELLCOME TRUST INSTITUTE OF METABOLIC SCIENCE

The IMS is a joint venture of the University of Cambridge, the Medical Research Council, the Wellcome Trust and Cambridge University Hospitals NHS Foundation Trust. Co-Directed by Professors Sir Stephen O’Rahilly and Nick Wareham, the IMS houses facilities for laboratory and clinical research at the University of Cambridge Metabolic Research Laboratories and MRC Metabolic Disease Unit, allied closely with epidemiological and public health research led by the MRC Epidemiology Unit (page 34). Purpose-built clinical areas, the Wolfson Diabetes and Endocrine Clinic, and the Weston Centre for Childhood and Adolescent Diabetes and Endocrinology, provide state-ofthe-art treatment facilities for children and adults with metabolic and endocrine disorders.

Heads of Department

Professor Sir Steve O’Rahilly Clinical Biochemistry

Professor Alastair Compston Clinical Neurosciences

Professor Tony Green Haematology

Professor Nick Coleman Histopathology Division

Professor Eamon Maher Medical Genetics

Professor Ken Smith Medicine

Professor Nick Wareham MRC Epidemiology Unit

Professor Gordon Smith Obstetrics and Gynaecology

Professor Sir Bruce Ponder Oncology

Professor Simon TavarĂŠ Cancer Research UK Cambridge Institute

Professor Ashok Venkitaraman MRC Cancer Unit

Professor David Dunger Paediatrics

Professor Ed Bullmore Psychiatry

Professor John Danesh Public Health and Primary Care

Professor Fiona Gilbert Radiology

Professor Andrew Bradley Surgery

HEADS OF DEPARTMENT

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Clinical Biochemistry Head of Department and Professor of Clinical Biochemistry and Medicine Professor Sir Steve O’Rahilly FRS Tel 01223 336855 Fax 01223 330698 Email so104@medschl.cam.ac.uk

Staff list Professors JP Luzio, Professor of Molecular Membrane Biology (Emeritus) IS Farooqi, Professor of Metabolism and Medicine FM Gribble, Professor of Endocrine Physiology

Research synopsis Research in the Department is focused on two areas: a) the aetiology and pathogenesis of obesity, diabetes and related metabolic disorders, and b) the molecular cell biology of membrane traffic. Investigators working in metabolic disorders are largely based in the Wellcome Trust-MRC Institute of Metabolic Science. The Cell Biology group is located entirely in CIMR. The Department has played a leading role in several recent major initiatives, including the development of the Wellcome Trust-MRC Institute of Metabolic Science with its embedded MRC Metabolic Diseases Unit. Professor Sir Stephen O’Rahilly is Scientific Director of the NIHR Cambridge Biomedical Research Centre and leads the Metabolic, Endocrine and Bone Theme.

DJ Owen, Professor of Structural and Molecular Biology SE Ozanne, Professor of Developmental Endocrinology MS Robinson FRS, Professor of Molecular Cell Biology D Ron FRS, Professor of Cellular Pathophysiology and Clinical Biochemistry K Siddle, Professor of Molecular Endocrinology (Emeritus) AJ Vidal-Puig, Professor of Molecular Nutrition and Metabolism Readers F Buss, Reader in Molecular and Cellular Dynamics DB Savage, Reader in Molecular Metabolism University Lecturers AP Coll F Reimann Senior Research Staff I Barroso (joint appointment with Wellcome Trust Sanger Institute) C Blouet H Harding J Hirst B Kelly S Miller H Murphy (NIHR Clinical Fellow) S Rodriguez-Cuenca N Schoenmakers RK Semple MNJ Seaman S Siniossoglou S Virtue PJ Voshol GS Yeo NHS Consultants (Dept of Clinical Biochemistry) J Calvin D Halsall A Park A Sarker

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CLINICAL BIOCHEMISTRY

Adipocytes in culture (Image courtesy of Jian-Hua Chen)

Diabetes, Obesity and Metabolism Group Research themes include the following: molecular mechanisms in human obesity, insulin resistance and type 2 diabetes (Barroso, Farooqi, O’Rahilly, Savage, Semple, in collaboration with Professor NJ Wareham and colleagues from the MRC Epidemiology Unit); neurobiology of hunger and satiety in humans (Farooqi, with Professor P Fletcher, Dept of Psychiatry) and of nutrient sensing and energy homeostasis in model organisms (Blouet); animal models of obesity and insulin resistance (Coll, O’Rahilly, Vidal-Puig, Yeo); adipocyte biology (Savage, Vidal-Puig) and how this relates to ‘lipotoxicity’ resulting from inappropriate storage of excess lipids (Rodriguez-Cuenca, Vidal-Puig, Virtue); developmental programming of late-onset metabolic disease (Ozanne); signaling by insulin and insulin-like growth factors (Semple, Siddle); entero-endocrine physiology (Gribble, Reimann); new insights into thyroid biology (Schoenmakers); and improving health outcomes in diabetes (Murphy).

Selected references Blouet C and Schwartz GJ. Brainstem nutrient sensing in the nucleus of the solitary tract inhibits feeding. Cell Metabolism 2012: 16 579–87.

Bochukova E*, Schoenmakers N*, Agostini M, Schoenmakers E, Rajanayagam O, Keogh JM, Henning E, Reinemund J, Gevers E, Sarri M, Downes K, Offiah A, Albanese A, Halsall D, Schwabe J, Bain M, Lindley K, Muntoni F, Vargha Khadem F, Dattani M, Farooqi S, Gurnell M, Chatterjee K. A Dominant Negative Mutation in the Thyroid Hormone Receptor Alpha Gene. New England Journal of Medicine 2012: 366, 243–249. (*coequal first authors)

Carr SK, Chen JH, Cooper WN, Constância M, Yeo GS, Ozanne SE. Maternal diet amplifies the hepatic aging trajectory of Cidea in male mice and leads to the development of fatty liver. FASEB J. 2014: 28; 2191–201. doi: 10.1096/fj.13–242727.

Gulati P, Cheung MK, Antrobus R, Church C, Harding H, Tung TCL, Rimmington D, Ma M, Ron D, Lehner PJ, Ashcroft F, Cox RD, Coll AP, O’Rahilly S and Yeo GSH. A role for the obesity-related FTO gene in the cellular sensing of amino acids. Proc. Natl. Acad. Sci. U.S.A. 2013: 110, 2557–62.

Lindhurst MJ, Parker VE, Payne F, Sapp JC, Rudge S, Harris J, Witkowski AM, Zhang Q, Groeneveld MP, Scott CE, Daly A, Huson SM, Tosi LL, Cunningham ML, Darling TN, Geer J, Gucev Z, Sutton VR, Tziotzios C, Dixon AK, Helliwell T, O’Rahilly S, Savage DB, Wakelam MJ, Barroso I, Biesecker LG, Semple RK. Mosaic overgrowth with fibroadipose hyperplasia is caused by somatic activating mutations in PIK3CA. Nat Genet 2012: 44, 928–33.

Murphy HR, Elleri D, Allen JM, Harris J, Simmons D, Rayman G, Temple RC, Umpleby AM, Dunger DB, Haidar A, Nodale M, Wilinska ME, Hovorka R. Pathophysiology of postprandial hyperglycaemia in women with type 1 diabetes during pregnancy.

Diabetologia 2012: 55, 282–93.

Pearce LR, Atanassova N, Banton MC, Bottomley B, Van der Klaauw AA, Revelli JP, Hendricks A, Keogh JM, Henning E, Doree D, Jeter-Jones S, Garg S, Bochukova EG, Bounds R, Ashford S, Gayton E, Hindmarsh PC, Shield JPH, Crowne E, Barford D, Wareham NJ, UK10K Consortium, O’Rahilly S, Murphy MP, Powell DR, Barroso I, Farooqi IS. KSR2 mutations are associated with obesity, insulin resistance and impaired cellular fuel oxidation. Cell 2013: 155, 765–77.

Virtue S, Even P, Vidal-Puig A. Below Thermoneutrality.

Changes in Activity Do Not Drive Changes in Total Daily Energy Expenditure between Groups of Mice. Cell Metab 2012: 16, 665–71.

Whittle AJ, Carobbio S, Martins L, Slawik M, Hondares E, Vázquez MJ, Morgan D, Csikasz RI, Gallego R, Rodriguez-Cuenca S, Dale M, Virtue S, Villarroya F, Cannon B, Rahmouni K, López M, Vidal-Puig A. BMP8B Increases Brown Adipose Tissue Thermogenesis through Both Central and Peripheral Actions. Cell 2012: 149, 871–85.

Intracellular Membrane Trafficking Group Investigators working on the molecular cell biology of intracellular membrane traffic are based in the Cambridge Institute for Medical Research (CIMR). These investigators are Paul Luzio (Emeritus Professor) working on endocytic pathways and lysosome biogenesis, Margaret Robinson studying adaptor complexes in coated vesicles, David Owen studying the structures of proteins involved in membrane traffic, Folma Buss studying molecular motors and their role in organelle/vesicle movement, Matthew Seaman studying retrograde/recycling traffic between endosomes and the Golgi complex or plasma membrane, and Symeon Siniossoglou studying how lipids regulate the structure and function of membranes and organelles.

Selected references Freeman CL, Hesketh G, Seaman MN. RME-8 coordinates the activity of the WASH complex with the function of the retromer SNX dimer to control endosomal tubulation. J Cell Sci. 2014: 127, 2053–2070.

Graham SC, Wartosch L, Gray SR, Scourfield EJ, Deane JE, Luzio JP, Owen, DJ Structural basis of Vps33A recruitment to the human HOPS complex by Vps16. Proc. Natl. Acad. Sci. U.S.A. 2013: 110, 13345–13350.

Hesketh GG, Pérez-Dorado I, Jackson LP, Wartosch L, Schäfer IB, Gray SR, McCoy AJ, Zeldin OB, Garman EF, Harbour ME, Evans PR, Seaman MN, Luzio JP, Owen DJ. VARP Is Recruited on to Endosomes by Direct Interaction with Retromer, Where Together They Function in Export to the Cell Surface. Dev Cell. 2014: 29, 591–606.

Hirst J, Borner GH, Antrobus R, Peden AA, Hodson NA, Sahlender DA, Robinson MS. Distinct and overlapping roles for AP-1 and GGAs revealed by the 'knocksideways' system. Curr. Biol. 2012: 22, 1711–1716.

Hirst J, Schlacht A, Norcott JP, Traynor D, Bloomfield G, Antrobus R, Kay RR, Dacks JB, Robinson MS. Characterization of TSET, an ancient and widespread membrane trafficking complex.

Elife 2014: 3, e02866.

Kelly BT, Graham SC, Liska N, Dannhauser PN, Höning S, Ungewickell EJ, Owen DJ. Clathrin adaptors. AP2 controls clathrin polymerization with a membrane-activated switch. Science 2014: 345, 459–63.

Miller SE, Sahlender DA, Graham SC, Höning S, Robinson MS, Peden AA, Owen DJ. The molecular basis for the endocytosis of small R-SNAREs by the clathrin adaptor CALM. Cell 2011: z147, 1118–1131.

Schäfer IB, Hesketh GG, Bright NA, Gray SR, Pryor PR, Evans PR, Luzio JP, Owen DJ. The binding of Varp to VAMP7 traps VAMP7 in a closed, fusogenically inactive conformation. Nat. Struct. Mol. Biol. 2012: 19, 1300–1309.

Sembongi H, Miranda M, Han GS, Fakas S, Grimsey N, Vendrell J, Carman GM, Siniossoglou S. Distinct roles of the phosphatidate phosphatases lipin 1 and 2 during adipogenesis and lipid droplet biogenesis in 3T3-L1 cells. J. Biol. Chem. 2013: 288, 34502–34513.

Tumbarello DA, Waxse BJ, Arden SD, Bright NA, Kendrick-Jones J, Buss F. Autophagy receptors link myosin VI to autophagosomes to mediate Tom1-dependent autophagosome maturation and fusion with the lysosome. Nat. Cell Biol. 2012: 14, 1024–35.

NHS Department of Clinical Biochemistry and Immunology Members of the NHS department run the Biochemical Assay (Keith Burling) Core Laboratory of the NIHR Cambridge Biomedical Research Centre. Dr Halsall runs specialist endocrine services with important links to genetic research.

CLINICAL BIOCHEMISTRY

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Clinical Neuroscience Head of Department and Professor of Neurology Professor Alastair Compston Tel 01223 217091 Fax 01223 336941 Email alastair.compston@medschl.cam.ac.uk

SJ Price

R Roberts

P Smielewski

G Toth

DJ Tozer

MS Zandi

Associate Lecturers R Laing

R MacFarlane

M Manford

P Kirkpatrick

E Warburton

Staff list

Main research themes

Professors FI Aigbirhio, Professor of Molecular Imaging Chemistry

Brain imaging The Wolfson Brain Imaging Centre (WBIC) uses positron emission tomography (PET) and magnetic resonance (MR) to investigate disease mechanisms. With recent investments in new facilities, Adrian Carpenter is establishing the technology for combined structural and functional imaging, especially PET/MR; Franklin Aigbirhio is developing novel radiopharmaceutical probes for molecular imaging using PET; Tim Fryer directs imaging analysis for experimental and clinical aspects of PET; and Guy Williams directs the computing and imaging MR science group with the development of real-time MR for brain-computer interface studies of patients with low awareness. The honorary scientific director is Ed Bullmore (Professor, Department of Psychiatry).

RA Barker, Professor of Clinical Neuroscience DAS Compston, Professor of Neurology, Head of Department of Clinical Neurosciences and Head of the Division of Neurology M Czosnyka, Professor of Brain Physics JW Fawcett, Professor of Experimental Neurology, Head of the John van Geest Centre for Brain Repair RJM Franklin, Professor of Stem Cell Medicine, Head of the Division of Stem Cell Neurobiology, Head of Translational Science at the Wellcome Trust/MRC Cambridge Stem Cell Institute, and Director of the MS Society Cambridge Centre for Myelin Repair PJA Hutchinson, Professor of Neurosurgery and NIHR Professor, Head of Division of Neurosurgery GR Mallucci, van Geest Professor of Clinical Neurosciences HS Markus, Professor of Stroke Medicine KRG Martin, Professor of Ophthalmology JD Pickard, Professor Emeritus of Neurosurgery SJ Sawcer, Professor of Neurological Genetics M Spillantini FRS, Professor of Molecular Neurology P St George-Hyslop FRS, Professor of Experimental Neuroscience Readers TA Carpenter, Reader in Imaging Sciences AB Reddy, Reader in Molecular Neurology JB Rowe, Reader in Cognitive Neurology University Lecturers D Chan

AJ Coles

S Pluchino

Clinical lecturers S Alexander

A Joannides

JL Jones

MR Kotter

CH Williams-Gray

C Watts

Assistant Directors of Research TD Fryer GB Williams

C Zhao

Senior Research Staff M Ban SN Bevan

KLH Carpenter

S Chennu

ZH Czosnyka

YT Hong

M Hornberger

CJ Kwok

B Lorber

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Traumatic brain injury Research in neurosurgery focuses on acute brain injury using multi-modality measurement in the intensive care setting.

Marek Czosnyka leads work of the neurosurgical physics group on cerebral autoregulation following head injury and subarachnoid haemorrhage, and the importance of cerebrovascular and CSF dynamics for hydrocephalus and idiopathic intracranial hypertension.

Piotr Smielewski has developed software required to capture and analyse real-time signals derived from bedside monitoring, now introduced into several neuroscience intensive care units worldwide.

Peter Hutchinson and Keri Carpenter have characterised the interplay of lactate, glycolysis and the pentose phosphate pathway in mechanisms of the response to traumatic brain injury; and they lead MRC/NIHR clinical trials of decompressive craniectomy following traumatic brain injury. Alexis Joannides has created the ORION platform that underpins all the neurosurgery cranial audits in the UK including the UK Paediatric Epilepsy Surgery Study and an interactive head injury database from which protocols for selection and outcome in clinical trials are derived. John Pickard’s work on the assessment of sentience in the persistent vegetative state is moving towards the development of bedside assessment techniques, computer-brain interface methods for enhanced communication, and a framework for clinical trials of stimulant and reparative drugs; and he leads the NIHR Brain Injury Healthcare Technology Cooperative that is systematically identifying areas of unmet need amongst patients, carers and the community amenable to a technological solution through networking with inventors and small and medium sized industries. With others, he established the Cambridge shunt evaluation laboratory which provides an international service for shunt testing in vivo.

Stroke Peter Kirkpatrick leads translational research into the pathophysiology of cerebrovascular disease using non-invasive assessments of cerebral haemodynamics to improve outcome from cerebrovascular neurosurgical procedures, and to develop new therapies for acute cerebral ischaemia. Elizabeth Warburton studies inflammation and atheroma in carotid plaques; and uses serial studies of individual patients to investigate plasticity in the motor, visual and language domains using fMRI and behavioural measures of deficit. Brain imaging is used to suggest strategies for manipulating pathophysiological processes and determine clinical recovery through serial study after ischaemic stroke.

Hugh Markus leads a programme on cerebral small vessel disease and vascular cognitive impairment using multimodal MRI to characterise mechanism of cognitive impairment, and develop new treatment approaches. With Stephen Bevan he also works on identifying genetic variants for polygenic ischaemic stroke, and has identified the first novel independent locus, HDAC9.

Neuro-oncology Research led by Colin Watts investigates how genetic and clonal heterogeneity evolves in response to treatment in patients with glioblastoma, including the impact of spatial and temporal diversity on the emergence of treatment resistance, with the aim of developing tumour sampling techniques and cancer stem cell derivation strategies to establish patient-specific in vitro and in vivo models of disease. Stephen Price is developing a research programme using MR and PET imaging to understand heterogeneity in brain tumours and the biology of glioma invasion.

Dementia and neurodegeneration Research in behavioural neurology addresses neuropsychology and imaging assessments of cognitive deficits in patients with Alzheimer’s disease, fronto-temporal dementia, progressive supranuclear palsy and Huntington’s disease.

James Rowe investigates behavioural disorders associated with neurodegenerative disease and focal brain injury using structural and functional magnetic resonance imaging and magnetoencephalography. The focus is on restoring function in the brain networks that enable the cognitive control of actions in neurodegeneration, especially Parkinson’s disease, frontotemporal dementia and progressive supranuclear palsy.

Maria-Grazia Spillantini has provided molecular classifications for disorders characterised by intracellular aggregates of microtubule-associated proteins and studies mechanisms of intracellular protein aggregation in human brain tissue and transgenic mice in the context of disorders such as Parkinson’s disease and dementia with Lewy bodies (alpha-synuclein) and Alzheimer’s disease, progressive supranuclear palsy, corticobasal degeneration and hereditary forms of frontotemporal dementia (tauopathies). Peter St George-Hyslop studies the genetics of Alzheimer’s and related disorders and is using structural biology to develop novel molecules for inhibiting the formation

of intracellular protein aggregates that destroy nerve cells.

Giovanna Mallucci works on mechanisms of neurotoxicity in neurodegenerative diseases; she recently identified the role of the unfolded protein response in mediating the toxic effects of protein misfolding in prion disease and manipulated this pharmacologically to prevent neurodegeneration. This work is now being applied in other neurodegenerative disorders with an emphasis on neuroprotection in the early stages of neuronal and synaptic regeneration dysfunction. Roger Barker conducts clinical work that improves prediction across the spectrum of clinical deficits in Parkinson’s and Huntington’s disease using biomarkers for the natural history and heterogeneity of these disorders in epidemiological studies of cohorts studied for clinical and imaging phenotypes, and genomics. He studies abnormalities in adult neural stem cell turnover and differentiation in transgenic models of neurodegeneration, work that has implications for the development of novel therapies including the use of cell-based therapies for Parkinson’s and Huntington’s disease.

Dennis Chan leads research on translational and clinical research into early Alzheimer’s disease, focusing on the study of altered brain function through clinical studies involving behavioural outcomes and functional MRI complemented by research on hippocampal function in mouse models of Alzheimer’s disease.

Plasticity and brain repair James Fawcett works on recovery of function through adaptation, plasticity regeneration and repair of the injured brain and spinal cord. Chondroitinase and other compounds are being used to modify the inhibitory proteoglycan perineuronal net structures that normally prevent plasticity and limit the success of rehabilitation. Engineering of integrins is being developed to promote axon regeneration in the adult nervous system.

Nanotech nerve interfaces have been developed to enable control of the bladder and limb prostheses. The work also has implications for neurodegenerative disease. Keith Martin studies the mechanisms of visual loss in glaucoma, and is currently investigating the integration of stem cells into the retina in experimental glaucoma, and studying the role of axonal transport dysfunction associated with glaucomatous retinal ganglion cell death. Stefano Pluchino studies the physiology of neural stem cells and their application in cell therapies for repair of the central nervous system, including the role of nanotechnology in delivering therapeutic agents. He also models the role of stem cells in modulating the fate of inflammatory and degenerative lesions.

Demyelinating disease As a member of the International Multiple Sclerosis Genetics Consortium (IMSGC), Stephen Sawcer has helped to identify 110 susceptibility genes that demonstrate a genetic basis for the primary role of T and B cell-mediated adaptive immune mechanisms in the pathogenesis of multiple sclerosis.

Alastair Compston has, with Alasdair Coles, also led the successful development of Alemtuzumab (Lemtrada)

CLINICAL NEUROSCIENCE

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Clinical Neuroscience through phase 2 and 3 clinical trials to a product licence for active relapsing-remitting multiple sclerosis in the European Community and elsewhere. With Joanne Jones, he is conducting early phase clinical trials in patients with multiple sclerosis aimed at addressing adverse effects of Alemtuzumab and restoring structure and function in the context of disability and progression.

Robin Franklin and Chao Zhao work on extrinsic factors and transcriptional and epigenetic signals that regulate the differentiation of adult neural stem cells into oligodendrocytes and other macroglia as the basis for enhancing remyelination in models of multiple sclerosis. This has led to the identification of a molecular target for remyelination therapy now in early phase clinical trials. Mark Kotter studies inflammation and oligodendrocyte neurobiology in models of central nervous system demyelination.

Other topics Akhilesh Reddy works in the Cambridge Institute of Metabolic Science on circadian rhythms in eukaryotic cells and microorganisms. Rhys Roberts works in the Cambridge Institute for Medical Research on membrane traffic and recirculating endosomes in the context of genetic disorders of peripheral nerve.

International awards and prizes (2012–14) Alastair Compston was elected Foreign Associate Member, Institute of Medicine of the National Academies of the USA (2012) and received the World Federation of Neurology Medal for Scientific Achievement in Neurology (2013) for contributions to the study of multiple sclerosis. Peter Hutchinson was awarded an NIHR Research Professorship (2013). Akhilesh Reddy was awarded the Colworth Medal (2012), a Lister Prize in Preventative Medicine (2012) and the Academy of Medical Sciences Foulkes Foundation Medal (2013); he was elected to the American Society of Clinical Investigation (2014), and awarded a Wellcome Trust Senior Fellowship (2013). James Rowe’s Wellcome Trust Senior Fellowship was renewed (2014). Maria-Grazia Spillantini was elected to Fellowship of the Royal Society (2013); awarded the International Fair Play ‘Semplicemente Donna’ award (2013), the Cotzias Prize of the Spanish Society of Neurology (2014), and the Prize for Scientific Achievements of the Associazione Italiana Malattia Frontotemporale (2014). Colin Watts received the Translation Science Award of the American Society of Neuro-Oncology (2013).

Selected references Chew DJ, Zhu l, Delivopoulos E, Minev IR, Musick KM, Mosse CA, Craggs M, Donaldson N, Lacour SP, McMahon SB, Fawcett JW. A Microchannel Neuroprosthesis for Bladder Control After Spinal Cord Injury in Rat. Science Translational Medicine 2013: 5; 210ra155 Coles AJ, Twyman CL, Arnold DL, Cohen JA, Confavreux C, Fox EJ, Hartung HP, Havrdova E, Selmaj KW, Weiner HL, Miller T, Fisher E, Sandbrink R, Lake SL, Margolin DH, Oyuela P, Panzara MA, Compston DA; for the CARE-MS II investigators.

Alemtuzumab for patients with relapsing multiple sclerosis after disease-modifying therapy: a randomised controlled phase 3 trial.

Lancet 2012: 380; 1829–39

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CD63-RFP membrane vesicles (red) being packed via target cell fEGFP (green) plasma membrane and accumulating at the level of the perinuclear compartment after translocation into cytoplasmic membranes at 24h in vitro after vesicle transfer. Design and artwork by CongJian Zhao

Cusimano M, Biziato D, Brambilla E, Donegà M, Alfaro-Cervello C, Snider S, Salani G, Pucci F, Comi G, Garcia-Verdugo JM, De Palma M, Martino G, Pluchino S. Transplanted neural stem/ precursor cells instruct phagocytes and reduce secondary tissue damage in the injured spinal cord. Brain 2012: 135; 447–60 Helmy A, Guilfoyle MR, Carpenter KL, Pickard JD, Menon DK, Hutchinson PJ. Recombinant human interleukin-1 receptor antagonist in severe traumatic brain injury: a phase II randomized control trial.

Journal of Cerebral Blood Flow and Metabolism 2014: 34; 845–51 Herva ME, Zibaee S, Fraser G, Barker RA, Goedert M, Spillantini MG. Anti-amyloid compounds inhibit alpha-synuclein aggregation induced by Protein Misfolding Cyclic Amplification (PMCA).

Journal of Biological Chemistry 2014 Feb 28. (Epub ahead of print) Hong YT, Veenith T, Dewar D, Outtrim JG, Mani V, Williams C, Pimlott S, Hutchinson PJ, Tavares A, Canales R, Mathis CA, Klunk WE, Aigbirhio FI, Coles JP, Baron JC, Pickard JD, Fryer TD, Stewart W, Menon DK. Amyloid imaging with carbon 11-labeled Pittsburgh compound B for traumatic brain injury. JAMA Neurology 2014: 71; 23–31 International Multiple Sclerosis Genetics Consortium. Analysis of immune-related loci identifies 48 new susceptibility variants for multiple sclerosis. Nature Genetics 2013: 45; 1353–60

Iovino M, Pfistererb U, Holton JL, Lashley T, Swinglerd RJ, Treacy R, Revesz T, Parmar M, Goedert M, Muqit MK, Spillantini MG. The novel MAPT mutation K298E: mechanisms of mutant tau toxicity, brain pathology and tau expression in induced fibroblast-derived neurons. Acta Neuropathol 2014: 127; 283–95

Tyzack GE, Sitnikov S, Barson D, Adams-Carr KL, Lau NK, Kwok JC, Zhao C, Franklin RJ, Karadottir RT, Fawcett JW, Lakatos A. Astrocyte response to motor neuron injury promotes structural synaptic plasticity via STAT3-regulated TSP-1 expression. Nature Communications 2014: 5; 4294

Johnson TV, DeKorver NW, Levasseur V, Osborne A, Tassoni A, Lorber B, Heller JP, Villasmil R, Bull ND, Martin KR, Tomarev SI. Identification of retinal ganglion cell neuroprotection conferred by platelet-derived growth factor (PDGF) through analysis of the mesenchymal stem cell secretome. Brain 2014: 137; 503–19 Jones JL, Thompson SA, Loh P, Davies JL, Tuohy OC, Curry AJ, Azzopardi L, Hill-Cawthorne G, Fahey MT, Compston A, Coles AJ. Human autoimmunity after lymphocyte depletion is caused by homeostatic T-cell proliferation. Proceedings of the National Academy of Sciences of the USA 2013: 110; 20200–5 Kirkpatrick PJ, Turner CL, Smith C, Hutchinson PJ, Murray GD; STASH Collaborators. Simvastatin in aneurysmal subarachnoid haemorrhage (STASH): a multicentre randomised phase 3 trial.

Lancet Neurology 2014: 13; 666–75 Mellone M, Kestoras M, Andrews MR, Dassie E, Crowther RA, Goedert M., Tolkovsky AM, Spillantini MG. Axonal transport alterations and increased sensitivity to toxic stimuli in a novel cellular model of progressive tau hyperphosphorylation and aggregation.

