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RA5a: Structure,environment and staffing policy

RELATIONSHIP TO 1996
We improved by three grades in the 1996 RAE (2 to 4) and since then have worked to increase our international research competitiveness. In the current period our research spend has about doubled, and we have achieved a more even and higher quality of research output.
Indicator
Research spend
Funding,active total
Res Councils and Wellcome
Doctorates awarded
Patents filed
1996 RAE
£18m
£18m
£2.8m
17
05
2001 RAE
£35m
£50m
£6.9m
65
57
We changed the organisation of the Medical School to reflect the unifying scientific advances of recent years. The School became a single cost centre and thirty four departments were replaced by three Divisions. An executive group is now responsible for strategic planning (Medical School Dean, Research Dean, Teaching Dean), and the School is managed by a Council comprising the executive group plus the Divisional Directors. The presence, in our Faculty, of the School of Health and Related Research (returned under UoA 2) allows us to concentrate on research in pathophysiology and the development of new diagnostic, therapeutic and preventive methods. Recently, we completed the re-organisation by incorporating a new Division made up of international research groups from the Faculty of Science: Alan.North’s (molecular physiology); Philip Ingham’s (developmental genetics); Mark Dunne’s (diabetes); Peter Andrews’ (stem cell biology), and we changed our name to the 'School of Medicine and Biomedical Sciences'. The new Division of Biomedical Sciences (BMS) is returned under UoA5. The School structure now encourages multidisciplinary convergence onto important questions. Our research themes map back to 1996 but are now stronger, more focused, and more inter-related. We achieved what we planned in 1996, except in areas that we subsequently decided not to pursue. We have established a strong upward trajectory and, including Wellcome SRIF money, researchers in UoA3 have generated £26m research funding in the last 3 months alone.

PHYSICAL ENVIRONMENT
We are consolidating our best laboratory research onto a single site in the main Medical School building to become a Medical Research Institute. Conversion of the Medical School building is funded by a grant of £9.5million from the Wellcome Trust through SRIF. Our translational research is being consolidated around a Clinical Research Facility. We developed a research technology policy where core facilities are available to all researchers in the School. The facilities are headed by academics with administrative support and most of our HEFCE-funded technicians are deployed in them. Technical support for projects derives from external funding. Core facilities have lowered technological barriers, increased quality, consolidated capital expenditure, and provided excellent training for the technical aspects of research. Core facilities:(on-site )statistics & informatics (inc. genetic epidemiology, databases, computing); genomics (sequencing, mapping, genotyping); DNA chemistry (cloning, recombinant construction & expression); cellular imaging (confocal microscopy); gDNA, cDNA and tissue archives; histopathology (including immuno- and hybridisation histochemistry); FACS facility. Within 500 metres: structural biology (crystallography, NMR, Biacore); developmental genetics (drosophila, zebra fish); stem cell facility; hybridoma & antibody unit; analytical chemistry (mass spec). In progress: mouse genetics; screening and molecular array technologies; interactive nucleic acid & protein databases; clinical research facility.

RESEARCH STRATEGY AND ORGANISATION
We focused on 6 research themes with the overall aim of developing genomic medicine, the translation of the nucleic acid and protein databases into health gains. We divested areas that lacked scope for international competitiveness and invested in areas where this was possible. We fostered problem-led research leading to translational research and patient benefits. Our teams are multidisciplinary, but integrated, with clinical and basic scientists working together on well-defined problems of public health significance. The staffing policy is that all decisions on refilling posts, creating new posts, and deployment of existing staff are guided by the research strategy. Our recruitment policy targets international researchers synergistic with our research groups. We are not returning a UoA 1 (graded 2 last time) because we disinvested in failing areas. The strongest researchers joined our themes in accordance with the strategy of forming groupings with a broad span of research skills and research vision.

Research themes
The themes are based on research strengths and public health priorities, bearing in mind those of the Research Councils, NHS and DTI Foresight exercises, to which we have actively contributed. To limit destabilisation, we initially defined themes to capture our best quality current research. Under the direction of clinical and biological science leaders appointed by the Council, the themes undergo progressive refinement to concentrate on specific campaigns.

Themes
Clinical research leader
Biological research leader
Cancer
Prof Rob Coleman
Prof Mark Meuth
Cardiovascular
Prof David Crossman
Prof Paul Helliwell
Human metabolism
Prof Richard. Eastell
Prof Mark Dunne (BMS)
Infection & Immunity
Prof Moira Whyte
Prof Steven Dower
Neurosciences
Prof Pamela Shaw
Prof Alan North (BMS)
Repro & Development
Prof Bill Ledger
Prof Harry Moore (MB&B)
Research plans are developed and co-ordinated across the school and beyond by the theme leaders who are responsible for identifying interdisciplinary opportunities and implementing strategies for research training, funding and publication. The School’s overall research strategy is formed by the School Council with advice from the research committee (theme leaders chaired by the Research Dean). Recommendations on staffing and resource management are transmitted to the Council. Theme leaders also play a role in developing intellectual property.

