Report from the visiting committee

Transcription

1 Section des Unités de recherche Report from the visiting committee Research unit : Immunology, Immunopathology, Immunotherapy UMR_S 543 University Paris 6 February 2008

2 Section des Unités de recherche Report from the visiting committee Research unit : Immunology, Immunopathology, Immunotherapy UMR_S 543 University Pierre et Marie Curie - Paris 6 February 2008

3 Report from the visiting committee The research unit : Name of the research unit : Laboratoire d Immunologie Cellulaire et Tissulaire Requested label : UMR_S INSERM N in case of renewal : 543 Head of the research unit : M. Patrice Debré University or school : Université Paris 6 Other institutions and research organization: INSERM Date(s) of the visit : février

4 Members of the visiting committee Chairman of the commitee : M. Jean-Laurent Casanova, Paris Other committee members : Mr Robert Menard, Paris Mrs Andrea Cooper, Trudeau Institute, USA Mr Charles Bangham, USA Mr Marc Parmentier, Brussels, Belgium Mr Guido Poli, Milano, Italy Mr Frédéric Geissman, Paris Mr Jean Dubuisson, Lille Mr Joost Van Meerwijk, Toulouse Mrs Pascale Mercier, Toulouse CNU, CoNRS, CSS INSERM, représentant INRA, INRIA, IRD..) representatives : Mr Camille Locht, Lille, INSERM representative Mr Pierre Galanaud, Paris, CNU representative Observers AERES scientific representative: Mr Nicolas Glaichenhaus University or school representative: Mrs Jacqueline Capeau, Université Paris 6 Research organization representative (s) : Mrs Christine Tuffereau, INSERM 3

5 Report from the visiting committee 1 Short presentation of the research unit Number of lab members with teaching duties : 18 including 15 with clinical duties Number of full time researchers : 11 Number of postdoctoral fellows : 11 Number of ingeneers, technicians and administrative assistants : 16 Numbers of HDR : 19 Numbers of PhD students currently present in the research unit : 31, all with a fellowship Numbers of PhD. students who have obtained their PhD since October 2003 : 22 Average lenght of a PhD during the past 4 years : 3 years and 6 months Number of «publishing» lab members : 29 out of 29 2 Preparation and execution of the visit The visit started by a 30 minutes presentation by the director the Unit. This was followed by 30 minutes presentations by each of the 4 team leaders (15 minutes presentation and 15 minutes discussion). 3 Overall appreciation of the activity of the research unit, of its links with local, national and international partners This unit results from the fusion of two INSERM units, U511 and U543. It belongs to the IFR113 that also includes UPRES EA1541, UPRES EA 2387, and UMR 7097, and clinical and biological departments. Of note, the campus Pitié Salpétrière includes IFR14, IFR50 and IFR113. Research axis include (i) Host-pathogen interactions and inflammation, (ii) Biodiversity, and (iii) Innovative therapy. The unit included 7 teams (of note, one team has withdrawn its application). Appreciation of Core facilities The unit benefit from access to several core facilities (animal facilities, genomics and post-genomics named P3S, flow cytometry and cellular imagery). These core facilities offer operational and technical supports to the 4 units of IFR113 and to the 2 other IFR located on the site as well. Each facility is managed by a qualified engineer with a permanent position as executive staff and with a scientific researcher as coordinator. A scientific committee including users from each IFR helps to set optimal operating modes (quality control, apparatus implementation, evolution). The executive staff makes sure the apparatus are working properly and provide a short training course to new users in order to make people fully competent and autonomous for use of some apparatus: The animal core facility has been recently restructured. It concerns two large animal facilities including type 3 confinement and room for rederivation and transgenic mice production using lentivirus. An operating director (DMV) has been recently recruited and the housing capacity will be significantly extended by 2008 (+1200m2). This evolution will require new technicians and equipments. 4

