The Wright-Fleming Institute was established in 2001, described below in the annual report for that year.
Annual Report 2001 - Contents
- Executive Summary
- New Grants and Research Income 2001
- Seminar & Lecture Series 2001
- Introduction
- Scientific summary
- Publications 2001
Executive Summary
Achievements
The Wright-Fleming Initiative proposed in 1999 was renamed theWright-Fleming Institute (WFI) in November 2000 following ratification of its status by Imperial College. This annual reports sets out to detail the achievements made by the constitutent members during 2001. There are 14 research groups from 6 divisions within the WFI.
Two prestigious Scientists joined the WFI in 2001. Professor Brian Spratt, FRS relocated his research group to the St Mary’s Campus from Oxford University in August of this year. Professor Catharina Svanborg is currently relocating her research group from Lund University in Sweden.
The St Mary’s Medical School Building is in significant need of refurbishment, as many of the labs and offices are old fashioned and not conducive to modern research techniques. We have estimated that the total requirement for refurbishment of the building is circa £35 million. Some refurbishment work was carried out in 2000 with a total spend of £2.88 million. The WFI, along with the Geoffrey Rose Institute (GRI) who will co-locate into this building following refurbishment have to date raised £25.725 million as listed below:
| Funding Source | Amount | Lead Academic | Group Beneficiary |
| HEFCE | £2.2 million | Prof. Paul Elliot | GRI |
| HEFCE | £1.5 million | None | Building Services infrastructure |
| JIF | £5.6 million | Prof. Geoffrey SmithProf. Peter OpenshawProf. Paul Farrell | WFI |
| SRIF | £15 million | Prof. Jonathan WeberProf. Paul Elliott | WFI, GRI |
| George John Livanos Trust | £0.75 million | Prof. Michael Levin | WFI |
| Wellcome Trust | £0.25 million | Prof. Geoffrey Pasvol | WFI |
| St Mary’s Development Trust | £0.375 million | Prof. Jonathan Weber | WFI |
| JREI 2001 | £50,000 | Prof. Jonathan Weber | WFI |
| | | | |
These monies will allow us to carry out a substantial part of our refurbishment programme over the next two years. Additional funding will be raised to complete the refurbishment plans.
New Grants and Research Income
As a group the WFI attracted approximately £26 million pounds of funding for scientific research. This is in addition to the money raised for the refurbishment. Please see the research grants page for more information.
The total includes four awards > £1 million and one for £16.3 million.
| Scientific Group | Number of awards | Total of Awards |
| | | |
| Jefferiss Research Trust Labs | 9 | £19,867,348 |
| Department of Immunology | 4 | £ 1,452,658 |
| Department of Infectious Disease and Microbiology | 2 | £ 60,000 |
| Virology and Cell Biology Group | 3 | £ 1,908,748 |
| Molecular Infectious Disease Group | 8 | £ 763,351 |
| Department of Respiratory Medicine | 5 | £ 258,585 |
| Hepatitis Research | 10 | £ 1,798,467 |
| | | |
Seminar and Lecture Series
Two seminar series are organised by members of the WFI.
- The Wright —Fleming Institute Seminar Series attracted 25 speakers in 2001;
- The Ludwig Institute of Cancer Research, St Mary’s Branch Seminar Series attracted 16 speakers.
The Almroth-Wright Lecture Series took place in May 2001. Four internationally renowned speakers gave lectures which were well received.
In addition there is the III Seminar Series which is shared by the Hammersmith Campus and St Mary’s Campus. Two seminars in this series took place on the St Mary’s Campus during the year.
Introduction
A focussed strategy for academic development on the St Mary’s Campus was developed in 1999 in response to two factors. Firstly the completion of the Sir Alexander Fleming building on the South Kensington Campus and subsequent relocation of the BMS Division groups to this building meant that space was available to attract new research groups to the Campus. Secondly the emergence of new infectious diseases, with fourteen new pathogenic human viruses alone identified since 1980, and the public health problems posed by the resurgence of infections such as tuberculosis and dengue fever have led to the recognition of an urgent need for enhancing research in infection and immunity.
The chief purpose of the Wright-Fleming Institute is to bring together, under one roof, internationally recognised groups that carry out basic and applied research in virology, bacteriology, parasite biology, immunology and population studies, embedded on a clinical site with ongoing commitment to clinical research.
