RA5a: Structure,environment and staffing policy
The School of Biological and Molecular Sciences is the major research School at Oxford Brookes University and during the last five years has attracted substantial funding, including two Wellcome Trust Showcase Awards and grants from the BBSRC, NERC, MRC, EC and MAFF. The School currently has 42 full-time and 46 part-time research students including NERC, BBSRC and MRC studentships. A number of the research groups are directed by academics who now have international reputations. Prof Groome's group has developed ultra-sensitive immunoassays for reproductive hormones that are used worldwide in clinical diagnosis and biomedical research. Profs King and Possee lead a group that is at the forefront of the molecular biology of insect viruses and their use as heterologous expression systems and biological control agents. Dr Smart's research into brewing yeast physiology has led to a worldwide reputation throughout the brewing industry and the award of the Institute of Brewing's Cambridge Prize for outstanding contributions to brewing science. Prof Henry's pioneering work on the biology of human starvation has revolutionised current thinking on limits of human survival and resulted in his appointment as the sole nutritionist on the Food Standards Agency. Prof Fell leads a group working on the control of metabolism and his concept of co-ordinated control at multiple sites and his novel analyses of metabolic pathways are internationally recognised. The plant cell biology group directed by Prof Hawes was one of the first to use the green fluorescent protein to reveal the dynamics of the plant endomembrane system and this work was chosen to be presented at the 1999 Royal Society New Frontiers in Science Exhibition.
The School teaches and researches a range of disciplines from environmental sciences to cell/molecular biology. As part of a restructuring plan we recently subsumed a small group of geologists. Therefore, we are making separate submissions in Biological Sciences and Environmental Sciences (21 research active staff). This submission covers our cell/molecular biology and human nutrition research groups. In order to capitalise on the rapid expansion in research within the School, as reported in the last RAE, we established a Research School of Biological and Molecular Sciences in 1996 (http://www.brookes.ac.uk/schools/bms/research/) headed by Prof Hawes who chairs the Management Committee that reports to the School Board and University Research and Consultancy Committee. The remit of the Research School is to enhance research ethos, develop research strategy, monitor and contribute towards postgraduate training and supervisory practice, administer and monitor research funding, produce reports and publicity, and oversee School industrial and consultancy policy.
The University Strategic Plan gives a high priority to the enhancement of research activity, the diversification of funding sources and the pursuit of excellence in research. It will continue to ring fence HEFCE research income, a strategy which allocates as much funding as possible to those who direct and undertake research along with the retention of an overhead for the provision and expansion of University research infrastructure and for the support of new initiatives. University research policy is managed through a Research and Consultancy Committee chaired by the Pro Vice-Chancellor (Research). Administration is based in the new Research Centre (opened in 1997), which is a focus for research and consultancy support and provides a research student common room, seminar and meeting facilities, computing and resources room. Here, postgraduate and supervisor training courses are run. Apart from the central training courses, our research students follow a monitored, tailor-made 3 year training programme within the School. They have full access to the University computer networks, to postgraduate modules and staff training and development programmes, plus reading rights at the Bodleian Library. Each research group (where appropriate) is based around individual laboratory suites, and is serviced by the School's central facilities such as graphics/photography, IT/computing, bioimaging (light, confocal and electron microscopy), microbiology/media supplies.
