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UOA 3 - Infection and Immunology

University of Cambridge

RA5a: Research environment and esteem

Part 1: Background

Research in the Schools of Clinical Medicine and Biological Sciences in Cambridge is pursued on a strong thematic basis which crosses Departments, and the submissions are thus organised on the basis of common research themes. For this Research Assessment Exercise, research in the Departments within the School of Clinical Medicine and the Department of Pathology in the School of Biological Sciences (the same Departments submitted in UOA 1-3 in the 2001 RAE) is submitted to the Units of Assessment under main panels A (UOA 1-5) and B (UOA 6, 8 and 9). Related work in other Departments of the School of Biological Sciences is being returned to UOAs under main panel D (14 - Biological Sciences and 16 - Veterinary Science) or main panel K (44 – Experimental Psychology). Within each of these submissions, cross reference is made to relevant related work submitted to other UoAs.

Major changes have continued, since the 2001 RAE, in both the organisation and infrastructure of research in the University relevant to Panels A, B and D. The creation of thematic research institutes, by new building and high quality recruitment, has gathered momentum. The Cambridge Institute for Medical Research on the University Hospital site had opened in 2000, and this site now includes the Institute of Metabolic Science (completed 2007) and the Cancer Research UK (CRUK) Cambridge Research Institute (completed 2006). The Gurdon Institute for Developmental Biology opened in 2005, and the Wellcome Trust Stem Cell Centre in 2007, on the Biological Sciences campus in central Cambridge. There has been extensive refurbishment of existing University space, including laboratories for clinical stem cell research on the Hospital campus, for molecular epidemiology in the adjacent Strangeways Laboratory, and for pathology on both campuses. In all 18,000m2 of high quality research space has been created since 2001, resourced by funding in excess of £80M from Research Councils, CRUK, Wellcome Trust, HEFCE and specific endowments. 16 new chairs have also been created, providing new strength in academic leadership in strategic topics that frequently bridge the interests of the sub-panels of Panels A, B and D.  These developments are underpinned by continuing collaboration with major research partners on the Clinical School/Hospital campus, principally the MRC (with the Laboratory for Molecular Biology and 4 MRC Units) and Cancer Research UK (with its new Cambridge Research Institute), and the Wellcome Trust Sanger Institute. The University’s partnership with its associated NHS institutions remains key to its translational research, and an NIHR Comprehensive Biomedical Research Centre Award is held in partnership with Cambridge University Hospitals NHS Foundation Trust. The net effect of these initiatives is greater than the sum of their parts, in creating a unique interdisciplinary biomedical research environment attracted the highest quality staff from within and beyond Cambridge.

1.1 Introduction to Infection and Immunity
Infection and Immunity are of key strategic importance to Cambridge University, for several reasons: because infectious disease with existing and emerging pathogens is a major continuing threat; because research in this area impinges on a wide range of clinical and basic research, such as biochemistry, cell biology and genetics, and because immunology promises some of the most promising therapeutic approaches to non-infectious diseases. These include not only autoimmune diseases, but also conditions ranging from cancer to dementia.

Cambridge's strategy has been to strengthen Infection and Immunity by new recruitment, emphasising excellence and leadership. The University recruited two Wellcome Trust Principal Research Fellows (Professors Griffiths and Rudd; immunologists) and created a Readership (Dr Field, parasitologist) during the census period to the University’s Infection and Immunity programme. The importance attached to the subject has attracted a number of clinician/researchers in the field and has aided the development of high quality training programmes, such the Wellcome 4 year PhD programme in Infection and Immunity (renewed in 2007 for a further 5 years). These developments contribute substantially to the maintenance of an historically unique research atmosphere.

Substantial funds were invested in Infection and Immunity during the RAE2001 census period, totaling over £100M building and research support grants from the MRC, Charities, HEFCE and specific donations. These investments led to the establishment of new research institutes mentioned in RAE2001 (including the MRC-Wellcome Building and the Wellcome Centre for Molecular Mechanisms of Disease) and substantial renovations and refurbishment, which have been finalized during the RAE2008 census period. Government and major Charity funding has provided a further £3million to finalize a refurbishment and infrastructure programme encompassing research in Infection and Immunity. Consequently, the new research environments, which have developed from the RAE2001 investment, have provided a firm foundation upon which Infection and Immunity have been able to thrive during the RAE2008 census period and these are evidenced below.

Research in Infection and Immunity spans departmental boundaries in Cambridge and integrated research programmes which bring together resources across Cambridge are represented in UoA3. UoA3 comprises a range of key laboratories but other related research is embedded in other assessment units, on 3 sites, including UoA5 (Medical Genetics; Todd, Wicker), UoA16 (Veterinary Medicine) and UoA4 (Transplantation Immunology; Bradley). Several Category A individuals are based within cross-departmental, research centres of excellence such as the Cambridge Institute for Medical Research (Griffiths, Rudd, Trowsdale and Lehner) and the MRC Laboratory for Molecular Biology (Fearon).

1.2 Cambridge has attracted substantial grant funding.

The strength of research programmes in UoA3 is evidenced by the following:

Major Grants (not including Project Grants)

Type of Award

Number AWARDED during Census Period

Total Award Value (£million)

Programme Grant

21

16.6

Principal Research Fellowship

2

5.9


Senior Research Fellowship

3

3.9


University Fellowship

20

  8.1

University Awards/New Investigator

2

0.8


Internationally competitive, peer-reviewed funding

   16  

5.7

Total

69

£41million

 

Fellowship Funding Sources

Fellowship Type

NHS/General Medical

OST/OSI Research Councils etc

UK-based charities

 International

PRF

 

 

2

 

 SRF

 

 

3

 

Research Fellowships (including Clinical)

1

4

14

1


Because the aim of the University of Cambridge is to provide the capacity for integrated research programmes, institutes have been established during the census period which generally benefit the research environment of UoA3 and facilitate the opportunity for new collaborations. These include the Cambridge Systems Biology Centre (SRIF-funded), the Wellcome Trust and MRC-funded Centre for Stem Cell Biology and the Centre for Microarray Facilities (with the assistance of HEFCE and BBSRC funds). In recognition of the potential for translational research into a wide spectrum of diseases, some of which are investigated in UoA3, Cambridge University Hospitals NHS Foundation Trust, in partnership with the University of Cambridge, has been designated as one of the new NHS Comprehensive Biomedical Research Centres, and will receive substantial new Research and Development funding from the National Institute for Health Research (NIHR) to the value of £55million over 5 years (awarded December, 2006).