Journal of Neuroscience 2013: 33; 18175–18189 Miron VE, Boyd A, Zhao JW, Yuen TJ, Ruckh JM, Shadrach JL, van Wijngaarden P, Wagers AJ, Williams A, Franklin RJ, ffrench-Constant C. M2 microglia and macrophages drive oligodendrocyte differentiation during CNS remyelination.

Nature Neuroscience 2013: 16; 1211–8 Moreno JA, Halliday M, Molloy C, Radford H, Verity N, Axten JM, Ortori CA, Willis AE, Fischer PM, Barrett DA and Mallucci GR. Oral Treatment Targeting the Unfolded Protein Response Prevents Neurodegeneration and Clinical Disease in Prion-Infected Mice, Science Translational Medicine 2013: 5; 206ra138 Moreno JA, Radford H, Peretti D, Steinert JR, Verity N, Guerra Martin M, Halliday M, Morgan J, Dinsdale D, Ortori CA, Barrett DA, Tsaytler P, Bertolotti A, Willis AE, M Bushell and Mallucci GR. Sustained translational repression by eIF2α−P mediates prion neurodegeneration. Nature 2012: 485, 507–11 Romberg C, Yang S, Melani R, Andrews MR, Horner AE, Spillantini MG, Bussey TJ, Fawcett JW, Pizzorusso T and Saksida LM. Depletion of Perineuronal Nets Enhances Recognition Memory and Long-Term Depression in the Perirhinal Cortex. Journal of Neuroscience 2013: 33; 7057–7065 Sottoriva A, Spiteri I, Piccirillo SG, Touloumis A, Collins VP, Marioni JC, et al. Intratumor heterogeneity in human glioblastoma reflects cancer evolutionary dynamics. Proceedings of the National Academy of Sciences of the USA 2013: 110; 4009–14 Tufi, R, Gandhi, S, de Castro IP, Lehmann S, Angelova PR, Dinsdale D, Deas E, Plun-Favreau H, Nicotera P, Abramov AY, Mallucci GR, Loh SHY, Martins LM. Enhancing nucleotide metabolism protects against mitochondrial dysfunction and neurodegeneration in PINK1-associated Parkinson’s disease. Nature Cell Biology 2014: doi: 10.1038/ncb2901

CLINICAL NEUROSCIENCE

13

Haematology Head of Department and Professor of Haemato-Oncology

Research synopsis

Professor Tony Green Tel 01223 336820 Fax 01223 622670 Email arg1000@cam.ac.uk

Staff list Professors B Göttgens, Professor of Molecular Haematology AR Green, Professor of Haemato-Oncology JA Huntington, Professor of Molecular Haemostasis WH Ouwehand, Professor of Experimental Haematology RJ Read FRS, Professor of Protein Crystallography AJ Warren, Professor of Haematology Directors of Research H Lee M Müschen Reader BJP Huntly, Reader in Leukaemia Stem Cell Biology Principal Research Associate N Soranzo University Senior Lecturer C Ghevaert Senior Research Staff EJ Baxter M Churcher M Frontini W Li C Pina A Ritchie S Tan C Wisniewski Clinical Lecturers N Bolli

C Bryson A Cvejic E Laurenti K Ottersbach CA Rendon Restrepo I Simeoni MR Tijssen

M Chapman J Deane J Li E Papaemmanuil I Ringshausen K Stirrups E Turro Bassols

Research in the department falls into three main areas with major relevance for human disease: the Haematopoiesis and Haematological Malignancies Group are based in the Cambridge Institute for Medical Research (Tony Green, Bertie Göttgens, Brian Huntly, Katrin Ottersbach, Alan Warren); the Clifford Allbutt Building (Markus Müschen, Ingo Ringshausen, Elisa Laurenti, Elli Papaemmanuil) and the NHS Blood and Transplant (Dr Chapman). The Structural Medicine and Thrombosis Group (Randy Read, James Huntington) are based in the CIMR, and the Transfusion Medicine Group (Willem Ouwehand, Cedric Ghevaert) are based in the NHS Blood and Transplant Building.

Haematopoiesis and haematological malignancies Haematopoiesis represents the best characterised adult stem cell system and continues to provide important paradigms for understanding stem cell and cancer biology. The focus of this group continues to be normal haematopoiesis and the mechanisms whereby it is subverted to generate haematological malignancies. Current research programmes include: 1) Myeloproliferative neoplasms, JAK/STAT signalling and stem cell subversion (Tony Green); 2) Transcriptional networks regulating blood stem cells (Bertie Göttgens); 3) The pathogenesis of bone marrow failure syndromes and leukaemia (Alan Warren); 4) Negative feedback and oncogene signaling in leukaemia (Markus Müschen); 5) The biology of leukaemia stem cells (Brian Huntly); 6) The developmental origin of haematopoietic stem cells (Katrin Ottersbach); 7) Signalling pathways underlying bi-directional communication with the microenvironment in B lymphoproliferative diseases (Ingo Ringshausen); 8) Stem cell biology and acute myeloid leukaemia (Elisa Laurenti); 9) Clinical and biological implications of acquired somatic mutations in MDS and related myeloid neoplasms (Elli Papaemmanuil).

P Gallipoli

NHS Consultants/Associate Lecturers/Affiliated Lecturers TP Baglin M Besser PJ Campbell JIO Craig C Crawley H El-Daly G Follows D Foukaneli M Gattens P Krishnamurthy D Perry M Scott A Sureda B Uttenthal M Van’t Veer G Vassiliou CALR mutations.

Novel somatic mutations in the endoplasmic reticulin chaperone gene Calreticulin (CALR) in patients with myeloproliferative neoplasms (Nangalia et al. NEJM 2013). Mutations lead to the generation of an altered C-terminus and reveal a novel biological pathway as a target for tumourigenic mutations in cancer. Identification of mutant CALR simplifies diagnosis of patients and provides a tumour-specific target for therapy.

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Selected references Calero-Nieto FJ, Ng FS, Wilson NK, Hannah R, Moignard V, Leal-Cervantes AI, Jimenez-Madrid I, Diamanti E, Wernisch L, Göttgens B. Key regulators control distinct transcriptional programs in blood progenitor and mast cells. EMBO J. 2014: 33(11); 1212–1226

Thrombin-Fab complex Thrombin is on the left with its active site bound to an inhibitor (sticks).

The Fab heavy chain is magenta and the light chain is cyan.

Structural medicine and thrombosis Structural biology gives an unparalleled insight into the molecular details of biological mechanisms, an insight that has the potential to lead to rationally-designed therapies. Current research programmes include: 1) The molecular events which regulate haemostasis through the biochemical and structural characterisation of the proteins involved (James Huntington); 2) Protein crystallography (Randy Read; Dr Deane).

Transfusion medicine The focus of research is in the biology and genomics of megakarypoiesis and platelets. Current research programmes include: 1) Generation of therapeutic blood cells from stem cells (Cedric Ghevaert); 2) Genomics of blood cells (Willem Ouwehand).

Papaemmanuil E, Rapado I, Li Y, Potter NE, Wedge DC, Tubio J, Alexandrov LB, Van Loo P, Cooke SL, Marshall J, Martincorena I, Hinton J, Gundem G, van Delft FW, Nik-Zainal S, Jones DR, Ramakrishna M, Titley I, Stebbings L, Leroy C, Menzies A, Gamble J, Robinson B, Mudie L, Raine K, O’Meara S, Teague JW, Butler AP, Cazzaniga G, Biondi A, Zuna J, Kempski H, Müschen M, Ford AM, Stratton MR, Greaves M, Campbell PJ. RAG-mediated recombination is the predominant driver of oncogenic rearrangement in ETV6-RUNX1 acute lymphoblastic leukemia. Nat Genet 2014: 46(4); 376–9 Dawson MA, Gudgin EJ, Horton SJ, Giotopoulos G, Meduri E, Robson S, Cannizzaro E, Osaki H, Wiese M, Putwain S, Fong CY, Grove C, Craig J, Dittmann A, Lugo D, Jeffrey P, Drewes G, Lee K, Bullinger L, Prinjha RK, Kouzarides T, Vassiliou GS, Huntly BJ. Recurrent mutations, including NPM1c, activate a BRD4dependent core transcriptional program in acture myeloid leukaemkia.

Leukemia 2014: 28(2); 311–20 Aziz A*, Baxter EJ*, Edwards C, Ito M, Cheong CY, Bench A… Campbell PJ, Ferguson-Smith AC$, Green AR$. *Joint first authors, $ joint last authors. Cooperativity of imprinted genes inactivated by acquired chromosome 20 deletions. Journal of Clinical Investigation 2013: 123(5); 2169–2182 Bunkóczi G, Echols N, McCoy AJ, Oeffner RD, Adams PD and Read RJ. Phaser.MRage: automated molecular replacement. Acta Cryst 2013: D69; 2276–2286 Nangalia J, Massie CE, Baxter EJ, Nice FL, Gunes G, Wedge DC… Papaemmanuil E, Campbell PJ and Green AR. Somatic CALR mutations in myeloproliferative neoplasms with nonmutated JAK2.

N Engl J Med 2013: 369(25); 2391–2405 Kent DG, Li J, Tanna H, Fink J, Kirschner K, Pask DC, Silber Y, Hamilton TL, Sneade R, Simons BD, Green AR. Self-renewal of single mouse hematopoietic stem cells is reduced by JAK2V617F without compromising progenitor cell expansion. PLoS Biology 2013: 11(6) e1001576 Hill CH, Graham SC, Read RJ, Deane JE. Structural snapshots illustrate the catalytic cycle of β-galactocerebrosidase, the defective enzyme in Krabbe disease. Proc Natl Acad Sci USA. 2013: 17; 110(51): 20479–84 Laurenti E, Doulatov S, Zandi S, Plumb I, Chen J, April C, Fan J-B, Dick JE. The transcriptional architecture of human hematopoiesis identifies multilevel control of lymphoid commitment.

Nature Immunology 2013: 14(7); 756–63 Lutzny G, Kocher T, Rudelius M, Schmidt-Supprian M, Klein-Hitpass L, Finch, Dürig J, Haferlach T, Seifert M, Wanninger S, Oostendorp R, Ruland J, Leitges M, Kuhnt T, Wagner M, Feuerstacke Y, Peschel C, Egle A and Ringshausen I. Proteinkinase C-β dependent activation of NF-κB in stromal cells is indispensable for the survival of chronic lymphocytic leukemia B-cells in vivo. Cancer Cell 2013: 23(1); 77–92

Megakaryocyte development model.

A regulatory network model for the development of megakaryocytes from blood stem cells.

HAEMATOLOGY

15

Haematology Moignard V, Macaulay IC, Swiers G, Buettner F, Schütte J, Calero-Nieto FJ, Kinston S, Joshi A, Hannah R, Theis FJ, Jacobsen SE, de Bruijn MFT, Göttgens B. Characterisation of transcriptional networks in blood stem and progenitor cells using highthroughput single cell gene expression analysis. Nature Cell Biology 2013: 15; 363–372.

Lechtenberg BC, Murray-Rust TA, Johnson DJ, Adams TE, Krishnaswamy S, Camire RM, Huntington JA. Crystal structure of the prothrombinase complex from the venom of Pseudonaja textilis Blood, 2013: 122(16); 2777–83.

Diffner E, Beck D, Gudgin E, Thoms JA, Knezevic K, Pridans C, Foster S, Goode D, Lim WK, Boelen L, Metzeler KH, Micklem G, Bohlander SK, Buske C, Burnett A, Ottersbach K, Vassiliou GS, Olivier J, Wong JW, Göttgens B, Huntly BJ*, Pimanda JE*.

Activity of a heptad of transcription factors is associated with stem cell programs and clinical outcome in acute myeloid leukaemia.

Blood 2013: 121(12); 2289–300. *joint senior author Swaminathan S, Huang C, Geng H, Chen Z, Ng C, Nowak D, Rand V, Graeber TG, Koeffler HP, Carroll WL, Willman CL, Hall AG, Igarashi K, Melnick A & Müschen M. BACH2 mediates negative selection and p53-dependent tumor suppression at the pre-B cell receptor checkpoint. Nature Medicine 2013: 19; 1014–1022 Albers CA, Paul DS, Schulze H, Freson K, Stephens JC, Smethurst PA, Jolley JD, Cvejic A, Kostadima M, Bertone P… and Ghevaert C. Compound inheritance of a low-frequency regulatory SNP and a rare null mutation in exon-junction complex subunit RBM8A causes TAR syndrome. Nat Genet 2012: 44; 435–439, S431–432 Duy C, Hurtz C, Shojaee S, Cerchietti L, Geng H, Klemm L, Kim YM, Jumaa H, Koeffler HP, Yu JJ, Heisterkamp N, Graeber TG, Wu H, Ye BH, Melnick A & Müschen M. BCL6 enables Ph+ acute lymphoblastic leukemia cells to survive BCR-ABL1 kinase inhibition. Nature 2012: 474; 384–388 Fitch SR, Kimber G, Wilson NK, Parker A, Mirshekar-Syahkal B, Göttgens B, Medvinsky A, Dzierzak E & Ottersbach K. Signaling from the sympathetic nervous system regulates hematopoietic stem cell emergence during embryogenesis. Cell Stem Cell 2012: 11; 554–566 Li W and Huntington JA. Crystal structures of protease nexin-1 in complex with heparin and thrombin suggest a two-step recognition mechanism. Blood 2012: 120(2); 459–67, 2012 van der Harst P, Zhang W, Mateo Leach I, Rendon A, Verweij N, Sehmi J… Penninger JM, Gieger C, Kooner JS, Ouwehand WH, Soranzo N, Chambers JC. Seventy-five genetic loci influencing the human red blood cell. Nature 2012: 492; 369–375

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Histopathology Division of Molecular Histopathology, Department of Pathology Professor Nick Coleman Tel 01223 766422 Fax 01223 586670 Email nc109@cam.ac.uk

Staff list Professors N Coleman, Professor of Histopathology M-Q Du, Professor of Oncological Pathology Senior University Lecturers S D Turner J Xuereb University Lecturers A Ibrahim (on leave of absence)

research/tissue-bank). The Bank is licenced by the Human Tissue Authority and ethically approved. It provides appropriately collected and consented human tissue (both normal and pathological) from Addenbrooke’s patients for research projects.

For details of access policies and how to apply for human tissue, see the document, 'Policy governing access to human samples for research at Cambridge University Hospitals NHS Foundation Trust' and the website (see bottom left). The Division is also responsible for the Cambridge Brain Bank. The Cambridge Brain Bank was established to enable brain tissue to be used after death for research into neurodegenerative disorders such as dementia (eg. Alzheimer’s, frontotemporal), motor neurone disease, Huntington’s disease, multiple sclerosis, Parkinson’s disease etc. The donation of post-mortem brain tissue for research is of fundamental importance to further our understanding of the causes of these disorders and to develop more effective diagnostic tools and treatments for these conditions. For access to the material in the Cambridge Brain Bank, call or email the Bank (brbank@addenbrookes.nhs.uk, telephone 01223 217336).

NHS Consultants and Associate/Affiliated Lecturers A F Dean R Ahmed V Bardsley R Brais V Broecker J Chan A Cluroe

S Davies

S De Sanctis

H Eldaly

M Griffiths

L Hook

J Grant

F Jessop

M J-Linan

M O’Donovan

B Mahler-Araujo

A Malaviya

S Malhotra

A Marker

Z Mead

G Meligonis

A Miremadi

D O’Donovan

A Patterson

E Provenzano

S Pursglove

R Moseley

B Rous

E Rytina

S Thiru

A Warren

A Watkins

P Wright Cancer cells

Research synopsis The Division combines research, teaching and diagnostic histopathology. The research focuses on analysing the molecular and cell biology of disease and applying advances in this area to Clinical Histopathology, and where relevant, therapy. The Division takes part in the teaching and examining of Pathological Sciences in Pt. Ib and Pt. II tripos as well as being responsible for the clinical pathology course at Addenbrooke’s and the Final MB Part I Examination. The Division has a number of major projects, studying, in particular neoplastic disease. These include the study of human tumours of the central nervous system, tumours of the lower intestinal tract, lymphomas, germ cell tumours, cervical tumours, breast tumours and ovarian tumours. Many of the projects are in collaboration with other research groups within Addenbrooke’s or the University of Cambridge. The Division has established a Human Research Tissue Bank together with Cambridge University Hospitals NHS Foundation Trust (www.cuh.org.uk/research-and-development/facilities-for-

Selected references Louis DN, Perry A, Burger P, Ellison DW, Reifenberger G, von Deimling A, Aldape K, Brat D, Collins VP, Eberhart C, Figarella-Branger D, Fuller GN, Giangaspero F, Giannini C, Hawkins C, Kleihues P, Korshunov A, Kros JM, Lopes MB, Ng HK, Ohgaki H, Paulus W, Pietsch T, Rosenblum M, Rushing E, Soylemezoglu F, Wiestler O, Wesseling P. International Society of Neuropathology-Haarlem Consensus Guidelines, for Nervous System Tumor Classification and Grading. Brain Pathol. 2014 Jul 2: doi: 10.1111/ bpa.12171.

Jones DT, Hutter B, Jäger N, Korshunov A, Kool M, Warnatz HJ, Zichner T, Lambert SR, Ryzhova M, Quang DA, Fontebasso AM, Stütz AM, Hutter S, Zuckermann M, Sturm D, Gronych J, Lasitschka B, Schmidt S, Seker-Cin H, Witt H, Sultan M, Ralser M, Northcott PA, Hovestadt V, Bender S, Pfaff E, Stark S, Faury D, Schwartzentruber J, Majewski J, Weber UD, Zapatka M, Raeder B, Schlesner M, Worth CL, Bartholomae CC, von Kalle C, Imbusch CD, Radomski S, Lawerenz C, van Sluis P, Koster J, Volckmann R, Versteeg R, Lehrach H, Monoranu C, Winkler B,

HISTOPATHOLOGY

17

Histopathology Unterberg A, Herold-Mende C, Milde T, Kulozik AE, Ebinger M, Schuhmann MU, Cho YJ, Pomeroy SL, von Deimling A, Witt O, Taylor MD, Wolf S, Karajannis MA, Eberhart CG, Scheurlen W, Hasselblatt M, Ligon KL, Kieran MW, Korbel JO, Yaspo ML, Brors B, Felsberg J, Reifenberger G, Collins VP, Jabado N, Eils R, Lichter P, Pfister SM; International Cancer Genome Consortium PedBrain Tumor Project. Recurrent somatic alterations of FGFR1 and NTRK2 in pilocytic astrocytoma. Nat Genet. 2013 Aug: 45(8): 927–32. doi: 10.1038/ng.2682.

Epub 2013 Jun 30 Rosebeck S, Madden L, Jin X, Gu S, Apel IJ, Appert A, Hamoudi R, Noels H, Sagaert X, Loo PV, Baens M, Du MQ, Lucas PC, McAllisterLucas LM. Cleavage of NIK by the API2-MALT1 fusion oncoprotein leads to noncanonical NF-kB activation. Science 2011: 331:468–72 Dong G, Chanudet E, Zeng N, Appert A, Chen YW, Au WY, Hamoudi R, Watkins AJ, Ye H, Liu H, Gao Z, Chuang SS, Srivastava G, Du MQ. A20, ABIN-1/2 and CARD11 mutations and their prognostic value in gastrointestinal diffuse large B-cell lymphoma.

Clinical Cancer Research 2011: 17(6); 1440–51 Scarpini CG, Groves IJ, Pett MR, Ward D, Coleman N. Virus transcript levels and cell growth rates after naturally-occurring HPV16 integration events in basal cervical keratinocytes. The Journal of Pathology 2014: 233; 281–93 Murray MJ, Saini HK, Siegler CA, Hanning JE, Barker EM, van Dongen S, Ward DM, Raby KL, Groves IJ, Scarpini CG, Pett MR, Thornton CM, Enright AJ, Nicholson JC, Coleman N. LIN28 expression in malignant germ cell tumors downregulates let-7 and increases oncogene levels. Cancer Research 2013: 73; 4872–84 Moti N, Malcolm T, Hamoudi R, Mian S, Garland G, Hook CE, Burke GAA, Wasik M, Merkel O, Lenner L, Laurenti E, Dick JE and Turner SD. Anaplastic large cell lymphoma-propagating cells are detectable by side population analysis and possess an expression profile reflective of a primitive origin. Oncogene 2014 May 12: doi; 10.1038/onc.

2014. 112 Laimer D, Dolznig H, Kollmann K, Vesely PW, Schlederer M, Merkel O, Schiefer A, Hassler MR, Heider S, Amenitsch L, Thallinger C, Staber PB, Simonitsch-Klupp I, Artaker M, Lagger S, Turner SD, Pileri S, Piccaluga PP, Valent P, Messana K, Landra I, Weichhart T, Knapp , Shehata M, Todaro M, Sexl V, Höfler G, Piva R, Medico E, Riggeri BA, Cheng M, Eferl R, Egger G, Penninger JM, Jaeger U, Moriggl R, Inghirami G and Kenner L. Identification of PDGFR blockade as a rational and highly effective therapy for NPM-ALK driven lymphomas. Nature Medicine 2012: 18(11); 1699–704 Alexander SK, Rittman T, Xuereb JH, Bak TH, Hodges JR, Rowe JB. Validation of the new consensus criteria for the diagnosis of corticobasal degeneration. J Neurol Neurosurg Psychiatry 2014 Aug: 85(8); 925–9 Charidimou A, Jaunmuktane Z, Baron JC, Burnell M, Varlet P, Peeters A, Xuereb J, Jäger R, Brandner S, Werring DJ. White matter perivascular spaces: an MRI marker in pathology-proven cerebral amyloid angiopathy? Neurology 2014 Jan 7: 82(1); 57–62 Ibrahim AE, Arends MJ, Silva AL, Wyllie AH, Greger L, Ito Y et al.

Sequential DNA methylation changes are associated with DNMT3B overexpression in colorectal neoplastic progression. Gut 2011: 60(4), 499–508 de la Roche M, Ibrahim AE, Mieszczanek J, & Bienz M. (2014).

LEF1 and B9L shield beta-catenin from inactivation by Axin, desensitizing colorectal cancer cells to tankyrase inhibitors. Cancer Res. 2014: 74(5), 1495–505

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HISTOPATHOLOGY

Medical Genetics Head of Department and Professor of Medical Genetics and Genomic Medicine Professor Eamonn Maher Tel 01223 746714 Fax 01223 746777 Email erm1000@medschl.cam.ac.uk

Staff list Professors ER Maher, Professor of Medical Genetics and Genomic Medicine JA Todd FRS, Professor Medical Genetics FE Karet, Professor of Nephrology DC Rubinsztein, Professor of Molecular Neurogenetics LS Wicker, Professor of Immunogenetics GC Woods, Professor in Human Genetics Readers FL Raymond, Reader in Neurogenetics RN Sandford, Reader in Renal Genetics University Lecturer M Tischkowitz EA Reid Senior Research Staff F Waldron-Lynch G Mells K Baker A-L Tavares NHS Consultants/Associate Lecturers H Firth

Research synopsis The Department of Medical Genetics adopts a broad approach to ‘Medical Genetics’, encouraging interests in genomics and the functional biology of genetic disease, as well as applying genetics to diagnostic and therapeutic approaches to disease.

Ongoing research addresses a broad range of monogenic and multifactorial genetic disorders and many research programmes and clinical activities are run jointly with other departments at Addenbrooke’s and elsewhere.

Major areas of interests are: cancer genetics; genetics of developmental disorders; genetics of inflammatory disorders and juvenile diabetes; genetic components of neurological disease, including cellular mechanisms of neurodegeneration and developmental biology of neural cell development and repair; genes contributing to X-linked disease, particularly intellectual disability; renal genetics; autoimmune liver disease; disorders of genomic imprinting.

HeLa cells depleted of spastin and labelled for SNX1 (green) and acetylated tubulin (red) show pronounced cellular protrusions and increased tubulation of the SNX1 endosomal compartment.

Groups include The JDRF/WT Diabetes and Inflammation Laboratory, including John Todd, Linda Wicker and Frank Waldron-Lynch: diabetes, inflammation, genome informatics, statistical and non-Mendelian genetics.

• Fiona Karet: renal genetics (acid base homeostasis).

• Eamonn Maher: Cancer genetics, genomic imprinting, autosomal recessive disease.

• David Rubinsztein: Autophagy and neurodegeneration and the biological effects of triplet repeat diseases.

• Lucy Raymond: Genetics of Learning Disability (GOLD) Study – applying genomic methods to X-linked learning disability.

• Evan Reid: studies on axonal degenerative disorders.

• Richard Sandford: Renal genetics (autosomal dominant polycystic kidney disease) and genetics of autoimmune liver disease. PBC Genetics Study – study to determine the genetic cause of Primary Biliary Cirrhosis, PSC Genetics Study – study to determine the genetic cause of Primary Sclerosing Cholangitis.

• Marc Tischkowitz: Cancer genetics.

•

There are close interactions between the University Department of Medical Genetics and members of the NHS East Anglian Medical Genetics Service including NHS consultants (Dr Helen Firth, Dr Ruth Armstrong, Dr Joan Paterson, Dr Soo-Mi Park, Dr Sarju Mehta and Dr Simon Holden) and the Directors of the NHS Molecular and Cytogenetics Laboratories (Dr Steve Abbs and Dr Ingrid Simonic). Medically qualified members of the University Department also have clinical duties in the NHS Clinical Genetics Department.

MEDICAL GENETICS

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Medical Genetics Selected references Astuti D, Morris MR, Cooper WN, Staals RH, Wake NC, Fews GA, Gill H, Gentle D, Shuib S, Ricketts CJ, Cole T, van Essen AJ, van Lingen RA, Neri G, Opitz JM, Rump P, Stolte-Dijkstra I, Müller F, Pruijn GJ, Latif F, Maher ER. Germline mutations in DIS3L2 cause the Perlman syndrome of overgrowth and Wilms tumor susceptibility.

Nat Genet. 2012 Feb 5: 44(3); 277–84 Grozeva D, Carss K, Spasic-Boskovic O, Parker MJ, Archer H, Firth HV, Park SM, Canham N, Holder SE, Wilson M, Hackett A, Field M, Floyd JA; UK10K Consortium, Hurles M, Raymond FL. De novo lossof-function mutations in SETD5, encoding a methyltransferase in a 3p25 microdeletion syndrome critical region, cause intellectual disability. Am J Hum Genet. 2014 Apr 3: 94(4); 618–24 Puri C, Renna M, Figueira Bento C, Moreau K and Rubinsztein DC. (2013) Diverse autophagosome membrane sources coalesce in recycling endosomes. Cell 2013: 154: 1285–1299 Liu JZ, Almarri MA, Gaffney DJ, Mells GF, Jostins L, Cordell HJ, Ducker SJ, Day DB, Heneghan MA, Neuberger JM, Donaldson PT, Bathgate AJ, Burroughs A, Davies MH, Jones DE, Alexander GJ, Barrett JC, Sandford RN, Anderson CA; UK Primary Biliary Cirrhosis (PBC) Consortium; Wellcome Trust Case Control Consortium 3. Dense fine-mapping study identifies new susceptibility loci for primary biliary cirrhosis. Nat Genet. 2012 Oct: 44(10); 1137–41 Lee JH, Silhavy JL, Lee JE, Al-Gazali L, Thomas S, Davis EE, Bielas SL, Hill KJ, Iannicelli M, Brancati F, Gabriel SB, Russ C, Logan CV, Sharif SM, Bennett CP, Abe M, Hildebrandt F, Diplas BH, Attié-Bitach T, Katsanis N, Rajab A, Koul R, Sztriha L, Waters ER, Ferro-Novick S, Woods CG, Johnson CA, Valente EM, Zaki MS, Gleeson JG. Evolutionarily assembled cis-regulatory module at a human ciliopathy locus. Science. 2012 Feb 24: 335(6071); 966–9 Norgett EE*, Golder ZJ* (*joint), Lorente-Canocas B, Ingham N, Steel KP and Karet Frankl FE. An Atp6v0a4 knockout mouse is a model of distal Renal Tubular Acidosis with hearing loss, with additional extrarenal phenotype. Proc. Natl. Acad. Sci. (USA) 2012: 109; 13775–8009 Witkowski L, Carrot-Zhang J, Albrecht S, Fahiminiya S, Hamel N, Tomiak E, Grynspan D, Saloustros E, Nadaf J, Rivera B, Gilpin C, Castellsagué E, Silva-Smith R, Plourde F, Wu M, Saskin A, Arseneault M, Karabakhtsian RG, Reilly EA, Ueland FR, Margiolaki A, Pavlakis K, Castellino SM, Lamovec J, Mackay HJ, Roth LM, Ulbright TM, Bender TA, Georgoulias V, Longy M, Berchuck A, Tischkowitz M, Nagel I, Siebert R, Stewart CJ, Arseneau J, McCluggage WG, Clarke BA, Riazalhosseini Y, Hasselblatt M, Majewski J, Foulkes WD. Germline and somatic SMARCA4 mutations characterize small cell carcinoma of the ovary, hypercalcemic type. Nat Genet. 2014 Mar 23: 46, 438–443 Allison R, Lumb JH, Fassier C, Connell JW, Ten Martin D, Seaman MNJ, Hazan J, Reid E. An ESCRT-spastin interaction promotes fission of recycling tubules from the endosome.