Highlights of research
Neuropharmacology and behaviour: The neuroscience group headed by Dr Bermudez and Prof Beadle has established itself as an important centre for electrophysiological studies of recombinant human neuronal nACh and GABAA receptors. The focus has changed from invertebrate neuropharmacology (Beadle 1,3, Bermudez 1) to the pharmacology of mammalian ligand and voltage gated ion channels, with particular emphasis on nicotinic acetylcholine (nACh) receptors, GABAA receptors and N-type calcium channels (Beadle 2, Bermudez 2,3,4) and the group will develop in this area. The projects on human nACh receptors have shown that L-type calcium channel antagonists used for the treatment of cardiovascular disorders are allosteric inhibitors of human a7 receptors at therapeutically relevant concentrations (Bermudez 4). Studies on human GABAA receptors have demonstrated that hexachlorocyclohexane isomers interact competitively with the picrotoxin site (g isomer) and barbiturate site (d isomer) (Bermudez 2). Work on calcium channels has described a novel ligand of the w conotoxin VIA binding site in N-type calcium channels (Bermudez 3) and has also shown for the first time that somatic release of substance P from peripheral sensory neurones is regulated by L- and N-type calcium channels (Beadle 4). Future work will focus on the development of novel tools to study the role of nACh receptors in diseases of the central nervous system. Work is supported by the Wellcome Trust (including a SHOWCASE award) and Royal Society plus major industrial funding and collaborations with Eli Lilly, Merck Sharp & Dohme, Synaptica and Vernalis Research (Teaching Company Scheme award). Collaborators include Prof A Vincent and Dr B Lang, Institute of Molecular Medicine (joint PhD student and Wellcome Trust funding); Prof R Lukas, Barrow Neurological Institute, Arizona, Prof Bertrand, Geneva, and Prof B Cassels, Department of Chemistry, University of Chile (two PhD students, Royal Society and Wellcome Trust exchange grants); and Dr L Troncone, Institute Butantan, Brazil (Wellcome Trust).
Dr Ray works on learning and memory in invertebrates and vertebrates focussing on olfactory and taste learning paradigms. Major outcomes of this work include establishing the developmental time scale of olfactory learning in the honeybee and relating this to neural development (4) and discovering that maturation of the brain is not the only factor in the ontogeny of learning and memory. Behavioural needs of the colony are also a major variable (1). Seasonal variation in bee learning has also been established which should improve both inter- and intra-laboratory replication of results on this ubiquitous invertebrate learning paradigm (2). It was discovered that memory survives cellular destruction in the brain during metamorphosis. Cellular transplants or macromolecular injections from trained pupae to naïve, resulted in memory transfer. This generates a novel assay to study the cellular and molecular basis of learning and memory (3).
Plant cell biology: Prof Hawes works on the dynamics of the higher plant endomembrane system (1) using fluorescent proteins for in vivo study of the secretory pathway. In collaboration with the SCRI, he demonstrated that plant Golgi stacks are mobile and track over the ER on an actin network (2). In contrast, the transport of material from ER to Golgi and back was shown to be independent of the cytoskeleton but regulated by Rab and Sar GTPases. His work has also demonstrated that the Golgi marker antibody JIM84 recognises a Lewis A antigen in plant cells similar to the well known signalling glycans in mammals (4). Based around a biotinylation recovery assay, work on endocytosis demonstrated the internalisation of the PM proton pump (3). Current and future work is using fluorescent proteins to demonstrate in vivo the plant ER associated degradation pathway and to dissect the molecular control of ER to Golgi and post-Golgi transport. The research has generated collaborations with CNRS laboratories in Gif-sur-Yvette and Rouen, the University of Neuchâtel, the Cell Biology group at SCRI, and Oxford University. Work has been funded by the Leverhulme Trust, Scottish Office and 3 current BBSRC grants.
Dr Evans works on plant membrane biology, specialising in primary ion motive ATPases, nutrient transporters and membrane traffic and transport, including membranes in programmed cell death. He was the first to demonstrate the presence of a calcium ATPase at the plant nuclear envelope (2) and was invited to write a major review on these proteins (3). His work has included study of the pH dependency of fluorescent dye uptake in plant cells (1) and he has characterised cell death mechanisms during aerenchyma formation in maize and demonstrated this to be a form of apoptosis (published in Planta, Jan 2001). He collaborates with Dr M Hawksford, IACR, on the distribution of sulphate transporters and also worked on the identification and description of novel plant protein phosphatases (with an HFSP Fellow; 4) and the use of GFP constructs to study the endomembrane system (with Hawes). These projects will continue through the next RAE period.