The particular need is for research on the basic biology of infectious agents and the host immune response to such agents, particularly for infections where vaccines and treatments are not currently available. An understanding of these fundamental aspects is required for the successful development of new drugs, new vaccines, and new strategies for the prevention and control of infectious diseases. A proper understanding of basic infectious disease biology and immunology also directly influences other areas of investigation such as fundamental cell and tumour biology. For example, in viral vector-mediated gene therapy, success will depend on understanding and controlling the relationship between the virus and the host cell, in terms of viral propagation in cell culture, tropism, receptor interactions and viral cell entry, efficiency of infection, and the immune response to the vector.
The absolute dependence of society on a vigorous basic research capability and a strong research-focused clinical interface is well demonstrated by recent epidemic threats to public health. The AIDS epidemic in the UK has been controlled through a co-ordinated scientific, clinical and epidemiological response. Current challenges include hepatitis C, TB, prions and new variant CJD. It must be anticipated that new infectious challenges will emerge regularly in the future, and large groupings of multidisciplinary researchers will be required to respond promptly in order to protect the public health.
Infection and immunity research will advance fastest where there is strong collaboration and regular dialogue between basic scientists, infectious disease clinicians and epidemiologists. This is what the WFI and Geoffrey Rose Institute have set out to achieve.
Main Officers
- Chair of the Wright-Fleming Institute - Professor Jonathan Weber
- Deputy Chair of the Wright-Fleming Institute - Professor Charles Bangham
- Administrator - Ms Hazel Lofthouse
- St Mary’s Development Project User Co-Ordinator - Ms Jane Lillywhite
Committees
WFI Management Group
Chair - Professor Jonathan Weber
Deputy Chair - Professor Charles Bangham
Secretary - Ms Hazel Lofthouse
Membership - All professors in the WFI
WFI Postgraduate Teaching Group
Chair - Professor Martin Allday
Professor Myra McClure
Professor Sebastian Johnston
St Mary’s Development Project User Groups, Chaired by User Co-Ordinator
2nd Floor Paediatrics User Group
Imaging Suite & Respiratory Medicine User Group
CBS User Group
CL3 Laboratories User Group
Scientific Groups
There are 14 scientific groups from 6 Divisions within the Faculty of Medicine.
Jefferiss Research Trust Laboratories; Medicine;
Department of Immunology; Investigative Sciences;
Department of Infectious Disease and Microbiology; Investigative Sciences;
Virology and Cell Biology Group/Ludwig Institute; Investigative Sciences;
Molecular Infections Diseases Group; Paediatrics, Obstetrics and Gynaecology;
Paediatric Infectious Diseases; Paediatrics, Obstetrics and Gynaecology;
Department of Respiratory Medicine; National Heart and Lung Institute;
Gastroenterology Research Laboratories; Medicine & Investigative Sciences;
Hepatology Group; Medicine;
Experimental Medicine Group; Medicine;
Microbial Population Genetics; Medicine & Primary Care and Population Health Sciences;
Department of Neurogenetics; Neurosciences and Psychological Medicine;
Medical Microbiology Group; Investigative Sciences.
Scientific summary
Jefferiss Research Labs
The department of GU Medicine and Communicable Diseases relocated to new purpose built laboratories on the 4th floor of the WFI building in January 2002, from its previous home since 1991 in the Jefferiss Wing. This refurbishment funded by the HEFCE laboratory refurbishment fund, the Jefferiss Trust and the St Mary’s Development Trust marked the end of the first phase of the WFI re-building project. The new laboratories were formally opened on November 13th 2001, by Professor Sir Leszek Borysiewicz. Both Professor Sir Christopher Booth (representing the Jefferiss Trust) and Sir Roger Bannister (representing the St Mary’s Development Trust) were in attendance. The new laboratories provide CL2 and CL3 culture suites and an open plan CL2 facility.
The department has been awarded two programme grants this year. Dr Quentin Sattentau was awarded his first MRC Programme Grant for the development of novel HIV-1 envelop glycoproteins, in collaboration with Professor Ian Jones at the University of Reading. Professor Jonathan Weber, Dr Charles Lacey and Dr Quentin Sattentau have been awarded a MRC / DfID Programme Grant to develop vaginal microbicides to phase III trial, in conjunction with the MRC Clinical Trials Unit. This grant will allow Dextrin-2-Sulphate gel, first characterised by Professor Myra McClure and Professor Jonathan Weber in 1988 and trialled at phase I and II at St Mary’s, to be taken to a trial of efficacy in the prevention of HIV infection.
Professor Myra McClure has been awarded a personal chair in Retrovirology by Imperial College, and Dr Graham Taylor a clinical senior lectureship in GU Medicine and Communicable Diseases.