Journal of Cell Biology 2013: 202; 527–43

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Waldron-Lynch F, Kareclas P, Irons K, Walker NM, Mander A, Wicker LS, Todd JA and Bond S. Rationale and study design of the Adaptive study of IL-2 dose on regulatory T cells in type 1 diabetes (DILT1D): a non-randomised, open label, adaptive dose finding trial.

BMJ Open 2014: 4, e005559.

Ferreira RC, Freitag DF, Cutler AJ, Howson JMM, Smyth DB, Kapotage S, Clarke P, Boreham C, Coulson RM, Pekalski ML, Wei-Min C, Onengut-Gumuscu S, Rich SS, Butterworth AS, Malarstig A, Danesh J and Todd JA. Functional IL6R variant impairs classical IL-6 receptor signalling and influences risk of diverse inflammatory diseases. PLoS Genet. 2013: 9, e1003444.

Medicine Head of Department and Professor of Medicine

Other Principal Investigators JR Bradley PW Ewan

JC Goodall

Professor Ken GC Smith Tel 01223 336848

JR James

SJ Marciniak

Y Modis

JA Nathan

S Nejentsev

KJ Patel

M Parkes

F Randow

S Sinha

Fax 01223 336846

MR Wills

Email hodmed@medschl.cam.ac.uk

Senior Research Staff C Berzuini MB Cachon-Gonzalez J Cheriyan

Staff list Professors M Ashcroft, Professor of Hypoxia Signaling and Cell Biology MR Bennett FRS, Professor of Cardiovascular Sciences Sir L Borysiewicz, Professor of Medicine and Vice-Chancellor MJ Brown, Professor of Clinical Pharmacology KK Chatterjee, Professor of Endocrinology

AS Cowburn

U Desselberger

J Garland

I Gorenne

H Jorgensen

T Littlewood

PA Lyons

C McEniery

J Maguire

R Mahadeva

J Murphy

M Murthy

A Rana

O Rajanayagam

FJ Roca Soler

P Upton

M Weekes

Li Wei

Y Yasmin

ER Chilvers, Professor of Respiratory Medicine

NHS Consultants/Associate Lecturers A Adler GJ Alexander

S Aliyu

MED Allison

P Barry

M Belham

R Biram

NP Burrows

T Burton

E Cameron

GA Campbell

AJ Carmichael

CA Carne

S Chan

A Chaudhry

M Chua

M Cranston

PB Deegan

E Gkrania-Klotsas

JD Firth

N Flanagan

PD Flynn

DR Forsyth

J Fuld

J Gass

AES Gimson

WJH Griffiths

CW Glazebrook

S Gunda

KE Gunning

A Gupta

T Ha

A Johnston

PM Jones

Y-M Lee

MS Lillicrap

BF Matta

SJ Middleton

F Mir

S Mulroy

S Nasser

C Nicholl

PG Norris

E O’Brien

S Ojha

AJK Ostor

M O’Sullivan

J Preller

P Pugh

NR Pritchard

R Rusk

IB Wilkinson, Professor of Therapeutics

C Sander

PM Schofield

LM Shapiro

Readers AP Davenport, Reader in Cardiovascular Pharmacology

N Shenker

L Sibal

JM Shneerson

P Sivasothy

H Smith

IE Smith

C Sonnex

S Stinchcombe

PM Todd

E Torok

NR Torpey

M Vindlacheruvu

University Senior Lecturers JC Sterling MS Sandhu

E Warburton

P Weissberg

L Willcocks

J Wilson

RJ Winter

J Woodward

University Lecturers MR Clatworthy

JP Coles

AM Condliffe

A Conway-Morris

H Knolle

LN Drumright

DP Dutka

ML Evans

Clinical Lecturers B Challis S Hoole

A McGeoch

EF McKinney

M Gurnell

T Krieg

M Lee

G Mells

HP Mok

T Raine

KES Poole

JHF Rudd

E Soon

C Stober

C Summers

TDC Thomas

U Vadakke-Puthanveettil

J Compston, Professor of Bone Research TM Cox, Professor of Medicine (1962) AW Cuthbert, Emeritus Shield Professor of Pharmacology RA Floto, Professor of Respiratory Biology JSH Gaston, Professor of Rheumatology GM Griffiths, Professor of Immunology and Cell Biology A Kaser, Professor of Gastroenterology PJ Lehner, Professor of Immunology and Medicine AML Lever, Professor of Infectious Diseases Z Mallat, BHF Professor of Cardiovascular Medicine PH Maxwell, Regius Professor of Physic DK Menon, Professor of Anaesthesia NW Morrell, BHF Professor of Cardiopulmonary Medicine S Peacock, Professor of Clinical Microbiology L Ramakrishnan, Professor of Immunology and Infectious Diseases JH Sinclair, Professor of Molecular Virology Sir P Sissons, Regius Professor Emeritus of Physic KGC Smith, Professor of Medicine

DRW Jayne, Reader in Vasculitis KM O’Shaughnessy, Reader in Clinical Pharmacology

A Waters E Yu MEDICINE

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Medicine Synopsis The Department of Medicine aims to foster medical research of the highest quality, in fundamental as well as translational and clinical science. It is committed to delivering high quality teaching of both medical students and post-graduate research students and contributes significantly to clinical care across the Cambridge University Hospitals NHS Trusts. It does this across a broad sweep of academic medicine, with 12 divisions aligned to different clinical specialties. These are: Anaesthesia Cardiovascular Medicine Clinical Pharmacology Diabetes and Endocrinology Experimental Medicine and Immunotherapeutics Gastroenterology and Hepatology

Immunology Infectious Diseases Metabolic Medicine Renal Medicine Respiratory Medicine Rheumatology

The Department employs over 500 research staff, and holds around £145m in external competitive grant income, making it the largest Department in the Clinical School. Principal investigators and their groups are housed in embedded space within Addenbrooke’s Hospital (CUH), as well as within the CIMR, Institute of Metabolic Sciences and West Forvie Site, among others.

translation in this area, which is particularly important in view of increasing potential for liaison with industry partners on the campus.

Recent developments within the Department include the establishment of a University Research Unit within the new MRC Laboratory for Molecular Biology. This unit, supported by the Wolfson Trust, has succeeded in recruiting exciting new investigators focussed in the areas of immunity and infection, interacting closely with researchers within the LMB. The appointment of Arthur Kaser as the foundation Professor of Gastroenterology allowed the establishment of the Division of Gastroenterology and Hepatology. The Department has also created a new division of Experimental Medicine and Immunotherapeutics, in order to enhance its capacity for

Major plans are underway to revolutionise the laboratory accommodation of the Department over the next four years.

This includes a £2.4m refurbishment of the main Departmental laboratory space embedded within Addenbrooke’s Hospital, which is underway. Funding has also been raised for a new Cambridge Institute for Therapeutic Immunology and Infectious Diseases, supported by a £25m grant from the HEFCE Research Partnership Infrastructure Fund and with completion due in 2017.

The prospect of Papworth Hospital’s move to the campus will also allow construction of a Heart and Lung Research Institute. These developments should ensure that the Department of Medicine is well placed to maintain its research trajectory over the next decade whilst reinforcing important commitments to teaching and patient care.

Anaesthesia The research in the Division has five main strands: the first involves physiological imaging in traumatic brain injury (TBI), at all stages, from ictus to late outcome. Positron emission tomography (PET) and magnetic resonance imaging (MRI) in the acute phase currently address novel mechanisms of energy failure, including diffusion hypoxia, inflammation, amyloid deposition, and mitochondrial dysfunction. Late MRI imaging is used to investigate mechanisms underlying neurocognitive deficits in TBI patients. A second strand focuses on the neuro-anatomical basis of coma and consciousness, both in pathological states, and in the controlled situation of sedation induced by anaesthetic agents. Third, the Division has a growing program in translational pain research, which focuses on analgesic discovery in collaboration with experimental pharmacology and clinical genetics. The methodologies we employ in pain research include early phase clinical trials, quantitative sensory testing, functional brain imaging and genotyping. Our fourth theme focuses on leukocyte biology in acute lung injury and critical 22

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Young et al. PIB-PET imaging of amyloid deposition in traumatic brain injury. JAMA Neurology, 2014.

illness, and aims to understand the role of host response in both injury and repair. Finally, a growing initiative in non-linear analysis of complex large datasets will make use of the implementation of the new eHospital system at Addenbrooke’s Hospital.

Selected references Hong YT, Veenith T, Dewar D, Outtrim JG, Mani V, Williams C, Pimlott S, Hutchinson PJ, Tavares A, Canales R, Mathis CA, Klunk WE, Aigbirhio FI, Coles JP, Baron JC, Pickard JD, Fryer TD, Stewart W, Menon DK. Amyloid imaging with carbon 11-labeled Pittsburgh compound B for traumatic brain injury. JAMA Neurol 2014: 71(1); 23–31 Newcombe VF, Williams GB, Outtrim JG, Chatfield D, Abate GM, Geeraerts T, Manktelow A, Room H, Mariappen L, Hutchinson PJ, Coles JP, Menon DK. Microstructural basis of contusion expansion in traumatic brain injury: insights from diffusion tensor imaging.

J Cereb Blood Flow Metab 2013: 33(6); 855–62 Veenith TV, Carter EL, Grossac J, Newcombe VF, Outtrim JG, Nallapareddy S, Lupson V, Correia MM, Mada MM, Williams GB, Menon DK, Coles JP. Use of diffusion tensor imaging to assess the impact of normobaric hyperoxia within at-risk pericontusional tissue after traumatic brain injury. J Cereb Blood Flow Metab 2014: 34, 1622–1627 Summers C, Singh NR, White JF, Mackenzie IM, Johnston A, Solanki C, Balan KK, Peters AM, Chilvers ER. Pulmonary retention of primed neutrophils: a novel protective host response, which is impaired in the acute respiratory distress syndrome. Thorax 2014: 69(7); 623–9 Adapa RM, Davis MH, Stamatakis EA, Absalom AR, Menon DK. Neural correlates of successful semantic processing during propofol sedation. Hum Brain Mapp 2014: 35(7); 2935–49

Cardiovascular medicine The Division has assembled a collaborative group of cardiovascular investigators who collectively provide expertise in basic, translational and clinical cardiovascular research and who employ cell and molecular biology, in vivo models, genomics, epigenetics, sequencing, biomarker identification and validation, through to novel imaging, diagnostics and experimental medicine studies to improve patient outcomes. Atherosclerosis leading to myocardial infarction (MI) and stroke is the commonest cause of death in the UK. Inflammation, immunity, cell death (apoptosis), and cell senescence in atherosclerotic plaques are major contributors to atherogenesis, plaque rupture and MI. Our research examines the causes and regulation of these processes in atherosclerosis, with a particular focus on smooth muscle and immune regulation of atherosclerosis and aneurysm formation. Sanjay Sinha and Helle Jørgensen are studying smooth muscle cells derived from embryonic and induced pluripotent stem cells as part of the Oxbridge Centre for Cardiovascular Regenerative Medicine Centre, a network of researchers focused on cardiovascular stem cells and development.

The Division’s major clinical research interests include heart failure, the assessment of viability in dysfunctional myocardium, and the utility of transient ischaemia or novel therapeutics to protect the heart from further insults. We have developed metabolic cardioprotection during percutaneous coronary intervention

Virtual histology intravascular ultrasound (VH-IVUS) (top panels) and band plots (bottom panels) for Stress-P1 along a VH-IVUS pullback (middle panel), illustrating locations of peak Stress-P1 values for four cross-sections within an atherosclerotic plaque. From Circulation Cardiovascular Imaging.

2014. 101; 513–521

(PCI) (both primary emergency and elective intervention), examined the effect of new agents to treat diabetes on cardiac performance in type 2 diabetes, and determined the optimum use of cardiac resynchronisation therapy based on the underlying pathophysiology. In our vascular imaging programme, led by James Rudd, we are determining whether inflammation, hypoxia and neovascularisation detected by PET/CT and MRI can improve risk prediction, and whether imaging can illustrate the efficacy of anti-atherosclerosis drugs. Martin Bennett’s group are exploring invasive imaging of atherosclerosis using virtual histology intravascular ultrasound (VH-IVUS), and trying to determine whether plaque disruption can be predicted using stress/strain modelling. This work is undertaken in collaboration with physical scientists in the Engineering and Radiology departments of the University as part of the new Cambridge Cardiovascular Strategic Research Initiative.

Selected references Khan FZ, Virdee MS, Palmer CR, Pugh PJ, O’Halloran D, Elsik M, Read PA, Begley D, Fynn SP, Dutka DP. Targeted left ventricular lead placement to guide cardiac resynchronization therapy: the TARGET study: a randomized, controlled trial. J Am Coll Cardiol. 2012: 59(17); 1509–18 Cheung C, Bernardo AS, Trotter MW, Pedersen RA, Sinha S. Generation of human vascular smooth muscle subtypes provides insight into embryological origin-dependent disease susceptibility.

Nat Biotechnol. 2012 Jan 15: 30(2); 165–73 Gorenne I, Kumar S, Gray K, Figg N, Yu H, Mercer J, Bennett MR. Vascular Smooth Muscle Cell Sirtuin 1 protects against DNA damage and inhibits atherosclerosis. Circulation. 2013: 127(3); 386–96 Zheng Y, Humphry M, Maguire JJ, Bennett MR, Clarke MCH. Intracellular IL-1 receptor 2 binding prevents cleavage and activity of IL-1α, controlling necrosis-induced sterile inflammation.

Immunity. 2013: 38; 285–295

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Medicine Deroide N, Li X, Lerouet D, Van Vré E, Baker L, Harrison J, Poittevin M, Masters L, Nih L, Margaill I, Iwakura Y, Ryffel B, Pocard M, Tedgui A, Kubis N, Mallat Z. MFGE8 inhibits inflammasomeinduced IL-1β production and limits post-ischemic cerebral injury.

J Clin Invest. 2013: 123(3); 1176–81 Mäki-Petäjä KM, Elkhawad M, Cheriyan J, Joshi FR, Ostör AJK, Hall FC, Rudd JH, Wilkinson I B. Anti-tumor necrosis factor-α therapy reduces aortic inflammation and stiffness in patients with rheumatoid arthritis. Circulation. 2012: Nov 20; 126(21); 2473–80

Brighton CA, Teo AE, Davenport AP, Dekkers T, Tops B, Küsters B, Ceral J, Yeo GS, Neogi SG, McFarlane I, Rosenfeld N, Marass F, Hadfield J, Margas W, Chaggar K, Solar M, Deinum J, Dolphin AC, Farooqi IS, Striessnig J, Nissen P, Brown MJ. Somatic mutations in ATP1A1 and CACNA1D underlie a common subtype of adrenal hypertension. Nat Genet 2013: 45; 1055–60 Burton TJ, Mackenzie IS, Balan K, Koo B, Bird N, Soloviev DV, Azizan EA, Aigbirhio F, Gurnell M, Brown MJ. Evaluation of the Sensitivity and Specificity of 11C-Metomidate Positron Emission Tomography (PET)-CT for Lateralizing Aldosterone Secretion by Conn’s Adenomas. J Clin Endocrinol Metab. 2012: 97; 100–9

Clinical pharmacology Clinical pharmacology concentrates on high impact research with a track record of changing clinical practice. Clinical research, using a novel 11C-metomidate PET CT, and laboratory research finding signature gain-of-function mutations in genes regulating calcium entry to adrenocortical cells, have identified a common curable cause of hypertension: microadenomas of the adrenal zona glomerulosa. One of these calcium entry genes has received a GSK Fast-track award as target for development of a novel therapeutic.

Diabetes and endocrinology This Division has three main areas of research: Mark Evans is interested in (1) how the brain detects changes in blood glucose and how this glucose-sensing interacts with peripheral metabolism, (2) how defences against hypoglycaemia may become abnormal in diabetes, (3) the effects of hypoglycaemia on the brain, and (4) improving the ability of patients with type 1 diabetes to manage their own diabetes through structured education and judicious use of new and innovative technology for monitoring and managing diabetes, including in collaboration with Dr Roman Hovorka and colleagues, the closed loop insulin pump systems (the 'artificial pancreas').

11C-metamidate PET CT detects a curable adrenal microadenoma in a patient with previously severe hypertension and apprently 'normal' magnetic resonance image (MRI) of the adrenal.

Several gifted PhD students have won national and international prizes for work addressing whether zona glomerulosa genes found on microarray to be uniquely upregulated in human adrenal, eg. LGR5, DACH1, NPNT, regulate the disappearance of cells making aldosterone, in response to excessive salt intake, and so create a selective advantage for cells which mutate to achieve constitutive aldosterone production. Clinically, 2015 will see the reporting of results from the BHF’s landmark multicentre programme of trials, PATHWAY, which are expected to lead to the routine use of plasma renin analysis in hypertension, and influence the revision of NICE guidance for hypertension in 2016.

Clinical Pharmacology also hosts the £5.5m Wellcome Trust/ GSK interdisciplinary training programme in Translational Medicine and Therapeutics, which includes a full- or part-time MPhil in Translational Medicine, and annual competitions for posts as MB/PhD, ACF, PhD Fellowship, and Clinical Lectureships.

The programme enables trainees in almost any branch of Medicine to acquire skills that bridge the bench-tobedside divide.

Azizan EA, Poulsen H, Tuluc P, Zhou J, Clausen MV, Lieb A, Maniero C, Garg S, Bochukova EG, Zhao W, Shaikh LH,

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A patient with uncontrolled acromegaly, but no apparent tumour on routine clinical MRI. 11C-methionine PET coregistered with MRI reveals circumferential tracer uptake corresponding to functioning tumour in the floor of the pituitary fossa (arrows), and guides surgical resection to induce disease remission.

Mark Gurnell’s research focuses on (i) genetic and acquired disorders of the hypothalamic-pituitary-thyroid axis, (ii) functional imaging in pituitary (11C-methionine) and adrenal (11C-metomidate) neoplasia, (iii) novel approaches to sparing hypothalamic-pituitary function in patients with sella/parasellar tumours and following cranial irradiation, and (iv) the endocrine and neural basis of financial decision making.

Krishna Chatterjee’s research relates to disorders of nuclear hormone synthesis and action. Human cohorts studied include: subjects with disorders of thyroid hormone metabolism and action including Resistance to Thyroid Hormone; and lipodystrophic insulin resistance associated with PPAR gamma gene defects. Candidate gene and whole exome approaches are used to identify novel genetic aetiologies, with complementary studies which define human phenotypes. The research is translated into genetic tests and biomarkers forming the basis of a national diagnostic service for rare/unusual thyroid disorders.

Experimental medicine and immunotherapeutics Research in this cross-cutting themed Division primarily concerns studies in healthy volunteers to dissect normal physiology and understand pharmacology of new molecules, and trials in patients including interventional clinical trials, end-point and outcome measure development and biomarker validation.

The division is developing an active programme to support career development in experimental medicine.

Selected references Leelarathna L, Little SA, Walkinshaw E, Tan HK, Lubina-Solomon A, Kumareswaran K, Lane AP, Chadwick T, Marshall SM, Speight J, Flanagan D, Heller SR, Shaw JAM, Evans ML. Restoration of self-awareness of hypoglycemia in adults with long-standing type 1 diabetes: hyperinsulinemic hypoglycemic clamp sub-study results from the HypoCOMPaSS trial. Diabetes Care December 2013: 36, 4063–4070 Osundiji MA, Lam DD, Shaw JS, Yueh CY, Markkula P, Hurst P, Colliva C, Roda A, Heisler LK, Evans ML. Brain Glucose Sensors Play a Significant Role in the Regulation of Pancreatic Glucose-Stimulated Insulin Secretion. Diabetes 2012 Feb: 61(2); 321–8 Kandasamy N, Hardy B, Page L, Schaffner M, Graggaber J, Powlson A, Fletcher P, Gurnell M, Coates J. Cortisol shifts financial risk preferences. Proc Natl Acad Sci USA. 2014: 111(9); 3608–13 Annamalai AK, Webb A, Kandasamy N, Elkhawad M, Moir S, Khan F, Maki-Petaja K, Gayton EL, Strey CH, O’Toole S, Ariyaratnam S, Halsall DJ, Chaudhry AN, Berman L, Scoffings DJ, Antoun NM, Dutka DP, Wilkinson IB, Shneerson JM, Pickard JD, Simpson HL, Gurnell M. A Comprehensive Study of Clinical, Biochemical, Radiological, Vascular, Cardiac, and Sleep Parameters in an Unselected Cohort of Patients With Acromegaly Undergoing Presurgical Somatostatin Receptor Ligand Therapy. J Clin Endocrinol Metab, 2013: 98(3); 1040–1050 Bochukova E, Schoenmakers N, Agostini M, Schoenmakers E, Rajanayagam O, Keogh JM, Henning E, Reinemund J, Gevers E, Sarri M, Downes K, Offiah A, Albanese A, Halsall D, Schwabe J, Bain M, Lindley K, Muntoni F, Vargha-Khadem F, Dattani M, Farooqi S, Gurnell M, Chatterjee K. A Dominant Negative Mutation in the Thyroid Hormone Receptor Alpha Gene. N Engl J Med, 2012: 366; 243–249 Moran C, Agostini M, Visser WE, Schoenmakers E, Schoenmakers N, Offiah AC, Poole K, Rajanayagam O, Lyons G, Halsall M, Chrysis D, Efthymiadou A, Buchanan C, Aylwin S, Chatterjee K. Resistance to thyroid hormone caused by a mutation in thyroid hormone receptor (TR) 1 and TR 2: a clinical, biochemical and genetic analysis of three related patients.

Lancet Diabetes Endocrinol, 2014: S2213-8587(14)70111–1

PET/CT image of 18F-FDG uptake in the aorta

Ian Wilkinson’s research centres on understanding the pathophysiology of arteriosclerosis and hypertension in older individuals. He is also interested in profiling vascular function and developing stratified approaches for treatment across a range of disease areas. Carmel McEniery specialises in cardiovascular phenotyping and is interested in the causal factors underlying the development of hypertension in young individuals, and the clinical importance of central blood pressure. Joseph Cheriyan’s research involves the translation of novel therapeutic agents in Phase I/II clinical development, which may improve endothelial function and vascular inflammation. In collaboration with GSK, this has led to the progress of losmapimod to Phase 3 development for acute coronary syndromes. Thomas Hiemstra investigates premature vascular ageing in chronic kidney disease, and interventions to reduce this. Several vascular calcification studies harnessing novel imaging and targeted proteomics are underway to dissect molecular pathways of vascular ageing.

David Jayne co-ordinates the research activity of the European Vasculitis Society and is chief investigator of two international randomised controlled trials in ANCA vasculitis: PEXIVAS and RITAZAREM. His Cambridge group is investigating the longterm efficacy and safety of B cell depletion with rituximab and conducting Phase II clinical trials of biologics in vasculitis and Behcet’s syndrome.

Kevin O’Shaughnessy’s group is interested in inherited forms of hypertension and the endocrine hypertension role

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Medicine of the adrenal gland. In collaboration with a group in Brisbane, they have identified rare functional gene variants in the K+ channel KCNJ5 of patients with primary aldosteronism, and further novel mutations in the CUL3 and KLHL3 genes causing familial hypertension with hyperkalaemia (Gordon Syndrome).

Anthony Davenport’s group focuses on the role of G-protein coupled receptors in the human cardiovascular system. Chemokines acting at the CCR5 receptor play a key role in vasoconstriction and intimal thickening in human vessels, which may be blocked by the selective CCR5 antagonist, maraviroc. The group has identified, with the Department of Chemistry, the first ‘biased’ agonist at the apelin receptor and conducted proof of principle, first in human studies with Wilkinson/Cheriyan to delineate the role of apelin and its potential for treatment of pulmonary arterial hypertension.

Pharmacological interventions against cardiac ischaemia/ reperfusion (IR) injury and the development of post-IR heart failure are the main focus for Thomas Krieg’s group.

In collaboration with Dr Mike Murphy’s group (MRC Mitochondrial Biology Unit) they tested various novel mitochondria-targeted compounds for their cardioprotective properties in mouse models of IR injury and heart failure.

Chouchani ET, Methner c, Nadtochiy SM, Logan A, Pell VR, Ding S, James AM, Cochemé HM, Reinhold J, Lilley KS, Partridge L, Fearnley IM, Robinson AJ, Hartley RC, Smith RAJ, Krieg T, Brookes PS, Murphy MP. Cardioprotection by S-nitrosation of a cysteine switch on mitochondrial complex I. Nat Med. 2013: 19(6); 753–9

Gastroenterology and hepatology Research in this Division focuses on immunity and inflammation and its consequences, and the genetic underpinning of gastrointestinal diseases.

Selected references Ben-Shlomo Y, Spears M, Boustred C, May M, Anderson SG, Benjamin EJ, Boutouyrie P, Cameron J, Chen CH, Cruickshank JK, Hwang SJ, Lakatta EG, Laurent S, Maldonado J, Mitchell GF, Najjar SS, Newman AB, Ohishi M, Pannier B, Pereira T, Vasan RS, Shokawa T, Sutton-Tyrell K, Verbeke F, Wang KL, Webb DJ, Hansen TW, Zoungas S, McEniery CM, Cockcroft JR, Wilkinson IB. Aortic pulse wave velocity improves cardiovascular event prediction: an individual participant meta-analysis of prospective observational data from 17,635 subjects. J Am Coll Cardiol. 2013: 63; 636–46 Maki-Petaja KM, Elkhawad M, Cheriyan J, Joshi FR, Ostor AJ, Hall FC, Rudd JH, Wilkinson IB. Anti-tumor necrosis factor-alpha therapy reduces aortic inflammation and stiffness in patients with rheumatoid arthritis. Circulation. 2012: 126; 2473–2480 Jones RB, Cohen Tervaert JW, Hauser T, Luqmani R, Morgan MD, Peh CA, Savage CO, Segelmark M, Tesar V, van Paassen P, Walsh D, Walsh M, Westman K, Jayne D. Rituximab versus cyclophosphamide in ANCA-associated renal vasculitis. N Engl J Med. 2010: 363; 211–220 Murthy M, Xu S, Massimo G, Wolley M, Gordon RD, Stowasser M, O’Shaughnessy KM. Role for germline mutations and a rare coding single nucleotide polymorphism within the KCNJ5 potassium channel in a large cohort of sporadic cases of primary aldosteronism.

Hypertension. 2014: 63(4); 783–9 Maguire JJ, Jones KL, Kuc RE, Clarke MC, Bennett MR, Davenport AP. The CCR5 chemokine receptor mediates vasoconstriction and stimulates intimal hyperplasia in human vessels in vitro. Cardiovasc Res 2014: 101; 513–21

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GFPn-LC3 punctae (green) indicative of autophagosomes, located in Paneth cells. Autophagy serves as a compensatory mechanism for endoplasmic reticulum (ER) stress in this cell type. When genetically hypomorphic, ER-stressed Paneth cells become a site of origin for small intestinal inflammation.