Dr Hodson pioneered work on the links between aluminium toxicity and silicon in plants, and studies the mechanism by which silicon ameliorates aluminium toxicity. He has shown that amelioration in cereals has an in planta component, and is not entirely due to the chemistry of the external solutions (1,3). Extrapolation of these experiments to agriculture offers the potential for major gains in crop productivity on acidic soils. It is also possible that silicon treatments may decrease forest die-back caused by the mobilization of aluminium in the soil due to acidic precipitation. He has undertaken a major survey of mineral deposition in conifer needles (2,4). These results have already been used by palaeoecological researchers interested in vegetation changes in previous times. Future work will concentrate on the silicon amelioration of aluminium toxicity in conifers.
Metabolic biochemistry: Prof Fell is a leading authority on the theory of control of metabolism (1), and has proposed the new concept of coordinated control at multiple sites (2) in contrast to the prevailing dogma of a single dominant control point. This work is internationally recognised as evidenced by reviews of his book on metabolic control analysis, lecture invitations, and contribution to the development of NIGMS (NIH) research policy. Recently he has developed a novel functional analysis method for metabolic networks (elementary modes analysis) that has applications in metabolic engineering and functional genomics (3). He has shown through quantitative analysis that that differences in feedback regulation could account for the characteristic patterns of MAP kinase cascade activation induced by epidermal and nerve growth factors in PC12 cells (4). Work has been supported by the Wellcome Trust (SHOWCASE grant), British Council and Royal Society and a new BBSRC award. His main collaborators include: Dr S Schuster, Humboldt University Berlin and Max Delbruck Centre and Dr T Dandekar, EMBL; Prof F Srienc, University of Minnesota; Dr M Burrell, Advanced Technologies (Cambridge) Ltd; Dr K Brindle, Cambridge University; and Prof J-P Mazat, University of Bordeaux II.
Molecular virology: Prof King's group collaborates closely with the insect virology section at the NERC CEH (Oxford) Institute and Prof Possee is a Brookes visiting Professor. The group has an international reputation for the development and application of insect virus expression systems and has collaborated on 4 grants, culminating in a major NERC award that will extend the collaboration to include the molecular ecology section of CEH. This will permit the group to continue their studies determining the molecular mechanisms of baculovirus latency (Possee 1) using an integrated approach involving ecology, virology and mathematical modelling. The group also researches into the molecular determinants of baculovirus host range and has discovered a new class of viral anti-apoptotic gene (Possee 4). Another key project has been the elucidation of the mechanisms by which baculoviruses, using viral chitinase and cathepsin, liquefy their host in the terminal stages of the virus-replication cycle (King 1) and have located viral encoded chitinase in the ER of the insect cells (King 2). This has resulted in spin-off developments for the improvement of the baculovirus expression system to give improved secretion of heterologous glycoproteins (Possee 2). The group has also identified and characterised several genes involved in key stages of the baculovirus and entomopox virus replication cycles (Possee 3, King 1,3,4). Finally the group has filed a joint patent to develop the third generation of baculovirus expression vectors aimed at the field of functional genomics. Future work will concentrate on the development of platform technologies for the development of baculoviruses for high throughput screening.
Immunodiagnostics, cancer studies and cell biology: Prof Groome heads the Centre for Proteins and Peptides and has a global reputation for the development of ultra-sensitive immuno-assays for the family of human reproductive hormones, the inhibins (1,2,4), activins and follistatins (3). The assays are now being adopted in biomedical research worldwide and increasingly in clinical diagnosis. The research has revealed a number of important uses of the assays including pre-natal screening for Down's syndrome and pre-eclampsia, infertility studies, diagnosis of ovarian cancer and monitoring of assisted conception. Assays have been developed for oestrogen receptors A and B and aromotase that will have important clinical applications. Collaborations include the MRC Reproductive Biology Unit, Edinburgh and the Monash Medical Centre, Melbourne. Industrial collaborations are with Oxford Bioinnovations (a Brookes spin-off) plus Serotec and Australia Biotech to exploit the immuno-assays. Work has been supported by the MRC and a major EC programme. Over 100 publications have arisen from the research on developing and applying the immunoassays. A new £250,000 EC contract, with partners in Helsinki and Rotterdam, to work on the development of assays for the oocyte-produced growth factors GDF9 and GDF9B has been awarded and is the focus for future research.