To further translational science, the Cambridge Hinxton Centre for Translational Research in Autoimmune Disease (CHiC TRIAD) was established in 2004, led by Professor Ken Smith. This is a collaboration between staff within UoA3, clinicians from Addenbrooke’s Hospital, immunologists and clinician scientists from the CIMR, and bioinformaticians from the European Bioinformatics Institute. The project is integrating clinical and laboratory data to examine how gene expression signatures determined by microarray can be used to study autoimmune diseases. The aim is to predict therapeutic responses, allow tailoring of treatment in individual patients, and deepen our understanding of the aetiology and pathogenesis of these medical problems.

Part 2: Research Training, Career Development

The University of Cambridge operates an annual scheme for personal promotion of academic staff to the Offices of University Senior Lecturer, Reader and Professor. Through this system, 11 existing staff in this UoA achieved promotion since 2001; 3 to Senior Lectureship, 2 to Readership and 6 to Professorship. Three new University Lecturers were appointed (Fraser, Digard and Hall) during the RAE2008 census period. A similar scheme operates for research staff, who have the possibility of promotion from Research Associate to Senior Research Associate, and thence to Principal Research Assocaite (equivalent to Reader) and Director of Research (equivalent to Professor). In certain circumstances, Senior Research Associates have also successfully applied to transfer to the academic track as Readers and Professors. The University of Cambridge offers sabbatical leave of one term for each six terms of service to all Academic Staff (Professors, Readers, University Senior Lecturers and University Lecturers).

PhD students have contributed to 238 publications during the census period. 32 international Fellows or postdoctorates have been hosted to undertake research programmes within the labs of individuals in UoA3.

The Graduate School of Life Sciences continues to coordinate the graduate affairs of the roughly 1500 students within these disciplines. The School monitors progress, provides training in transferable skill, maintains a web-based directory of supervisors’ expertise, and ensures permeation of good practice in research, study and supervision. Roberts Funding is awarded bi-annually and the 2006/07 award to the Graduate School was £309,000, used to promote the graduate and postgraduate training of students and researchers to assist them develop skills transferable within research and outside research. Cambridge has recognized the need to provide support to graduate students with the provision of a Careers Adviser for graduate students. That postdoctoral researchers also require secondary support was recognized with the appointment of a Careers Adviser for postdoctoral life scientists. Researchers within UoA3 were successful in being awarded the Wellcome Trust 4-year PhD programme in Infection and Immunity, competitively renewed in 2007 for an additional five years to support an annual intake of five new students. Similar bids to the MRC and BBSRC were successful in securing annual quota studentships within thematics relating to UoA3 and MRC Capacity studentships in Infection Research have been awarded during the census period.

Part 3: Current Research Structure in UoA3

Research in UoA3 is presented in thematic research groupings. They are broadly divided into the categories of:
Group A: Molecular and Cellular Bacteriology
Group B: Virology
Group C: Parasitology
Group D: Autoimmunity
Group E: Molecular and Cellular Immunity


*Investigators comprising new faculty appointments to Cambridge since the last RAE submission are identified in italics at the first mention of their names.

3.1 Group A: Molecular and Cellular Bacteriology

Research in Molecular and Cellular Microbiology (UoA3) focuses on the molecular mechanisms underlying infectious diseases caused by bacterial pathogens. This Grouping has expanded rapidly since RAE 2001.
The research programmes directed by Hughes and Koronakis has generated significant funding evidenced by successive Programme grants from the Medical Research Council and Wellcome Trust awarded during the census period (£3.5 million), as well as from further Project grants and Fellowships (£1.4 million), in addition to providing training excellence. Two of their postdoctoral colleagues were recently awarded Research Fellowships [*Hayward (Royal Society) and Symmons (Oppenheimer)], and Fraser a University Lectureship following a Wellcome Trust International Fellowship that established strong external collaborations. This has facilitated the development of an expansive programme of interrelated research, focusing on understanding pathogenic microorganisms including Salmonella (Hughes, Koronakis, Fraser, Hayward, Symmons), pathogenic E.coli (Koronakis, Hayward, Fraser), Vibrio cholerae (Fraser) and Chlamydia (Hayward).

At the core of this grouping is research directed by Koronakis and Hughes investigating trans-membrane transport mechanisms, with particular emphasis on the export of bacterial toxins and the related pumping mechanisms conferring antibiotic resistance. It applies biochemical and biophysical methods in combination with structural biology to probe protein export and drug efflux mechanisms and to identify potential inhibitory agents. Following on from RAE 2001, they have followed up their seminal crystallography studies that elucidated the structure of TolC, a unique cell exit duct anchored in the bacterial outer membrane. They have since established the iris-like mechanism controlling TolC ‘channel-tunnel’ opening, demonstrated the basis for blocking the channel, and investigated the structure and function of the central periplasmic hairpin-like adaptor protein family that recruit TolC to inner membrane translocase complexes. Their most recent findings unravel key adaptor-TolC interactions in the cell envelope, allowing the first model of a bacterial tripartite drug efflux pump to be proposed (Koronakis, Hughes, Symmons).

Hughes’ work on bacterial motility addresses the mechanism by which pathogenic bacteria assemble flagella on their cell surface, facilitating cell swimming and population swarming in the environment and during colonisation of mammalian hosts. In particular, Hughes’ research focuses on the type III protein export pathway used to achieve ordered delivery of structural subunits from the cell cytosol to the nascent macromolecular structure. The flagellar export pathway is closely related to that used by extracellular and intracellular pathogens to deliver subversive virulence effectors into human and animal cells during infection (as studied by Koronakis and Hayward). Work has revealed a number of key mechanistic activities and events in the pathway, including chaperone bodyguard function, membrane targeting and activation of the oligomeric export ATPase, chaperone piloting of subunits to the ATPase docking platform, and post-docking escort of unladen chaperones to establish a selective chaperone cycle. Ongoing genetic, biochemical and structural studies aim to describe the sequence of events, defined by transient protein-protein interactions, that underlie piloting, docking, sorting, selection and release of subunits along the translocation pathway.