6 The P3S core facility is particularly well furnished and has been up-graded from transcriptomics in 2001 to proteomics in It makes use of a large panel of apparatus as bioanalyzer, scanner microarrays, bioinformatics software tools and applies analytical and preparative high-resolution 2-D PAGE, high-throughput mass spectrometry analysis for proteomics, operated by highly-qualified staff who assist with projects and their troubleshooting in an interactive environment. The engineer having in charge this core facility still does not have a permanent position. The flow cytometry core facility is more recent (2006). It benefits a well experimented engineer and is under the supervision of a scientific committee which has recently established a well detailed manual describing procedures and recommendations to users. With several analysers and one multi-parametric cell sorter (FACS Aria) this facility offers a unique opportunity for high speed sorting of pathogen-infected cells. This facility is already overbooked only by on site researchers with strong requests from outside laboratories. There is a real need for a multi-parametric analyser and most likely for an additional technician. The cellular imagery core facility is well furnished (from confocal microscopy and time laps video recording to electronic microscopy) and well managed by an engineer assisted by a researcher. The goal of this core facility is to maintain and provide the necessary instrumentation and training required by investigators. It will benefit soon from the acquisition of a bi-photon microscope for intravital imaging in mice. In summary most of the core facilities are well furnished and well managed. Their visibility is pretty good. They all benefit from a web site (that need for some of them to be updated) and scientific animations (training courses, technical seminars ). A particular weakness is the invoicing to facility s users of functioning expenses or running costs which lack constant follow up (imagery, P3S, cytometry?). This is not the case for animal facility which has a part-time technician dedicated to this task. The help of administrative staff could resolve this issue. Although the capability of the ITA/ITAOS to manage the different facilities appears satisfactory, in some cases the large number of apparatus (imagery and P3S) or the increasing charge of work (animal facilities) is not related to the number of dedicated technicians /engineers. In the long term this could be detrimental for their optimal performance. 4 Specific appreciation team by team and/or project by project Team 1 : Immunity and immunogenetics of viral infections and vaccines The head of this team is a senior researcher with a PU-PH position. The team leader presented a succinct summary of the work of the I2V2 unit. This work covers a broad range of activities in a number of viral infections, including HIV, CMV, HHV-8 and vaccinia virus. Indeed, there was discussion in the Audit Committee as to whether the range of subjects covered was excessively broad. However, it was evident from the documentation supplied, from the bibliography of recent publications and from the presentation that the team has maintained both an appropriate focus on a small number of themes (see below) and a high standard of publications. The chief themes of the group are the attempt to define, measure and improve the efficiency of the cell-mediated immune response to viruses, whether elicited by natural infection or vaccines, and the study of the cell-mediated immune response to viruses in the context of immune deficiency (especially HIV infection and AIDS). The team leader illustrated this theme in the presentation by presenting recent progress on two projects: the host immunogenetics of the immune response to HIV, and in particular the role of the cytotoxic T lymphocytes (CTL) response to HIV. The Audit members commented on the importance of the questions being studied, the excellent group of international collaborators in Europe and the U.S with which the group maintains a close liaison, and on the excellent publication record. It is highly creditable that the team has long maintained its high stature in this intensely competitive field. The committee ranks this team among the top 10% internationally in its field. Team 2 : Immune regulation and immune therapies The head of this team is a senior researcher with a PU-PH position. Projects include (1) Analysis of CD4 + CD25 + FoxF3 + T cells in humans, (2) Comparative analysis of regulatory and conventional T cell repertoires in 5