Informatics
The development of genomic medicine depends upon strong informatics, a discipline that underpins all of our research rather than being a theme in itself. We recruited Chris Cannings as Professor of Genetics & Informatics in the Division of Genomic Medicine. Cannings, a long-term collaborator with the Salt Lake City Genealogy Consortium, has galvanised informatics in our School with the recent recruitment of Nick Monk (Oxford), Dawn Teare (Sanger Centre, Cambridge) and, very recently, Professor Alun Thomas (Head of Informatics at Miriad Genetics Inc, Salt Lake City). Angela Cox, previously a fellow in Molecular Medicine, was appointed lecturer in genetics & informatics to work in cancer studies. The group is supported by Research Council, Wellcome Trust, ARC and Glaxo Smithkline funding. Cannings is in one of our MRC CoGs (vascular inflammation). The group’s research is in genetic epidemiology, database design, and mathematical modelling. As well as collaborating in disease genetics and the modelling of signal transduction pathways, this group fulfils a research training role in genetic epidemiology, a key international priority area. In its first year, their MSc received 10 HEFCE-funded places and MRC studentship support.

Clinical research facility (CRF)
Following the model of our recently-opened Cancer Research Centre (see Cancer theme), a general CRF is now an important goal in our research strategy. We are planning a CRF on a larger scale than usual, with facilities for inpatients/outpatients and minor procedures. The CRF will have a dedicated informatics group, an integral processing laboratory and dedicated nursing and support staff. It will operate at regulatory standards of GCP and GLP. The business plan includes the subsidy of academic studies by income from commercial contracts, and human genomic physiology will be a target area for development.

Monitoring and Assessment of Postgraduate Students
Each Division has a Graduate Research Committee, with student representatives, chaired by a senior academic. The committee implements: (1) assignment of an advisor to each student in addition to a supervisor; (2) six monthly progress reports agreed by the student and supervisor and discussed with the advisor; (3) annual formal oral presentations at Divisional Graduate Research Symposia; (4) monthly progress assessments made by the student and supervisor and kept by the supervisor. Problems may be referred by the student, supervisor or advisor to the Graduate Research Committee and then, if necessary, to the Divisional Director. All students take a research training programme and register for an MSc, progressing to PhD if satisfactory.

Intellectual property (IP), enterprise and support of industry
We take a vigorous approach. In 1997 we began mandatory record-keeping at the standard of the international agreement on ‘Trade-Related Aspects of Intellectual Property’, thereby raising awareness and creating appropriate development records. Researchers in this UoA have been notably successful with some 57 patents filed since 1996, (counting only primary filings). A Boston-based company founded on Sheffield patents is listed on the US Nasdaq stock exchange (Interleukin Genetics Inc) and 4 new companies have been formed from the School in the last 6 months alone (Adjuvantix, Asterion, BioActa, and Molecular HealthWorks). We have IP pipeline agreements with a London Stock Exchange company (Medical Solutions plc), another with Catalyst Biomedica (Wellcome Trust company, of whom we are one of the biggest University partners), Oxagen (Oxford biotechnology company) and Interleukin Genetics. We are part of GlaxoSmithkline’s international network of academic centres (Word-wide Genetics Division, others are Harvard, Duke, and Perth, Australia), both for clinical accrual and, in future, for field testing of high-throughput technology (contracts for ~£2 million, as well as equipment). GSK also support the genetic epidemiology MSc. Other major industrial collaborators are Proctor & Gamble, Zeneca and Lilley (total £3.5 million).

RESEARCH GROUPS - ACTIVITIES, ACHIEVEMENTS AND PLANS
The main research achievements of contributors to the six research themes, and the focus areas for future research are listed below, theme by theme. Strong interactions between the themes are actively developed and individuals who link between themes are indicated.