Since returning to Cambridge in 2002, Fraser has continued her work on the flagellar type III export pathway in close collaboration with Hughes. BBSRC project funding has facilitated the expansion of Fraser’s research into the field of bacterial cell polarity, focusing in particular on protein targeting in the pathogen Vibrio cholerae. A further BBSRC joint project grant, with Dr Nicholas Luscombe at the EMBL-EBI, has allowed Fraser to initiate a cross-disciplinary collaboration that combines molecular genetics and functional genomics with computational approaches to carry out a systems-level analysis of regulatory networks in E. coli and the uropathogen Proteus mirabilis.

Koronakis also investigates how Salmonella force entry into host cells. Since the 2001 RAE, research has illuminated how Salmonella actin-binding proteins cooperate to re-organize the cell cytoskeleton to drive bacterial internalization, and has identified the cell plasma membrane as a critical hub for interactions between Salmonella effectors and their host targets. Parallel studies have addressed how bacterial proteins are delivered into the target cell, defining the essential bacterial translocase as a cholesterol-binding protein that penetrates the target cell membrane. A recombinant polypeptide was also generated that acts as a dominant-negative translocase inhibitor and blocks cell entry by both Salmonella and Shigella, indicating a potential novel therapeutic strategy. Recent findings indicate that invasion proteins also continue to act later during infection to promote intracellular replication of the pathogen by subverting endosomal trafficking, opening up a new research focus.

A further research project has also evolved from this Salmonella programme during the census period, which addresses how enteropathogenic (EPEC) and enterohaemorrhagic (EHEC O157:H7) E.coli restructure the host cell cytoskeleton to adhere to host cells. To achieve this, E.coli delivers its own receptor into target cells. Research identified the host kinase that initiates downstream signalling to the actin cytoskeleton (Koronakis, Hayward). This breakthrough has attracted new funding from the Medical Research Council to pursue how to exploit these bacterial factors to probe cellular signalling pathways.

The award of a Royal Society University Fellowship also enables the expansion of Hayward’s research into defining the actions and interactions of Chlamydial virulence factors and their cellular targets to decipher the molecular basis of infection and identify potential targets for novel diagnostics, drugs and vaccines.

3.2 Group B: Virology

The research covers a broad range of viral pathogens of importance to man, including basic studies of virus assembly, virus cell interactions and pathogenesis. Collaborative work between all of the individuals in this Research Group is underpinned by joint infrastructure funding awarded in 2001 and commented upon in RAE2001 to the Infectious Disease unit, Department of Medicine and Division of Virology Department of Pathology for refurbishment of general laboratory space, new Category II and III containment laboratories and new confocal and FACS facilities. MRC & Wellcome Programme grants, a current renewed MRC co-operative group grant and Senior/Principal Research Fellowships totalling £9.3million were awarded during the census period and University Fellowships and University Awards totaling £1.8million are supporting new researchers in this Research Group. The major research areas and investigators in this grouping are listed below.
1. Virus Entry: Brown, Browne, Minson
2. Virus assembly and exit: Browne, Crump, Digard, Greatorex, Lever and Minson
3. Translational control of virus gene expression: Brierley, Lever
4. Transcriptional control and latency: Efstathiou, Sinclair and Sissons.
5. Immune Evasion: Efstathiou, Sinclair, Sterling, Stevenson, and Wills
6. Translation of Viral Pathogenesis to the Field: Lee

Virus entry

Brown has studied receptor usage in enteroviruses and with Dr. Susan Lea (University of Oxford) derived the crystal structure of decay accelerating factor (DAF), dependent and independent echovirus 11 strains identifying critical capsid residues necessary for receptor interaction. DAF dependent enteroviruses associate with lipid rafts, a novel entry pathway using this receptor. Feline calicivirus (cf. norovirus) entry has been shown to depend on an alpha 2,6-linked sialic acid bearing receptor, clathrin-mediated endocytosis and endosome acidification.

In herpes simplex virus type-1 (HSV-1) entry Minson (FMedSci) has identified the minimum glycoprotein requirements for virus cell membrane fusion including the critical need for glycoprotein H (gH) and studies of receptor binding have demonstrated an interaction between αVβ3 integrin and gH (Minson and Browne). A Wellcome Trust University award for Browne has resulted from this work. Interdisciplinary collaborations have led to the development of novel optical trapping methods for single molecule fluorescence microscopy for studies of virus compositional heterogeneity (Browne in collaboration with Prof. D. Klenerman, UoA18) and the development of highly sensitive rupture event scanning methodologies for virus detection/diagnosis (Minson in collaboration with Prof. D. Klenerman, UoA18)

Viral assembly and exit

The Royal Society University Research Fellowship awarded to Crump following on from a Wellcome Trust International Travelling Fellowship has facilitated his work on mechanisms of herpesvirus assembly and egress and the role of the cellular membrane budding machinery and glycoprotein trafficking. This has resulted in the first demonstration of the endosomal sorting machinery’s involvement in envelopment of large DNA viruses. In Wellcome Trust Programme Grant supported research Minson and Browne showed HSV-1 egress from infected cells occurs by a two-step envelopment pathway.

Capture of the RNA genome in lentiviruses is at a critical stage of virus assembly studied by Lever’s (FRSC, FMedSci) group supported by an MRC Programme Grant and two Wellcome Trust Project Grants, one collaboration with the University of the United Arab Emirates. Within this, Greatorex (promoted to Senior Research Associate in 2002) in a collaboration with Dr. Varani from the MRC LMB has generated NMR data on RNA structures in the 5’ untranslated region of HIV identifying a novel binding site for the HIV Rev protein. Greatorex subsequently showed this influenced nuclear/cytoplasmic viral RNA distribution. Greatorex has studied the RNA dimer linkage in a number of retroviruses and identified novel structures in the human pathogen HTLV-1 and in Maedi-Visna. Lever has identified different RNA packaging mechanisms between HIV-1 and HIV-2 including non-reciprocity of packaging. His group was the first to describe cotranslational packaging in lentiviruses. The site of RNA capture in the cell was demonstrated to be the centrosome using confocal microscopy and FRET, the first use of FRET for direct RNA protein interaction studies in retroviruses. Collaborations with Dr. Gabriel Varani (past), Dr. Peter Lukavsky (present) in the MRC LMB have helped elucidate RNA structures by NMR and ongoing collaborations with Dr. Susan Lea in Oxford are aimed at crystallographic analysis of packing signals. Ongoing collaborations with Desselberger (Category C) in rotavirus packaging have recently been supported by a Wellcome Trust project grant. Lever and Kumararatne (Category C) also conduct a tertiary referral clinical for patients with increased susceptibility to infection, leading to research programmes into the increased susceptibility to mycobacterial infection in the absence of known risk factors.  