Arthur Kaser’s group investigates the mechanisms that underlie inflammation at mucosal surfaces. A single layer of intestinal epithelial cells – which may be considered the evolutionary most ancient innate immune cell type – separates the complex and densely populated habitat of the microbiota from the sterile host tissue of the gut, which itself harbours the majority of the host’s bona fide immune cells.

A loss of the mutualistic relationship between host and microbiota is thought to be at the basis of the inflammatory bowel diseases Crohn’s disease and ulcerative colitis. Using a variety of techniques, including complex genetic models, we explore the major biological mechanisms that are affected by risk genes of inflammatory bowel disease. This approach opens up a window to explore the environmental factors that may trigger disease in genetically susceptible individuals, and which are the cause for the steep increase in incidence and prevalence of these diseases around the world. Following this path, we have reported mechanisms of how hypomorphic autophagy and mediators of the unfolded protein response lead to inflammatory bowel disease, defining a key pathway of Crohn’s disease pathogenesis.

Miles Parkes investigates the genetic basis of inflammatory bowel disease through genome-wide association studies, which are performed in collaboration with the Wellcome Trust Sanger Centre. He leads the UK IBD Genetics consortium and is the past founding chair of the international consortium, which has driven the discovery of now >150 genetic loci associated with risk for IBD. Dr Patel, group leader at the MRC Laboratory of Molecular Biology and holding a co-affiliation with our Division within the Department of Medicine, investigates the molecular basis of chromosome stability in human cells. Most recently, his group has made seminal discoveries linking aldehyde metabolism to genotoxic DNA damage with important consequences for stem cell biology and implications for alcohol-related diseases.

Further research topics covered in the Division are the genetic basis of chronic liver disease (primary sclerosing cholangitis and primary biliary cirrhosis), and the role of senescence in liver disease (Dr Alexander), liver transplantation (Dr Gimson), small bowel transplantation and intestinal failure (Dr Middleton and Dr Woodward), non-alcoholic fatty liver disease (Dr Allison), inherited liver disease (Dr Griffiths), and endoscopy (Dr Metz).

Professor Fitzgerald investigates methods of early detection of cancer of the oesophagus, and is affiliated with the Dept of Oncology and the MRC Cancer Unit.

In translational research, multi-centre trials of novel biological therapies for IBD, which target specific immune functions, are pursued within the Division.

Hodskinson MR, Silhan J, Crossan GP, Garaycoechea JI, Mukherjee S, Johnson CM, Schärer OD, Patel KJ. Mouse SLX4 is a tumor suppressor that stimulates the activity of the nuclease XPF-ERCC1 in DNA crosslink repair. Mol Cell. 2014 May 8: 54(3); 472–84 Aravinthan A, Pietrosi G, Hoare M, Jupp J, Marshall A, Verrill C, Davies S, Bateman A, Sheron N, Allison M, Alexander GJ. Hepatocyte expression of the senescence marker p21 is linked to fibrosis and an adverse liver-related outcome in alcohol-related liver disease. PLoS One. 2013 Sep 23: 8(9); e72904

Immunology Immunology is a key discipline in the Department of Medicine: The Griffiths lab (based in CIMR, of which Professor Griffiths is the Director) studies cytotoxic T lymphocytes (CTL) and natural killer (NK) cells, which use polarized secretion to destroy virally infected and tumorigenic target cells. Specialised secretory lysosomes, containing the pore forming protein perforin and a series of serine proteases, termed granzymes, deliver the lethal hit in a specialized domain of the immunological synapse. The research is focused on understanding the molecular basis of polarized secretion from CTLs and has used a series of rare genetic diseases including Hermansky-Pudlak and Haemophagocytic syndromes to identify the roles of proteins involved in secretion from CTL and NK cells.

Selected references Adolph TE, Tomczak MF, Niederreiter L, Ko HJ, Böck J, Martinez-Naves E, Glickman JN, Tschurtschenthaler M, Hartwig J, Hosomi S, Flak MB, Cusick JL, Kohno K, Iwawaki T, Billmann-Born S, Raine T, Bharti R, Lucius R, Kweon MN, Marciniak SJ, Choi A, Hagen SJ, Schreiber S, Rosenstiel P, Kaser A*, Blumberg RS* (*denotes shared senior and corresponding authors). Paneth cells as a site of origin for intestinal inflammation. Nature 2013: 503; 272–6 Niederreiter L, Fritz TM, Adolph TE, Krismer AM, Offner FA, Tschurtschenthaler M, Flak MB, Hosomi S, Tomczak MF, Kaneider NC, Sarcevic E, Kempster SL, Raine T, Esser D, Rosenstiel P, Kohno K, Iwawaki T, Tilg H, Blumberg RS, Kaser A. ER stress transcription factor Xbp1 suppresses intestinal tumorigenesis and directs intestinal stem cells. J Exp Med. 2013 Sep 23: 210(10); 2041–56 Parkes M, Cortes A, van Heel D, Brown M. Analysis Article: Genetic insights into common pathways and complex relationships among immune mediated diseases. Nature Reviews Genetics 2013: 14(9); 661–73 Ellinghaus D, Zhang H, Zeissig S, Lipinski S, Till A, .., Annese V, Halfvarson J, D’Amato M, Daly MJ, Nothnagel M, Karlsen TH, Subramani S, Rosenstiel P, Schreiber S, Parkes M*, Franke A* (*denotes shared senior author). Association Between Variants of PRDM1 and NDP52 and Crohn’s Disease, Based on Exome Sequencing and Functional Studies. Gastroenterology. 2013 Aug: 145(2); 339–47 Garaycoechea JI, Crossan GP, Langevin F, Daly M, Arends MJ, Patel KJ. Genotoxic consequences of endogenous aldehydes on mouse haematopoietic stem cell function. Nature 2012 Sep 27: 489(7417); 571–5

A haploid genetic screen identifies genes required for MHC-1 expression.

The James lab (based in the University Research Unit in the MRC-LMB) focuses on how T cells discriminate between healthy and infected cells to initiate an appropriate immune response.

The T-cell signalling network is complex, making it difficult to understand how these cells function at the level of the individual molecules involved. The James lab have created a ‘model’ T cell, capable of replicating the early decision-making process. The lab uses confocal microscopy with chemical or light-mediated control of cell signalling to probe the molecular details of T-cell activation.

They have shown how T‑cell receptor engagement initiates downstream signalling and this has allowed new hypotheses of ligand discrimination to be tested back in T cells.

The Lehner lab (based in CIMR) uses genetic (human haploid genetic screens) together with functional proteomic approaches

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Medicine to study the mechanisms by which viruses evade immune recognition. They recently developed ‘plasma membrane profiling’ – an unbiased proteomic approach to analyze how viruses alter expression of any cell surface receptor to enable their replication.

This powerful approach has identified novel immune as well as metabolic receptors, such as ABC transporters downregulated by latent human cytomegalovirus infection, and is now being used to interrogate cell surface receptor regulation by different intracellular pathogens.

The Ramakrishnan lab (based in the University Research Unit in the MRC-LMB) studies tuberculosis using the zebrafish as a model host. The optical transparency and genetic tractability of the zebrafish have allowed for real-time viewing of the steps of disease pathogenesis, their molecular and cellular mechanisms and their consequences. The ability to directly visualize the disease process has in turn led to surprising discoveries that have direct implications for both shorter and more effective treatment of human tuberculosis, and clinical trials and observational studies based on these findings are now in progress.

The Randow lab (based in the MRC-LMB) studies cell autonomous immunity. Our view of vertebrate host defense is shaped by the notion of a specialized set of immune cells as sole guardians of antimicrobial resistance, a concept that greatly underestimates the capacity of most cell lineages to defend themselves against infection. The aim of the Randow lab is to understand the principles and mechanisms for pathogen detection and destruction. Current emphasis is on the role of galectins as danger receptors, the ubiquitin-coating of cytosol-invading bacteria, and the role of autophagy cargo receptors in defending the cytosol against infection.

Infectious diseases Infectious diseases research encompasses basic studies on viruses, bacteria and host immune responses.

Sergey Nejentsev’s group investigates genetic and functional mechanisms of susceptibility to infection. The group is conducting large genome-wide association studies aiming to identify human variants that control immune responses to M tuberculosis infection and predispose to pulmonary TB. The group also studies patients with primary immunodeficiencies using whole exome sequencing to discover new causative mutations, followed by detailed functional analyses of the affected cellular pathways.

Sharon Peacock’s group aims to introduce high-throughput whole genome sequencing technologies into diagnostic and public health microbiology for outbreak investigation and to optimise antimicrobial therapy of individual patients. She works in close collaboration with the Wellcome Trust Sanger Institute and the Health Protection Agency. John Sinclair’s group studies how human cytomegalovirus (HCMV) persists in healthy individuals studying cellular factors which control virus latency and reactivation.

Wills’ group, with Professor Sissons, study the control of HCMV infection by the immune system. In collaboration, their work on latent carriage of the virus and host immune responses to latent infection has now identified changes in the latently infected cells which can act as targets for novel chemotherapeutic and immunotherapeutic strategies with an aim to clearing latent infection in some clinical settings.

Selected references James JR, Vale RD. Biophysical mechanism of T cell receptor triggering in a reconstituted system. Nature 2012: 487; 64–9.

Cambier CJ, Takaki KK, Larson RP, Hernandez RE, Tobin DM, Urdahl KB, Cosma CL, Ramakrishnan L. Mycobacteria manipulate macrophage recruitment through coordinated use of membrane lipids.

Nature 2014: 505, 218–22.

Randow F, MacMicking JD, James LC. Cellular self-defense: how cell-autonomous immunity protects against pathogens.

Science 2013: 340, 701–706. de la Roche M, Ritter AT, Angus KL, Dinsmore C, Earnshaw CH, Reiter JF, Griffiths GM. Hedgehog signaling controls T cell killing at the immunological synapse Science. 2013: 342(6163); 1247–50.

Weekes MP, Tan SYL, Poole E, Talbot S, Antrobus R, Smith DL, Montag C, Gygi SP, Sinclair JH, Lehner PJ. Latency-associated degradation of the MRP1 drug transporter offers a therapeutic target for latent human cytomegalovirus (HCMV) infection.

Science 2013: 340(6129); 199–202.

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The RNA structure of the major packaging signal region of HIV-1 showing the long distance helical pairing between the U5 and Gag AUG segments (U5/AUG), the primer binding site (PBS), the dimer linkage stem loop (SL1), the major splice donor stem loop (SL2) and the principal packaging determinant (SL3).

Andrew Lever’s group studies retroviruses, including structural and molecular studies of RNA and RNA: protein interactions involved in genome encapsidation and the development of gene vectors. He and Dr Desselberger are investigating rotavirus RNA structures involved in encapsidating the viral genome and which host cell proteins or organelles may interact with the virus and be involved in viral assembly.

Lydia Drumright’s group takes a multidisciplinary approach to infectious disease epidemiology integrating classical and molecular epidemiology with clinical informatics, statistical and mathematical modelling, and behavioural and environmental sciences. This systems-level way of thinking helps to maximise our understanding of how infectious diseases are transmitted, resulting in more effective interventions. Recent work includes the characterisation of norovirus transmission dynamics within healthcare settings, and the use of electronic hospital data for infectious disease surveillance.

Manjinder Sandhu’s group integrates approaches spanning epidemiology, genomics and public health to assess the patterns and determinants of chronic diseases in a global health context.

Sandhu holds a joint faculty position in the Department and the Wellcome Trust Sanger Institute.

Selected references Angulo I, Vadas O, Garçon F, Banham-Hall E, Plagnol V, Leahy TR, Baxendale H, Coulter T, Curtis J, Wu C, Blake-Palmer K, Perisic O, Smyth D, Maes M, Fiddler C, Juss J, Cilliers D, Markelj G, Chandra A, Farmer G, Kielkowska A, Clark J, Kracker S, Debré M, Picard C, Pellier I, Jabado N, Morris JA, Barcenas-Morales G, Fischer A, Stephens L, Hawkins P, Barrett JC, Abinun M, Clatworthy M, Durandy A, Doffinger R, Chilvers ER, Cant AJ, Kumararatne D, Okkenhaug K, Williams RL, Condliffe A, Nejentsev S. Phosphoinositide 3-kinase δ gene mutation predisposes to respiratory infection and airway damage. Science. 2013: 342 (6160); 866–71 Thye T, Owusu-Dabo E, Vannberg FO, van Crevel R, Curtis J, Sahiratmadja E, Balabanova Y, Ehmen C, Muntau B, Ruge G, Sievertsen J, Gyapong J, Nikolayevskyy V, Hill PC, Sirugo G, Drobniewski F, van de Vosse E, Newport M, Alisjahbana B, Nejentsev S, Ottenhoff TH, Hill AV, Horstmann RD, Meyer CG. Common variants at 11p13 are associated with susceptibility to tuberculosis. Nat Genet. 2012: 44 (3); 257–9 Köser CU, Bryant JM, Becq J, Török ME, Ellington MJ, Marti-Renom MA, Carmichael AJ, Parkhill J, Smith GP, Peacock SJ. Whole-genome sequencing for rapid susceptibility testing of M. tuberculosis. New Engl J Med. 2013: 369; 290–292 Harris SR, Cartwright EJP, Török ME, Holden MT, Brown NM, Ogilvy-Stuart AL, Ellington MJ, Quail MA, Bentley SD, Parkhill J, Peacock SJ. Whole-genome sequencing for analysis of an outbreak of meticillin-resistant Staphylococcus aureus: a descriptive study.

Lancet Infect Dis. 2013: 13; 130–6 Mason GM, Jackson S, Okecha G, Emma Poole, Sissons JGP, Sinclair JH, Wills MR. Human cytomegalovirus latency-associated proteins elicit immune-suppressive IL-10 producing CD4+ T cells.

Plos Pathogens 2013: 9(10); e1003635

Mason GM, Poole E, Sissons JG, Wills MR, and Sinclair JH. Human cytomegalovirus latency alters the cellular secretome, inducing cluster of differentiation (CD)4+ T-cell migration and suppression of effector function. Proc Natl Acad Sci USA 2012: 109; 14538–14543 Stephenson JD, Li H, Kenyon JC, Symmons M, Klenerman D, Lever AML. 3D RNA structure of the major HIV-1 packaging signal region.

Structure 2013: 21(6); 951–962 Kenyon JC, Prestwood LJ, Le Grice SFJ, Lever AML. In-gel probing of individual RNA conformers within a mixed population reveals a dimerisation structural switch in the HIV-1 leader. Nucleic Acids Research 2013: 1–11 Richards JE, Desselberger U, Lever AM. Experimental pathways towards developing a rotavirus reverse genetics system: synthetic full length rotavirus ssRNAs are neither infectious nor translated in permissive cells. PLoS One. 2013: Sep 3; 8(9); e74328 Riha J, Karabarinde A, Ssenyomo G, Allender S, Asiki G, Kamali A, Young EH, Sandhu MS, Seeley, J. Ubanicity and Lifestyle Risk Factors for Cardiometabolic Diseases in Rural Uganda: A Cross-Sectional Study.

PLoS Med. 2014 July 29: 11(7); e1001683 Gurdasani D, Carstensen T, Tekola-Ayele F, Pagani L, Tachmazidou I, Hatzikogtoulas K, Karthikeyan S, Iles L, Pollard M, Choudhury A, Ritchie GRS, Xue Y, Asimit J, Nsubuga RN, Young EH, Pomilla C, Kivinen K, Rockett K, Kamali A, Doumatey AP, Asiki G, Seeley J, Sisay-Joof F, Jallow M, Tollman S, Mekonnen E, Ekong R, Oljira T, Bradman N, Bojang K, Ramsay M, Adeyemo A, Bekele E, Motala A, Norris S, Pirie F, Kaleebu P, Kwiatkowski D, Tyler-Smith C, Rotimi C, Zeggini E, Sandhu MS. The African Genome Variation Project: Insights into genetic variation, structure and positive selection within Africa. Nature. 2014: In press

Metabolic medicine Tim Cox’s group explores the molecular pathogenesis of lysosomal diseases with particular emphasis on the development of definitive treatment. With Dr Deegan, Clinical Director of the national centre for the treatment and diagnosis of lysosomal diseases, several clinical trials of substrate reducing drugs, pharmacological chaperones and innovative enzyme therapies are underway, particularly for Gaucher’s disease and Fabry disease.

Marchesan conducts studies of the molecular targeting and delivery of lysosomal proteins to their sites of action.

With Elena Pavlova, promising experimental studies are underway to investigate the causation and treatment of B-cell proliferation and myelomatosis – now a leading cause of death in Gaucher’s disease. She has been awarded a Gaucher Generation Grant and independent support from Genzyme-Sanofi.

The group has secured a 4-year Stratified Medicine award from the Medical Research Council: 'GAUCHERITE'. The aim is to guide therapy by predicting long-term risk in Gaucher patients using clinical data, imaging and biomarkers to ensure optimal intervention before irreversible injury is established: by securing long-term data from this diverse national cohort, we will investigate hitherto unknown aspects of pathogenesis.

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Medicine Menna Clatworthy’s group is based within the Department of Medicine Research Unit in the new LMB. The group is interested in understanding how IgG antibodies and their receptors contribute to disease pathogenesis in autoimmunity, and to pathogenassociated and sterile inflammation, particularly in acute kidney injury. Menna Clatworthy has also established a two-photon imaging facility, and is using this technology to investigate how IgG can impact on the dynamic behaviour of leukocytes.

Clatworthy’s clinical interests are in antibody-mediated rejection and B cell modulation in renal transplantation.

Bone marrow showing pathological macrophages and malignant plasmacell infiltration.

Overall the laboratory has been central to the formation of an International Tay-Sachs disease Gene Therapy Consortium to translate successful gene therapy first conducted in experimental models into a viable therapy in man. With Begoña CachónGonzález, Tim Cox has secured 5 years funding (DPFS-DCS award) from the Medical Research Council to develop clinical gene therapy in the UK. In collaboration with colleagues, and a joint award at the Weizmann Institute of Science, the group is investigating necroptosis as a potential cause of oligodendrocyte loss and demyelination and predict that blocking this cell-death programme will benefit Krabbe disease and another sphingolipidosis – diseases in which there is a compelling unmet medical need.

Selected references

Patrick Maxwell’s group is based in CIMR and works on genetic renal diseases and cellular oxygen sensing. He is supported by a Wellcome Trust Senior Investigator Award and is also Head of the School of Clinical Medicine.

John Bradley’s group has been studying the pathways involved in signalling by TNF-alpha family members in endothelial cells and their relevance to renal inflammation and transplant rejection.

He coordinates the Yale-Cambridge Research Initiative, and is the Director of the NIHR Cambridge Biomedical Research Centre.

Margaret Ashcroft’s group is based in the Clifford Allbutt Building, and primarily focuses on elucidating the key regulatory mechanisms involved in hypoxia signalling in mammalian cells.

The Ashcroft group has a strong interest in the hypoxia inducible factor (HIF) family of transcription factors and understanding their role in cancer, renal disease and other diseases. In particular, the Ashcroft group has been elucidating the role of mitochondria in oxygen sensing. In addition, Margaret Ashcroft takes multidisciplinary collaborative approaches for leading the therapeutic development of novel small molecule hypoxia signalling targeting agents.

Cachón-González MB, Wang SZ, Ziegler R, Cheng SH, Cox TM. Reversibility of neuropathology in Tay-Sachs related diseases.

Human Molecular Genetics 2014: 23; 730–748 Pavlova EV, Wang S, Archer J, Dekker N, Aerts JMFG, Karlsson S, Cox TM. B-cell lymphoma and myeloma in murine Gaucher disease.

Journal of Pathology. 2013: 231; 88–97

Renal medicine Ken Smith’s group is based in the CIMR, and works on immune regulation in autoimmune and inflammatory disease. This has focused on how naturally occurring variants in immune molecules such as FcγRIIB alter immune function and predispose to autoimmunity. The accumulation of these risk variants in the population has been shown to be, at least in part, due to their ability to protect against infections such as malaria. With Paul Lyons and key clinical collaborators , Smith runs a translational programme studying the pathogenesis of human disease that has discovered novel prognostic biomarkers entering clinical trials, and now focuses on the biology that determines long-term clinical outcome in autoimmune, inflammatory and infectious disease. The European Vasculitis Genetics Consortium is also led from the laboratory.

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Confocal micrograph of a murine kidney showing an accumulation of macrophages (green) in the medulla and pelvis of the kidney (right side) in response to ascending urinary tract infection with uropathogenic E.Coli.

Some tissue-resident mononuclear phagocytes interdigitate between cortical tubules (left). Renal tubules stained with phalloidin (red).

Selected references Al-Lamki RS, Lu W, Wang J, Yang J, Sargeant TJ, Wells R, Suo C, Wright P, Goddard M, Huang Q, Lebastchi AH, Tellides G, Huang Y, Min W, Pober JS, Bradley JR. TNF, acting through inducibly expressed TNFR2, drives activation and cell cycle entry of c-Kit+ cardiac stem cells in ischemic heart disease. Stem Cells 2013 Sep: 31(9); 1881–92 Lyons PA, Rayner TF, Trivedi S, Holle JU, Watts RA, Jayne DRW, Baslund B, Brenchley P, Bruchfeld A, Chaudhry AN, Cohen Tervaert JW, Deloukas P, Feighery C, Gross WL, Guillevin L, Gunnarsson I,

Harper L, Hrušková Z, Little MA, Martorana D, Neumann T, Ohlsson S, Padmanabhan S, Pusey CD, Salama AD, Sanders J-S F, Savage CO, Segelmark M, Stegeman CA, Tesař V, Vaglio A, Wieczorek S, Wilde B, Zwerina J, Rees AJ, Clayton DG and Smith KGC. Genetically Distinct Subsets within ANCA-Associated Vasculitis. N Engl J Med, 2012: 367; 214–223 Lee JC, Espéli M, Anderson CA, Linterman MA, Pocock JM, Williams NJ, Roberts R, Viatte S, Fu B, Peshu N, Hien TT, Phu NH, Wesley E, Edwards C, Ahmad T, Mansfield JC, Gearry R, Dunstan S, Williams TN, Barton A, Vinuesa CG; UK IBD Genetics Consortium, Parkes M, Lyons PA, Smith KGC. Human SNP Links Differential Outcomes in Inflammatory and Infectious Disease to a FOXO3-Regulated Pathway. Cell. 2013: 155; 57–69 Clatworthy MR, Petrie Aronin CE, Mathews RJ, Morgan N, Smith KGC, Germain RN. Immune complexes stimulate CCR7dependent dendritic cell migration to lymph nodes. Nature Medicine 2014.

In press

Stefan Marciniak is interested in the cell biology of protein folding within the endoplasmic reticulum and how failure of this process manifests as disease. This is relevant to malignancy, hypoxia and conformational diseases such as alpha1-antitrypsin.

Andres Floto works on the molecular basis of phagocytosis and phagosomal function, how these processes influence the host responses to bacterial and mycobacterial infection, and how cell-autonomous immunity can be therapeutically enhanced. The group is also utilising population-level whole genome sequencing to understand the epidemiology and pathophysiology of non-tuberculous mycobacteria.

James Nathan studies the regulation of the ubiquitin proteasome system in disease and, in particular, how different cellular proteins are efficiently targeted for degradation. The group also has an interest in the regulation of hypoxic response by ubiquitination.

Barriga EH, Maxwell PH, Reyes AE, Mayor R. The hypoxia factor Hif-1α controls neural crest chemotaxis and epithelial to mesenchymal transition.

J Cell Biol. 2013: 201; 759–76 Connor TM, Oygar DD, Gale DP, Steenkamp R, Nitsch D, Neild GH, Maxwell PH. Incidence of end-stage renal disease in the Turkish-Cypriot population of Northern Cyprus: a population based study. PLoS One. 2013: 8(1); e54394 Yang J, Staples O, Thomas LW, Briston T, Robson M, Poon E, Simões ML, El-Emir E, Buffa FM, Ahmed A, Annear N, Shukla D, Pedley B, Maxwell PH, Harris A L, Ashcroft M. Human CHCHD4/MIA40 mitochondrial proteins regulate cellular oxygen consumption rate and metabolism, and provide a critical role in hypoxia signalling and tumour progression. J Clin Invest 2012: 122(2); 600–11

Respiratory medicine The Respiratory Medicine Division has research interests in granulocyte cell biology and trafficking, the genetic and molecular basis of pulmonary hypertension, the structure and function of alpha1-antitrypsin and related serpins, the immunopathology of allergic diseases, phagosome maturation and bacterial killing, and the molecular mechanisms of ER stress and ubiquitination.

Edwin Chilvers and Alison Condliffe interests relate to granulocyte cell biology, in particular, the mechanisms underlying neutrophil priming, activation and apoptosis. The group also has an interest in P13-kinase and hypoxia signalling, neutrophil and eosinophil trafficking in vivo and primary immunodeficiency.

Nick Morrell is studying novel approaches to the treatment of pulmonary arterial hypertension (PAH). In particular, his laboratory has elucidated the ways in which mutations in the bone morphogenetic protein type II receptor (BMPR-II), which underlie the majority (80%) of familial PAH and 20% of idiopathic PAH, cause disease. The lab is identifying further rare genetic variation underlying PAH.

A scanning electron micrograph of a Drosophila fly’s eye. The genotype is gmg-gal4>uas-GADD34;PERK. This shows rescued eye development by expressing the phosphatase GADD34 along with the kinase PERK. PERK alone prevents eye development.

Selected references Angulo-Herrera I, Vadas O, Garson F, Banham-Hall E, Plagnol V, Leahy R, Baxendale H, Coulter T, Curtis J, Wu C, Perisic O, Smith D, Fiddler C, Juss J, Cilliers D, Markelj G, Farmer G, Stephens L, Hawkins P, Abinum M, Clatworthy M, Doffinger R, Chilvers ER, Cant AJ, Kumararatne D, Okkenhaug K, Williams RL, Condliffe AM*, Nejentsev S*. Phosphoinositide 3-kinase delta activity mutation predisposes to infection and airway damage. Science 2013: 342; 866–71 (*joint senior authors) Cowburn AS, Takeda N, Boutin AT, Kim JW, Sterling J, Nakasaki M, Southwood M, Goldrath AW, Jamora C, Nizet V, Chilvers ER*, Johnson RS*. Differential regulatin of systemic arterial pressure by the skin: role of HIF isoforms. Proc Natl Acad Sci USA 2013: 110; 17570–5 (*joint corresponding authors) Farahi N, Singh NR, Heard S, Loutsios C, Summers C, Simmonds RP, Solanki CK, Solanki K, Balan KK, Ruparelia P, Peters AM, Condliffe AM, Chilvers ER. Use of III-Indium-labelled autologous eosinophils to

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Medicine establish the in vivo kinetics of human eosinophils in healthy subjects.

Blood 2012: 120; 4068–71 Long L, Yang X, Southwood M, Lu J, Marciniak SJ, Dunmore BJ, Morrell NW. Chloroquine prevents progression of experimental pulmonary hypertension via inhibition of autophagy and lysosomal bone morphogenetic protein type II receptor degradation. Circ Res 2013: 122; 1159–70 Geti I, Ormiston ML, Rouhani F, Toshner M, Movassagh M, Nichols J, Mansfield W, Southwood M, Bradley A, Rana AA*, Vallier L*, Morrell NW*. A practical and efficient cellular substrate for the generation of induced pluripotent stem cells from adults: blood-derived endothelial progenitor cells. Stem Cells Transl Med 2012: 12; 855–65 (*joint senior authors) van ‘t Wout EFA, Dickens JA, van Schadewijk A, Haq I, Kwok HF, Ordóñez A, Murphy G, Stolk J, Lomas DA, Hiemstra PS, Marciniak SJ. Increased ERK Signalling promotes inflammatory signalling in primary airway epithelial cells expressing Z α1-antitrypsin. Hum Mol Gen 2014: 23; 929–41 Ordóñez A, Snapp EL, Tan L, Miranda E, Marciniak SJ*, Lomas DA*.