CANCER
We recruited Mark Meuth from Salt Lake City as Professor of Cellular Genetics to lead basic research in cancer and to form an axis with our excellent clinical research groups. Meuth and Rob Coleman now head our cancer theme, giving strength across the spectrum of research. Barry Hancock & Coleman established a Cancer Research Centre, a £2m purpose-built facility for clinical trials and drug development, underpinning their highly successful interface with NHS R&D (£250k/year since 1998). Meuth’s group has worked on mechanisms of genomic instability, including: structure-function of mismatch repair proteins in relation to apoptosis; characterisation of a new pathway of homologous recombination repair at replication forks; and molecular events in the initiation of DNA replication. Meuth’s translational projects include: defining the incidence of genes that disrupt the fidelity of genetic information transfer, and the consequences for tumour development; devising therapies against tumours exhibiting specific pathways of genomic instability; and determination of the incidence and effect of common polymorphisms in key repair enzymes. DNA banks (colon, breast and prostate cancers) were made in collaboration with the clinical groups. In collaboration with Angela Cox (new lecturer in genetics & informatics) work has begun on identification of disease genes in cancer families. Dawn Teare (new lecturer in genetics & informatics) was a major contributor to international collaborations in the genetics of both breast cancer and testicular germ-line tumours. Teare also reported a variant of BRCA2 associated with pre-natal viability. Clare Lewis (new Prof of Molecular Pathology) successfully developed the use of macrophages as cellular vehicles to target therapeutic gene expression to hypoxic or ischaemic sites. Lewis also discovered a potent anti-angiogenic fragment of human fibrinogen. Nicola Brown developed a microcirculatory chamber to study neoangiogenesis. The technique proved valuable in analysing cellular infiltration and responses to treatment in models of cancer and wound healing. Lewis & Brown established a University company that is finalising a ~£7m industrial partnership. Michael Wells (new Prof of Gynaecological Pathology) helped to define the relationship between HRT and endometrial hyperplasia, reported the smoking-related risk of neoplastic progression (see DoH Electronic Research Findings Register) and developed use of an antibody for the detection of high risk human papillomavirus (HPV) in the cervix. Colin Sanders (new lecturer) reported ground-breaking work on the structure of HPV E2 protein and analysed molecular assemblies of HPV initiator proteins of relevance to the pathogenesis of cervical cancer. John Tidy was part of an international collaboration that discovered a genetic modifier of mutated p53 function. Janice Royds continued her work on molecular genetics of cancer in relation to function and clinical ourtcomes. She was among the international group that reported the relation of kip-1 to malignant phenotype in breast and colon cancer. Ian Rennie and Shiela MacNeil focused on melanoma, discovering cytogenetic correlates of ocular melanoma and dissecting melanoma cellular responses to endocrine and paracrine factors relevant to disease. Freddie Hamdy, (Prof of Urology), with colleagues in Bristol and Newcastle, pioneered new methods to randomise men with early prostate cancer for a treatment trial. The feasibility study was funded by the HTA NHS R&D programme (~£1m). The full-scale, multi-centre trial, led by Hamdy, has recently been awarded funding of £13m, of which around £5m comes to Sheffield. He and Sheffield colleagues (inc Lewis & Brown) joined forces with Newcastle, York, Manchester and Bristol to make a successful SPORE application to the Cancer Research Funders Forum (MRC, ICRF, CRC and DoH) to establish a centre of excellence in prostate cancer research. It takes the form of an MRC strategic grant of ~£2.7m. Hamdy’s group also investigates mechanisms of progression in prostate cancer, focused on bone metastasis, and were first to identify BMP-6 as a mediator of osteoblastic metastases in prostate cancer. Hamdy & Brown developed, with workers in Leiden, in vivo models of bone metastasis and angiogenesis in prostate cancer. Collaboration continues on metastatic bone cancer with Graham Russell and Peter Croucher (now moved from Sheffield to Oxford). The Bone Oncology group has been strengthened by the recent appointment of a Clinical Senior Lecturer in Urology (Bryden starting on 1.5.2001) with expertise in PTHrP in prostate cancer metastasis. A further lecturer appointment is pending, to continue work with Coleman, Hamdy and Brown on the bone micro-environment in breast and prostate cancer. Barry Hancock had a key role in the MRC collaborative group that confirmed, for the first time, the efficacy of interferon in renal cancer, and he also advanced the management of gestational trophoblastic tumours. Coleman helped to establish the rational use of bisphosphonates in metastatic bone disease and biochemical methods to monitor treatment responses. The Coleman & Hancock teams identified the clinical utility of a range of new anticancer agents for advanced breast, ovarian and other solid tumours. With Meuth, they hold Programme funding from YCR (>£1.5m). Through NHS R&D they established a successful clinical research network across North Trent, a model adopted for the 34 regional units in the recent National Cancer Research Network. North Trent was in the first wave of specifically-funded networks, with Coleman as the lead co-ordinator. Lynne Lennard studies metabolism of thiopurine drugs by thiopurine methyltransferase (TPMT), low levels of which lead to thiopurine-induced myelotoxicity while high producers do not respond to standard drug doses. Lennard’s group, with colleagues at the Mayo Clinic, cloned the human TPMT gene and reported variant alleles with low enzyme activity. Her work in thiopurine pharmacology has been incorporated into international protocols for the treatment of childhood lymphoblastic leukaemia in the UK (MRC ALL trials), the USA (Childrens Cancer Study Group) and Germany (COALL group). The current nationwide UK MRC protocol for childhood ALL includes thiopurine pharmacogenetic and pharmacokinetic studies centred on Lennard’s laboratory. Ann Goodeve and Ian Peake (who link the cancer and cardiovascular themes) discovered mutations in the c-kit and FLT-3 genes in AML patients and are testing tyrosine kinase inhibitors in cells with these mutations with a view to drug development. International collaborators with the cancer grouping include Harvard, Yale, Lawrence Livermore National Laboratory, The Mayo Clinic, Univ of California Berkeley, (joint grant), Thomas Jeffereson Univ Philadelphia, (joint papers), Univ of Utah Salt Lake City, (joint papers), Univ of Louisville, Hershey Medical Centre, Pennsylvania, National Cancer Center Tokyo (joint paper), Weizmann Institue Israel, Institute Jules Bordet Brussels, Trinity College Dublin, Univs of Mainz, Leiden, Copenhagen, Nijmegen, and Novartis, Switzerland.