Digard (Senior Lecturer – previously Royal Society Fellow) is studying nuclear export of virus mRNAs during Influenza virus infection has shown dependency on cellular gene expression for this process. Interdisciplinary studies with Dr. Julia Gog, (UoA21) Department of Mathematics, Dr Laurence Tiley, (UoA16) have identified codon conservation in gene segments in Influenza, helping to find the location of RNA packaging signals. This will aid understanding of both packaging and re-assortment of Influenza virus RNA and its contribution to virus evolution with respect to future pandemic threats.

Translational control of virus gene expression

Studies on translational control in retroviruses and coronaviruses have resulted in major advances in understanding how viral RNA pseudoknot structures induce ribosomal frameshifting. Brierley's work in this area has extended into the role of cellular tRNAs in translational regulation and identification of novel stimulatory RNA elements which can subvert ribosomes during translation of cellular mRNAs. Brierley (in collaboration with Robert Gilbert and David Stuart, University of Oxford) have identified structures of frameshift and read-through stimulatory RNAs and cryo-EM structure of ribosome confirmation during the process of frameshift/read-through. Translation of unspliced RNA in HIV-1 has been shown by Lever to be regulated by the Gag structural protein in a bimodal system.
Transcriptional control and latency

Sissons (FMedSci) and Sinclair (supported continuously by MRC Programme funding since 1993, renewed during the census period) have elucidated sites of human cytomegalovirus (HCMV) latency and reactivation in healthy carriers. They have also identified transcriptional control mechanisms of viral immediate early gene expression in HCMV, establishing the importance of viral chromatin structure in the control of HCMV latency and reactivation (collaborative work with Lehner (Lister Prize winner, FMedSci; [Group E]) and Professor E. Verdin, Gladstone Institute for Virology and Immunology, University of California, USA). Studies on HCMV latency in the myeloid lineage have also successfully identified a novel latency-associated viral RNA (collaboration with Professor T. Shenk, Princeton University, USA), Recent work by Sinclair (in collaboration with Professor G. Wilkinson, University of Cardiff, UK), has identified a novel mechanism by which HCMV blocks cellular apoptosis using a viral non-coding RNA and was published in Science.

In HSV Efstathiou using in vitro and in vivo neuronal model systems has studied patterns of HSV virus gene expression during the establishment of latency and reactivation and, again, confirm the importance of histone deacetylase mediated repression during latency. HSV encoded latency-associated transcripts have been implicated in posttranscriptional regulation of the virus encoded ICP0 transactivator (international collaboration with Dr. M. Labetoulle). Latency in HIV has been studied in Lever’s group, in which two mechanisms of latency have been uncovered with implications for treatment of HIV infection.

Immune Evasion

Stevenson has used murine gammaherpesvirus 68 as a model organism to elucidate in vivo mechanisms of immune evasion relevant for the human pathogens Epstein Barr Virus and Kaposi’s Sarcoma herpesvirus. The K3 gene product has been shown to cause proteosomal degradation of the MHC class I peptide loading complex (Stevenson in collaboration with Lehner [Group E]). Virus mutants deleted for K3 fail to establish a normal latent viral load in vivo, a phenotype fully reversed by CD8 T-cell depletion (Stevenson and Efstathiou). This is the first demonstration of the significance of gammaherpesvirus MHC class I evasion mechanisms in pathogenesis. The critical importance in host colonization of cis-acting CTL evasion of the MHV-68 episome maintenance protein has also been defined (Stevenson). Plasmid maintenance was identified as critical for host colonisation and latency deficient mutants were shown to have vaccine potential (Efstathiou). MHV-68 encodes a chemokine binding protein important in virus pathogenesis (Efstathiou) and the anti-inflammatory properties of M3 have triggered filing of an international patent and licensing to the Genetrix group. Sissons and Wills have made major contributions to understanding how the memory CTL response to HCMV is regulated involving collaborations with Lehner, and  Trowsdale (both Group E). Alcami (Category C staff) a Wellcome Senior Research Fellowship from 2002 moved to a permanent position at the University of Madrid in 2004 but his work was converted to a Special Project Grant and has been continued in collaboration with Sinclair (co-awardee). Pox-virus immune evasion mechanisms from this work was recently published in EMBO journal. Sterling (FRCP), who has a strong collaboration with Professor Margaret Stanley (UoA2), has published work on the interface between viral studies and cancer, in particular working on human papillomavirus and vulval and vaginal neoplasia. Sterling has devised clinical studies and obtained grant funding to review the immunopathogenic aspects of papillomavirus infection and the potential for vaccinia expressed HPV proteins as potential vaccines. She has examined HPV gene expression in tumours from immunosuppressed and immunocompetent individuals. Sterling also collaborates with the Department of Neurology studying neural precursors from adult human skin.

Translation of Viral Pathogenesis to the Field

The objective of Lee’s research programme is to develop innovative, simple, rapid and inexpensive tests for the detection of infectious agents in resource-limited settings, and particularly in developing countries. This is an interdisciplinary research programme encompassing nucleic acid chemistry, monoclonal antibody production, material science and assay and product development. Technologies under development involve sample preparation and rapid detection of infectious disease targets (DNA, RNA, antigen or antibodies). Collaborations between Lee and Allain (UoA4) have worked on immunity and epidemiology towards viral diseases such as HIV within the developing countries. The research programme is interdisciplinary, however, also involving research into parasitological infection and immunity. Lee’s research has led to the filing of eleven patent applications (two during the census period), two of which involve signal amplification that has enabled the improvement in sensitivity of rapid tests and four in the area of nucleic acid detection.

Additional to the promotions and awards mentioned above, Brierley and Efstathiou were promoted to Readers during the census period and Sinclair promoted to a Personal Chair. Alcami was recruited to a permanent position at the University of Madrid and retains an honorary position with the Department of Medicine in Cambridge University. Wills was promoted to SRA with independent project grant and PhD grant funding.

3.3 Group C: Parasitology

Ajioka, Blackwell, Dacks, Dunne and Field are all researching fundamental aspects of protozoan pathogens that are of major public health and veterinary significance, including the causative organisms of leishmaniasis, African Sleeping sickness, toxoplasmosis, and malaria. Four programme grants have been awarded to this Research Group during the census period, totalling £3.3million and Fellowships awarded to the value of £1.2million.