Endoplasmic reticulum ploymers impair liminal protein mobility and sensitise to cellular stress in α1-antitrypsin deficiency. Hepatology 2013: 57; 2049–60 (*joint senior authors)

Genome Campus on the genetics of CT and their relevance to the pathogenic properties of the organism. Recent work has examined the cytokine TSLP which also shows, like IL-23, major up-regulation by cellular stress. This is induced in dendritic cells by fungi and yeast which are in turn implicated in inflammatory arthritis in a major murine model of spondyloarthritis. Whereas TSLP production by epithelial cells has previously been mainly shown to be involved in allergic asthma in humans, this new work on dendritic cell production raises the possibility of its involvement in joint inflammation. Lastly, these groups work on human regulatory T cells ('Treg') and have recently developed a reliable way of identifying them ex vivo without destroying the cells. Using these techniques they have also shown that non-regulatory cells (which would previously not have been reliably distinguished from Treg) are major producers of IL-17 (Figure). Furthermore, some appear to be 'ex-Treg' cells based on expression of the same T cell receptor. In spondyloarthritis there is a relative deficit of Treg and an excess of IL-17 producing cells.

Bryant JM, Grogono DM, Greaves D, Foweraker J, Roddick I, Inns T, Reacher M, Haworth CS, Curran MD, Harris SR, Peacock SJ, Parkhill J, Floto RA. Whole-genome sequencing to identify transmission of Mycobacterium abscessus between patients with cystic fibrosis: a retrospective cohort study. Lancet 2013: 381; 1551–60 Nathan JA, Spinnenhirn V, Schmidtke G, Basler M, Groettrup M, Goldberg AL. Immuno- and constitutive proteasomes do not differ in ability to degrade ubiquitinated proteins. Cell 2013: 152; 1184–94 Nathan JA, Kim HT, Ting L, Gygi S, Goldberg AL. Why do cell proteins linked to K63-polyubiquitin chains not associate with proteasomes?

EMBO J 2013: 32; 552–65

Rheumatology Research in this division covers the basic mechanisms underlying inflammatory arthritis and metabolic bone disease.

Hill Gaston and Jane Goodall study the immunologic basis of inflammatory arthritis, and the factors which influence differentiation of pro-inflammatory T lymphocytes, particularly the role of dendritic cells in integrating signals from pathogens and cellular stress to alter cytokine production. They have a special interest in the IL-17/IL-23 cytokine axis, since this has been implicated in inflammatory arthritis, with very strong genetic evidence for a critical role in one form of joint disease, spondyloarthritis. Reactive arthritis, which is a member of the spondyloarthritis family, is triggered by specific infections, one of which is the important genitor-urinary tract pathogen, Chlamydia trachomatis (CT). Accordingly, they study the ability of CT infection to induce cytokines in dendritic cells, and the mechanisms underlying this; recent work has shown a crucial role for the cytoplasmic danger-sensing kinase, PKR. The groups also collaborate with colleagues at the Wellcome Trust 32

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Identification of regulatory T cells (G2, red) and their precursors (G3, green), as distinct from non-regulatory cells (G1, Blue), which are enriched in IL-17 producing cells. These subsets are identified by surface expression of CD39 and CD45RO, and are within the CD4+CD25hi+ population previously used to define regulatory T cells.

Ken Poole’s group applies novel imaging techniques, including high resolution CT, to investigate human bone diseases.

With the Engineering for Clinical Practice team of Graham Treece and Andrew Gee, they have studied focal thinning as a cause of femoral neck fracture and have discovered that bone building drugs have targeted effects at key sites within the osteoporotic femur and vertebrae. Research into prediction of future osteoarthritis by automated mapping of subchondral sclerosis

and the joint space width is also pursued, using large cohorts of patients with imaging, genetic and outcome data in Iceland.

Ken Poole and colleagues recently developed a technique for extracting bone mineral density data from routine CT scans such as those used to screen for malignancy, and this has been recognized by an NHS Innovation 2014 award. Ken Poole and NHS colleagues run a tertiary service for the diagnosis and management of rare metabolic bone diseases.

Selected references

Prevosto C, Goodall JC, Gaston JSH. Cytokine secretion by Pathogen Recognition Receptor-stimulated dendritic cells in rheumatoid arthritis and ankylosing spondylitis. J Rheumatol. 2013: 39; 1918–28 Poole KE, Treece GM, Mayhew PM, Vaculik J, Dungl P, Horak M, Stĕpán JJ, Gee AH. Cortical thickness mapping to identify focal osteoporosis in patients with hip fracture. PloS ONE. 2012: 7(6); e38466http://www.ncbi.nlm.nih.gov/pubmed/22701648 Gregson CL, Poole KE, McCloskey EV, Duncan EL, Rittweger J, Fraser WD, Smith GD, Tobias JH. Elevated circulating sclerostin concentrations in individuals with high bone mass, with and without LRP5 mutations. J Clin Endocrinol Metab. 2014: 99(8); 2897–907

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MRC Epidemiology Unit Professor and Director of the MRC Epidemiology Unit and the Centre for Diet and Activity Research (CEDAR): A UKCRC Centre of Public Health Research Excellence Professor Nick Wareham Tel 01223 330315 Fax 01223 330316 Email nick.wareham@mrc-epid.cam.ac.uk

Staff list Programme Leads NJ Wareham (Professor of Epidemiology) SJ Griffin (Professor of General Practice) M White (Director of Research) K Ong (Affiliated Lecturer in Paediatrics) D Ogilvie (Hon Consultant in Public Health)

Research synopsis

NG Forouhi (Hon Consultant in Public Health P Monsivais (Senior University Lecturer) S Brage (Programme Lead Track) C Langenberg (Programme Lead Track) E van Sluijs (Programme Lead Track) J Woodcock (MRC Fellow) Senior Research Staff A Abbasi (Rubicon Fellow) J Adams (Senior Research Associate and NIHR Fellow) A Cooper (Investigator Scientist) K Corder (Senior Investigator Scientist) U Ekelund (Senior Investigator Scientist) E Heinen (Investigator Scientist) F Imamura (Senior Investigator Scientist) R Lakshman (Clinical Senior Investigator Scientist) J Luan (Senior Statistician) J Panter (NIHR Fellow) JRB Perry (Senior Investigator Scientist) R Scott (Senior Investigator Scientist) S Sharp (Senior Statistican) S Wheeler (Investigator Scientist) K Wijndaele (BHF Senior Investigator Scientist) Z Ye (Investigator Scientist) J-H Zhao (Senior Investigator Scientist) Honorary NHS Consultants N Wareham D Ogilvie

K Ong

N Forouhi

R Lakshman

S Griffin

M White

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MRC EPIDEMIOLOGY UNIT

The MRC Epidemiology Unit aims to understand the genetic, developmental and environmental determinants of obesity, diabetes and related metabolic disorders and to translate this understanding into preventive action. The Unit is physically located within the Institute of Metabolic Science (IMS), providing a disease-specific focus and strong linkage to basic science. Nick Wareham is Co-Director of the IMS. The Unit is also a constituent part of the Cambridge Institute of Public Health (IPH), which facilitates close collaboration with the MRC Biostatistics Unit, the University Department of Public Health and Primary Care, the Primary Care Unit and the Department of Health funded Behaviour and Health Research Unit (BHRU).

The Unit hosts the Centre for Diet and Activity Research (CEDAR), a Centre of Excellence in Public Health Research funded through the UK Clinical Research Collaboration (UKCRC) which aims to understand the population-level factors that influence diet and physical activity behaviour, developing and evaluating interventions, and helping shape public health policy and practice. CEDAR is a partnership between the University of Cambridge, the University of East Anglia and MRC Units in Cambridge.

The Unit’s research aims are addressed through a core set of MRC-funded research programmes, and research programmes located within CEDAR. These programmes are supported by a core set of prospective cohort studies, detailed quantitative trait metabolic studies, case-control studies and trials that serve both aetiological and preventive purposes. The Unit leads many studies including the Fenland cohort, ADDITION trials, the EU EPICInterAct study and co-leads the EPIC-Norfolk cohort study with the Clinical Gerontology Unit.

Aetiology of diabetes and related metabolic disorders programme The overall goal of this programme (Wareham) is to use epidemiological methods to investigate aetiological pathways to type 2 diabetes and to translate that knowledge into preventive action. Research focuses on the genetic basis of type 2 diabetes, studying both the genetic determinants of quantitative traits in order to identify and validate potential modifiable pathways to diabetes risk, and the basis for gene-lifestyle interactions in the causation of type 2 diabetes.

Growth and development programme The goal of this programme (Ong) is to describe and understand the trajectories linking childhood growth and development to later type 2 diabetes and other obesity-related outcomes, and the epigenetic, hormonal and metabolic mechanisms that underlie them, in order to to use that understanding to inform early life interventions to prevent such diseases.

Selected references

Selected references

Elks CE, Perry JR, Sulem P, et al. Thirty new loci for age at menarche identified by a meta-analysis of genome-wide association studies Nat Genet 2010: 42(12); 1077–1085

Scott RA, Lagou V, Welch RP, et al. Large-scale association analyses identify new loci influencing glycemic traits and provide insight into the underlying biological pathways. Nature Genetics 2012: 44(9); 991–1005

Perry JR, Day FR, Elks CE, et al. Parent-of-origin specific allelic associations among 106 genomic loci for age at menarche.

Nature 2014: 514 (7520); 92–97

Pfister R, Sharp S, Luben R, et al. Mendelian randomization study of B-type natriuretic peptide and type 2 diabetes: evidence of causal association from population studies. PLoS Medicine 2011: 8(10); e1001112

Elks CE, Ong KK, Scott RA, et al. Age at menarche and type 2 diabetes risk: the EPIC-InterAct study. Diabetes Care 2013: 36(11); 3526–34

Manning AK, Hivert MF, Scott RA, et al. A genome-wide approach accounting for body mass index identifies genetic variants influencing fasting glycemic traits and insulin resistance. Nature Genetics 2012: 44(6); 659–69 Langenberg C, Sharp SJ, et al. Gene-Lifestyle Interaction and Type 2 Diabetes: The EPIC InterAct Case-Cohort Study. PLoS Medicine 2014: 11(5); e1001647

Nutritional epidemiology programme The nutritional epidemiology programme (N Forouhi) investigates the role of dietary and nutritional factors in the development of diabetes, obesity and related metabolic disorders, using large epidemiological studies. The programme also develops and uses improved methods to assess diet, including the use of objectively measured nutritional biomarkers, and promotes methodological knowledge exchange and transfer via online toolkits for researchers.

Selected references Forouhi NG, Koulman A, Sharp SJ et al. Differences in the prospective association between individual plasma phospholipid saturated fatty acids and incident type 2 diabetes: the EPIC-InterAct case – cohort study.

Lancet Diabetes and Endocrinology 2014: 2; 810–818 InterAct Consortium. Adherence to predefined dietary patterns and incident type 2 diabetes in European populations: EPIC-InterAct Study Diabetologia 2014: 57; 321–333 Forouhi NG, Zamora-Ros R, Sharp SJ et al. The association between dietary flavonoid and lignan intakes and incident type 2 diabetes in European populations: the EPIC-InterAct study. Diabetes Care 2013: 36; 3961–3970 InterAct Consortium. Consumption of sweet beverages and type 2 diabetes incidence in European adults: results from EPIC-InterAct. Diabetologia 2013: 56; 1520–1530

Elks CE, Loos RJ, Hardy R, et al. Adult obesity susceptibility variants are associated with greater childhood weight gain and a faster tempo of growth: the 1946 British Birth Cohort Study. Am J Clin Nut. 2012: 95(5); 1150–6

Physical activity epidemiology programme This programme (S Brage) seeks to understand the role of physical activity in determining health in populations. This research focuses on understanding the differences in activity behaviours between different populations, locations, and over time, and the environmental, personal and social influences that determine them, and on investigating the relationships between physical activity and fitness with obesity and metabolic disorders across the life course, and ultimately how this impacts on hard disease endpoints, including mortality.

Selected references den Hoed M, Brage S, Zhao JH, et al. Heritability of objectively assessed daily physical activity and sedentary behavior. Am J Clin Nutr 2013: 98(5); 1317–25 Golubic R, Ekelund U, Wijndaele K, et al. Rate of weight gain predicts change in physical activity levels: a longitudinal analysis of the EPICNorfolk cohort. Int J Obes 2013: 37(3); 404–9 The InterAct Consortium. Physical activity reduces the risk of incident diabetes in general and abdominally lean and obese men and women; the EPIC-InterAct study. Diabetologia 2012: 55(7); 1944–52 Assah F, Ekelund U, Brage S, et al. Urbanization, physical activity, and metabolic health in sub-Saharan Africa. Diabetes Care 2011: 34(2); 491–6.

Physical activity and public health programme The overall goal of the programme (D Ogilvie) is to investigate the potential of population-level approaches to the promotion of active living by producing and synthesising evidence regarding the effects of environmental and policy interventions and related patterns and mechanisms of behaviour change.

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MRC Epidemiology Unit Selected references Goodman A, Sahlqvist S, Ogilvie D. Do new walking and cycling routes increase physical activity? One- and two-year findings from the UK iConnect study. Am J Public Health 2014: 104(9); e38–46

Griffin SJ, Borch-Johnsen K, Davies MJ, et al. Effect of early intensive multifactorial therapy on 5-year cardiovascular outcomes in individuals with type 2 diabetes detected by screening (ADDITION-Europe): a cluster-randomised trial. Lancet 2011: 378; 156–167

Goodman A, Panter J, Sharp S, et al. Effectiveness and equity impacts of town-wide cycling initiatives in England: a longitudinal, controlled natural experimental study. Soc Sci Med 2013: 97; 228–237

Chamnan P, Simmons RK, Khaw K-T, et al. Estimating the population impact of screening strategies for identifying and treating people at high risk of cardiovascular disease: modelling study. BMJ 2010: 340; c1693

Goodman A, Sahlqvist S, Ogilvie D. Who uses new walking and cycling infrastructure and how? Longitudinal results from the UK iConnect study.

Prev Med 2013: 57; 518–524.

Pratt M, Sarmiento O, Montes F, et al. The implications of megatrends in information and communication technology and transportation for changing global physical activity. Lancet 2012: 380; 282–293

Behavioural epidemiology programme The goal of the Behavioural Epidemiology programme (E van Sluijs) is to generate knowledge on how to promote sustained active living in young people, by developing and evaluating interventions to change young people’s activity behaviour through a thorough understanding of the patterns, consequences, correlates and determinants of the behaviour of interest.

Selected references Hesketh K. Goodfellow L, Ekelund U, et al. Activity levels in mothers and their preschool children. Pediatr 2014: 133(4); e973–80 Atkin AJ, Corder K, Van Sluijs EMF. Bedroom media, sedentary time and screen-time in children: A longitudinal analysis. Int J Behav Nutr Phys Act 2013; 10(1); 13 Van Sluijs EMF, McMinn AM, Inskip HM, et al. Correlates of light and moderate-to-vigorous objectively measured physical activity in four-year old children. PLoS ONE 8(9): e74934 Atkin AJ, Corder K, Ekelund U, et al. Determinants of change in children’s sedentary time. PLoS ONE 2013: 8(6); e67627

Prevention of diabetes and related metabolic disorders programme The Prevention programme (Griffin) seeks to translate knowledge gained from epidemiological studies into action to prevent T2D and related metabolic disorders and to assess the effects of different approaches to disease prevention. It currently focuses on individual approaches to primary and secondary prevention, and the promotion of physical activity among older people. Research includes a range of projects that focus on both preventing the development of the disease before it starts, and identifying those people that have the disease whether they are showing symptoms of the disease or not.

Selected references Griffin SJ, Simmons RK, Prevost AT, et al. Multiple behaviour change intervention and outcomes in recently diagnosed type 2 diabetes: the ADDITION-Plus randomised controlled trial. Diabetologia 2014: 57; 1308–19 Simmons R, Echouffo-Tcheugui J, Sharp S, et al. Screening for type 2 diabetes on population mortality over ten years: the ADDITIONCambridge cluster-randomised controlled trial. Lancet 2012: 380; 1741–8

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Dietary public health research programme The CEDAR Dietary Public Health programme (Monsivais) aims to identify and measure social and economic factors that influence food choice, and looks at the ways that food choices and diet quality can vary across physical space and among different groups in society.

Selected references Burgoine T, Forouhi NG, Griffin SJ, et al. Associations between exposure to takeaway food outlets, takeaway food consumption, and body weight in Cambridgeshire, UK: population based, cross sectional study. BMJ 2014: 348; g1464 Conklin AI, Forouhi NG, Surtees P, Khaw KT, Wareham NJ, Monsivais P. Social relationships and healthful dietary behaviour: evidence from over-50s in the EPIC cohort, UK. Social Science & Medicine 2014: 100; 167–75 Monsivais P, Rehm CD, Drewnowski A. The DASH diet and diet costs among ethnic and racial groups in the United States.

JAMA internal medicine 2013: 173(20); 1922–4 Conklin AI, Forouhi NG, Suhrcke M, Surtees P, Wareham NJ, Monsivais P. Socioeconomic status, financial hardship and measured obesity in older adults: a cross-sectional study of the EPIC-Norfolk cohort.

BMC public health 2013: 13; 1039

Public health modelling programme The CEDAR Public Health Modelling programme (Woodcock) combines evidence from many different primary studies with insights from experts and other stakeholders. Simulation of models containing uncertainty can be used to indicate where the gaps in our knowledge are most critical for decision making and to investigate how health related practices might change in complex systems.

Selected references Woodcock J, Tainio M, Cheshire J, O’Brien O, Goodman A. Health effects of the London bicycle sharing system: health impact modelling study. BMJ 2014: 348; g425 Maizlish N, Woodcock J, Co S, Ostro B, Fanai A, Fairley D. Health cobenefits and transportation-related reductions in greenhouse gas emissions in the San Francisco Bay area. American Journal of Public Health 2013: 103(4); 703–9 Woodcock J, Givoni M, Morgan AS. Health impact modelling of active travel visions for England and Wales using an Integrated Transport and Health Impact Modelling Tool (ITHIM). PloS one 2013: 8(1); e51462 Jarrett J, Woodcock J, Griffiths UK, et al. Effect of increasing active travel in urban England and Wales on costs to the National Health Service.

Lancet 2012: 379(9832); 2198–205

Obstetrics and Gynaecology Head of Department and Professor of Obstetrics and Gynaecology

Email gcss2@cam.ac.uk

adverse pregnancy outcome and, it is hoped, to identify novel biomarkers which may be clinically useful. A major component of this research involves application of next generation sequencing to the stored samples. The Department has extensive collaborative links with the School of Biological Sciences, in particular with the University’s Centre for Trophoblast Research (www.trophoblast.cam.ac.uk).

Staff list

There are also close collaborative links with the Babraham Institute and the Wellcome Trust Sanger Centre.

Professor Gordon Smith Tel 01223 336871 Fax 01223 215327

Professor DS Charnock-Jones

Selected references Oliver-Williams, C, Fleming M, Monteath K, Wood AM, Smith GCS. Changes in association between previous therapeutic abortion and preterm birth in Scotland, 1980 to 2008: a historical cohort study. PLoS Medicine 2013: 10; e1001481

University Readers F Colucci University Lecturer M Constancia

Wood AM, Pasupathy D, Pell JP, Fleming M, Smith GCS. Trends in socioeconomic inequalities in the risk of sudden infant death syndrome, other causes of infant mortality and stillbirth in Scotland: a population based study. BMJ 2012: 34; e1552

A Prentice NHS Consultants/Associate Lecturers P Baldwin S Bhatti

J Brocklesby

RAF Crawford

GA Hackett

F Hoveyda

R Kearney

J Latimer

C Lees

J MacDougall

R Mathur

H Missfelder-Lobos

C Patient

C Prasannan-Nair

M Shafi

M Slack

A Wilson

J Brewster

Research synopsis The Department of Obstetrics and Gynaecology has programmes of basic, translational and clinical research addressing the determinants of pregnancy complications. We make extensive use of transgenic mouse models to identify key genes involved in murine placentation with the aim of better understanding normal reproductive function. Charnock-Jones studies the effect of oxygen on endothelial cells and trophoblasts in the placenta.

Constancia has a major interest in placental epigenetics, in particular genomic imprinting (ie. selective epigenetic silencing of genes according to parent of origin). Colucci aims at understanding how natural killer cells impact on reproduction, cancer and transplantation. Other basic work in the department addresses preparative changes in gene expression in the fetus for post-natal life and the control of uterine smooth muscle contraction. Epidemiological research in the Department has also made major use of secondary analysis of diverse data sources to study determinants and predictors of pregnancy outcome.

The major focus of translational research in the Department is a prospective cohort study of women in their first pregnancy, which recruited 4,512 women between January 2008 and July 2012 and is funded by the NIHR Cambridge Comprehensive Biomedical Research Centre. The project has created a central resource of data, blood samples taken throughout pregnancy, and samples of placenta obtained at birth. The resource is being used to understand better the role of the placenta in determining

Smith GCS. Researching new methods of screening for adverse pregnancy outcome: lessons from pre-eclampsia. PLoS Medicine 2012: 9; e1001274 Aiken C, Smith GCS. Early fetal life and cardiovascular risk in childhood.

BMJ 2014: 348; g175 Moffett A, Colucci F. Uterine NK cells: active regulators at the maternalfetal interface. J Clin Invest 2014: 124; 1872–9 Kieckbusch J, Gaynor LM, Moffett A, Colucci F. MHC-dependent inhibition of uterine NK cells impedes fetal growth and decidual vascular remodelling. Nat Commun 2014: 5; 3359 Xiong S, Sharkey AM, Kennedy PR, Gardner L, Farrell LE, Chazara O, Bauer J, Hiby SE, Colucci F, Moffett A. Maternal uterine NK cell-activating receptor KIR2DS1 enhances placentation. J Clin Invest 2013: 123; 4264–72 Mikaelsson MA, Constância M, Dent CL, Wilkinson LS, Humby T. Placental programming of anxiety in adulthood revealed by Igf2-null models. Nat Commun 2013: 4; 2311

Pre-implantation mouse embryo stained for Pon 3 (green), trophectoderm (red) and nuclei (blue).

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Cancer Research in Cambridge Department of Oncology and Cancer Research UK Cambridge Institute Synopsis Cancer research in the Clinical School is centred around four departments that interact with each other and across the School.

These are the Department of Oncology, the Cancer Research UK Cambridge Institute, the Department of Haematology and the MRC Cancer Unit.

The Department of Oncology works closely with the CRUK Cambridge Institute and the MRC Cancer Unit, which following their integration into the University (2013), have also become University Departments. The CRUK CI is a translational Institute with a focus on the practical application of science to clinical practice. Its present 18 research groups are planned to increase to 30 with the opening of a new floor. These are supported by world class scientific core facilities which are accessible to cancer researchers across Cambridge. The MRC Cancer Unit studies the molecular and cellular mechanisms underlying early steps in

Cancer Research UK Cambridge Institute

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carcinogenesis, and exploits this knowledge in new approaches for early detection, risk stratification and therapy, through the development of innovative enabling technologies.

Its 10 research groups are supported by advanced core facilities in purpose-built laboratories. Research into hematopoiesis and leukaemia is carried out by the Department of Haematology, led by Professor Tony Green (see page 14).

Each of the departments is a member of the wider Cambridge Cancer Centre, a framework organisation that brings together over 170 independent scientists and their groups, and over 90 consultant clinicians from the Cambridge University Hospitals NHS Foundation Trust, the University of Cambridge, independent research institutes, and pharmaceutical and biotechnology industries in the Cambridge area. The aim of the Centre is to catalyse and support collaborative research across clinical, biological and physical sciences that creates a pathway for the application of laboratory research to the clinic. The Cancer Centre is supported by substantial funds from CRUK and from the NHS Biomedical Research Centre, and has been designated by CRUK as one of three potential ‘Major Centres’ in the UK.

Head of Department of Oncology and Cancer Research UK Cambridge Institute Professor Sir Bruce AJ Ponder, FRS (Emeritus Director of Cancer Research UK Cambridge Institute) Director of the Cancer Research UK Cambridge Institute S TavarĂŠ, FRS, Professor of Cancer Research (Bioinformatics), Professor in Department of Applied Mathematics and Theoretical Physics Professors N Burnet, Professor of Radiation Oncology T Eisen, Professor of Medical Oncology Readers H Earl, Reader in Clinical Cancer Medicine A Philpott, Reader in Cancer and Developmental Biology Associate Director of Research A Dunning Group Leaders in CI S Balasubramanian, FRS, Professor in Chemistry JD Brenton S Bohndiek KM Brindle, Professor in Biochemistry C Caldas JS Carroll D Fearon, FRS F Gergely JR Griffiths G Hannon DI Jodrell F Markowetz M Narita DT Odom N Rosenfeld J Stingl D Winton Clinical Senior Research Associates R Baird B Basu S Pacey Clinical Principal Senior Research Associate R Jena Clinical Lecturers E Beddows

High-grade serous ovarian cancer cell with abnormal DNA content, DNA stained in red and the microtubules which form the cytoskeleton are stained in yellow.

The Department of Oncology has three laboratory based groups. The Ponder laboratory investigates the mechanisms of polygenic inherited susceptibility to breast and lung cancer, using gene expression in normal tissue as an integrated readout of polygenic and environmental effects. Alison Dunning runs a specialist high throughput genomics laboratory in the Centre for Cancer Genetic Epidemiology in the Strangeways Laboratory, which is a leader in the International collaborations for GWAS studies in breast, ovarian and prostate cancer. Anna Philpott works on transcriptional regulators that control proliferation or differentiation in development. Her laboratory aims to manipulate this regulation to promote differentiation of cancer cells, and for applications in regenerative medicine.

The Department includes several senior academic clinicians.

Neil Burnet combines novel imaging and computational methods to refine dosage and distribution of radiation therapy in brain and other cancers, and co-leads the RAPPER study of the inherited genetics of radiation sensitivity with Professor West (Manchester).

Helena Earl is a leader in phase 3 trials in breast cancer which have provided practice-changing data. Tissue and data collection from these trials has underpinned the molecular genetic classification of breast cancers by the Caldas laboratory (Oncology/CRUK CI) and the pharmacogenetic studies by Jean Abraham (Clinical Fellow). Tim Eisen studies the biology of VHL mutations in renal cancer and develops novel therapies for this cancer. Richard Baird, Bristi Basu and Simon Pacey each work with Group Leaders in CRUK CI to develop investigator-led early phase/ experimental medicine studies in metastatic breast, pancreatic and prostate cancer, based on CRUK CI laboratory research.

T Janowitz S Welsh

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Department of Oncology and Cancer Research UK Cambridge Institute Duncan Jodrell coordinates phase I trial activity. His laboratory contributes to clinical investigations including pre-clinical and phase I trials. Recent pre-clinical studies have demonstrated the effectiveness of a combination immunotherapy in a pancreatic cancer model. The first clinical trials should start in late 2014.

Translational research on other cancers focuses on finding new biomarkers for prostate cancer, on understanding the process of drug resistance in ovarian cancer (James Brenton); this work includes collaborations with the Rosenfeld and Caldas labs on ctDNA (circulating tumour DNA) as a non-invasive method to monitor treatment response and the emergence of drug resistance.

An extensive programme in genomics and the genetics of cancer is led by Carlos Caldas who was co-lead of the METABRIC study, an international 10-year study of the genomics of 2,000 breast cancers with clinical follow-up. This study showed that there are 10 distinct genetic subtypes of breast cancer. The Ponder laboratory, as discussed above, studies polygenic susceptibility to cancer. Jason Carroll leads a research programme on nuclear receptor transcription, focusing on oestrogen receptor biology and drug resistance.

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Groups at the CRUK CI with expertise in bioinformatics, statistics and computational biology collaborate extensively with our wet lab groups and are also involved in international collaborations such as the International Cancer Genome Consortium projects on oesophageal and prostate cancers (Tavaré laboratory with Fitzgerald (MRC CU) and Neal (CI, Oncology)). Florian Markowetz’s laboratory are developing a systems genetics understanding of cancer, and developing techniques to analyse next generation sequencing data.