Special focus areas for next 5 years: (1) genetic mechanisms of cancer in collaboration with the Informatics group and the Developmental Genetics group in BMS; (2) development/evaluation of cancer therapies; (3) metastatic bone cancer, (2&3 with the Human Metabolism theme).

CARDIOVASCULAR
This strong theme led by David Crossman and Paul Hellewell covers genetic, cellular and clinical research in cardiovascular medicine. Main areas are: (1) coronary artery disease, especially mechanisms of presentation, inflammatory pathogenesis, and restenosis following coronary angioplasty and stenting; (2) cardiovascular pharmacology; and (3) haemostasis and thrombosis. Crossman is a member of one of our MRC COGs and his group is at the forefront of studies on the role of cytokines, chemokines, and selectins in vascular inflammation and artery wall remodelling. They defined molecular and cellular responses to angioplasty injury, and developed ultrasound-based methods to enhance vascular gene delivery, a basis for gene therapy. Cathy Holt, Sheila Francis and Crossman developed methods for the local delivery of anti-proliferative agents to sites of angioplasty injury. Francis and Crossman showed a potentially important role for the anti-inflammatory cytokine, IL-1 receptor antagonist, in atherosclerosis in both cellular and population genetic studies. This molecule is available as a drug and therefore their findings have high therapeutic potential. Hellewell links this theme with the I&I theme and has defined clearly the role of selectins in leukocyte adhesion and recruitment into tissues. International collaborations of this grouping include: Glaxo Smithkline (affected sibling pair study of early onset coronary artery disease); Amgen, USA, (IL-1ra and vascular response to injury); Masachussetts Institute of Technology (Francis) Genentech, USA (integrin antagonists and vessel wall response to injury); Univ of Virginia Charlottesville, (bone marrow transfer); and Univ of Michigan, Ann Arbor, (chemokine biology). Larry Ramsay, an international authority on the treatment of hypertension and the prevention of coronary artery disease, is an author of the British Hypertension Society’s treatment guidelines and, with Peter Jackson and colleagues, created and validated the ‘Sheffield Table’ that is used internationally for estimation of cardiovascular disease risk. Jackson also authored a new regime for induction of warfarin therapy and, with Ramsay, reported a cost-effectiveness analysis on statin drugs in the prevention of coronary disease. Tim Higenbottam (now with AstraZeneca) and colleagues described the link between anorectic drugs and pulmonary artery hypertension, these drugs were subsequently largely withdrawn in the UK, Europe and USA because of this adverse effect. Higenbottam’s group also defined a central role of nitric oxide in pulmonary hypertension and invented a patented device for respiratory cycle-activated delivery of exogenous nitric oxide as a therapy for this disease. Richard Wood’s group in surgery described the effects of exercise training (upper and lower limbs) on peripheral vascular disease and defined the haemodynamic effects of peripheral artery angioplasty. The haemostasis-thrombosis group, headed by Ian Peake, leads an EU consortium on the genetics of type1 von Willebrand disease (1.32m, 12 labs, 9 countries). With David Barnett (Sheffield Teaching Hospitals Trust), Peake and colleagues also have 2.8m support to set up a central facility for the production of European Flowcytometric Reference Preparations. This group expressed vWF mutants identified in type 1 families, to assess the effects on intracellular trafficking. The group defined gene mutation-phenotype mechanisms in von Willebrand disease and in antithrombin deficiency (Martina Daly, Mchael Makris, Ann Goodeve and Peake). They also determined the risk of venous thromboembolism associated with phenotypic and genotypic deficiency of protein S (Makris and Daly). Their studies on familial thrombophilia have also elucidated the role of gene-gene and gene-environment interactions in determining thrombotic risk (Peake, Daly and Makris). The superiority of clotting factor concentrates over fresh frozen plasma in the treatment of life-threatening bleeding on warfarin was shown by Makris and colleagues and standard practice is now changing internationally. The effects of polymorphisms in prothrombin and platelet glycoprotein genes were analysd in relation to myocardial infaction risk by Eddy Hampton and Daly. Mutation-function studies of factor 1X gene were reported by Peter Winship, who is also developing a new transgenic mouse model of haemophilia B. A new DNA inversion causing haemophilia A was discovered by Goodeve and, with Peake, Winship and Hampton, she described new genetic diagnostic methods for haemophilia A and new genetic anomalies in two families with von Willebrand disease. Edwin van Beek performed landmark studies in the diagnosis and treatment of pulmonary embolism, helping to define the role of low mw heparin in treatment. As well as the EU network this grouping has especially close links with Paris, Leiden, Bonn, Amsterdam and Kingston, Ontario.

Special focus areas for next 5 years: (1) disease genes in early-onset coronary artery disease (linkage analysis in collaboration with the Informatics group); (2) methods to control inflammation in arteries in vivo, in collaboration with the I&I theme; (3) vascular responses to sepsis and multiple organ failure including ARDS ( with the I&I theme); (4) definitive genetic diagnosis of type 1 von Willebrand disease (commonest bleeding disorder in humans).