Ajioka’s research led to the discovery that the global success and ubiquitous distribution of the protozoan parasite Toxoplasma gondii was due to its evolutionary acquisition of oral transmission. He has been awarded a significant grant by Einstein College of Medicine NIH to continue to study the development of T. gondii by analyzing transcriptomic and metabolic data.

Field (recruited as Reader during the census period) was part of the international consortium that sequenced the genome of Trypanosoma brucei. In collaboration with Dr Mark Carrington (UoA14) he has discovered that endocytosis in trypanosomes is exclusively via clathrin-dependent processes and has also characterized multiple intracellular compartments, demonstrated PI-based signaling in transporter and cell cycle progression, implicated ubiquitination as an endocytosis signal, probed developmental aspects of trafficking and provided a framework for functional genomics. Field has recently been joined by Dacks (Early Career Researcher; Wellcome Trust Travelling Fellow recruited during the census period) to continue collaborations in these studies.

Blackwell’s (FMedSci, 2000) research focuses on the role of macrophages in regulating susceptibility to, and vaccination against, intra-macrophage pathogens (Leishmania, Mycobacteria, Salmonella). The research involves a genetic approach to identifying genes/mechanisms involved in disease susceptibility, with a particular focus on the interplay between infectious and autoimmune disease susceptibility genes. This research led to: the collaborative effort to sequence the genome of the kinetoplastid parasite, Leishmania major, use of DNA and DNA/MVA (collaboration with Alcami, Category C) vaccination methods to screen potential new candidate vaccines and to the first demonstration of a regulatory T cell role in vaccine immunity. Blackwell’s research programme into infectious diseases particularly affecting developing countries also includes investigations of genetic risk factors for leishmaniasis, congenital toxoplasmosis, leprosy and tuberculosis.

Dunne’s laboratory carries out multidisciplinary research on human schistosomiasis and other infections endemic in tropical areas, through long-term collaborations with the Health Ministries and National Research Institutes of Kenya, Uganda and, more recently, Mali, to evaluate interactions between host, parasite and environmental factors in immunity and morbidity responses. This includes studies of disease caused by chronic co-exposure to different infections, e.g. schistosomiasis/malaria, and the balance between promoting infection immunity and controlling of the adverse impacts of allergy, autoimmunity and other immune-morbidities. Conversely, by cross-discipline collaborative experimental studies with Cooke (UoA3, Group D) the ability of helminth infections to prevent autoimmune diabetes have been awarded project grant support from the Wellcome Trust and BBSRC.

There has been significant movement during the census period in this Research Grouping. Melville (Category B), holder of a Wellcome Trust Programme Grant, and a major contributor to the sequencing of the trypanosome genome, was forced to retire due to ill-health. MacKinnon (Category B, holder of a Royal Society Dorothy Hodgkin Fellowship during the census period) and who carries out multidisciplinary research on the interaction of host, parasite and environmental factors in the pathogenesis of human malaria, secured an appointment at the University of Oxford. Newport, a University Fellow collaborating with Blackwell, was awarded a post as Senior Lecturer in Infectious Diseases and International Health. Fallon left to establish his own laboratory in Trinity College Dublin and Hoffmann will become Professor of Parasitology at University of Wales, Aberystwyth, in September 2007. Within the Research Group, Ajioka was promoted to Senior Lecturer, Field was recruited as Reader in Molecular Biology, and Dunne was promoted as Professor of Parasitology.

3.4 Research Group D: Autoimmunity

Research in autoimmunity encompasses diabetes (Cooke, Green), inflammatory arthritis (Busch, Gaston, Goodall, Hall) and systemic autoimmune disorders, particularly SLE (Clatworthy, Floto, Smith). Programme grants totaling £1.9million have been awarded during the census period to support the research in this Research Group. Fellowships totaling £2.5million have been awarded showing a strongly supportive environment for postdoctoral career development supported by senior researchers with a research programmes sustained by programme and project grants.

Diabetes. Cooke (FMedSci) has studied the role that infection might play in inhibiting the development of Type 1 diabetes. The Cooke laboratory has used the NOD mouse model of Type 1 diabetes to show that this is accomplished through effects on both the innate and adaptive arms of the immune response. Mechanisms of diabetes prevention include the expansion and activation of NKT cells following infection with Schistosoma mansoni, generation of immunomodulatory dendritic cells following intracellular infection with Salmonella typhimurium (collaboration with Dr. Mastroeni, UoA16) and development of regulatory T cells. Treatment with cyclophosphamide, long known to accelerate disease development, was shown to reduce numbers of “natural” CD4+ regulatory T cells. The Cooke laboratory additionally demonstrated the presence of progenitor cells in the pancreatic ducts of both adult humans and mice but reversal of autoimmune destruction of β cells in the NOD mouse and inhibition of inflammation was not followed by regeneration to restore β cell mass.

Green (awarded a Wellcome Trust/Juvenile Diabetes Research Foundation Career Development Award in 2001 and successfully awarded a Wellcome Trust Senior Fellow in 2005) uses the NOD model of diabetes, and has also investigated regulatory mechanisms. This work was begun in collaboration with Prof. Richard Flavell at Yale, and continued on Green’s move to Cambridge, utilizing the informative gene targeted mice generated in the Flavell laboratory. The work includes characterizing CD4+CD25+ regulatory T cells and showing their localization in pancreatic lymph nodes rather than in the spleen, which had previously been investigated. These cells required RANK-RANK ligand interactions, and also CD40-CD154 interactions for their expansion; CD154 is also involved in the delivery of regulatory signals to autoimmune CD8+ T cells. In addition signalling through the TGFβ receptor on these cells is also absolutely required. Recently, in collaboration with Prof. Linda Wicker (UoA5), who has developed congenic strains of mice expressing the major genetic regions which confer susceptibility to type 1 diabetes, Green has shown that ability of the Idd9.1 region to suppress autoreactive CD8+ T cells even in the presence of inflammation.

Inflammatory arthritis. Gaston (FMedSci) is investigating the basis of the HLA-B27-associated research on spondyloarthritides (MRC programme grant) and has identified interactions between Chlamydia trachomatis and dendritic cells, together with targets of the response of both CD4+ and CD8+ T cells. A novel subset of CD8+ T cells with regulatory properties was identified that is expanded in spondyloarthritis patients. The role of CD4+ regulatory T cells has also been investigated to determine whether arthritis might relate to excessive regulation of the immune response to bacteria (and hence failure to clear bacteria). However, in a large multi-centre, pan-European trial of long-term antibiotics, coordinated by Gaston, no effect on clinical outcomes was observed. 