Research groups in basic molecular and cellular biology cover studies on centrosome biology (Fanni Gergely), genomic and regulatory variation (Duncan Odom), cellular senescence (Masashi Narita), and the chemical biology of nucleic acids, including understanding the role that four-stranded DNA structures – G-quadruplexes – play in cancer cells (Shankar Balasubramanian). Greg Hannon, recently recruited from the Cold Spring Harbor Laboratory, brings expertise in RNA biology, mammalian genetics and genomics.

Work on stem cells focuses on the role of tissue stem cells in the initiation and maintenance of cancer, with particular emphasis on intestinal cancer (Doug Winton) and breast, ovarian and prostate cancers (John Stingl).

DEPARTMENT OF ONCOLOGY AND CANCER RESEARCH UK CAMBRIDGE INSTITUTE

Sarah Bohndiek’s group work on new imaging modalities, particularly photoacoustic imaging. The new hyperpolariser imaging facility opened in the Addenbrooke’s Radiology Department in May 2014, introducing into the clinic a technique developed by Kevin Brindle’s laboratory, in collaboration with GE Healthcare. Institute researchers are also involved in the CRUK and EPSRC Cancer Imaging Centre in Cambridge and Manchester, and regularly collaborate with other CRUK CI groups to conduct studies on patients, for example looking at response to treatment in ovarian cancer, and metabolomics studies (John Griffiths laboratory).

Selected references Biffi G, Di Antonio M, Tannahill D and Balasubramanian S. Visualization and selective chemical targeting of RNA G-quadruplex structures in the cytoplasm of human cells. Nat Chem. 2014: 6; 75–80 Fachal L, Gómez-Caamaño A, Barnett GC, Peleteiro P, Carballo A, Calvo-Crespo P, Kerns SL, Sánchez-García M, Lobato-Busto R, Dorling L, Elliott RM, Dearnaley D, Sydes MR, Hall E, Burnet NG, Carracedo A, Rosenstein BS, West CML, Dunning AM, Vega A. A three-stage genome-wide association study identifies a susceptibility locus for late radiotherapy toxicity at 2q24.1.

Nature Genetics 2014 Jun 29: doi; 10.1038/ng.3020.

Rodrigues TB, Serrao EM, Kennedy BW, Hu DE, Kettunen MI and Brindle KM. Magnetic resonance imaging of tumor glycolysis using hyperpolarized C-labeled glucose. Nat Med. 2014: 20; 93–7 Buczacki SJ, Zecchini HI, Nicholson AM, Russell R, Vermeulen L, Kemp R and Winton DJ. Intestinal label-retaining cells are secretory precursors expressing Lgr5. Nature. 2013: 495; 65–9 Feig C, Jones JO, Kraman M, Wells RJ, Deonarine A, Chan DS, Connell CM, Roberts EW, Zhao Q, Caballero OL, Teichmann SA, Janowitz T, Jodrell DI, Tuveson DA and Fearon DT. Targeting CXCL12 from FAP-expressing carcinoma-associated fibroblasts synergizes with anti-PD-L1 immunotherapy in pancreatic cancer. Proc Natl Acad Sci U S A. 2013: 110; 20212–7 Kozar S, Morrissey E, Nicholson AM, van der Heijden M, Zecchini HI, Kemp R, Tavaré S, Vermeulen L and Winton DJ. Continuous clonal labeling reveals small numbers of functional stem cells in intestinal crypts and adenomas. Cell Stem Cell. 2013: 13; 626–33

Luminal side of the intestine with the finger like projections (villi) in green, cell nuclei in blue and in red small clones of which the more differentiated cells migrate up the villi.

Curtis C, Shah SP, Chin SF, Turashvili G, Rueda OM, Dunning MJ, Speed D, Lynch AG, Samarajiwa S, Yuan Y, Gräf S, Ha G, Haffari G, Bashashati A, Russell R, McKinney S, METABRIC group, Langerød A, Green A, Provenzano E, Wishart G, Pinder S, Watson P, Markowetz F, Murphy L, Ellis I, Purushotham A, Børresen-Dale AL, Brenton JD, Tavaré S, Caldas C and Aparicio S. The genomic and transcriptomic architecture of 2,000 breast tumours reveals novel subgroups. Nature.

2012: 486; 346–52 Kutter C, Watt S, Stefflova K, Wilson MD, Goncalves A, Ponting CP, Odom DT and Marques AC. Rapid turnover of long noncoding RNAs and the evolution of gene expression. PLoS Genet. 2012: 8; e1002841 Ross-Innes CS, Stark R, Teschendorff AE, Holmes KA, Ali HR, Dunning MJ, Brown GD, Gojis O, Ellis IO, Green AR, Ali S, Chin SF, Palmieri C, Caldas C and Carroll JS. Differential oestrogen receptor binding is associated with clinical outcome in breast cancer. Nature. 2012: 481; 389–93 Yuan Y, Failmezger H, Rueda OM, Ali HR, Graf S, Chin SF, Schwarz RF, Curtis C, Dunning MJ, Bardwell H, Johnson N, Doyle S, Turashvili G, Provenzano E, Aparicio S, Caldas C and Markowetz F. Quantitative image analysis of cellular heterogeneity in breast tumors complements genomic profiling. Sci Transl Med. 2012: 4; 157ra143

Murtaza M, Dawson SJ, Tsui DW, Gale D, Forshew T, Piskorz AM, Parkinson C, Chin SF, Kingsbury Z, Wong AS, Marass F, Humphray S, Hadfield J, Bentley D, Chin TM, Brenton JD, Caldas C and Rosenfeld N. Non-invasive analysis of acquired resistance to cancer therapy by sequencing of plasma DNA. Nature. 2013: 497; 108–12 Sharma NL, Massie CE, Ramos-Montoya A, Zecchini V, Scott HE, Lamb AD, MacArthur S, Stark R, Warren AY, Mills IG and Neal DE. The androgen receptor induces a distinct transcriptional program in castration-resistant prostate cancer in man. Cancer Cell. 2013: 23; 35–47 Chandra T, Kirschner K, Thuret JY, Pope BD, Ryba T, Newman S, Ahmed K, Samarajiwa SA, Salama R, Carroll T, Stark R, Janky R, Narita M, Xue L, Chicas A, Nunez S, Janknecht R, Hayashi-Takanaka Y, Wilson MD, Marshall A, Odom DT, Babu MM, Bazett-Jones DP, Tavaré S, Edwards PA, Lowe SW, Kimura H, Gilbert DM and Narita M. Independence of repressive histone marks and chromatin compaction during senescent heterochromatic layer formation. Mol Cell. 2012: 47; 203–14

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Medical Research Council Cancer Unit Director and Head of Medical Research Council Cancer Unit Professor Ashok Venkitaraman Tel 01223 336901 Fax 01223 763374 Email pa-venkitaraman@mrc-cu.cam.ac.uk MRC Programme Leaders C Frezza RC Fitzgerald PH Jones CP Martins JD Shields S Vanharanta AR Venkitaraman Clinical Lecturers A Balakrishnan G Doherty S Liau Independent Fellows B Hall A Samarajiwa Research in the Medical Research Council (MRC) Cancer Unit investigates the molecular and cellular mechanisms underlying early steps in the development of cancer, and exploits this knowledge in new approaches for early detection, risk stratification and therapy, through the development of innovative enabling technologies.

The Unit’s eight scientific programmes are individually focused on different aspects of these goals. They are highly integrated to achieve maximum scientific impact from laboratory research to clinical studies at specific sites including the oesophagus, skin, lung and pancreas. Ongoing research is driven by the following questions.

What are the molecular and cellular events that drive epithelial cancer progression from pre-neoplastic to invasive disease?

Phil Jones studies squamous epithelial carcinogenesis, focusing on the evolution of mutant clones into dysplastic lesions and early cancers. Rebecca Fitzgerald studies the multistep progression of oesophageal adenocarcinoma from the pre-invasive stage Barrett’s oesophagus through to invasive cancer. Ashok Venkitaraman and Carla Martins use distinct but overlapping models to study the evolution of mutant Kras-driven cancers in different tissues – the lung and the pancreas – in transgenic models and human patient samples.

Sakari Vanharanta analyses how transcriptional regulatory

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networks that define tissues and drive organ development interact with tumour-initiating genetic pathways during tumour progression. Christian Frezza investigates early alterations in the metabolism of cancer cells (metabolic reprogramming) that drive oncogenesis. Ashok Venkitaraman studies how genomic instability is initiated at early steps in carcinogenesis, and how its initiation drives tumour progression past evolutionary bottlenecks imposed by the mutator phenotype. Jacqui Shields studies how non-cancer cells (stroma) within the tumour microenvironment influence tumour progression, through immune modulation.

How can understanding of these events be exploited in early diagnosis and risk stratification in patients with early disease?

Our research translates biological insights to early detection and risk stratification in the clinic. Fitzgerald investigates early diagnosis and risk stratification in oesophageal cancer.

She has developed a new device, the CytoSponge, for simple early diagnosis of oesophageal cancer without endoscopy.

Frezza studies metabolic changes that signify cancer onset.

Jones, Vanharanta, Martins and Venkitaraman have identified genomic and proteomic alterations accompanying cancer progression in different tissues. Vanharanta’s work has particular relevance in the early detection of relapse after therapy.

Venkitaraman is developing new cellular imaging methods for cancer diagnosis.

How can understanding of these events be exploited in new approaches for cancer prevention and therapy?

Jones is developing new approaches for prevention or early treatment that eliminate cell clones carrying specific mutations.

Venkitaraman leads an initiative for drug discovery that has established new methods and platforms for efficient target identification and validation, and for chemical lead discovery against novel targets, which has led to potent new chemical entities now being tested in preclinical models.

The research activities in the Unit provide a unique crossdisciplinary environment for the training of scientists and clinicians in translational cancer research. The Unit also has several collaborations with other groups in Cambridge, as well as internationally. The medically qualified members of the Unit have clinical duties, ensuring that there is a close link between our research and benefit to patients, and the MRC Cancer Unit is also a major participant and contributor to the Cambridge Cancer Centre, with particular emphasis on the area of early detection.

Further details Website: www.mrc-cu.cam.ac.uk Blog: mrccancerunit.wordpress.com Twitter: @MRC_CU Facebook: www.facebook.com/MRC.Cancer.Unit

Selected references Alcolea MP, Greulich P, Wabik A, Frede J, Simons BD, Jones PH. Differentiation imbalance in single oesophageal progenitor cells causes clonal immortalization and field change. Nature Cell Biol. 2014: 16(6); 615–22 Bird-Lieberman EL, Neves AA, Lao-Sirieix P, O’Donovan M, Novelli M, Lovat LB, Eng WS, Mahal LK, Brindle KM, Fitzgerald RC. Molecular imaging using fluorescent lectins permits rapid endoscopic identification of dysplasia in Barrett’s esophagus. Nature Med. 2012: 18(2); 315–21 di Pietro M, Lao-Sirieix P, Boyle S, Cassidy A, Castillo D, Saadi A, Eskeland R, Fitzgerald RC. Evidence for a functional role of epigenetically regulated midcluster HOXB genes in the development of Barrett esophagus. Proc Natl Acad Sci USA. 2012: 109(23); 9077–82 Doupé DP, Alcolea MP, Roshan A, Zhang G, Klein AM, Simons BD, Jones PH. A single progenitor population switches behavior to maintain and repair esophageal epithelium. Science. 2012: Aug 31; 337(6098); 1091–3 Jeyasekharan AD, Liu Y, Hattori H, Pisupati V, Jonsdottir AB, Rajendra E, Lee M, Sundaramoorthy E, Schlachter S, Kaminski CF, Ofir-Rosenfeld Y, Sato K, Savill J, Ayoub N, Venkitaraman AR. A cancer-associated BRCA2 mutation reveals masked nuclear export signals controlling localization. Nature Struct Mol Biol. 2013: 20(10); 1191–8 Liang H, Esposito A, De S, Ber S, Collin P, Surana U, Venkitaraman AR. Homeostatic control of polo-like kinase-1 engenders non-genetic heterogeneity in G2 checkpoint fidelity and timing. Nature Comms. 2014: 4; 5; 4048 Weaver JM, Ross-Innes CS, Shannon N, Lynch AG, Forshew T, Barbera M, Murtaza M, Ong CA, Lao-Sirieix P, Dunning MJ, Smith L, Smith ML, Anderson CL, Carvalho B, O’Donovan M, Underwood TJ, May AP, Grehan N, Hardwick R, Davies J, Oloumi A, Aparicio S, Caldas C, Eldridge MD, Edwards PA, Rosenfeld N, Tavaré S, Fitzgerald RC; the OCCAMS Consortium. Ordering of mutations in preinvasive disease stages of esophageal carcinogenesis.

Nature Genet. 2014 Jun 22: doi; 10.1038/ng.3013 Venkitaraman AR. Cancer suppression by the chromosome custodians, BRCA1 and BRCA2. Science. 2014: 343(6178); 1470–5 Wickramasinghe VO, Savill JM, Chavali S, Jonsdottir AB, Rajendra E, Grüner T, Laskey RA, Babu MM, Venkitaraman AR. Human inositol polyphosphate multikinase regulates transcript-selective nuclear mRNA export to preserve genome integrity. Mol Cell. 2013: 51(6); 737–50

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Paediatrics Head of Department and Professor of Paediatrics

Research synopsis

Professor David Dunger (from 2014) Tel 01223 336886

Genetics and pathophysiology of diabetes The genetics and pathophysiology of diabetes, its complications and treatment strategies during childhood and adolescence is a major theme of research for the Department. David Dunger’s group has been following the progress of over 12,500 young people with Type 1 diabetes (T1D) and their parents; contributing to the discovery of the genes that predispose to T1D, as well as exploring the genetic and biochemical factors which predispose to diabetic complications in these young people. Ongoing studies include examination of the role of the growth hormone/ insulin-like growth factor 1 axis in the development of insulin resistance and microalbuminuria, and the place of growth hormone inhibitors in preventing diabetic complications.

Preventative treatment strategies include work with John Todd’s group in Cambridge where extensive genetic/phenotypic analysis for the risks of developing T1D have led to the development of early immune therapy interventions. With respect to diabetic complications, David Dunger and his team have launched the first international study of the use of ACE inhibitors and statins in adolescents with T1D (AdDIT trial). David Dunger and Carlo Acerini are also involved in the clinical testing of closed loop insulin delivery in T1D using algorithms developed by Roman Hovorka which could reduce the risk of hypoglycemia in patients undergoing intensive insulin therapy and thus improve long term outcomes.

The Department’s research covers a wide range of themes:

Fax 01223 336996 Email dbd25@cam.ac.uk Further details www.medschl.cam.ac.uk/paediatrics

Staff list Professors D Dunger University Senior Lecturers C Acerini University Lecturer K Beardsall

N Pathan

M Zilbauer

Affiliated MRC Programme Leader K Ong Director of Research R Hovorka Senior Research Staff C Petry Clinical Lecturers D Elleri

R Willemsen

Associate Lecturers A Burke P Heinz S Morley R Ross-Russell

A Clark R Iles D O’Donnell P Set

D Conlan W Kelsall A Parker R Williams

NHS Consultants N Abdullah L Allen T Austin S Broster M Chitre S Farrell P Hall C Jackson A Khan A Maw M Murray A Ogilvy-Stuart A Rehm C Salvestrini Y Singh K Stohr B Ulbrich D Williams

S Agrawal G Ambegaonkar H Bailie R Campbell A Curley J Gass R Heuschkel N Jonas D Krishnakumar D McShane J Nicholson S O’Hare A Robb A Sansome H Smith F Torrente V Venkatesh M Williams

T Ahmad A Aslam S Benson R Chaudhary A D’Amore M Gattens S Hoodbhoy R Kayani E Lewis B Messahel G Noble-Jamieson L Preston M Robertson P Sartori N Smith L Treharne A West A Wong

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Genetic and enviromental effects on growth and future cardio-metabolic disease David Dunger and Dr Ken Ong (MRC Epidemiology) have long been involved in studying the genetic and environmental determinants of size at birth, post natal growth and risks for future adult cardio-metabolic disease. These studies are based around extensive birth cohorts such as ALSPAC and the Cambridge Baby Growth study and are enhanced by Clive Petry’s work looking at the effects of both maternal and foetal imprinted genes and pregnancy exposures and outcomes in the new born.

Epigenetics of the intestinal immune system in health and disease Another strong research theme in the Department is focused on epigenetics of the intestinal immune system in health and disease. This programme, led by Matthias Zilbauer, University Lecturer in the Department (working closely with the Adult University Gastroenterology Team), aims to explore the impact of epigenetic mechanisms such as DNA methylations and histone modifications on regulating gene expression and cellular function in purified cell subsets such as the intestinal epithelium, as well as the peripheral blood mononuclear cells in children with inflammatory bowel disease. Ongoing projects have a strong translational aspect including the search for disease prognostic

the assessment of long term outcomes. These studies blend well with those being undertaken in the Cambridge Baby Growth Study, established by Ieuan Hughes and Carlo Acerini, where over 2000 families have been recruited during pregnancy, with detailed child post-natal follow-up. These studies have provided a unique platform for studying effects of pre-natal diabetes, exposures of growth restraint, as well as the influence of post natal feeding practice on long term metabolic and neuro developmental outcomes. The original aim of the Cambridge Baby Growth Study is being maintained through detailed studies of endocrine disrupters and their potential effects on male and female genital development, growth and metabolism.

Selected references Cooper WN, Khulan B, Owens S, Elks CE, Seidel V, Prentice AM, Belteki G, Ong KK, Affara NA, Constancia M, Dunger DB. DNA methylation profiling at imprinted loci after periconceptional micronutrient supplementation in humans: results of a pilot randomised controlled trial. FASEB J. 2012: 26(5); 1782–90

Immunofluorescence staining for polymeric immunoglobulin receptor stained intestinal epithelial cells (pink) and DAPI stained blue nuclei in paediatric colonic biopsy.

biomarkers and are supported by a number of collaborations both within the Biomedical Research Campus, the Sanger Institute as well as abroad.

Inflammation and infection in the critical care setting Critical Care research is led by Nazima Pathan, a University Lecturer in the Paediatric Intensive Care Unit. Her research interests are focused on inflammation and infection in the critical care setting and her group is undertaking a number of NIHR portfolio studies as well as smaller early pilot studies.

A major focus of her scientific research is the role of gut-barrier dysfunction in the pathogenesis and subsequent outcomes of critical illness. Her team are undertaking research into the role of gut-derived bacteria endotoxin in the pathology of inflammation and organ dysfunction in critically ill children.

These studies parallel those being undertaken by Katharine Beardsall and Zilbauer.

Effects of infant feeding, blood glucose and insulin levels on pre-term infant growth Katharine Beardsall is a University Lecturer in Neonatology, who is studying the effects of early infant feeding, changes in blood glucose and insulin levels and their impact on growth in the pre-term infant. Data from large multi-national trials run from Cambridge, such as NIRTURE have highlighted the need for new methods of controlling blood glucose levels in the pre-term infant using insulin therapy, and her group are currently involved in further evaluation of continuous glucose measurements and closed loop insulin delivery in these vulnerable infants as well as

Perry J, Day F, Elks CE, Sulem P…, Stefansson K, Murabito JM, Ong KK. Parent-of-origin specific allelic associations among 106 genomic loci for age at menarche. Nature 2014: DOI 10.1038/nature1345 Beardsall K, Vanhaesebrouck S, Frystyk J, Ogilvy-Stuart AL, Vanhole C, van Weissenbruch M, Midgley P, Thio M, Cornette L, Gill B, Ossuetta I, Iglesias I, Theyskens C, de Jong M, Ahluwalia JS, de Zegher F, Dunger DB; NIRTURE Study Group. Relationship between Insulin-Like Growth Factor I Levels, Early Insulin Treatment, and Clinical Outcomes of Very Low Birth Weight Infants. J Pediatr. 2014 May: 164(5); 1038–1044.e1 Thabit H, Lubina-Solomon A, Stadler M, Leelarathna L, Walkinshaw E, Pernet A, Allen JM, Iqbal A, Choudhary P, Kumareswaran K, Nodale M, Nisbet C, Wilinska ME, Barnard KD, Dunger DB, Heller SR, Amiel SA, Evans ML, Hovorka R. Home use of closed loop insulin delivery improves overnight glucose control in adults with type 1 diabetes: a four-week multicentre randomised crossover study.

Lancet Diabetes Endocrinol. 2014: 2(9); 701–9 Zilbauer M, Rayner TF, Clark C, Coffey AJ, Joyce CJ, Palta P, Palotie A, Lyons PA, Smith KG. Genome-wide methylation analyses of primary human leukocyte subsets identifies functionally important cell-type-specific hypomethylated regions. Blood. 2013 Dec 12: 122(25); e52–60 Thankamony A, Capalbo D, Marcovecchio ML, Sleigh A, Wanda Jørgensen S, Hill NR, Mooslehner K, Yeo GS, Bluck L, Juul A, Vaag A, Dunger DB. Low Circulating Levels of IGF-I in Healthy Adults are Associated with Reduced β-cell Function, Increased Intramyocellular Lipid and Enhanced Fat Utilisation During Fasting. J Clin Endocrinol Metab.

2014 Mar 11: jc20134542 Marino LV, Pathan N, Meyer R, Wright V, Habibi P. Glutamine depletion and heat shock protein 70 (HSP70) in children with meningococcal disease. Clin Nutr. 2013 Oct 9: pii; S0261-5614(13)00253–7

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Psychiatry Head of Department and Professor of Psychiatry

Affiliated Lecturers ICH Clare

Professor Ed Bullmore Tel 01223 336582

A Humphrey

Fax 01223 336581 Email etb23@medschl.cam.ac.uk

Staff list Professors S Baron-Cohen, Developmental Psychopathology GE Berios (Emeritus) PB Jones, Psychiatry

T Dalgleish P Nathan SH Zaman Associate Lecturers/NHS consultants FMC Denman DM Girling

NJ Hunt

J Perez

R Ramana

A Michael

S Robling

J Shapleske

M Stefan

C Walsh

R Chipperfield

E Hegazi

R Zaman

D Christmas

PC Fletcher, Health Neuroscience (Bernard Wolfe Professorship) IM Goodyer, Child and Adolescent Psychiatry AJ Holland, Learning Disability (Healthcare Foundation Professorship) J O’Brien, Old Age Psychiatry ES Paykel (Emeritus) BJ Sahakian, Cognitive Neuropsychology Director of Research J Suckling University Lecturers (honorary NHS consultants) KD Ersche G Murray HA Ring PO Wilkinson Senior Research Associates J Murray M Redley L Su Clinical Senior Research Associates E Fernandez Egea V Voon H Ziauddeen Clinical Lecturers R Cardinal SR Chamberlain JB Deakin VB Dobler GM Khandaker

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Research synopsis The Department boasts innovative, high quality psychiatry research when measured against any metrics. This work is focused on major disease areas using a range of investigative techniques. Developmental paradigms are central in much of the Department’s work from the point of view of pathological states, life course models of child and adult health and the application of novel statistical techniques. Contemporary neuroscience techniques such as structural and functional MRI, neuroendocrinology, cognitive psychology and molecular genetics are used to characterize large, epidemiologically principled or longitudinal samples, and smaller scale, more mechanistic, experimental designs elucidate neuropsychological and pharmacological models of disorders and their treatments.

There are cognate methodological strengths in many of these techniques, especially neuroimaging, cognitive psychology, psychopharmacology and epidemiology; the interface between immunological and neural systems is a new focus and recent funding by MRC for PET/MRI and imaging at 7T opens new vistas.

The full gamut of translational clinical research is an increasing priority, including health neuroscience supported through the Bernard Wolfe endowment. Research activity in the Department benefits from a wide range of national and international collaborations. These include leadership roles in the MRC/ Wellcome Trust Behavioural & Clinical Neurosciences Institute, the NIHR Collaboration for Leadership in Applied Health Research and Care (CLAHRC) East of England, in Wellcome Trust strategic initiatives and within GSK as a primary but not the sole industrial partner. In the NHS, ties are strong with the Cambridgeshire & Peterborough Foundation Trust and with other stakeholders in Cambridge University Health Partners.

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Selected references Baron-Cohen S, Auyeung B, Nørgaard-Pedersen B, Hougaard DM, Abdallah MW, Melgaard L, Cohen AS, Chakrabarti B, Ruta L, Lombardo MV. Elevated fetal steroidogenic activity in autism.

Mol Psychiatry. 2014 Jun 3: doi; 10.1038/mp.2014.48

Functional coactivation network based on meta-analysis of task-related fMRI studies. The network is shown in both anatomical (left) and topological space (right).

Brown R, Banerjee S, Onions C, Griffin M, Adams J, Gray R, Johnson T, Bentham P, Phillips P. Donepezil and memantine for moderate-to-severe Alzheimer’s disease. N Engl J Med. 2012 Mar 8: 366(10); 893–903

Bernacer J, Corlett PR, Ramachandra P, McFarlane B, Turner DC, Clark L, Robbins TW, Fletcher PC, Murray GK. Methamphetamineinduced disruption of frontostriatal reward learning signals: relation to psychotic symptoms. Am J Psychiatry. 2013 Nov 1: 170(11); 1326–34

Khandaker GM, Pearson RM, Zammit S, Lewis G, Jones PB. Serum Interleukin 6 and C-Reactive Protein in Childhood as Predictors of Depression and Psychosis in Young Adult Life: A Population-Based Longitudinal Study. JAMA Psychiatry. doi:10.1001/ jamapsychiatry.2014.1332. Published online August 13, 2014

Cambridge VC, Ziauddeen H, Nathan PJ, Subramaniam N, Dodds C, Chamberlain SR, Koch A, Maltby K, Skeggs AL, Napolitano A, Farooqi IS, Bullmore ET, Fletcher PC. Neural and behavioral effects of a novel mu opioid receptor antagonist in binge-eating obese people.

Biol Psychiatry. 2013 May 1: 73(9); 887–94

Owens M, Herbert J, Jones PB, Sahakian BJ, Wilkinson PO, Dunn VJ, Croudace TJ, Goodyer IM. Elevated morning cortisol is a stratified population-level biomarker for major depression in boys only with high depressive symptoms. Proc Natl Acad Sci U S A. 2014 Mar 4: 111(9); 3638–43

Catarino A, Andrade A, Churches O, Wagner AP, Baron-Cohen S, Ring H. Task-related functional connectivity in autism spectrum conditions: an EEG study using wavelet transform coherence.

Mol Autism. 2013 Jan 12: 4(1); 1

Phillips AC, Sleigh A, McAllister CJ, Brage S, Carpenter TA, Kemp GJ, Holland AJ. Defective mitochondrial function in vivo in skeletal muscle in adults with Down’s syndrome: a 31P-MRS study. PLoS One. 2013 Dec 31: 8(12); e84031. doi: 10.1371/journal.pone.0084031

Crossley NA, Mechelli A, Vértes PE, Winton-Brown TT, Patel AX, Ginestet CE, McGuire P, Bullmore ET. Cognitive relevance of the community structure of the human brain functional coactivation network. Proc Natl Acad Sci U S A. 2013 Jul 9: 110(28); 11583–8

Pironti VA, Lai MC, Müller U, Dodds CM, Suckling J, Bullmore ET, Sahakian BJ. Neuroanatomical Abnormalities and Cognitive Impairments Are Shared by Adults with Attention-Deficit/Hyperactivity Disorder and Their Unaffected First-Degree Relatives. Biol Psychiatry. 2013 Oct 5: pii: S0006-3223(13)00866–4. doi: 10.1016/j.biopsych.2013.09.025

Ersche KD, Hagan CC, Smith DG, Abbott S, Jones PS, Apergis-Schoute AM, Döffinger R. Aberrant disgust responses and immune reactivity in cocaine-dependent men. Biol Psychiatry.