Dr Brooks works on the nature, mechanisms of synthesis and function of metastasis-associated glycosylation changes in breast cancer. She has made significant advances in optimising methodology for detection (1) and analysis of the glycoconjugates of interest. Novel and highly sensitive techniques have been developed to analyse glycans derived from microdissected areas of processed archival specimens, facilitating retrospective analysis (collaboration with the Glycobiology Laboratories, UCL Medical School) (2). Metastasis-associated aberrantly glycosylated glycoproteins have been analysed and characterised and mechanisms of their biosynthesis are being investigated (3) with future work concentrating on their role in metastatic cell adhesion. The functional significance of these moieties has been established in in vitro assays resulting in an invited review of this research (4).
Dr Rettenberger works on the urokinase plasminogen activator (uPA) system, which is involved in tumour progression and metastasis. He produced a series of site-directed mutants of uPA and identified amino acids that are important for binding to the uPA receptor (uPAR) (1). This will help the development of uPA-derived peptide analogues as therapeutic agents to block tumour cell associated uPA/uPAR interaction. He has developed a micro titre plate based assay allowing large scale screening of such uPA analogues and for quantification of uPA molecules capable of binding to uPAR (2) to assess the importance of fully functional active uPA in biological samples as compared to total uPA antigen. He characterised splice variants of VLDLR (very low density lipoprotein receptor), a multi ligand receptor that can mediate endocytosis of uPAR/uPA/uPA-inhibitor complexes. He analysed expression patterns of these variants in human breast carcinomas (3) and investigated the mechanism of molecular recognition of VLDLR ligands (4). Future work will focus on cell surface dynamics of uPAR, its endocytosis and recycling.
Dr Goode's major research interest is the investigation of putative peptide-binding sites in a crystallin, a mammalian chaperone-like protein (1,2,3). Previously, he has investigated the protective activity of native and mutant recombinant forms of this protein in bacterial and mammalian expression systems. He is now using the baculovirus expression system to study the behaviour of native and mutant a crystallin in insect cells. This has demonstrated significant protection by native recombinant a crystallin of insect cells exposed to heat, osmotic stress and oxidative stress. He has identified a mutant form of the protein that gives significantly reduced protection against osmotic stress and fails to protect against oxidative or heat stress and is continuing to characterise its behaviour. His second research interest is in food-safety, particularly in relation to poultry, and he has filed a patent application (4). He is currently collaborating with Dr Paul Barrow at the IAH at Compton on a project to investigate the use of bacteriophage treatment to reduce the levels of Salmonella and Campylobacter on chicken carcasses.
Microbial physiology and molecular biology: Dr Smart's yeast group has demonstrated that brewing yeast fermentation performance may be affected by several forms of physiological stress. The group was the first to demonstrate that physiological stress affects flocculation performance in brewing yeast and developed methods by which flocculation performance can be determined. A novel viability dye reduction assay that is being ratified for recommendation for worldwide use throughout the brewing industry was perfected. In S cerevisiae ageing they have elucidated the impact of mitochondrial integrity (1,3) and the roles of mitochondrial transmembrane proteins and the antioxidants glutathione, catalase A and catalase T in replicative longevity. They also demonstrated cell surface changes during progression through lifespan, bud scar breaks and scar expansion through lifespan and that chain forming or pseudohyphal forming yeasts exhibit reduced lifespans. Dr Smart was the first to demonstrate that nutrient availability modifies longevity potential in both haploid (2) and polyploid strains (3,4). Work in the group is funded by international and national brewers plus BBSRC CASE and J & J Morison Trust studentships. Recent developments have resulted in a patent application and a major EC contract to look at the molecular detection of microbial contaminants during brewing.