Professor McClure has been awarded a Wellcome project grant to develop Foamy Virus vectors. Professor Weber and Dr Sattentau have been successful in extending the European HIV vaccine grant (EuroVac), and EuroVac-II will commence in January 2002.
The department has settled into the WFI, and now relishes the challenges of the next year.
Department of Immunology
In 2001 we have appointed two new Senior Lecturers (Clinical) in Immunology, both from Oxford: Sara Marshall, an MRC Clinician Scientist, and Peter Kelleher. Both Dr Kelleher and Marshall hold PhDs in immunology in addition to their clinical qualifications, and will make a substantial contribution to both clinical and basic immunology on the St Mary’s site. Dr Keith Gould has been reappointed to the post of Lecturer in the Department. The Department has published 9 papers so far in 2001, and has won grants from the W.H.O. (Müller: Leishmaniasis) and the Wellcome Trust (Bangham: HTLV-I; Müller: Leishmaniasis) totalling over £1 million. A research assistant, Lambrini Kaftantzi, has joined the Department on a newly awarded Wellcome Trust Project Grant (Bangham: HTLV-I). The degree of PhD has been awarded to two members of the Department: Dr Mehnaaz Lomas and Dr Pascale Kropf. Dr Alison Vine won a Young Investigator Award at the 10th International Conference on Human Retrovirology in Dublin (June 2001). The Department is looking forward to the rapid continuing development of the Wright Fleming Institute as a major centre for research in infection and immunity.
Department of Infectious Disease and Microbiology
After their arrival from Oxford in October 2000, Prof. Geoffrey Smith’s group have settled in to the Wright-Fleming Institute, vacant posts have been filled and the research is up and running. The research programme is studying i) how vaccinia virus enters into, replicates in and leaves infected cells, ii) the mechanisms by which vaccinia virus and other poxviruses evade the host immune response to infection, and iii) the evolutionary relationships of poxviruses via sequencing of their genomes and phylogenetic analyses. The report that follows concerns project i).
The morphogenesis and cell-to-cell spread of vaccinia virus. Vaccinia virus produces two types of infectious virion called intracellular mature virus (IMV) and extracellular enveloped virus (EEV). In addition, cell associated enveloped virus (CEV) is structurally identical to EEV but is retained on the cell surface rather than being released (EEV). Intracellular enveloped virus (IEV) is an intermediate form of virus that facilitates the transport of membrane-wrapped intracellular virions to the cell surface. These virions play differing roles in the virus life cycle and CEV and EEV are essential for efficient virus spread from cell-to-cell or over long distances, respectively. We have identified an IEV-specific protein (F12L) that is necessary for the movement of IEV particles to the cell surface, and the virus mutant lacking the F12L gene has defined a new step in the virus morphogenic pathway. In another study using a recombinant virus in which the B5R protein of the EEV/CEV outer envelope is tagged with the enhanced green fluorescent protein, we have demonstrated that IEV particles moved form the site of wrapping to the cell surface on microtubules, rather than actin tails as proposed previously by others. Actin tails form beneath CEV particles at the cell surface to drive CEV particles away from the cell. Thirdly, we have demonstrated that vaccinia virus utilizes different mechanisms to spread from cell-to-cell that are either sensitive or resistant to inhibition by polyclonal antibody. The A33R protein of the EEV/CEV outer enveloped has been shown to have a role in the antibody-resistant spread of virus.
Virology and Cell Biology/Ludwig Institute
The Virology and Cell Biology section works closely with the Ludwig Institute branch at St Mary's. The research is a combination of molecular biology of the control of cell proliferation and apoptosis with studies of virology, particularly Epstein-Barr virus and cytomegalovirus. Cell proliferation is controlled by proteins involved in the cell cycle including B-Myb, cyclins, E2F transcription factors and the inhibitors p21 and p27. The ability of Epstein-Barr virus to cause cell proliferation, related to its role in some human cancers, is mediated through viral proteins such as EBNA-2, EBNA-3C and LMP-1, which modify these cell control pathways. We have made considerable progress in understanding the links between these factors affecting cell proliferation.
Programmed cell death (apoptosis) is a key aspect of cell behaviour in development of tissues, in cancer and during infection. The p53 family of proteins are mediators of apoptosis in development and in various conditions of cell stress, such as DNA damage and hypoxia. DNA damage is a factor in cancer development. Novel proteins named the ASPP proteins were found to be important modulators of the ability of p53 to cause apoptosis. Our research in this area is directed towards identifying the mechanisms governing apoptosis and the roles of these and other genes affecting apoptosis in human cancer.