HUMAN METABOLISM
This theme, led by Richard Eastell and Mark Dunne (UoA5) includes musculoskeletal medicine, endocrinology, diabetes, GI & nutrition, drug metabolism and nephrology. The theme unites high-quality clinical scientists (and large, well-defined patient populations) with basic science laboratories to achieve increasing focus on detailed genotype-phenotype analysis. Eastell and his colleagues are world leaders in osteoporosis research. They validated pyridinium crosslinks of type I collagen as markers of bone resorption. They showed that age-related bone loss in men was primarily cancellous, and that it was associated with declines in testosterone, oestradiol and IGF-1. In collaboration with the Mayo Clinic, they showed that testosterone affects bone resorption through its conversion to oestradiol and this hormone modulates cytokine production in the bone environment. Margo Barker and Eastell reported beneficial effects of calcium-rich diets on the growing skeleton, a finding of high public health importance. John Kanis, with MRC programme funding, is also an international leader of clinical research into bone diseases. With Eugene McCloskey he co-ordinated the skeletal aspects of the VI MRC trial of bisphosphonates in myeloma and found an increase in median survival of 22 months in myeloma patients treated with bisphosphonates. Kanis’s WHO Collaborative Centre co-ordinates the ‘Mediterranean Osteoporosis Study’ (13 European centres) and the 'European Prospective Osteoporosis Study’ (40-centres) with subsidiary studies in Asia and North America. Anthony Hollander (now at Bristol) reported definitive findings on the changing biochemistry of the intervertebral disc during human development and ageing. Graham Russell (now in Oxford) elucidated the two key mechanisms of the pharmacological action of bisphosphonates. Russell also showed that environmental exposure to fluoride had no impact on fracture rates in the UK. David Buttle’s group discovered that cartilage proteoglycan breakdown is probably not mediated by MMPs, but by aggrecanases produced in joint tissues other than cartilage. They contributed to the discovery of a new cysteine proteinase of NK and cytotoxic T-cells. They also discovered that nucleotide triphosphate ligands of P2Y2 purinoceptors are anabolic for cartilage and, therefore, provide important leads for anti-arthritic drug development. Gareth Evans (new lecturer) links Human Metabolism with the Reproduction & Development and the I&I themes. He discovered increased proteolysis in chronic inflammatory bowel disease by developing a novel antibody specific for degradation products of basement membrane type IV collagen produced by MMP-2 and MMP-9 activity. Subsequently, there is wide international interest in synthetic inhibitors of these proteases as drug candidates for inflammatory bowel disease. Peter Grabowski, (new lecturer) demonstrated inhibition of bone resorption by non-antibiotic tetracycline analogues that work by suppressing osteoclast development and inducing apoptosis in osteoclasts, a finding with therapeutic potential. The recruitment of Nick Bishop (ARC Professor) augments the traditional strength of bone research at Sheffield. Bishop, an authority on bone disease in children, is listed in the Reproduction & Development theme but his close collaboration with Eastell provides a strong link between the themes. Richard Ross’s endocrine group identified the first dominant-negative cytokine receptor, a truncated growth hormone receptor, providing a new mechanism for regulating cytokine signalling. They established the mechanism of dominant negative action which led to new ideas for drug development and formed the basis of a new University company. Simon Heller’s work on hypoglycaemia revealed a possible mechanism of the "dead in bed syndrome", the unexpected deaths of young people with IDDM. He showed that hypoglycaemia induces abnormal cardiac repolarisation that can lead to fatal arrhythmias. Prophylaxis with beta-blockers might be possible. Barry Brown dissected intracellular signalling pathways from endocrine and cytokine receptors, defining a role for PI-3 kinase in prolactin signalling. Meguid El Nahas’ group demonstrated key interactions betweeen growth factors and ECM in renal fibrosis. El Nahas directs the Sheffield Kidney Institute which increasingly focuses on remodelling and degenerative diseases of the kidney. Albert Ong (new senior lecturer) demonstrated overlapping expression of polycystin-1 & -2 in human development and isolated a polycystin-1/-2 complex, disruption of which is the likely basis of cyst formation in autosomal dominant polycystic kidney disease (affecting up to 15% of patients on renal replacement therapy). Alan Johnson, a world authority on the pathophysiology of the gall bladder, reported a comparative trial of laparoscopic surgery (of which he was a pioneer). Gary Mills defined clinically important temperature effects on respiratory neuromuscular function during anaesthesia and in endocrine disease while Hilary Powers reported important physiological effects of micronutrients on vascular and intestinal structure and function. Geoff Tucker’s group in molecular pharmacology elucidated molecular structure-function relationships in cytochrome P450 2D6, and developed software to predict pharmacokinetic and dynamic consequences of genetic and environmental variability in drug metabolising enzymes (forming a University company, SIMCYP). Tucker also reported effects of CYP2D6 variants on the risk of lung cancer and Parkinson’s disease. Major collaborations in Human Metabolism theme will continue with the Mayo Clinic (USA), Garvan Institute (Sydney), Shriner's Hospital (Montreal), Free University of Berlin (Germany) and the Rene Descartes University (Paris).