Goodall (ARC Career Development Fellowship, 2001 renewed 2006) examined the molecular and cellular mechanisms of HLA-B27 (Group E, Molecular and Cellular Immunity) and hypotheses for its role in conferring susceptibility to spondyloarthritis, including its atypical recognition by CD4+ T cells. This occurrence may relate to inefficient folding of HLA-B27 in the endoplasmic reticulum (ER), which may induce an intracellular stress response that could modify pro-inflammatory cytokine production in monocytes and dendritic cells.

Hall (ARC lecturer, 2003 previously working in Oxford and Stanford) and Busch (Early Career Researcher, previously at Stanford and KineMed, a biotech company) have investigated the role of HLA-DM in the loading of optimal antigenic peptides onto Class II HLA molecules, particularly HLA-DRB1*0401 which is strongly associated with rheumatoid arthritis,and showed that different self peptides alter cytokine production by CD4+ T cells. Hall also found a role for CD4+ T cells in controlling joint inflammation in collagen-induced arthritis, and an unexpected effect of ACE inhibitors on joint inflammation. These latter observations in the mouse model are being followed up in a large randomised controlled trial in rheumatoid arthritis.

SLE. There is considerable interest in the genes which confer susceptibility to SLE and related disorders, and a large number of loci influencing susceptibility or conferring protection have been identified in SLE-prone mice. Smith’s (Lister Prize winner, FMedSci) research programme has included Clatworthy and Floto (funded on an independent Fellowship during the census period) and spans autoimmunity, molecular and cellular immunity and parasitology and molecular and cellular microbiology. He has investigated genes associated with SLE susceptibility in mice and humans, particularly the inhibitory receptor for IgG, FcRγIIb. Absence of this inhibitory receptor was shown in mice to enhance uptake of streptococci (Research Group A) thus enhancing resistance to infection, but at the same time render immunized mice more susceptible to septic shock due to increased production of pro-inflammatory cytokines post uptake of organisms. In a similar vein, a polymorphism in the receptor which predisposes to SLE affords protection against malaria, accounting for the persistence of an autoimmune associated allele in populations at risk of malaria (Research Group C). The polymorphism decreases recruitment of the receptor to lipid rafts and hence its effect on signalling. FcRγIIb has also been shown to be important in controlling plasma cell apoptosis, again with implications for the production of autoantibodies. Finally IL-4 was shown to at least partly exert its stimulatory effect in B cells by down regulating FcRγIIb expression. These studies have been conducted together with Floto and Clatworthy. Clatworthy's focus on proteins associated with autoimmunity has resulted in publications spanning molecular and cellular immunity and parasitology. Clatworthy has also described the role of a novel receptor, SIGN-R1, on protection against infection by Streptococcus pneumoniae. She contributed to studies of the von Hippel landau protein on neutrophil function (collaboration with Prof. E. Chilvers, UoA4). Clatworthy’s research progamme has been supported by a recent Wellcome Trust Intermediate fellowship. Floto has also diveresified his research into autophagy and has worked closely with Rubinsztein (UoA5) to apply this research to diseases such as lung disease and Huntingdon's disease. 

Clinical studies in SLE are also being conducted; Smith has initiated gene profiling studies of patients with active SLE 9and other forms of vasculitis) in collaboration with the Human Genome Centre at Hinxton, and there is a particular interest in the effects of the B cell depleting antibody, rituximab, on SLE patients and the mechanisms involved in its efficacy.

3.5 Research Group E: Molecular and Cellular Immunology

The strength of the research programme in this Research Grouping is evidenced by programme grants totalling £9.4million being awarded during the census period and emerging scientists (Fellowships and New Investigator awards) receiving £1.6million to support their research programmes.
The major research areas and investigators in this grouping are listed below. Investigators comprising new faculty appointments to Cambridge since the last RAE submission have strengthened four of the seven areas of research.
1. Molecular biology of the MHC: Trowsdale
2. Antigen-processing/presentation: Busch, Kelly, Lehner
3. Receptor regulation by ubiquitin: Lehner
4. NK cell functions and receptors: Reyburn, Trowsdale, Vales-Gomez, and Young
5. Signal transduction: Holmes, Rudd, Schneider, and Smith
6. CD8+ T cell functions: Fearon, Griffiths, Sissons, and Wills
7. Antibody engineering/biotechnology: Clark

The human MHC is associated with more diseases than any other region of the genome, including infections, autoimmunity and cancer. Trowsdale (FMedSci) has extended his long-term commitment to the molecular biology of this set of loci by heading a collaboration between several groups in Cambridge (UoA5 [Todd] and UoA9 [Sawcer]) and the Sanger Institute (Beck, Category C) to sequence eight complete MHC haplotypes, encompassing 5.2 Mbp each. This study has provided the majority of the data in public SNP databases; the haplotypes have set the ‘gold standard’ for MHC-linked disease studies. This is exemplified by a follow-up international collaboration that provided informative tag SNPs capturing much of the common variation in the MHC region and that can be used in disease association studies. In addition to the polymorphic class I and class II molecules, novel functions have followed from the MHC sequence. Trowsdale structurally characterized the PRYSPRY protein domain, a component of multiple novel MHC-encoded proteins, the BTNs and TRIMs, and 50 other human proteins. The specific protein Trowsdale studied is a superantigen analogous to bacterial protein A that may contribute to the pathogenic accumulation of anti-TRIM21 autoantibody immune complex in autoimmune disease. However, this first crystal structure of the PRYSPRY domain has broader implications. The structure exhibits a conserved backbone with variable loops which facilitate targeting of other proteins, such as primate HIV in the case of TRIM5-alpha.

The study of viral evasion of MHC class I molecules has identified the critical role played by ubiquitin in regulating cell surface MHC class I molecules and other important immunoreceptors. In studying the Kaposi’s sarcoma-associated herpesvirus, Lehner and Stevenson identified viral ubiquitin E3 ligases which regulate cell surface MHC class I molecules through ubiquitination. Specifically, the formation of lysine-63 linked polyubiquitin conjugates are required for internalisation and lysosomal degradation of MHC class I molecules. Lysine-63 linked ubiquitination appears to be a more general mechanism for the regulation of an increasing number of cell surface receptors both within and outside the immune system. The realisation that the KSHV-encoded viral genes were appropriated from the vertebrate host led to the identification of a novel family of ubiquitin E3 ligases the ‘Membrane Associated RING-CH’ (MARCH) family. Lehner’s work on the MARCH genes has identified a critical role for these cellular ubiquitin E3 ligases in regulating cell surface receptors.