Molecular Infectious Diseases Group
Research in the Molecular Infectious Diseases Group (MIDG) is focused on understanding the molecular basis for the virulence of important human (and one animal) bacterial pathogens causing acute, life-threatening, infections such as meningitis. The programme has evolved over fifteen years to include projects on the genetics of polysaccharide capsulation and various protein virulence determinants in Haemophilus influenzae, and Neisseria meningitidis and in the field of bacterial anti-oxidant defences. Current projects include studies to clarify the role of bacterial extra-cytoplasmic superoxide dismutase ([Cu,Zn]-cofactored SOD) and of the disulphide bond-forming catalyst DsbA in the biology of various pathogens, including Neisseria meningitidis, Shigella flexneri and the porcine pathogen Actinobacillus pleuropneumoniae.
The setting in which this work is carried out is unique in the UK. The Department of Paediatrics at Imperial College comprises the largest grouping of Paediatric Infectious Diseases specialists in the UK, and the busiest service in this speciality. MIDG accordingly has a major interest in meningococcal disease, a major infectious cause of disability and death in previously healthy children, and in three current projects we are establishing the vaccine candidacy of a range of meningococcal proteins. In addition, in the last year we have been collaborators in two substantial national and international research programmes to answer important questions on the epidemiology of meningococcal infection: whether there are hypervirulent lineages of bacteria, and whether there will be a shift in the meningococcal population towards serogroup B strains following the introduction of the meningococcal C vaccine in the UK. This latter study is currently the largest point prevalence survey of meningococcal colonisation ever attempted, and promises to yield unique data on the nasopharyngeal carriage of this major pathogen.
A true understanding of host-pathogen interactive biology can only come from studies of bacterial pathogens in their natural hosts. Accordingly, we have a long-standing collaborative research programme with Dr Andrew Rycroft at The Royal Veterinary College, University of London, studying a major bacterial pathogen of pigs, Actinobacillus pleuropneumoniae. Current projects include the application of the techniques of signature-tagged mutagenesis and various proteomic methodologies (including SELDI mass spectrometry) to identify determinants of virulence and potential vaccine candidates.
Department of Respiratory Medicine
Our broad aims are to understand and manipulate inflammatory lung disease caused by viruses and to design protective vaccines. We also study the relationship between viral infection and asthma, focussing on the immunology and biology of respiratory viral infections. Respiratory syncytial virus (RSV) is the major cause of bronchiolitis in infancy, while rhinovirus (RV) is the main causes of asthma exacerbation in older children and adults.
Openshaw’s group mainly studies RSV. Using the mouse as a guide to immunopathogenesis, the group has shown that virus-induced lung disease is critically dependent on the balance of different subsets of T cells (both in Th1 vs. Th2 and CD4 vs. CD8). His studies have shown that NK cells and CD8+ cells producing IFN-gamma are major factors that regulates virus-induced eosinophilia. Recent findings include that TNF has a pivotal role in enhanced RSV disease in pre-sensitised mice; that school age children who have recovered from RSV bronchiolitis show enhanced virus-specific IL-4 responses; that natural killer cells are an important source of interferon-gamma capable of inhibiting the virus-induced eosinophilia in mice, and that specific deletions of the conserved central ectodomain of RSV G protein eliminates the ability to induce eosinophilia in mice. We have recently studied the role of chemokines in RSV disease in mice, developed methods of recovering live RSV from cDNA clones (allowing engineering of mutations) and tested these novel viruses for the ability to produce pathogenic or non-pathogenic immune responses. We are also studying the influence of postnatal age on immune responses to viral infection and the role of regulatory T cells in viral persistence.
Johnston's expertise is primarily in molecular virology and applied human studies. His group studies the molecular and cellular mechanisms of asthma exacerbations caused by respiratory viruses in man using ex vivo and in vitro approaches.
His group has continued to expand and now includes three Postdoctoral Scientists (Dr Luminita Stanciu and Dr Patrick Jourdan and Dr Michael Edwards), two Clinical Research Fellows (Dr Simon Message and Dr Patrick Mallia), three full time graduate students, three visiting scientists, three full time technicians and one half time technician. In addition to substantial funding from the MRC and Industry via a MRC LINK Strategic Project Grant, a programme grant has been awarded by the British Lung Foundation and EU funding has been approved.
The major research outputs of the last year have included finalising the results of 2 clinical studies investigating interactions between environmental agents in precipitating exacerbations of asthma. These include a paper accepted by the British Medical Journal demonstrating synergy between viral infections and allergen exposure in increasing the risk of admission with acute asthma amongst adult subjects. A further study has been completed demonstrating a similar interaction between air pollution (NO2) and virus infection — this work is currently submitted for publication.