Special focus areas for next 5 years: (1) childhood origins of metabolic disease, including late effects on cancer survivors, in collaboration with Reproduction & Development theme; (2) bone cancer, especially prostate, breast, and myeloma in collaboration with Freddy Hamdy and Rob Coleman in the Cancer theme; (3) The endocrine/renal interface aimed at understanding the pathophysiology of renal impairment and osteoporosis.

INFECTION AND IMMUNITY (I&I)
Steven Dower
and Moira Whyte lead this theme. Dower, EvaQwarnstrom, Chris Cannings, Gordon Duff and David Crossman formed an MRC Co-operative group linking I&I with the cardiovascular theme. The link was strengthened by the addition of Whyte, Ian Sabroe (MRC Clinician Scientist), Keith Norman and Jon Sayers to the Co-op. Whyte’s group is in the vanguard of research on inflammatory diseases of lung and airways, especially the control of leukocyte apoptosis in the mechanism of inflammation. Whyte discovered that programmed cell death could occur without activation of caspases (CED-3 homologues) and with Colin Bingle showed that alternative splicing of Mcl-1 (Bcl-2 family) produced either death or survival forms. They also showed that the Fas pathway induced apoptosis in inflammatory neutrophils. In collaboration with the inflammation genetics group, Whyte and Bingle discovered the first genetic association in cryptogenic fibrosing alveolitis. Sabroe brings to this group an expertise in chemokine receptors. Sabroe & Whyte now collaborate with Dower on the role of Toll receptors in inflammation. Hellewell and Norman (new lecturer) link this theme with cardiovascular. Hellewell defined the role of selectins in eosinophil migration, and showed that a receptor-operated event on eosinophils is essential for response to chemoattractants. He also confirmed that endogenously generated eotaxin mediates eosinophil accumulation in allergic inflammation and, with Norman, that PSGL-1 is a functional E-selectin ligand in vivo. Norman reported the relationship of leukocyte transit time in venules with tissue infiltration, and defined disruption of selectin-mediated leukocyte rolling as a target for anti-inflammatory drug development. Dower’s group made important discoveries in cytokine/Toll signalling. He discovered the IL-18 receptor, and viral dominant-negative inhibitors of IL-1 and Toll signalling. Dower (with Qwarnstrom) also defined structure/function aspects of the TIR signalling domain. He also showed that Tolls form combinatorial pathogen recognition sites, a fundamental mechanism for expanding the repertoire of the innate immune response (with Duff). Qwarnstrom, notable for the maintenance of over £1m NIH funding, defined biomechanical regulation of IL-1 signalling to NF-
kB, including discovering a novel receptor component, and determining signal divergence through receptor adapter proteins. The Qwarnstrom and Dower groups collaborated on innovative studies imaging spatial kinetics of NFB and inhibitor dissociation in living cells. Robert Read heads clinical infectious diseases. He showed that N.meningitidis trafficks to terminal phagolysosomes in human macrophages and that this is influenced by virulence determinants and the receptor that mediates phagocytosis. Read’s group also showed that meningococcal activation of human macrophages is mediated by TLR-2 (in addition to TLR-4, published in 2001). With Jon Sayers, Read also identified increased IgA protease activity as a determinant of meningococcal invasiveness and, with Franco diGiovine and Duff, described a strong relationship between death and IL-1 genotype in meningococcal sepsis. Jon Sayers leads the bacterial enzyme group and focuses on exonucleases. Sayers performed structure-function analysis of T5 5’exonuclease, defining its mechanism of binding to DNA in a series of landmark studies that create new targets for antibiotic drug development. Mark Thomas identified a previously unknown role in transcription anti-termination for the alpha subunit of eubacterial RNA polymerase. He also identified the linker region between the two domains of the subunit and showed that linker mutations strongly inhibited activator-dependent but not constitutive promoters, again with implications for antibacterial development. David Dockrell (new lecturer) contributed key observations on the role of the Fas system and its interaction with CD4. He was in the team that demonstrated the role of macrophage FasL in the pathogenesis of HIV- associated CD4 T-cell apoptosis. James Underwood described the relationship of MHC alleles to clearance of HCV and, with colleagues in the CV theme, provided a definitive report on the natural history of HCV infection in haemophiliacs. Andrew Heath discovered that immune responses against capsular polysaccharides (normally T independent, low titre IgM) could be turned into strong T dependent-like IgG responses in vivo by agonistic anti-CD40 antibodies. This occurred in the absence of T cells, and so remained T independent. Adam Finn (now at Bristol) reported salivary antibody responses to pneumococcal vaccination in infants, and defined the role of pneumococcal factors in increasing neutrophil adherence to respiratory epithelium. Tony Weetman’s group in endocrine autoimmunity, with Philip Watson, defined clinically important autoantigens including: the first description of autoantibodies against human Na+/I- symporter; confirmation of the immunodominant epitopes of thyroid peroxidase; and defining melanogenic enzymes as autoantigens in vitiligo. Weetman & Watson invented an assay for thyroid stimulating antibodies and defined immunoregulatory properties of thyoid follicular cells in collaboration with RPMS. Peter Grabowski (new senior lecturer) defined determinants of retinal pigment cells that activate T cells through CD2 and discovered a pathogenic role of nitric oxide in experimental autoimmune uveoretinitis. Weetman, Watson & Grabowski link I&I with the Human Metabolism theme. The inflammation genetics group pioneered the field of cytokine gene variants in inflammatory and infectious diseases (diGiovine, Gerry Wilson, Michael Cork, Angela Cox, Martin Nicklin & Duff). This research is now greatly strengthened by the appointment of Chris Cannings, who, with a long-established record in mathematical genetics, is now devising new methods to model complex traits. Cannings has active collaborations with Wilson, Nicklin, Duff and Dower. Nicklin’s group achieved the full mapping of the IL-1 and the IL-1receptor gene families, defining gene organisation and discovering new genes, including an IL-1 homologue. Nicklin also deleted the IL-1receptor antagonist gene in mice and observed either a lethal inflammation of the arteries, or joint disease resembling rheumatoid arthritis, depending on the genetic background. Cox analysed linkage disequilibrium across the IL-1region, identifying common haplotypes later shown to have a role in susceptibility to inflammatory diseases. She also devised the use of exonic mutations to determine allele-specific RNA differences in heterozygous cells. Wilson reported transcriptional effects of a polymorphism of the TNF gene (-308). This polymorphism, originally described by Wilson etal, has been extensively used internationally in population studies and, for example, has been associated with cerebral malaria, meningococcal disease and septic shock. Wilson also contributed to genetic studies in myasthenia gravis, defining a region telomeric to HLA-C, concordant with recent findings in rheumatoid arthritis and coeliac disease. DiGiovine’s group followed up their original findings of disease association with the IL-1ra gene by defining functional consequences of IL-1ra variants in IBD, as well as important ethnic differences. DiGiovine also extended TNF gene studies into liver diseases, and contributed to the construction of the cline of the CCR5 deletion that confers resistance to HIV infection. Cork and colleagues discovered the association between psoriasis and the corneodesmosin gene, now the subject of much industrial investment. Cork’s group also described the structure of the MX1 gene and characterised a variant that is associated with alopecia. Duff et al analysed IL-1 gene control, (now related to gene variation) and, with Cox, reported genetic linkage of the IL-1 region with rheumatoid arthritis (with the ARC Epidemiology Unit, Manchester). In collaboration with the Mayo Clinic and the Munich Herz Zentrum, Duff’s group discovered a genetic predictor of coronary artery re-stenosis following angioplasty. In industrial collaboration, the group introduced a pharmacogenomic approach in the clinical development of an anti-inflammatory drug (now in licensing process). Major collaborations of this theme include three different institutes of the NIH (USA), Stanford, Harvard, Dartmouth, Cornell, Washington (Seattle), Salt Lake City, San Francisco, Wisconson, EMBL Heidelberg, Strasbourg and several European centres.