7 healthy humans and patients withg systemic inflammatory disorders and (3) Molecular evolution of TCR in vitro. The research is good and original, with a good list of publications (including a landmark paper in the J Exp Med). Both leaders are also well recognized in their own line of research. However the integration of these lines of research into a global project could be improved. The leadership of the whole team itself is not yet clearly defined. The director and the investigators should foster and encourage productive interactions within the entire team. Two patents have been produced in the last 4 years, based on the work on NK cells in HIV disease. The two main lines of research (Treg in immunopathology and NK cells in HIV disease) are relevant and integrate both fundamental and applied research. The project research plans have good potential, in view of the work performed so far (particularly the recent work on repertoire), of the strong collaborations with local teams in the field of autoimmunity, and with other teams expert in the field of HIV. The comitee ranks this team among the top 25% internationally in its field. Team 3 : Chemokines in pathology and inflammation The head of this team is a senior researcher with a DR2 position. This team also includes 2 researchers with permanent positions and one enginneer. The research program includes clinical studies, preclinical models and structural and functional studies. The team leader is a very good researcher and an expert in the biology of chemokines receptors in mouse models. He has organized in the past 5 years collaborations with expert teams in the fields of vascular biology and eye biology, that have led to very good publications on the roles of chemokines receptors in atherosclerosis and age related macular degeneration. This line of research is very relevant to human health. The potential for future success is high. However, the second line of research of the team (structure/function relationship) by the co-pi is far less successful or productive by any criterion. The committee stress that the A mark only apply to the main line of research of the group. The line of research on structure/function relationship is not competitive. The committee thinks that the leader of the team should probably focus the work and resources of the lab on the mouse models. The committee ranks this team among the top 25% internationally in its field. Team 4 : Routes of immunization, vaccines and immune memory The head of this team is a senior researcher with a DR2 INSERM position. This team also includes 2 postdoctoral fellows, 3 PhD students and one technician. Another senior researcher with a CR1 position will soon join the team. The head of the team has a good record of publications as first or last author during the last four years, usually in excellent journals of hemato-immunology (Blood, J Immunol) and even multidisciplinary journals (J Exp Med). The head of the team was regularly invited to international meetings, demonstrating her recognition in the field. A patent related to the transcutaneous route of immunization was filed in The second senior researcher is less productive. The projects of Team 4 include basic aspects of immunology, such as the understanding of immune responses to vaccines and the bases of vaccine memory. They also involve more applied research themes, including the testing of diverse vaccination routes in preclinical models and clinical trials, and the use of chemokine analogs as vaccination adjuvants. The transcutaneous vaccination approach appears as one of the strengths of the group. The presentation of the team's project was excellent, with a clear description of achievements and perspectives. Although of high quality, the projects were perceived as rather diffuse, spreading across a large area for a relatively small group. Focusing the activities would likely increase their impact on the scientific community. Team 4 is well integrated in the Unit, with productive interactions with teams 1, 2 and 3. The team has also a large number of collaborations with other French and foreign groups, including in the frame of EU-funded programs. Several collaborations have also been established with industries. The team has access to most of the necessary equipment through platforms (cell sorting, microscopy, genomics, proteomics, animal facility) available in the Unit or on the campus. They declare the need of a L2 and animal A2 facilities for the manipulation of pathogens. This is indeed necessary for the development of the team. The head of the team is well funded by various sources including the ANR, ARC, La Ligue, the Cancéropole, the ANRS and the Ministry of Defence. The perspectives of team 4 appear therefore excellent. Altogether, Team 4 was rated in the top 25% internationally in the field. Team 5 : Immunity and immunogenetics of viral infections and vaccines The head of this team is a senior researcher with a CR1 INSERM position who was granted an AVENIR label. This team also includes 1 postdoc, 1 PhD student and one technician. Projects include (1) the study of clonal exhaustion of HIV-specific CD8 + T cells and (2) the study of global exhaustion. The team is lead by a young, yet already well established investigator in the field of immunology and immunopathology of HIV infection. The central hypothesis of the Team (i.e., immunosenescence as a pathogenetic mechanism contributing to the relative inefficiency of the CTL response in clearing or keeping in check virus replication) has the plus of the originality, but also a minus in terms of specificity of this hypothetical central mechanism of T cell exhaustion. Is the accelerated aging of T cells cause or consequence of the chronic viral infection and stimulation? The articulation of the project seems not to fully exploit 6