There is considerable interest in whether asthmatic subjects are more susceptible to respiratory virus infections than are normal subjects. This question has been addressed in another clinical study in which we demonstrate that asthmatic subjects do not get more frequent rhinovirus infections, but do get more severe and longer lasting lower respiratory symptoms than do normal subjects when infected. This report has been accepted by the Lancet for publication.
Other work accepted for publication in journals such as the Journal of Infectious Disease and International Immunology has investigated the molecular and cellular mechanisms of asthma exacerbations caused by respiratory viruses using both human ex vivo studies and in vitro studies.
We continue to investigate the role of acute and chronic respiratory viral infections in respiratory disease, principally asthma and COPD. These studies include both clinical and basic science studies. We are collaborating with several other international groups in studies investigating the role of viral infections in respiratory diseases.
The Department has particular expertise in multicolour flow cytometry, ELISPOT and multiplex PCR. We have been awarded a refurbishment grant by the Joint Infrastructure Fund, and hope to have completed the new department by the summer of 2002.
Hepatitis Research
The Hepatology section, Department of Medicine A within the Division of Medicine has a long standing research programme in the pathogenesis of persistent viral hepatitis and its treatment. This encompasses studies in molecular virology, biology, host genetics and immunology as well as clinical studies including trials of antiviral therapy. The department is headed by Professor Howard Thomas and includes both academic clinicians and scientists, as well as research fellows and postgraduate students. The department has been running a successful MSc in the Molecular Biology and Pathology of Viruses for the last five years.
The role of the host responses to virus infections in the development of viral persistence have been investigated from a number of perspectives; the cellular immune response (Jenny Waters, Andrew Godkin), a -interferon subtypes (Graham Foster), genetic polymorphisms associated with viral persistence or recovery (Mark Thursz, Howard Thomas), viral inhibition of gene induction using gene array technology in cells treated with interferons (Jorg Schlaak, Howard Thomas, Sahar Khan, Michael McGarvey, and Ian Kerr) and gene arrays and confocal microscopy to examine the expression of viral proteins in infected cells and their effect on host gene expression (Sahar Khan, Jonathan Hoare and Michael McGarvey).
The interest in the role of viral variants of HBV in disease and response to therapy continues. There are also ongoing studies of the role of hepatitis C quasispecies variation in interferon response, and of extrahepatic sites of replication and protein translation (Peter Karayiannis, Daniel Forton, Simon Taylor-Robinson and Howard Thomas). The role of hepatitis B variants in vaccine escape and fulminant hepatitis is still the theme of several ongoing studies (Peter Karayiannis, Jenny Waters, Howard Thomas).
Studies have been carried out, to obtain structural and functional information on some of the key virus replication proteins and the inhibitory effects of novel antiviral agents, with the NS3 protease/helicase of HCV and other flaviviruses (GBV-B hepatitis virus and tick-borne encephalitis) (John-Paul Gallivan and Michael McGarvey) and the NS5 RNA polymerase (J. Monjardino) of hepatitis C virus.
Novel approaches to the targeting of genes to the liver are also underway (Jonathan Hoare and Michael McGarvey). The use of bone marrow derived stem cells, which differentiate into hepatocytes, to deliver genes to correct inherited and inflammatory liver diseases, has been started in collaboration with ICRF.
Both hepatitis B and C viruses cause chronic infections and liver disease, which respond to antiviral treatment. However, current therapies are sub-optimal, necessitating the development of new treatment regimes. The department has established the Antiviral Clinical Trials Centre, which coordinates a number of trials of novel therapies. Currently, the department is running a national NHS Research and Development Trial evaluating the health benefits of antiviral therapy in mild chronic hepatitis C infection (Janice Main, Howard Thomas). Other trials include treatment of chronic hepatitis B and hepatitis C/HIV coinfected patients.
Using cerebral proton magnetic resonance spectroscopy (MRS), specific cerebral metabolite abnormalities, associated with cognitive dysfunction have been demonstrated in patients with chronic hepatitis C. This has led to molecular virological studies seeking evidence of infection of the CNS (Daniel Forton, Simon Taylor-Robinson, Peter Karayiannis, Howard Thomas).
A combination of microbubble contrast enhanced liver ultrasound and liver MRS are being used to develop a non-invasive method of quantifying liver fibrosis as a potential alternative to liver biopsy (Simon Taylor-Robinson) in chronic hepatitis C infection.