Special focus areas for next 5 years: (1) pharmacogenomics of anti-inflammatory and immunomodulating therapy; (2) discovery of critical molecules in cytokine signalling (potential drug targets); (3) genetic control of inflammation and disease-susceptibility, in collaboration with Cardiovascular and Neurosciences themes; (4) identification of further novel regulators of inflammatory cell apoptosis and in vivo testing of therapeutic potential (5) defining key molecules in bacterial pathogenesis and bacterium-host interactions.

NEUROSCIENCES
We have entirely reconfigured this area and the researchers are almost all new appointments. The focus is on mechanisms of neurodegeneration. We recruited Pamela Shaw as Professor of Neurology to head and develop this theme. In recognition of her excellence in motor neurone disease research, Shaw received the highly prestigious ‘Sheila Essey Award’ of the American Academy of Neurology (2001), she is the first non-American recipient. With Wellcome Trust Programme funding her group has performed clinical, cellular and molecular studies that elucidate key pathogenic mechanisms operating in motor neurone degeneration. Gavin Reynolds' recent transfer from BMS further strengthens neurodegeneration research. Reynolds, with a long-established track record in brain neurotransmitter pathophysiology, defined neurotransmitter deficits in the Huntington's mouse model (perhaps a more general effect of a severe CAG repeat disease) and showed increased NMDA receptors in the putamen in schizophrenia. Paul Ince was recruited as Professor of Neuropathology to underpin clinical research in neurodegeneration. With MRC programme funding, Ince is a lead investigator in the MRC Co-operative Group ‘Cognitive Function and Ageing Study’. Sheffield is the lead laboratory for pathological studies in CFAS including collaborative work with the MRC Centre Development Group in Newcastle. Jamil Nasir (new lecturer, ex-MRC fellow in neurogenetics) contributed to gene mapping in Huntington’s disease, schizophrenia, and specific language impairment. He developed transgenic mouse models of Huntington’s disease and collaborates with the Wellcome Centre for Human Genetics in Oxford, the Centre for Molecular Medicine in Vancouver and Johns Hopkins Medical School in Baltimore. Michael Barker (new lecturer) reported TIMP-3 mutations related to inherited dystrophic eye disease. Jon Wood (new lecturer from Johns Hopkins) brings major additional strength in the molecular genetics of neurogeneration. Wood analysed the role of atrophin-1 in transgenic mouse models and described the subcellular localisation of huntingtin in rodents and humans. Peter Monk (new lecturer) links this theme with the I&I theme. He has focused on detailed analysis of G protein-coupled cell surface receptors and played a prominent role in the international collaborative effort that provided the first structural information on a putative cellular receptor for Hepatitis C Virus. Paul Griffiths and Martin Paley (Neuroimaging) made important clinical advances in diagnostic imaging of neurodegenerative and neuroproliferative diseases in collaborations with the RPMS, the Superconductivity Centre, Cambridge, and Marconi Medical Systems, Cleveland, USA. Paley links this theme with Reproduction and Development. Ian Wilkinson (new senior lecturer in neuroimaging) developed monitoring of responses to carotid stenting and pioneered cerebral proton MR spectroscopy in HIV, CMV and SLE encephalopathies.