There is considerable local expertise in the molecular biology of MHC class II: studies of peptide loading of MHC class II by fine mapping of the contact residues between HLA-DM for HLA-DR help to reveal how DM catalyses peptide exchange of MHC class II by diminishing the selectivity of the MHC class II groove (Busch, Group D). Mycobacterial HSP70 facilitates immune recognition by activating dendritic cells through binding to CCR5, providing an example of a host adaptation that promotes the immune response to microbial infection (Lehner and Javid [Early Career Researcher]). Javid’s research into the functionality of HSP70 proteins provides an example of a host adaptation that promotes the immune response to microbial infection (Lehner and Javid) and was published in Science. Javid’s continuing interest in mycobacteria and immune-evasion mechanisms has led to the award of a recent MRC Clinician-Scientist Intermediate Fellowship.

The Natural Killer (NK) cell system has evolved as an area of major study in this Research Group, both in its molecular study (Reyburn, Trowsdale, Vales-Gomez and Young) and its involvement in viral pathogenesis (Reyburn, Vales-Gomez and Young), a thematic which is further expanded in Research Group B. The immune system has responded to these viral strategies for impairing CD8+ T cell recognition by the NK cell system that responds to class I as a ligand for inhibitory receptors. However, CMV appears to have adapted to this means for immune recognition by expressing the product of the UL18 gene that binds to the inhibitory ILT2 receptor on NK cells. Interestingly, the affinity of this protein for ILT2 shows a variation that correlates with differences in the UL18 gene between different CMV isolates (Vales-Gomez, Early Career Researcher, MRC New Investigator Award, 2007). The absence of class I on a virally infected cell is not the only mechanism that an NK cell uses for recognition, as cells infected with vaccinia or Herpesvirus up-regulate their expression of ligands for Natural Cytotoxicity Receptors (Reyburn, Young). The interaction of MHC class I molecules with inhibitory receptors on NK or myeloid cells is a theme that several of the groups have contributed to (Reyburn, Trowsdale, Young). Collaborations between Trowsdale and Dr Moffett (UoA4) have resulted in grants being awarded to study the role of NK cells in miscarriage and other reproductive malfunctions.

The key recent appointment of Rudd (Wellcome Trust PRF; FRCP, FMedSci), provides leadership in the area of signal transduction, a field which impacts on multiple groups in the immunology arena. Understanding of immunological problems at the level of signal transduction has focused on several proteins central to immune cell function: CD4/CD8-p56lck (Rudd), CD28 (Rudd), CTLA-4 (Rudd and Schneider), ADAP (Rudd), SKAP-55 (Rudd), FcgRII (Smith, Group D) and CD45 (Holmes). Rudd is continuing to understand the mechanism of CD4-p56lck and other receptor kinase interactions and the co-receptor CD28 that provides an essential second signal in T-cell activation by recruiting phosphatidylinositol 3-kinase (PI-3K). Drugs against the immune specific form of PI 3K have recently shown promise in the treatment of cancer and immune disorders. Conversely, CTLA-4 ,which suppresses T cell activation/function and inhibits autoimmune syndrome in mice and possibly several human autoimmune disorders such as human Type 1 diabetes (Group D) has been shown to reverse the TCR ‘stop signal’ to impair interaction with antigen-presenting cells (APCs). The additional discovery that CD28 and CTLA-4 modulate raft expression on the T-cell surface and that the chaperone TRIM controls CTLA-4 expression (Rudd and Schneider) adds to the molecular basis for their function. Rudd has also uncovered the key components of ‘inside-out’ signalling pathway that controls T-cell adhesion/migration and T cell/APC conjugation with the discovery of the adaptor proteins, ADAP and SKAP-55. ADAP and SKAP-55 deficient mice are immune-compromised in their response to foreign antigen. The inhibitory FcγRII has been found to come in at least two allotypic forms that differ in their inhibitory capability. The relatively weaker inhibitory form that is excluded from lipid rafts may predispose to autoimmune disease, but conversely may be associated with resistance to malaria (Smith, Group D). The immune system appears to have dealt with the compromise between host defense versus autoimmunity in this instance by having selected for two allotypic forms of this inhibitory receptor.

The emphasis on virology/viral pathogenesis/class I antigen presentation/NK cells in the Infection and Immunity program of the University, outlined above, is complemented by an increasing development of research on the CD8+ T cell. This represents a strategic commitment to further strengthening this aspect of immunology in Cambridge, as exemplified by a recent important addition to the faculty with internationally recognised expertise in this area (Griffiths; Wellcome Trust PRF, FMedSci, EMBO Member) and a change to this field of research by a senior faculty member (Fearon, FRS, NAS member, FMedSci, EMBO Member, FRCP). Fearon's research programme is enhanced through interactions with Betz (Category C) and Neuberger (Category C) from the MRC-LMB. The critical effector cell of the adaptive immune system for controlling viral infections is the cytotoxic T lymphocyte (CTL) which uses a novel form of polarized vesicle to deliver a lethal hit (Griffiths). Understanding of this process is, of course, also relevant to the mechanism for cytolysis by the NK cell. Analysis of the human CD8+ T cell response to CMV has shown that there are long term stable clonal populations in both the CD45RO+ and CD45RA+ populations of antigen-experienced cells (Wills). This observation indicates that clonal maintenance rather than clonal succession is the mechanism by which new effector CD8+ T cells are generated in response to this persistent viral infection. The late diversification of the clonal CD8+ T cell response to CMV following allogeneic hemopoietic stem cell transplantation emphasizes the need for other strategies for immune reconstitution (Sissons, FMedSCi), and is relevant to studies of how CD8+ T cell clonal expansion and effector differentiation occurs. Expansion by repetitive TCR ligation and IL-2 causes effector differentiation and loss of replicative function after adoptive transfer, whereas expansion via the newly identified TCR/CD27 pathway maintains the CD8+ T cell in an undifferentiated state that is capable of mediating normal expansion in vivo in response to viral infection (Fearon). This finding supports an earlier proposal that the CD8+ T cell response to persistent and repetitive infections requires a self-renewing stage of pre-effector development, and is consistent with the clonal persistence of human CD8+ T cells specific for CMV.