8 expertise existing in the Unit in order to clarify this fundamental aspect (for example, taking advantage of protocols of experimental vaccination in order to compensate for the substantial loss of anti-gens associated with HAART). Nevertheless, the quality of the methodological approach, the competence of the team leader and the overall environment of the Unit are almost a warranty of success and discovery of novel aspects of T cells Immunopathology regardless of the solidity of the central hypothesis. The comitee ranks this team among the top 25% internationally in its field. Team 6 : Malaria : identification and preclinical validation of drug and vaccine targets The head of this team is a senior researcher with a permanent position. The team is associated with the Laboratory of Malaria Immunobiology in Singapore. The committee noted a good productivity of the Team in the last 4 years and recognized the discovery of a new lead compound active against liver stages of the malaria parasite, but also expressed concerns with the plans for future research. The traditional strength of the Team is on pre-erythrocytic stages of the malaria parasite. In 2003, the Team made a seminal contribution with the demonstration of the important role of host CD81 in sporozoite invasion of host cells, thus identifying the first host molecule playing a role during parasite entry. Unfortunately, the 2003 breakthrough was not followed by further significant insights into sporozoite invasion of host cells. Instead, the Team is pursuing various highly ambitious projects tackling different topics including (i) the biology of pre-erythrocytic stages (including the molecular basis of parasite entry into cells and the identification/characterization of parasite products expressed when the parasite is transmitted to the mammalian host), (ii) the identification of new compounds active against liver stages, (iii) the design of a cell line permissive to P. falciparum, (iv) the discovery of new vaccine candidates against liver stages, (v) the identification and characterization of parasite factors playing a role in induction of apoptosis in endothelial cells, and of the signalling pathways induced in the latter, and (vi) the identification of molecules involved in cerebral malaria by mass spec. The committee felt there were (too) many unrelated projects tackled by groups that might not have the sufficient human resources for yielding significant advances. It was also not obvious how the various groups in the Team could easily cross-fertilize. Additional concerns were (i) the fate of a senior researcher working on transcription factors in the parasite, after the dissolution of Team 7, (ii) how a researcher of this group will be able to capitalize on his important recent insights into parasite retention in the spleen, and (iii) the as yet undefined role of another researcher in linking a group in Singapore, and that of Team 6. The integration of these new groups into the work of the whole Team, as well as the key biological questions asked by the Team, were unfortunately poorly outlined both in the oral and written presentations. In conclusion, the committee thought that fewer and more focused goals, following up on previous achievements of the Team, might help to increase the output and visibility of the Team. The committee ranks this team among the top 50% internationally in its field. Team 7 : withdrawn Team 8 : Evolution and pathogenicity of yeast candida glabatra The head of this team is a senior researcher with a MCU-PH position. This team also includes 2 MCU-PH and 1 PH. The team was score C (bottom 50%). The scientific production is below average, only rarely in the leading specialized journals (Clin Infect Dis, J Clin Microbiol), and never in multidisciplinary journals. The scientific projects are most unlikely to result in any important discovery. Team 9 : B cell receptors and lymphoid B cells oncogenesis The head of this team is a senior researcher with a PU-PH position. This team also includes 2 postdocs, 3 PhD students and one technician. Regular publications in leading scientific journals in the field (leukaemia, blood), but no publication in multidisciplinary journals. The lack of in-depth biological investigation accounts partly for the lack of major discovery. The theme of research is however of scientific and medical interest, and the cohort of patients provides a unique added value. This team should recruit a scientific leader, who would benefit from the clinical and haematological expertise of the current leader. The committee ranks this team among the top 50% internationally in its field. 7

9 5 Appreciation of resources and of the life of the research unit Management : A positive aspect is that there are truly independent teams, with a good support provided by the laboratory director, in particular with emerging young group leaders. A weak aspect is that the teams are involved in too diverse fields and that the laboratory lacks a clear scientific strategy. There is neither a strategic theme nor a collection of outstanding individuals. Human resources : The human resources are well managed. Communication strategy : The communication strategy is obviously a weak point of the laboratory. For example, there were no page number and no table of content in the laboratory s report sent to the members of the committee. 6 Recommendations and advice Strengths : The laboratory is meritoriously interested in conducting human research of clinical relevance. There seems to be positive scientific interactions and collaborations between certain groups. The laboratory provides a good environment for young investigators to foster and thrive. Some teams are solid and a few are innovative. This largesized laboratory offers good resources, facilities and platforms to the investigators. Weaknesses : There is clearly a lack of synergy, with little interaction and collaboration if any between certain teams. There is also a considerable scientific heterogeneity, both in terms of themes of research (e.g. biology of fungi and investigation of HIV-specific T cell responses) in terms of the quality of the teams (see individual team assessment forms). Only one of the seven teams can be considered as an international leader (top 10%). The other teams, including those three ranking in the top 25% did not make any path-breaking scientific contribution in the last 5-10 years. As a result, the laboratory publishes most papers in specialized journals, with the exception of a few teams with one or more high-profile publication. The overall productivity of the laboratory is therefore low. Likewise, the projects of the lab are poorly imaginative and daring, and are therefore not expected to yield paradigm-shifting scientific results. Recommandations : The laboratory should develop a long-term strategy to enhance scientific coherence and to foster experimental collaboration between its teams. The laboratory might recruit new teams in other, unrelated fields, yet only if they were exceptional, high-quality teams widely recognized as international leaders. The laboratory cannot improve merely by growing in size; on the contrary, this will most likely result in a further decrease of its scientific productivity. The conditions to reach a scientific leadership impose either a tight synergy between the teams or the recruitment of outstanding scientists, or both. A first step may be to dismantle the present structure to focus more financial ad human resources into the best teams of the laboratory. Conclusions : The laboratory was scored among top 50% in its field, internationally. Despite the presence of one very good team and three good teams, there is clearly a missed opportunity to develop a coherent scientific strategy, with no clear hypothesis and experimental plan for the laboratory as a whole. The laboratory has the potential to improve and reach the top 25% in its field if the coordination was improved, with a focus on a general question that the various teams may tackle from different angles, and if the individual quality of the teams was higher and more homogeneous. 8

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