Special focus areas for next 5 years: (1) mechanisms of neurodegeneration and repair, in collaboration with I&I theme and Molecular Pharmacology (BMS); (2) creating cellular and animal models to test hypotheses arising from human clinical and genetic studies (in collaboration with Developmental Genetics and Stem Cell Biology in BMS).

REPRODUCTION AND DEVELOPMENT
Sheffield’s international standing in the field of fertility and implantation was established over many years by Ian Cooke. Now, with Cooke’s retirement, this theme is headed by Bill Ledger (new professor) and Harry Moore (UoA5). Reproductive medicine has now moved into the new Jessop Wing, adjacent to the Royal Hallamshire Hospital. In the assessment period, Cooke analysed the contribution of mitochondrial mutations to male infertility. He also reported important original findings in the physiology of implantation. His group found that in women with recurrent failure of embryo implantation, there was a preponderance of Th1 cytokines in the endometrium (IFN, IL-2, IL-12 and TNF beta) whereas Th2 cytokines were predominant in women with normal implantation (IL-4 and IL-6). This opened a different understanding of the immunology of human implantation, and the possibility of immunomodulation to treat infertility caused by implantation failure. Ledger focused on the involvement of inhibins and activins in the establishment of early pregnancy and implantation, and developed the use of an inhibin assay for the early detection of pre-eclampsia. Ledger's plan now is to research the interaction between the human embryo and Fallopian epithelium, in collaboration with Moore. They have gained permission from HFEA to begin studies of human embryonic stem cells. Robert Fraser provides a link between this theme and the Human Metabolism theme. Fraser (with Eastell ) described the effects of pregnancy on bone remodelling, an area where there had been a relative paucity of information. Fraser also described the relationship between fetal growth and polycystic ovarian disease in adulthood, as well as reporting on the physiology of insulin resistance during pregnancy. His group’s current studies suggest that placental amino acid transport may trigger fetal hyperinsulinaemia in those 30% of fetuses of diabetic mothers at risk of major perinatal morbidity. This is important because it occurs despite good diabetic control. Mike Makris, who links with the cardiovascular theme, was part of the first group to report increased fetal loss in women with inherited thrombophilia which led to a new area for investigation of these women. Martyn Paley, who links with the Neurosciences theme, developed a dedicated MR system for neonatal imaging that achieved FDA approval and is distributed internationally. The system has produced award winning clinical research and was awarded ‘Millennium Product’ status by the Design Council (featured in the Dome). Paley also developed a high field 3 Tesla research system for interventional and functional MRI. Stuart Tanner continued to make important contributions to the genetics and pathophysiology of liver diseases of childhood. Tanner initiated the international collaboration that identified mutations in a liver-specific member of the ABC gene family in progressive familial intrahepatic cholestasis (PFIC2). Tanner's work on copper hepatotoxicity continued with the development of the copper / retrorsine animal model, identification of Wilson's disease mutations, and collaboration with Wijmenga (Utrecht) to identify the locus for infantile copper toxicosis. Chris Taylor showed the involvement of matrix metalloproteinases in inflammatory bowel disease and reported on upper GI motility in cystic fibrosis. Nick Bishop, (new professor) is another link between this theme and Human Metabolism. Bishop pioneered the revolution in treatment of children with brittle bone diseases. In clinical trials of bisphosphonates he and colleagues reported major efficacy in terms of relief from bone pain, improved mobility, reconstruction of crush-fractured vertebrae, increased bone mass, and reduced fracture rates in children and infants with severe osteogenesis imperfecta. International collaborations in this theme include: Univs of Innsbruck, Utrecht, Bochum, Rotterdam, Karolinska, Montreal, Melbourne, Prune (India), Albert Einstein (New York), Special  Programme of Research Development in  Human Reproduction,WHO, Geneva.

Special focus areas for next 5 years: (1) gene-environment mechanisms of fetal and childhood origins of metabolic disease, including late effects on childhood cancer survivors, in collaboration with the Human Metabolism theme. (2) Early human developmental genetics in collaboration with BMS Divison.

Users of this website should note that the information is not intended to be a complete record of all research centres in the UK

Copyright 2002 - HEFCE, SHEFC, ELWa, DEL

Last updated 17 October 2003

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