2014 Jan 15: 75(2); 140–7 Howard R, McShane R, Lindesay J, Ritchie C, Baldwin A, Barber R, Burns A, Dening T, Findlay D, Holmes C, Hughes A, Jacoby R, Jones R, Jones R, McKeith I, Macharouthu A, O’Brien J, Passmore P, Sheehan B, Juszczak E, Katona C, Hills R, Knapp M, Ballard C,

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Public Health and Primary Care Head of Department and Professor of Epidemiology and Medicine Professor John Danesh Tel 01223 748655 Email john.danesh@phpc.cam.ac.uk

Staff list Professors C Brayne, Professor of Public Health Medicine (Director, Institute of Public Health) C Deaton, Florence Nightingale Professor of Clinical Nursing DF Easton, Professor of Clinical Epidemiology KT Khaw, CBE, Professor of Clinical Gerontology SJ Griffin, Professor of General Practice JW Mant, Professor of Primary Care Research TM Marteau, Director of Research (Honorary Professor and Director of Policy Research Unit) PD Pharoah, Professor of Cancer Epidemiology M Roland, Professor of Health Services Research SR Sutton, Professor of Behavioural Science SG Thompson, Director of Research (Honorary Professor in Biostatistics) Reader AC Antoniou, Reader in Cancer Risk Prediction Senior Cancer Research Fellow University Senior Lecturers JA Benson P Monsivais University Lecturers SIG Barclay

AS Butterworth

E Di Angelantonio

Clinical Lecturers GJ Irving

N Mavaddat

R Payne

J Usher-Smith

J Yip

Affiliated Lecturers A Hibble

MH Reacher

J Howard

R Fordham

AM Wood

R Chowdhury

M Farquhar

W Hardeman

GJ Hollands

J Howson

S Kaptoge

T Minett

CS Moore

R Mullis

F Naughton

D Nunn

CAM Paddison

ID Shemilt

MJ Sweeting

M Walker

I Wellwood

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G Lyratzopoulos

FM Walter

NHS Consultants/Associate Lecturers TS Alderson LK Atkinson

P Badrinath

F Crawley

RG Davies

J Ferdinand

E Fistein

S Forrest

SJ Gilliam

SM Holmes

R O’Donnell

DC Pencheon

AO Spathis

K Watson

Research synopsis The 400-person Department of Public Health and Primary Care (DPHPC) is one of Europe’s leading academic departments of population health sciences. Its overall research mission is to generate evidence that will inform the prevention of premature death and disability, the promotion of health, and the formulation of evidence-based health policy. There is a focus on the study of common chronic conditions (eg. cardiovascular disease, cancers, dementia), as well as their major modifiable determinants (eg. smoking, alcohol consumption, diet).

A key component of the Department’s research strategy is to engage with external partners in order to benefit from complementary perspectives and expertise and to accelerate the impact and dissemination of our research findings. Examples of recent key external partnerships include: the NIHR School for Public Health Research, NHS Blood and Transplant Centre for Donor Health, Cambridge Centre for Health Services Research in conjunction with RAND-Europe, the Pfizer-Cambridge Centre for Cardiovascular Genomics, the Department of Health’s Behaviour and Health Research Unit. We also have joint appointments with Cambridge-based strategic partners, including the Wellcome Trust Sanger Institute, MRC Biostatistics Unit, and various University Departments (eg. Medicine, Oncology, Haematology).

Exemplars of the Department’s many research and teaching activities are described below.

Cardiovascular Epidemiology Unit The Cardiovascular Epidemiology Unit encompasses five inter-linked applied research programmes, all underpinned by research into quantitative methods.

Senior Research Staff GA Able JK Barrett

KM Williams

Clinical Research Fellows /Associates DA Edwards JP Graffy

The themes relate to: 1. Screening and risk prediction 2. Genetic epidemiology for medicines development 3. International vascular health 4. Integrative genomics 5. Blood donor health.

Clinical Gerontology Unit The Clinical Gerontology Unit aims to understand how best to maintain health in older populations. The overall research aim is to quantify the combined role of lifestyle, environmental and genetic factors in the aetiology of the major disabling diseases of later life, focusing in particular on cardiovascular disease, cancer and osteoporosis and to identify effective prevention strategies. The European Prospective Investigation into Cancer is a ten country collaboration involving half a million participants.

The EPIC-Norfolk cohort of 30,000 men and women aged 45–79 in Norfolk is part of this collaboration. Work from this group directly influenced the Department of Health’s 'Small change big difference' public health campaign and underpins the East of England initiative to promote behaviour change.

Examples of studies that cut across these research programmes include the 2.5 million-participant Emerging Risk Factors Collaboration, the 50,000-participant INTERVAL bioresource, and 50,000-participant case-control studies of acute vascular events in South Asia (eg. 'BRAVE' and 'PROMIS'). Work from this group has had a substantial impact on contemporary cardiovascular guidelines, cited in 10 different guidelines published between 2010 and 2013.

Centre for Cancer Genetic Epidemiology The major focus of this group is the genetic epidemiology of common cancer. The major themes are risk prediction, linking genetic epidemiology with functional biology, and methodology in statistical genetics. It is the co-ordinating centre for three large international consortia that contain data from over 200,000 individuals. These studies include genome-wide association studies, customised gene arrays (eg. iCOGS, OncoArray), and targeted sequencing projects. The group leads SEARCH, a population-based study of 30,000 cancer cases in Eastern England, and EMBRACE, a prospective national epidemiological study of families with BRCA1 and BRCA2 mutations. The group devised and developed two widely used online prediction tools: the BOADICEA model for predicting risks of breast and ovarian cancer, and PREDICT for predicting breast cancer prognosis in the context of adjuvant therapy.

Primary care research The goal of the Primary Care Unit is to reduce the societal burden of ill health by targeting the individual and collective behavioural determinants of chronic disease, by improving early detection, and by improving the delivery of health services in community settings. The Unit aims to achieve this by delivering research and education at the highest international levels of excellence.

A widely diverse current research profile includes optimising primary care uptake of statins and antihypertensives in patients with cerebrovascular disease through use of a polypill and novel approaches to smoking cessation. Publications from this group were recognised in 2012 by the award of the BMJ paper of the year, RCGP cancer paper of the year, and RCGP diabetes paper of the year.

Behaviour and Health Research Unit The Behaviour and Health Research Unit (BHRU) aims to bring contemporary understandings of behaviour and brain sciences to national and international effort to achieve sustained behaviour change that improves health outcomes and reduces health inequalities. The BHRU is funded as part of the Department of Health Policy Research Programme to provide policy makers with timely and authoritative information to support decisions on investing or disinvesting in interventions designed to change health-related behaviour.

Public health, ageing and the brain Research is primarily in the study of ageing and in neuropsychiatry.

This includes a number of population groups (or cohorts), where people have volunteered to participate in the study over a period of many years so that their ageing process can be recorded and analysed for factors and trends which might explain the natural history, risk and expected course of the ageing process. One of these population studies is the MRC Cognitive Function and Ageing study (CFAS), which is a longitudinal multi-centre study of ageing with research hubs throughout the country with Cambridge as the administrative hub. Work from this group was influential in informing the report 'Dementia UK', which led to the development of the 2009 National Dementia Strategy.

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Public health and primary care Teaching and training The Department takes great pride in its contributions to academic capacity in epidemiology, public health and primary care at all levels, ranging from undergraduate medical students to academic clinical fellows. Since 2008, the Department has graduated 171 MPhil students and over 100 PhD students.

Selected references Kaptoge S (310 co-authors), Danesh J. C-reactive protein, fibrinogen, and cardiovascular disease prediction. N Engl J Med 2012: 367; 1310–20 Sarwar N (352 co-authors), Danesh J. Interleukin-6 receptor pathways in coronary disease. Lancet 2012: 379; 1205–1213 Di Angelantonio E (205 co-authors), Danesh J. Lipid-related markers and cardiovascular disease prediction. JAMA 2012: 307; 2499–2506

Health Services Research Health Services Research focuses on developing methods of measuring quality of care, and evaluating innovative approaches and policies to improving care. The Cambridge Centre for Health Services Research was formed in 2010 as a formal collaboration between the University of Cambridge and RAND-Europe. In 2013, this Centre was judged to be one of the two top health policy think tanks worldwide, according to an independent report from the University of Pennsylvania.

Clinical Nursing Research Group Current research activity focuses on patients with heart disease, diabetes and stroke. The goal is to help patients live healthier lives through exercise and physical activity, supported selfmanagement, and improved care. The Group also has a focus on building research knowledge and skills among nurses, midwives and allied health professionals at Cambridge University and Cambridge University Hospitals NHS Foundation Trust, and supporting them in developing clinical academic careers.

Michailidou KM, Easton DF. (2013) Large-scale genotyping identifies 41 new loci associated with breast cancer risk. Nat Genet. 2013 Apr: 45(4); 353–61 Antoniou AC et al. Breast-cancer risk in families with mutations in PALB2 N Engl J Med. 2014 Oct 23: 371(17); 1651–2 Pharoah PD et al. GWAS meta-analysis and replication identifies three new susceptibility loci for ovarian cancer. Nat Genet. 2013: 45(4); 362–70 Arthur A, Barnes L, Bond J, Jagger C, Robinson L, Brayne C. A two-decade comparison of prevalence of dementia in individuals aged 65 years and older from three geographical areas of England: results of the Cognitive Function and Ageing Study I and II. Lancet 382, no. 9902 (2013): 1405–1412 Matthews FE, Brayne C, Lowe J, McKeith I, Wharton SB, Ince P. Epidemiological pathology of dementia: attributable-risks at death in the Medical Research Council Cognitive Function and Ageing Study. PLoS Med, 2009: 6(11); e1000180. doi: 10.1371/journal.pmed.1000180 Sutton M, Nikolova S, Boaden R, Lester H, McDonald R, Roland M. Reduced mortality with hospital pay for performance in England.

New England Journal of Medicine 2012: 367; 1821–28 Marteau TM, Hollands GJ, Fletcher PC. Changing human behaviour to prevent disease: the importance of targeting automatic processes.

Science 2012: 337(6101); 1492–1495 doe: 10.1126/science.1226918 Simmons RK, Echouffo-Tcheugui JB, Sharp SJ, Sargeant LA, Williams KM, Prevost AT, Kinmonth AL, Wareham NJ, Griffin SJ. Screening for type 2 diabetes and population mortality over 10 years (ADDITION-Cambridge): a cluster-randomised controlled trial. Lancet 2012: 380; 1741–48

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Radiology Head of Department and Professor of Radiology

Research synopsis

Professor Fiona J Gilbert Tel 01223 336890 Fax 01223 330915 Email fjg28@.medschl.cam.ac.uk

Staff list Professors AK Dixon, Emeritus Professor of Radiology

The research activity of the department spans a wide range from molecular imaging developments at a 'bench' level, through novel imaging technique development to clinical studies of new imaging applications. These activities involve numerous multidisciplinary collaborations across the campus and the wider university, including links with Engineering, Physics, Medical Physics, the Cancer Institute and the major themes of the NIHR Cambridge Biomedical Research Centre of which Imaging forms a key cross-cutting theme. Cancer Imaging Centre status was awarded in 2013.

DJ Lomas, Professor of Clinical MRI JH Gillard, Professor of Neuroradiology University Lecturers LH Berman FA Gallagher T Barrett T Matys Senior Research Staff Z Teng NHS Consultants/Associate Lecturers N Antoun J Babar A Balan K Balan

S Barter

P Bearcroft

P Britton

J Buscombe

N Carroll

HK Cheow

C Cousins

J Cross

T Das

J Dutton

S Freeman

M Gaskarth

E Godfrey

A Gomez

D Gopalan

N Higgins

M Hopper

B Khoo

M Krokidis

S McDonald

D Scoffings

N Screaton

T See

P Set

A Shaw

R Sinnatamby

A Tasker

S Upponi

M Wallis

S Whitley

A Winterbottom

Clinical Lecturers I Mendichovszky K Mortensen Affiliated Lecturers MJ Graves

Cambridge has installed one of the world’s first clinical hyperpolarisers for carbon-13 MRI. Hyperpolarisation increases the signal-to-noise of carbon-13 on MRI by 10,000-100,000 fold and allows metabolism of 13C containing molecules to be detected and imaged in real-time.

The department benefits from access to an extensive portfolio of modern imaging equipment including advanced colour Doppler Ultrasound, 1.5T and 3T MRI, MRS and Hyperpolarised MRI, 16, 64 and 128 detector and dual energy CT as well as PET-CT and advanced radiochemistry. There are close research links with the neurosciences utilising CT, MR and PET techniques in studies involving stroke and carotid disease in particular. Multiple new clinical trials in oncology have been established, investigating both new imaging based biomarkers and the evaluation of new therapeutic agents in early phase 1 trials. A particular focus of current and future work has been molecular imaging with hyperpolarized 13C agents and related imaging applications in collaboration with the CRI and Biochemistry.

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Radiology Individual groups have undertaken research in the identification and characterization of vulnerable plaques, the improved definition and characterization of brain tumours, the development of new interactive real-time techniques for paediatric and neonatal MRI, the development of noncontrast enhanced 3D vascular imaging techniques, the clinical applications of ultrasound and MR based elastography for malignant lymph node detection and focal liver lesion and renal characterization. Extensive breast imaging research is undertaken with Tomosynthesis, functional MRI, novel PET tracers and contrast enhanced mammography.

Our previous work on the impact of imaging techniques on clinical decision making continues to be cited in national guidelines, notably involving breast cancer and chest disease management.

Selected references 2013–2014 Arthurs OJ, Edwards AD, Joubert I, Graves MJ, Set PA, Lomas DJ. Interactive magnetic resonance imaging for paediatric vesicoureteric reflux (VUR). Eur J Radiol 2013: 82(3); e112–9 Clatworthy MR, Kettunen MI, Hu DE, Mathews RJ, Witney TH, Gallagher F, Jarvis L, Smith KG, Brindle KM. Hyperpolarized (1,4–13C2) fumarate allows early, non-invasive diagnosis of acute tubular necrosis. Proc Natl Acad Sci U S A. 2012 Aug 14: 109(33); 13374–9 Gilbert FJ, van den Bosch HCM, Petrillo A, Siegmann K, Heverhagen JT, Panizza P, Gehl H-B, Pediconi F, Diekmann F, Peng W-J, Ma L, Sardanelli F, Belli P, Corcione S, Zechmann CM, Faivre-Pierret M, Martincich L. Comparison of gadobenate dimeglumine-enhanced breast MRI and gadopentetate dimeglumineenhanced breast MRI with mammography and ultrasound for the detection of breast cancer. Journal of Magnetic Resonance Imaging 2013: doi: 10.1002/jmri.24434 Lawrence EM, Tang SYW, Barrett T, Koo B, Goldman DA, Warren AY, Axell R, Doble A, Gallagher FA, Gnanapragasam VJ, Kastner C, Sala E. Prostate cancer: Performance characteristics of combined T2W and DW-MRI scoring in the setting of template transperineal rebiopsy using MR-TRUS fusion. Eur Radiol. 2014. In press Miller NA, Gregory JS, Aspden RM, Stollery PJ, Gilbert FJ. Using active shape modelling based on MRI to study morphological and pitch-related functional changes affecting vocal structures and the airway Journal of Voice 2014: doi: 10.1016/j.jvoice.2013.12.002 Sadat U, Howarth SP, Usman A, Taviani V, Tang TY, Graves MJ, Gillard JH. Effect of low-and high-dose atorvastatin on carotid artery distensibility using carotid magnetic resonance imaging – a post-hoc sub group analysis of ATHEROMA (Atorvastatin Therapy: Effects On Reduction Of Macrophage Activity) Study. J Atheroscler Thromb 2013: 20(1); 46–56

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Surgery Head of Department and Professor of Surgery

J Melton

R Miller

D Moffat

A Nashef

A Norrish

PJ Owen

M Power

R Praseedom

R Price

M Rajan

A Rehm

A Riddick

Email jab52@cam.ac.uk

R Rimes

A Robinson

P Safranek

N Shah

K Stohr

V Sujendran

Staff list

N Thiruchelvam

M Thompson

L Treharne

S Tsui

W Turner

J Tysome

G Tytherleigh-Strong

L Van-Rensburg

K Varty

C J Watson, Professor of Transplantation

A Vince

D Wallace

F Wells

A McCaskie, Professor of Orthopaedic Surgery

J Wheeler

J Williams

O Wiseman

Professor Andrew Bradley Tel 01223 336976 Fax 01223 762523

Professors J A Bradley, Professor of Surgery

University Readers GJ Pettigrew, Reader in Clinical and Experimental Transplantation L Vallier, Reader in Stem Cells and Regenerative Medicine University Lecturers A Butler

P Gibbs

VJ Gnanapragasam

K Saeb-Parsy

P Hayes

S Quillagan

Assistant Director of Research EM Bolton Senior Research Staff S Liau RA Brooks M Birch R Wardale Clinical Lecturers R Motallebzadeh

A Barlow

V Kosmoliaptsis

A Lamb

MGB Tran

NHS Consultants/Associate Lecturers T Ahmed TF Aho

S Al-Hayek

J Armitage

P Axon

A Barber

J Benson

S Benyon

S Biers

J Boyle

M Cameron

A Carrothers

T Chandrappa

C Chileshe

A Colquhoun

S Connolly

P Coughlin

R Davies

A Doble

N Donnelly

A Durrani

D Edwards

P Ellis

N Fearnhead

B Fish

P Forouhi

J Fraser

P Gillespie

M GohelI Grant

R Gray

N Hall

P Hall

R Hardwick

S Harper

J Hopkinson-Woolley A Hindmarsh

E Huguet

P Hull

M Irwin

A Jah

N Jamieson

Jani

H Jeremiah

D Jenkins

P Johnstone

N Jonas

S Kang

C Kastner

G Keene

V Khanduja

M Krkovic

S Large

C Malata

D McKiernan

Research synopsis The Department of Surgery has a strong clinical emphasis and the overall research strategy is to improve the surgical management of disease through developments in both basic and translational research. There is a major focus on applied clinical research and a key feature of the department is the close integration of University and NHS surgeons. University surgeons in parallel with directing programmes of research play an important role in the development and delivery of specialist surgical services. Similarly, many NHS surgeons are, in addition to their clinical responsibilities, undertaking high quality clinical research supported through close collaboration with University colleagues. In contrast with the trend in many other UK Universities, academic surgery in Cambridge is flourishing and the department continues to expand.

The Department has a large and vibrant academic surgical training programme and has been particularly successful in attracting local and national funding for Academic Clinical Fellows and Clinical Lecturers. The principal research interests are transplantation, stem cell medicine, surgical oncology, orthopaedic surgery and vascular surgery. In addition, clinical research of international importance is being led by NHS surgical colleagues across a range of surgical disciplines, including ear, nose and throat surgery, plastic surgery and gastrointestinal surgery.

Division of Transplantation The Division, directed by Andrew Bradley, has been at the international forefront of clinical developments in organ transplantation for many years and the world-renowned clinical programmes in abdominal organ transplantation based at Addenbrooke’s, and thoracic organ transplantation based at Papworth NHS trusts, are each underpinned by well-established multidisciplinary research programmes. Research ranges from basic molecular and cellular immunology to translational research and evaluation of new technologies. The Division includes the Transplantation Theme of the NIHR Biomedical Research Centre.

The major aims are to address the severe shortage of human organs for transplantation and to improve transplant outcomes.

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Surgery There are strong programmes of basic research into the molecular basis of allograft rejection, with a particular focus on the role of B cells and alloantibody in acute and chronic rejection, interactions between endothelial and immune cells in allograft vasculopathy, molecular mechanisms underlying the induction and maintenance of immunological tolerance, and analysis of physicochemical properties determining the immunogenicity of HLA molecules. The division is undertaking a number of investigator led single and multi-centre clinical research programmes aimed at evaluating novel immunosuppressive agents, extending donor organ use and minimising organ injury prior to transplantation. Senior investigators in the department are also working closely with scientists and statisticians in the Division of Organ Donation and Transplantation at NHS Blood and Transplant to maximize the outcome of organ transplantation in the UK.

Watson CJ, Johnson RJ, Birch R, Collett D, Bradley JA. A simplified donor risk index for predicting outcome after deceased donor kidney transplantation. Transplantation. 2012: 93; 314–8 Kosmoliaptsis V, Gjorgjimajkoska O, Sharples LD, Chaudhry AN, Chatzizacharias N, Peacock S, Torpey N, Bolton EM, Taylor CJ, Bradley JA. Impact of donor mismatches at individual HLA-A, -B, -C, -DR, and -DQ loci on the development of HLA-specific antibodies in patients listed for repeat renal transplantation. Kidney Int. 2014 Nov: 86(5); 1039–48; Doi: 10.1038/ki.2014.106 Sivaganesh S, Harper SJ, Conlon TM, Callaghan CJ, Saeb-Parsy K, Negus MC, Motallebzadeh R, Bolton EM, Bradley JA, Pettigrew GJ. Copresentation of intact and processed MHC alloantigen by recipient dendritic cells enables delivery of linked help to alloreactive CD8 T cells by indirect-pathway CD4 T cells. J Immunol. 2013: 190; 5829–38 Butler AJ, Randle LV, Watson CJ. Normothermic regional perfusion for donation after circulatory death without prior heparinization.

Transplantation. 2014: 97; 1272–8 Conlon TM, Cole JL, Motallebzadeh R, Harper I, Callaghan CJ, Bolton EM, Bradley JA, Saeb-Parsy K, Pettigrew GJ. Unlinked memory helper responses promote long-lasting humoral alloimmunity.

J Immunol. 2012: 189; 5703–12 Desai R, Collett D, Watson CJ, Johnson P, Evans T, Neuberger J. Cancer transmission from organ donors – unavoidable but low risk.

Transplantation. 2012: 94; 1200–7

Interaction between an alloantibody (orange) produced by a transplant recipient against the donor kidney Human Leukocyte Antigen (HLA-A*02:01; green). The affinity of alloantibody-HLA binding is mediated through electrostatic interactions (represented by blue and red lines).

Computational and experimental analysis of these interactions may provide insight into the mechanism of humoral rejection in kidney transplantation.

Selected references Summers DM, Johnson RJ, Hudson A, Collett D, Watson CJ, Bradley JA. Effect of donor age and cold storage time on outcome in recipients of kidneys donated after circulatory death in the UK: a cohort study. Lancet. 2013 Mar 2: 381(9868); 727–34 Taylor CJ, Peacock S, Chaudhry AN, Bradley JA, Bolton EM. Generating an iPSC bank for HLA-matched tissue transplantation based on known donor and recipient HLA types. Cell Stem Cell.

2012 Aug 3: 11(2); 147–52

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Division of Stem Cell Medicine The Division, led by Ludovic Vallier is undertaking research into the early stages of embryonic stem cell differentiation and the genetic mechanisms responsible for these processes. Both human embryonic stem cells (hESCs) and human Induced Pluripotent Stem cells (hIPSCs) are being studied, and interfering shRNAs are being used to modify gene function and examine the role of specific genes, with the aim of ultimately controlling differentiation into specialised cell types for potential therapeutic use in patients with liver disease, diabetes and cardiovascular disease. Research is also being undertaken into the mechanisms responsible for the maintenance of pluripotency in hESCs and the formation of mesodermal and endodermal cell lineages, as well as the epigenetic stability of pluripotent stem cell lines.

The Division interacts extensively with other leading investigators nationally and internationally. Vallier is based in the Anne McLaren Laboratory for Regenerative Medicine (LRM) and is a key member of the Wellcome Trust and MRC Cambridge Stem Cell Institute.

The LRM has played a pivotal role in the Cambridge Stem Cell Initiative, serving as the Clinical School host for the MRC Centre for Stem Cell Biology and Regenerative Medicine, which together with the Wellcome Trust Centre for Stem Cell Research on Tennis Court Road constitute the hubs of the Cambridge Stem Cell Institute. Vallier established and oversees the human induced pluripotent stem cell Core Resource, with support from the NIHR Cambridge Biomedical Research Centre. During the past two years, the hIPSC Core Facility has derived more than 500 hIPSC lines from 150 patients suffering from neurodegenerative diseases, cardiovascular syndromes, metabolic and blood disorders. In parallel, the hIPSC Core Facility has become a

major training centre by accommodating more than 20 visiting scientists and by supporting the development of similar platforms in several European countries.

Selected references Siim P and Vallier L. Cell Cycle Directs Differentiation of Human Pluripotent Cells. Cell. 2013: 155; 135–147 Cho CCH, Hannan N, Docherty FM, Docherty HM, Lima MJ, Trotter M, Kevin Docherty K and Vallier L. Inhibition of Activin/Nodal signalling is necessary for pancreatic differentiation of human pluripotent stem cells. Diabetologia. 2012: 55; 3284–95 Hannan N, Segeritz CP, Touboul T, Vallier L. Production of hepatocyte like cells from human pluripotent stem cells. Nature Protocols. 2013: 8(2); 430–7 Lima MJ, Docherty HM, Chen Y, Vallier L, Docherty K. Pancreatic transcription factors containing protein transduction domains drive mouse embryonic stem cells towards endocrine pancreas. PLoS One. 2012: 7; e36481 Weedon MN, Cebola I, Patch AM, Flanagan SE, De Franco E, Caswell R, Rodríguez-Seguí SA, Shaw-Smith C, Cho C, Lango Allen H, Houghton JAL, Roth CL, Chen R, Hussain K, Marsh P, Vallier L, Murray A, International Pancreatic Agenesis Consortium, Ellard S, Ferrer J and Hattersley AT. Recessive mutations in a distal PTF1A enhancer cause isolated pancreatic agenesis. Nat Genet.

2014: 46; 61–4

Selected references Chow WY, Rajan R, Muller KH, Reid DG, Skepper JN, Wong WC, Brooks RA, Green M, Bihan D, Farndale RW, Slatter DA, Shanahan CM, Duer MJ. NMR spectroscopy of native and in vitro tissues implicates polyADP ribose in biomineralization. Science 2014: 344; 742–746 Howard D, Shepherd JH, Kew SJ, Hernandez P, Ghose S, Wardale JA, Rushton N. Release of growth factors from a reinforced collagen GAG matrix supplemented with platelet rich plasma: Influence on cultured human meniscal cells. J. Orthop. Res. 2014: 32; 273–278 Power J, Hernandez P, Guehring H, Getgood A, Henson F. Intra-articular injection of rhFGF-18 improves the healing in microfracture treated chondral defects in an ovine model. J. Orthop. Res. 2014: 32; 669–676 Barr L, Getgood A, Guehring H, Rushton N, Henson FM. The effect of recombinant human fibroblast growth factor-18 on articular cartilage following single impact load. J. Orthop. Res. 2014: 32; 923–927 Enea D, Gwynne J, Kew S, Arumugam M, Shepherd J, Brooks R, Ghose S, Best S, Cameron R, Rushton N. Collagen fibre implant for tendon and ligament biological augmentation. In vivo study in an ovine model. Knee Surg. Sports Traumatol. 2013: 21; 1783–1793

Fordham RP, Yui S, Hannan NR, Soendergaard C, Madgwick A, Schweiger PJ, Nielsen OH, Vallier L, Pedersen RA, Nakamura T, Watanabe M, Jensen KB. Transplantation of expanded fetal intestinal progenitors contributes to colon regeneration after injury. Cell Stem Cell.

2013: 13; 734–44

Division of Trauma and Orthopaedic Surgery The Division, led by Andrew McCaskie is undertaking translational research to transfer innovative therapies from the laboratory to the clinic. A particular focus is the application of regenerative techniques, both cell and cell free, to important musculoskeletal diseases, such as osteoarthritis.

There is a strong interdisciplinary approach, facilitated by the Arthritis Research UK Tissue Engineering Centre (Director, Andrew McCaskie) and the recent creation of the Cambridge Centre for Musculoskeletal Repair, Regeneration and Replacement. Recent research highlights include novel findings on the bone-signalling molecule Sclerostin and a study with the Department of Chemistry (published in Science), illustrating the power of nuclear magnetic resonance spectroscopy for extending understanding of extracellular matrix. The Division is undertaking various preclinical studies of joint repair arising from novel advances in materials development and basic science, with an emphasis on novel collagen-based structures for cartilage and meniscal repair.

Fluorescent staining of a meniscal tissue section showing cell nuclei (DAPI – blue), meniscal fibroblast plasma membrane (Wheat-Germ Agglutinin Alexa Fluor 488 conjugate - green) and vascular cells (phalloidin TRITC – red). Residual platelets are stained orange.