Dr McCready, a new member of the School, works on the genetics and molecular biology of cellular repair mechanisms for UV-damaged DNA. She has developed a novel immunoassay for quantifying DNA damage caused by UV and sunlight and has applied this to studies of DNA repair, principally in yeast and human cells. This has led to the discovery and characterisation of a novel mechanism for repair of UV-damaged DNA in fission yeast, and contributes to UV resistance (2,3). She has uncovered repair pathways for UV damage in the extremely halophilic archaea, organisms that can withstand high levels of sunlight in their natural environment. She is currently investigating the nature of the repair mechanisms involved and the relationship of these mechanisms to eukaryotic and prokaryotic repair pathways. Her work is funded by the Wellcome Trust. She was invited to write a major review for Mutation Research (4) and also co-authored a recent BioEssays review paper on DNA repair pathways. Her main collaborations are with Prof D Williamson, MRC Mill Hill (1), Prof A Yasui, Tohoku University, Japan and Profs A Lehmann and A Carr, MRC Cell Mutation Unit, Sussex University.
Nutritional biochemistry: Prof Henry's pioneering work on the biology of human starvation has not only revolutionised our current thinking on the limits of human survival to food deprivation (1,2), but also enabled aid agencies to modify their practices of feeding during famines to improve survival. His research in the area of energy metabolism has highlighted the role of the menstrual cycle influencing energy balance and body weight regulation in women. He is a world expert on the determination and use of basal metabolic rate to compute human energy requirements (4). He has been commissioned by the international dietary energy consultative group in Switzerland to produce predictive equations to estimate basal metabolic rate in humans (3). His most recent innovative study has been in the use of red palm oil (a rich source of beta carotene) to improve the vitamin A status of lactating mothers in Tanzania. One focus for future work will be targeted nutritional intervention based on individual's genetic make-up. Work is supported by MAFF, the Meat and Livestock Commission, various industrial collaborations and a major EC contract on nutrition in the elderly. Collaborations have been established with Universities and Institutes in Thailand, Malaysia, Vietnam and the United Arab Emirates.
Prof Hardy joined the School in 1998 and researches into the pharmaceutical and metabolic aspects of amino acids, vitamins, trace elements and other immune-enhancing nutrients (2,3). Collaborative studies with the intensive care units and nutrition support teams at Whiston Hospital, Liverpool and the Royal London Hospitals on diet supplementation have demonstrated significantly improved reduced mortality rates in intensive care patients and decreased hospital stay for surgical patients. He has demonstrated the suitability of L-glutamine supplementation of total parenteral nutrition mixtures for critically ill patients (1), along with enhanced performance and reduced respiratory tract infections in endurance athletes after diet supplementation with the amino acid. The role of glutathione in cell protection is also an ongoing interest of the group (4). Future research will be centred on improving nutritional status and immunocompetence of the critically ill and the effect of immuno-nutrients on motor neurone disease patients.
The School staffing policy is to support the most successful research active staff by competitive promotion to senior posts such as readerships and chairs and appointing younger staff to work with or in collaboration with the existing research groups. Internal funding is made available to all newly appointed staff to pump-prime their research programmes. This policy is implemented by holding biennial appraisal interviews that produce individual development plans. As a result of this policy Dr Evans (plant cell biology) has now been appointed to a full-time readership after several years as a Royal Society University Research Fellow and Dr Brooks (cancer research) has been appointed to a permanent senior lectureship. Dr Avery left the Microbiology Group after being approached to join the University of Georgia, and has been replaced by Dr McCready a yeast/bacterial molecular biologist with an international reputation who has received start up funding and a University funded studentship. Research based promotions (readerships) are financed by the Research School (currently Dr Bermudez and Dr Evans) and by industrial sponsorship (eg Dr Smart's Scottish Courage Readership). Research staff development follows the guidelines of the Concordat for Contract Researchers and several of our recent postdoctoral researchers have been appointed to academic posts in HEIs. All temporary research staff are supplied with a copy of the Research School staff development policy and are subject to annual staff development interviews. Procedures within the Research School are available on the web site.
Copyright 2002 - HEFCE, SHEFC, ELWa, DEL
Last updated 17 October 2003