The therapeutic application at an academic level of basic molecular and cellular immunity in Cambridge is being continued by antibody engineering of Fc domains with diminished or altered interaction with FcγR’s. This development has been applied to an anti-Rh antibody that, when bound to Rh-positive erythrocytes, does not result in the extremely rapid clearance observed with the antibody having an unmodified Fc domain (Clark). It is well known that Cambridge contributed the development of the therapeutic use of antibodies. Clark continues to guide this development through his input into the use of CAMPATH-1, research which was initiated in Cambridge. Clark was successful in obtaining 4 US patents during the census period, in addition to other European patents.

3.6 The Future

The critical mass of investigators engaged in high-quality research in UoA3 provides a platform for strengthening in the future. The key objectives will be to enhance our existing flagship programmes and to develop new ones. Future initiatives will focus on expanding research activity in the areas of strength. The common underpinning theme will be the integration of high quality basic research with the study of important host pathogen interactions, in order to achieve translation into clinical, pharmaceutical, veterinary and public health applications.

There is continuing need to underpin research programmes with core infrastructural funding for basic and clinical research, and to provide high quality training/capacity building. The investment since RAE2001 and the sustained infrastructure development during the census period have provided a strong foundation. It is necessary to continue to provide key research infrastructure funding. The School's future strategy is to provide key research infrastructure and core physical facilities that are essential in order to recruit leading scientists within and without the University.

There are excellent interdisciplinary collaborations particularly those in which clinical research and basic research are integrated within the University to assist in the continuing, crucial training of PhD students. Nonetheless, opportunities exist to further extend current networks across the University to include those working in public health, health economics, geography, and anthropology of infection and immunity, as well as the more traditional sciences such as physics, chemistry, materials science and nanotechnology. This will result in a truly multidisciplinary infection and immunity enterprise and the benefits of these synergies will be realised in further collaborations and funding.

The broader strategic objective underpinning the Infection and Immunity programme is to increase the University of Cambridge’s contribution to reducing the global burden and impact of disease, particularly in developing countries. It is the University’s aim to enhance its capacity in infection and immunity (research and teaching) by attracting new research partnerships and funding.

Our strategy, in summary, is to enhance our current strengths, to promote interdisciplinary interaction through new posts and structures, to expand the research programmes, and to provide and sustain high quality infrastructure.

Part 4: Esteem Document

During the census period, 19 individuals have served on national and international research boards and panels (MRC, Wellcome Trust, ARC amongst others). 18 have acted as members of editorial boards for 35 journals.

Individual Contribution to Major Advisory Boards:

• Dunne: WHO expert committee on Schistosomiasis (2005) and advisor to the Gates-funded schistosomiasis Initiative to mass treat schistosomiasis in sub-Saharan Africa.
• Cooke, Lee and Gaston, Fearon, Minson, Brown, Blackwell, Sinclair, Clark and Holmes act on scientific advisory boards to numerous panels advising MRC research institutes, WHO, governments (British, Finnish, Chinese, Dutch and American) and national and international companies (including NOVACTA, KineMed and Domantis).

Exploitation of Research Outcomes to Users/Public

• Dunne: Field clinical and ultrasound examination methods developed in studies in Kenya and Uganda have been transferred to the Gates Schistosomiasis Control Initiative to monitor effectiveness of morbidity control in the National Schistosomiasis Control Programmes in Uganda, Mali, Tanzania, Zambia, Niger, and Burkina Faso. Uganda was chosen to launch this pan-African schistosomiasis control initiative in 2003, because capacity building in long-term collaborative projects provided a cohort of highly trained Ugandan scientists, technicians, and community workers trained in parasitological, clinical and epidemiological methods
• Clark: has established work as a protein engineering specialist. Collaborative research (with Waldmann, now at Oxford University) resulted in the therapeutic antibody, CAMPATH, which obtained FDA (USA) and MCA (Europe) approval in Europe in 2001 and in 2005 was entered for clinical trials broadening its application to the treatment of Multiple Sclerosis. Clark has other antibodies also currently being trialled in Phase I studies.
• Hall: clinical trial being undertaken as a result of research in inflammatory arthritis and the publication of an algorithm for cardiovascular risk reduction in various arthritic diseases.
• Minson: new diagnostic technique developed for the detection and quantification of virus particles (in collaboration with Dr David Klenerman; UoA18).
• Lee: established a spin-out company, Diagnostics, for the Real World Ltd with the University of Cambridge and the Wellcome Trust as shareholders.

Election to Prestigious Research-Based Bodies

• Fellow of the Academy of Medical Sciences: Cooke, Gaston, Griffiths, Lehner, Minson, Rudd, Smith
• Fellow of the Royal College of Physicians: Lehner, Smith
• Fellow of the Royal College of Pathologists: Rudd
• Fellow of the Royal Society of Chemistry: Lever
• Henry Kunkel Society: Smith, Lehner, Sissons
• Member, National Academy of Sciences (USA); Fearon
• Fellow of the World Innovation Foundation: Trowsdale
• EMBO: Griffiths
• Gene Therapy Advisory Committee: Lever

Major Personal Awards/Prizes

• Lever: Lennox Black International Prize in Medicine
• Lee: European Woman of Industry (2006), British Female Inventor, Best Diagnostic Innovation Award (Medical Futures Innovation Competition), Lord Lloyd of Kilgerran Award (British Foundation for Science and Technology).
• Lehner: Lister Prize
• Smith: Lister Prize and Lockwood Award from the British Renal Association
• Green: GJ Thorbeck Award (International Society for Leukocyte Biology)
• Clatworthy (Early Career Reseracher): British Renal Association Raine Award (Young Investigator Award) 2005, 2006; Mary Evelyn Lucking Prize in Medicine
• Javid (Early Career Researcher): Metachem Prize at the British Society of Immunology (BSI) 2002
Promega ‘Young Immunologist of the Year’ at the BSI annual congress in 2003.
Prize winner ‘Max Perutz’ MRC essay competition 2003.
Finalist, Royal Institution L’Oreal competition 2004.

Cooke has been made an Honorary Fellow to University College London. Four (Blackwell, Cooke, Gaston and Smith) have been awarded Visiting Professorships to various international Universities (8 in total).