Division of Surgical Oncology The Division, led by Vincent Gnanapragasam, has a primary research focus in urological cancer and in pancreatic cancer (Liau). Research comprises both basic science and translational research with an emphasis on translation of laboratory research findings into clinical practice to improve the early detection, risk stratification and treatment outcomes in patients with aggressive primary urological and pancreatic cancers. The Division undertakes collaborative multi-disciplinary research with colleagues in radiology, pathology, basic sciences, oncology and epidemiology, together with NHS colleagues in the Departments of Urology and hepatobiliary surgery that provide a world-class

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Surgery surgical oncology service. The Cambridge urology clinical trials team and pancreas cancer centre recruit patients into a diverse range of studies. Current studies in urological cancer include the evaluation of imaging techniques to guide therapy response and surgical approaches, and the development of novel imaging biomarkers in high-risk prostate cancer. A novel biopsy device for detection of prostate cancer in an out-patient setting is being evaluated along with an improved risk stratification scheme for aggressive prostate cancer.

Translational research in the Division is underpinned by The Cambridge Urological Biorepositor – a leading international collection of tissue and biological fluids collected from over 3,500 men diagnosed at all stages of prostate cancer as well as other urological cancers. The repository includes targeted collections of fresh and formalin fixed prostate tissue, metastatic deposits, blood, urine and seminal fluid. The Biorepository is allied to a well-annotated database of clinical data on tumour and patient features including serial monitoring and therapy outcome.

Selected references Cassidy LD, Liau SS, Venkitaraman AR. Chromosome instability and carcinogenesis: insights from murine models of human pancreatic cancer associated with BRCA2 inactivation. Mol Oncol. 2014: 8; 161–8 T Mitchell, Ramos-Montoya A, Di Antonio M, Murat P, Ohnmacht S, Micco M, Jurmeister S, Fryer L, Balasubramanian S, Neidle S, Neal DE. Down-regulation of androgen receptor transcription by promoter G-quadruplex stabilization as a potential alternative treatment for castrate-resistant prostate cancer. Biochemistry. 2013: 52(8); 1429–36.

Nelson AW, Harvey RC, Parker RA, Kastner C, Doble A, Gnanapragasam VJ. Repeat prostate biopsy strategies after initial negative biopsy: meta-regression comparing cancer detection of transperineal, transrectal saturation and MRI guided biopsy.

PLOS One 2013: 8(2); e57480 Kachroo N, Valencia T, Warren A, Gnanapragasam VJ. Evidence for down-regulation of the negative regulator SPRED2 in clinical prostate cancer. British Journal of Cancer. 2013: 108; 597–601 Serag H, Banerjee S, Parsy KS, Irving S, White K, S Stearn, Doble A, Gnanapragasam VJ. Risk profiles of prostate cancers identified from UK primary care using national guidelines.

British Journal of Cancer. 2012: 106; 436–9 Lamb AD, Ramos-Montoya A, Russell R, Carroll T, Jurmeister S, Galeano-Dalmau N, et al. HES6 drives a critical AR transcriptional programme to induce castration-resistant prostate cancer through activation of an E2F1-mediated cell cycle network. EMBO Mol Med. 2014: 6; 651–61 Sharma NL, Massie CE, Ramos-Montoya A, Zecchini V, Scott HE, Lamb AD, MacArther S, Stark R, Warren AY, Mills IG, Neal DE. The androgen receptor induces a distinct transcriptional program in castration-resistant prostate cancer in man. Cancer Cell 2013: 23; 35–47

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Division of Vascular Surgery This new Division, led by Paul Hayes, is closely aligned with the Cambridge Regional Vascular service. There is a major focus on the clinical evaluation of innovative techniques and novel devices in vascular surgery. University staff in association with NHS vascular surgeons are undertaking research to evaluate endovascular repair of aortic aneurysms, and performing studies in peripheral vascular disease, leg ulceration, remote ischaemic pre-conditioning and aspects of the diabetic foot. There are close collaborative links with radiology, cardiology and metabolic medicine and the Division is leading and participating in a range of regional, national and international clinical trials for patients with peripheral vascular disease.

Selected references Tang T, Sadat U, Walsh S, Hayes PD. Comparison of the Endurant Bifurcated Endograft vs. Aortouni-iliac Stent-Grafting in Patients With Abdominal Aortic Aneurysms: Experience From the ENGAGE Registry.

J Endovasc Ther. 2013: 20; 172–81 McMahon GS, Jones CI, Hayes PD, Naylor AR, Goodall AH. Transient heparin-induced platelet activation linked to generation of platelet 12-lipoxygenase. Findings from a randomised controlled trial.

Thromb Haemost. 2013: 14; 1099–107 Rollins KE, Shak J, Ambler GK, Tang TY, Hayes PD, Boyle JR. Mid-term cost-effectiveness analysis of open and endovascular repair for ruptured abdominal aortic aneurysm. Br J Surg. 2014: 101; 225–31

Medical Education and Postgraduate Study The School of Clinical Medicine at the University of Cambridge (the Clinical School) is one of the UK’s leading medical schools.

There are approximately 2,200 staff and 750 medical and postgraduate students in the School. Its strength is built on close relationships with pre-clinical science and translational partnerships with NHS organisations.

Medical education Cambridge aims to educate students to become compassionate, thoughtful, skilled members – and leaders – of the medical profession.

There are three undergraduate courses for medical students: the Standard Course (272 places per year), the Graduate Course (20 places) and the MBPhD programme in which standard course students may integrate a PhD during their clinical course (5–10 places).

Medical education in the Clinical School builds on the scientific basis to medicine developed in the Medical and Veterinary Sciences Tripos in the first three years of the Cambridge medical studies programme. Grounded in the principles of scientific enquiry and evidence based medicine, the clinical teaching programme allows students to develop excellence in the clinical, communication, attitudinal, professional and practical skills required for good medical practice. The School is based on the Cambridge Biomedical Campus together with our partner NHS Trusts in the Cambridge University Health Partners (CUHP) where high quality clinical care is supported by excellent teaching and research.

Student teaching also occurs in a network of regional hospitals throughout the East of England regions, all formally associated with the Clinical School and CUHP. Together with a large network of General Practices, the clinical

education programme is linked by the Clinical Skills Unit network and the online virtual learning environment which allows curriculum delivery simultaneously across a wide range of sites.

Admissions information Information about admissions for both the Standard Course and the Graduate Course can be found here: www.study.cam.ac.uk/undergraduate/ courses/medicine

Postgraduate study The Departments and Institutes of the School of Clinical Medicine offer a wide range of research and taught courses www.gradschl.lifesci.cam.ac.uk/ Prospective The PhD degree and the pure research Master of Philosophy (MPhil) course are offered by every Department and Institute within the School. In addition, there are a number of Integrated Masters/PhD programmes (1+3 programmes) in which a research preparation Masters (an MRes) is undertaken in the first year, leading on to a three year PhD programme. Opportunities also exist for pursuing a Doctor of Medicine (MD) degree which is awarded to clinicians who have undertaken an extended period of scientific research, as well as for applying for a higher doctorate or a higher degree by special regulations: www.medschl.cam.ac.uk/graduatestudies

The School also offers a number of MPhil programmes with both taught and research components. These courses attract a diverse range of students from around the world, and provide exciting opportunities for clinicians and non-clinicians to work alongside each other. A significant proportion of students on these courses go on to undertake PhD study.

The School also plays a key role with regard to clinical academic training pathways, and the Clinical Academic Training Office (CATO) administers core programmes such as the Academic Foundation Year programme and Clinical Academic Fellowships. In addition, the office oversees a number of graduate programmes with strong international links, that cross Departmental and School boundaries.

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Translational Research The road to drug development The European Union and the US Food and Drugs Administration has recently licenced a new treatment for multiple sclerosis (Alemtuzumab, marketed under the name Lemtrada) in which an old medicine (Mabcampath) has been repurposed based on 25 years of research in Cambridge. NICE has also approved the medicine for use in the NHS as a transformative and cost-effective treatment for active relapsing-remitting disease. We summarise the history of this development in order to emphasize the long and arduous path of translational medicine from the lab to the bedside.

Lemtrada, marketed by pharmaceutical company Genzyme (a Sanofi Company), began life as Campath-1H, a drug developed out of research by Herman Waldmann and colleagues in the Department of Pathology at the University of Cambridge which began in 1979.

However, the story of Campath stretches even further back to research by César Milstein and George Köhler at Cambridge’s MRC Laboratory of Molecular Biology in 1975 to develop monoclonal antibodies – a potentially unlimited supply of artificially-produced antibody directed against one particular target. In 1984, César Milstein and George Köhler received the Nobel Prize for Physiology or Medicine for this work.

Campath-1H was originally developed in order to induce immunological tolerance by substantially reducing the number of lymphocytes in the body and hence their chances of interaction in generating an autoimmune response. The original versions of the drug – Campath-1M and Campath-1G – were developed using mouse and rat antibodies; it required the development of ‘humanised’ monoclonal antibodies, which replace regions of the animal antibody with human equivalent, for the drug to be usable in humans. This version, Campath-1H, was successful at treating two types of blood cancer, lymphocytic leukaemia and nonHodgkin lymphoma,

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and in preventing the rejection of organ transplants.

In discussions with Herman Waldmann, Campath-1H was identified as a potential treatment for multiple sclerosis by Alastair Compston, Professor of Neurology and Head of the Department of Clinical Neurosciences, in the late 1980s. Multiple sclerosis is an autoimmune disease in which the immune system begins to attack the body’s own healthy nerve cells, stripping away their protective myelin sheath and preventing electrical signals from passing smoothly and quickly throughout the brain and spinal cord. The drug reboots the immune system by first depleting a key class of immune cells, called lymphocytes. The system then repopulates, leading to a modified immune response that no longer regards myelin and nerves as foreign.

The first patient with multiple sclerosis was treated with Campath1H in 1991 and as evidence began to mount that the drug would be effective, if used to treat people before the disease process had progressed too far, Alastair Compston and his colleague Alasdair Coles, who joined the team in 1994, expanded the trials. Eventually, the results of phase II and III clinical studies (published in 2007 and 2012, respectively) confirmed that the drug is effective both in patients with multiple sclerosis who are previously

Professor Alastair Compston

Dr Alasdair Coles

untreated (‘first-line’ therapy) and those who have already failed another treatment.

As with any medication, however, the drug is not without its side-effects – roughly one third of treated patients with multiple sclerosis develop another autoimmune disease, mainly targeting the thyroid gland and more rarely other tissues especially blood platelets. The research team is now investigating how to identify people who are susceptible to this complication and testing whether the side-effect can be prevented using an additional drug that boosts repopulation of the immune system. www.cam.ac.uk/research/news/niceapproves-ms-drug-developed-byuniversity-of-cambridge-researchers

New molecular testing device for oesophageal cancer Oesophageal cancer (cancer of the gullet or food pipe) is the sixth most common cause of cancer death in the UK, with only around 13% of patients surviving for more than five years after diagnosis. Incidences of this cancer are also rapidly rising across the Western world, with over 8,000 people diagnosed with oesophageal cancer each year in the UK alone.

A key risk factor in the development of this cancer is a condition called Barrett's oesophagus. Barrett's oesophagus results from long-term, persistent acid reflux or heartburn which changes the cells lining the gullet, making people with this condition much more likely to go on to develop oesophageal cancer.

About 3% of the UK population with a history of heartburn are affected, although the majority are undiagnosed.

Currently Barrett's oesophagus patients are diagnosed and monitored via regular endoscopies, involving the insertion of a small camera into the gullet to examine it.

This process is both uncomfortable for the patient, requiring a visit to hospital and sedation, as well as expensive for the NHS. However, a new less-invasive and more cost-effective method for the diagnosis and monitoring of patients at risk of developing oesophageal cancer has been developed by Professor Rebecca Fitzgerald at the MRC Cancer Unit. The method involves a cell-collection device coupled with molecular assays.

The device, which is now CE marked and FDA cleared in the United States, is called Cytosponge. It comprises a small sponge compressed whithin a dissolvable capsule attached to a string. Once the capsule is swallowed by the patient, it moves into the stomach and dissolves, thus releasing

the sponge. A nurse then pulls the expanded sponge back up through the oesophagus, collecting cells along the way. The sponge is then placed into a standard preservative and tested for a protein called TFF3 which is specific to the condition Barrett’s oesophagus. If Barrett’s is detected then a second round of genetic testing is done to see how far the condition has progressed towards cancer. Patients with early cancerous changes can then be treated endoscopically. The Cytosponge has a number of advantages compared to diagnosis and monitoring via endoscopy; it is far less invasive and can be administered in a GP's surgery, it doesn't require a visit to hospital, and is also much more cost-effective.

The molecular tests are binary and objective, compared with the current histopathological diagnoses.

Professor Rebecca Fitzgerald

So far this approach has been tested in two large multicentre trials in the UK comprising over 2,000 patients.

The results are extremely encouraging and the ultimate aim of this work is to introduce the test routinely to give patients the best chance of early detection and cure from oesophageal cancer.

The development of the Cytosponge and related research has been supported by the Medical Research Council, MRC Technology, Cancer Research UK, and the NIHR Cambridge Biomedical Research Centre.

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The School of Clinical Medicine Administration The School of Clinical Medicine is led by Professor Patrick Maxwell, Regius Professor of Physic.

He is supported by: Dr Diana Wood, the Director of Medical Education, who is responsible for all aspects of undergraduate medical education in the School; Professor Peter Jones, Deputy Head of School; and Dr Caroline Edmonds who leads the Clinical School Office and is overall head of administration for the School.

Professor Patrick Maxwell Regius Professor of Physic

Dr Diana Wood Director of Medical Education

Professor Peter Jones Deputy Head of School

Dr Caroline Edmonds Secretary to the School

The School Office is organised into three teams – the Resources Division, the Education Division and the General Division. These are complemented by the HR Division Clinical School team and the Clinical School Computing Service, the Research Governance Officer and other research support services.

Resources Division

Education Division

General Division

Responsible for the finances of the Clinical School and all departments.

Responsible for administration of the clinical component of Cambridge Medical Student programme and higher degrees.

Responsible for estates, departmental and general administration in the School.

Led by Robin Uttin

Led by Dr Litsa Briggs

Led by Jackie Hall

HR Division

Computing Service

Research Governance

Led by Gail Christy

Led by Richard Barlett

Carolyn Read

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Research support for the Clinical School The Research Operations Office The Clinical School Research Office is led by Dr Jo Martindale and offers expert guidance and support in securing and administering research funding. There are two divisions within the team: the Grant Team provides both pre- and post-award support, administering over 500 applications per annum and managing over 1,200 live awards.

The Contracts Team negotiates and executes all the Ciinical School research agreements (over 1,400 per annum), ranging from confidentiality agreements to framework agreements with industrial partners.

Dr Jo Martindale

www.admin.cam.ac.uk/offices/research

Office for Translational Research This is a new office within the School of Clinical Medicine, set up in October 2013, led by its Director Professor Ian Wilkinson with day to day activities run by the Programme Manager Dr Jana Voigt. Its remit is to support investigators in their efforts to translate findings from their basic biological, biomedical or clinical research into interventions, therapeutics and diagnostics that will improve human health. www.medschl.cam.ac.uk/research/office-for-translational-research-otr General enquiries: translation@medschl.cam.ac.uk Dr Jana Voigt

Cambridge Clinical Trials Unit (CCTU) The CCTU is a fully registered CTU and part of the NIHR UKCRC CTU network working with investigators across CUH-P and beyond in the design, set-up and conduct of clinical trials. Support covers grant applications, trial design, regulatory affairs, coordination, data management, safety monitoring, statistics and health economy. The unit is led by Professor Ian Wilkinson (Director) and Dr Sabine Kl채ger (Operations Director). Investigators wishing to run their trials with the CCTU are encouraged to contact the CCTU at the earliest stages of conceiving a new trial.

Professor Ian Wilkinson and Dr Sabine Kl채ger

www.cuh.org.uk/cctu General enquiries: cctu@addenbrookes.nhs.uk

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Cambridge University Health Partners Cambridge University Health Partners is a partnership between one of the world’s leading universities and three NHS Foundation Trusts. It is delivering world-class excellence in health care, research and clinical education; and improving health for people across the Cambridgeshire region and beyond.

Cambridge University Health Partners (CUHP) is one of only six Academic Health Science Centres (AHSCs) in England, recognised by the Department of Health (DH) as internationally competitive centres of excellence in the integrated delivery of healthcare, health research and the education of health professionals.

and local economic success by attracting global investment in medical research and innovation, and creating and sustaining jobs.

of service delivery, scientific research and clinical education and open partnerships with industry and other stakeholders.

Recent achievements

Strategic programmes of work

CUHP’s partners are Cambridge and Peterborough NHS Foundation Trust, Cambridge University Hospitals NHS Foundation Trust, Papworth Hospital NHS Foundation Trust and the University of Cambridge. The primary CUHP partnership is between the School of Clinical Medicine (SCM) and NHS partners, although there are increasing interactions with other departments across the University.

CUHP is rolling out an Associates programme to broaden the impact and reach of our strategic priorities and strengthen relationships across the region.

• Leading the development of the

CUHP is at the heart of the Cambridge Biomedical Campus (CBC), a community of world-leading academics, clinicians, scientists and businesses working together with patients, to improve healthcare and quality of life. Based on a single site south of the city centre, the campus supports ground-breaking research into the causes of disease, better prevention, faster diagnosis, more effective treatment and the best way to care for patients. In addition to cutting-edge scientific research, the campus contributes to national

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• Development of a major trauma centre, supporting the provision of trauma care across the eastern region; Eastern Academic Health Science Network (EAHSN) as a system wide integrator across the East of England for improving clinical care and wealth creation;

• Sponsorship of the University Technical College to provide science training for 14–19 year olds;

• Renewal of the Cambridge NIHR Biomedical Research Centre with a 40% funding uplift to £110m over the period 2012–2017;

• Innovation in educational provision with development of a surgical training facility; a surgical simulation centre; and a range of leadership programmes;

• Working in partnership to support the move of Papworth Hospital to the CBC; and development of an on site Heart Lung Research Institute.

CUHP vision CUHP will be a world-leading academic clinical partnership centred on the CBC. It will be a global leader in improving patient care, and will deliver outstanding patient outcomes and progressively better population health. This will be achieved through innovation, the integration

CAMBRIDGE UNIVERSITY HEALTH PARTNERS

CUHP is working to achieve this vision through delivery of six strategic programmes of work:

• Supporting translational research; • Educating and training tomorrow’s workforce;

• Development of the CBC; • Philanthropy; • Service innovation and improvement; • Medical informatics.

CUHP’s Board, chaired by Baroness Helene Hayman, comprises the CEO, Chairs and clinical leads from the NHS partners, as well as the Vice Chancellor and Registrary of the University.

Delivery is led with an exceptionally strong clinical and academic team: Executive Director, the Regius Professor of Physic, Professor Patrick Maxwell; Director of Research, Dr John Bradley; and Director of Education, Dr Arun Gupta.

More details about our work can be found on our website www.cuhp.org

Cambridge University Hospitals NHS Foundation Trust Cambridge University Hospitals (CUH) NHS Foundation Trust comprises Addenbrooke’s Hospital and the Rosie Hospital in Cambridge. The Trust provides accessible high-quality healthcare for the local people of Cambridge, together with specialist

services, dealing with rare or complex conditions, for a regional, national and international population. The Trust is recognised as a centre of excellence and innovation with many of the hospital specialists being leaders in their field.

Papworth Hospital NHS Foundation Trust Currently based in the village of Papworth, the Trust is moving to a new purpose built facility on the Cambridge Biomedical Campus in 2016.

Papworth is the UK’s largest specialist cardiothoracic hospital

and the country’s main heart and lung transplant centre. Its services are internationally recognised and include cardiology, respiratory medicine and cardiothoracic surgery and transplantation.

Cambridgeshire and Peterborough Foundation Trust (CPFT) CPFT is a partnership organisation providing mental health and specialist learning disability services and statutory social care services across Cambridgeshire and Peterborough, and children’s community services in Peterborough. There are two main facilities at the Cavell Centre Peterborough and Fulbourn Hospital Cambridge and staff are based in around 50 facilities.

The Trust provides nationally recognised specialist services in many areas including specialist eating

disorders services for adults and young people, specialist learning disability services and child and adolescent in-patient services. It is the biggest provider of psychological therapies in the East of England, as well as being a partner in the local Collaborations for Leadership in Applied Health Research and Care (CLAHRC) and a partner in the first national consortium of leading mental health trusts providing secondary mental health services to serving Ministry of Defence and US Air Force staff.

CAMBRIDGE UNIVERSITY HEALTH PARTNERS

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The NIHR Cambridge Biomedical Research Centre (BRC) The NIHR Cambridge Biomedical Research Centre (BRC) is a partnership between Cambridge University Hospitals NHS Foundation Trust and the University of Cambridge. The partnership between the hospital and the University creates an environment where internationally outstanding biomedical and clinical scientists work alongside clinical practitioners to achieve translation of research for the benefit of patients. The centre was established in 2007 to facilitate this partnership, and in 2012 we were delighted to receive a further £110 million of government funding to invest in existing and new research themes.

The BRC fosters interdisciplinary initiatives and innovates research training and learning to generate new ideas and attract talented individuals.

Since its inception, our centre has evolved into a coherent, democratic organisation that enables, and adds value to, scientific research. It provides an intellectual home and core critical mass for world class translational research, supported by a high degree of public involvement, and connects the laboratory bench to the treatment of patients in and out of hospital.

Dr John Bradley

This is the UK’s biggest-ever investment in early-stage health research. In Cambridge, the money will back projects designed to benefit patients with diseases such as cancer, heart disease and diabetes, specifically targeting advances in diagnosis, prevention and treatment.

The Cambridge partnership has also been awarded £4.5m funding for a new specialist Biomedical Research Unit focused on dementia – a field in which it was identified as a national research leader. This unit will work at the interface of many disciplines in the physical, chemical and biological sciences to provide solutions to improve the diagnosis and care of dementia patients.

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Cambridge BRC investment has facilitated, and in many cases, provided full investment for a widereaching research infrastructure that includes the Core Biomedical Assay Laboratory, Cambridge NIHR Genomics CoreLab, the GMP Resource for Stem Cells and Regenerative Medicine, MRI core facilities, PET/ CT, and the Addenbrooke’s Clinical Research Centre. Without support via our NIHR funding many of these facilities, now used widely across the research campus, would not be available.

Future plans Future investment in new genomics technology will bring the latest in DNA analysis to the bedside. In 2012 the BRC facilitated through leadership

NATIONAL INSTITUTE FOR HEALTH RESEARCH (NIHR)

and funding the creation of the NIHR BioResource and in 2013 established the NIHR Translational Research Collaboration in Rare Diseases in collaboration with Newcastle. Working with Illumina and Genomics England Ltd, the Cambridge BRC is part of a pilot project to sequence 100,000 genomes; bringing the reality of personalised treatments for patients a step closer.

The Chief Medical Officer for England has identified anti-microbial resistance as a major threat to health.

Continuing investment in genomics technologies, which are providing mechanisms for the rapid diagnosis and identification of bacterial pathogens, including MRSA, is a key part of the BRC future strategy.

The establishment of a new crosscutting theme in informatics will provide support across the whole of the BRC as scientific research increasingly relies on ‘big data’.

Genomic data, microarray profiles and large epidemiological studies require computational support to interrogate and analyse variables across data sets.

This new theme will drive forward the collaborations between mathematics and medicine.

Strategic Partners MRC Laboratory Molecular Biology

European Bioinformatics Institute

www2.mrc-lmb.cam.ac.uk

www.dbi.ac.uk

University of Cambridge Honorary Professorships held

by M Goedert (Experimental Molecular Neurology)

University of Cambridge Honorary Professorships held by

MRC Mitochondrial Biology Unit

J M Thornton (Biomolecular Sciences and Informatics) E Birney (Bioinformatics)

www.mrc-mbu.cam.ac.uk

Astra Zeneca

Directed by Professor Massimo Zeviani, Department of Clinical Neuroscience

www.astrazeneca.co.uk

University of Cambridge Emeritus Honorary Professorship held by Sir John Walker (Molecular Bioenergetics)

MRC Cognition and Brain Sciences Unit www.mrc-cbu.cam.ac.uk

GSK www.gsk.com NHS Blood and Transplant Service www.nhsbt.nhs.uk

Directed by Professor Susan Gathercole

Public Health England

MRC Human Nutrition Unit

www.gov.uk/government/ organisations/public-health-england

www.mrc-hnr.cam.ac.uk The Babraham Institute www.babraham.ac.uk University of Cambridge Honorary Professorships held by: M J O Wakelam (Lipid Signalling) W Reik (Epigenetics)

The Wellcome Trust Sanger Institute www.sanger.ac.uk University of Cambridge Honorary Professorships held by: G Dougan (Pathogen Genomics) J Parkhill (Microbial Genomics) A Bradley (Mammalian Genetics) Sir Michael Stratton (Genomic Sciences) R Durbin (Computational Genomics)

STRATEGIC PARTNERS

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History of the Clinical School and Biomedical Campus

1540 1817 1829 1842 1948 1962

Henry VIII endowed the University’s first Professorship of Physic held by Dr John Blyth Dr John Haviland appointed Regius Professor of Physic and formal teaching of undergraduates was given consideration University Senate agreed to the introduction of a more comprehensive medical curriculum and examination George Paget pioneered bedside examinations – first to be carried out in UK hospitals and became an integral part of the Bachelor of Medicine finals With the advent of the National Health Service teaching moved forward again Addenbrooke’s Hospital opened on its current Hills Road site First MRC LMB Building opened

Addenbrooke's new site in 1962 The MRC Laboratory of Molecular Biology (LMB) was built in Cambridge in 1962 to bring together several distinguished MRC-funded Cambridge research groups.

That same year saw two of its groups awarded the Nobel Prize: – Max Perutz and John Kendrew received the Chemistry prize for determining the structure of haemoproteins.

– James Watson, Francis Crick and Maurice Wilkins, received the Nobel Prize in Physiology or Medicine for determining the structure of DNA.

1972

Stage 2 of Addenbrooke's Hospital built

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Complete medical course re-established in Cambridge with the opening of the School of Clinical Medicine at the new Addenbrooke's site

HISTORY OF THE CLINICAL SCHOOL & BIOMEDICAL CAMPUS

1980

21 November – Clinical School building officially opened

HRH Duke of Edinburgh at the opening in 1980

1993 1998 2001 2007

Institute of Public Health set up to facilitate collaboration between population health scientists and the health service First researchers moved into Cambridge Institute for Medical Research following the award of Wellcome Trust funding in 1993 Wellcome Trust Clinical Research Facility opened NIHR Cambridge Biomedical Research Centre established as a partnership between the Trust and the University Li Ka Shing Centre officially opened with the aim of carrying out research from basic cancer biology to practical clinical applications

The Li Ka Shing Centre

2008 2012 2013 2017 2018

Institute of Metabolic Sciences officially opened to address the growing health threat posed by obesity, diabetes and related diseases Deakin Centre opened providing two floors of clinical skills facilities for medical students New expansion to the Rosie hospital, making it one of the biggest neonatal units in the UK, opened by the Queen Completion of new MRC-LMB, twice the size of the previous building New Wellcome Trust Clinical Research Facility expected to open Scheduled opening of new building to house the Wellcome-MRC Stem Cell Institute, Centre for Haematopoiesis and Haematological Malignancies and the The Cambridge Institute of Therapeutic Immunology and Infectious Disease’ (CITIID).

New Papworth Hospital building expected to be completed on the Cambridge Biomedical Campus Projected opening of the Heart and Lung Research Institute

HISTORY OF THE CLINICAL SCHOOL & BIOMEDICAL CAMPUS

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The Biomedical Campus The Campus in 2014

Proposed Campus 2020 1. AstraZeneca Global R&D Centre and Corporate HQ 2. The Forum 3. New Papworth Hospital 4. Heart and Lung Institute

5. AstraZeneca R&D Enabling 6. Future development for Cambridge University Hospitals 7. Proposed energy centre by Cambridge University Hospitals 8. Phase 2 development land

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© University of Cambridge School of Clinical Medicine 2015 • MS134188