Report from the visiting committee

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1 Section des Unités de recherche Report from the visiting committee Research unit: Architecture et Réactivité de l'arn UPR 9002 University of Strasbourg 1 April 2008

2 Section des Unités de recherche Report from the visiting committee Research unit : Architecture et Réactivité de l'arn - UPR 9002 University of Strasbourg 1 april 2008

3 Report from the visiting committee The research unit : Name of the research unit : Architecture et Réactivité de l'arn Requested label : UPR CNRS N in case of renewal : UPR 9002 Head of the research unit : M. Eric Westhof University or school : University Strasbourg 1 Other institutions and research organization: CNRS Dates of the visit : February 19th-21st,

4 Members of the visiting committee: Chairman of the commitee : M. Bertrand Séraphin, Gif sur Yvette Other committee members : M. Frédéric Allain, Zurich, Switzerland Ms. Renée Schroeder, Vienne, Austria M. Roland Hartmann, Philipps-Universitaet, Marburg, Germany M. Walter Keller, Basel, Switzerland M. Felix Rey, Paris Mme Geneviève Ball, Paris CNU, CoNRS, CSS INSERM, représentant INRA, INRIA, IRD ) representatives : Gilbert Deléage, Lyon, CoNRS and CNU representative Observers AERES scientific representative: M. Philippe Bouvet, Lyon University or school representative: M. Mir Wais Hosseini, Université Strasbourg 1 Research organization representative : M. Thierry Meinnel, CNRS 3

5 Report from the visiting committee 1 Short presentation of the research unit Numbers of researchers with teaching duties : 11 Number of full time researchers : 27 Number of PhD students : 24, all with funding Number of ingeneers, technicians and administrative assistants : 20 Numbers of HDR : 27 Numbers of PhD students who have obtained their PhD since 2004 : 20 Average lenghth of a PhD during the past 4 years: 4 years and 1 month Numbers of lab members who have been granted a PEDR : 3 Numbers of publishing lab members: 35 out of 38 2 Preparation and execution of the visit The schedule of the visit was prepared through s and phone call exchanges between the Lab Director, the AERES representative and the Evaluation Committee director, taking into account directives transmitted by the AERES. communication between the committee members was used to prepare the on-site evaluation. The visit started at 14H00 on Tuesday February 19, 2008 and ended on Thursday February 21, The visit of UPR9002 was followed by the visit of the Institute that took place on Thursday February 21, 2008 afternoon and that was performed by the same committee. A bief overview of the vist schedule is given below. Overall, the visit took place in very good conditions, thanks to the efficient local organisation under the supervision of the lab director. Day 1: 14h00-14h15 : 14h15-14h45 : 14h45-15h25 : 15h25-17h40 : 17h40-18h25 : 18h25-19h10 : Committee meeting Closed doors meeting of the committee with the Director Open presentation by the unit Director First round of team presentation (30 min + 10 min question) Meeting with permanent researcher and teachers representatives Meeting with PhD students and post-docs Day 2 9h00 10h30 : 9h10-12h10 : 13h45-16h55 : 16h45-16h55 : Meeting of ITA with the committee (9h00-9h10) and the ITA representative (9h00-10h30) Second round of team presentation Third round of team presentation Presentation of the future department 4

6 16h55-17h15 : 17h15-20h00 : Closed doors meeting of the committee to prepare lab visits Lab visits Day 3 9h00-10h00 : 10h00-12h00 : 12h00 : Meeting of the committee, unit director and representatives of the local CNRS administration and the University Louis Pasteur Closed doors meeting of the committee Brief oral summary by the Evaluation Committee director 3 Overall appreciation of the activity of the research unit, of its links with local, national and international partners The CNRS unit UPR9002 is recognized internationally as a major center for the analysis of the structure and function of RNA, with some of its teams being leaders at the worldwide level in this domain. During the past years, the unit has experienced the departure of several permanent research staff members who have had a major role in the functioning of the institute for many years. This was taken as an occasion to see the emergence of new teams, traditionally (with one exception for the time being) resulting from the burgeoning of internal groups. Future recruitments of new groups, always in the area of RNA biology, are already programmed to further reinforce this unit. This trend is likely to continue in the next years and the committee would encourage the establishment of new teams bringing in new subjects related to RNA. The reorganization of the institute four years ago had seen the creation of three departments. In the new organigramme, these have essentially disappeared; a situation that is understandable given the limited size of the UPR9002 unit. For the forthcoming contractual period, four groups will remain associated in a department to foster work on trna synthetases. Overall, the committee got the impression that technicians, students, post-docs and permanent researchers were generally pleased by the stimulating working atmosphere within the unit, which they recognized as a place of expertise to work on RNA. UPR9002 is well connected to other units in the wide Rhine valley area (Strasbourg, Basel), as inferred from joint retreats and numerous collaborations. It will be important that the work of UPR9002 in these collaborative projects is adequately recognized. The UPR9002 unit also appears to have established good relationships with its local contact administration (CNRS, University Louis Pasteur). Of further note is the considerable number of staff members strongly engaged in university teaching, documenting the integral role of this CNRS UPR in university education at Strasbourg and University Louis Pasteur in particular. Overall, the UPR9002 appears to be an internationally competitive unit. The current director can be acknowledged for the successful work toward modernizing this unit and maintaining its international competitiveness. Appropriate support should be provided in the forthcoming years to further stimulate its development, in part through the recruitment of dynamic young teams. 4 Specific appreciation team by team and/or project by project Group ARN messagers et ARN régulateur procaryotiques : This is a young and dynamic team with an excellent publication record and that includes permanent researchers, students and post-docs. The team studies two very topical projects, the first dealing with the regulation of translation initiation for bacterial messenger RNAs with structured 5 UTRs. This project led to the elucidation of the mechanism of translation regulation at a blocked ribosome at high resolution. The second deals with regulatory RNAs in Staphylococcus aureus. This is an excellent project, because it spans from the biology of bacterial virulence to the molecular mechanism of ncrna-mediated regulatory networks with potential medical applications. The team has a strong integration into European research networks working on bacterial non-coding RNAs, from which two international post-docs were recruited. Therefore, the external funding of this team is excellent. The publication record is also excellent and the international visibility and recognition of this team is very good. We yet recommend that reported research results 5

7 considered to be intellectual property of the group leader should be better identifiable as such by last and/or corresponding authorships. This team is among the very best of the unit and deserves full support in the future. The projects are suitable to achieve long-term goals toward understanding ncrna networks. The team is also in a good position to promote the mobility of the post-docs. Group Réplication des virus à ARN et des rétrotransposons : Although seen as an interesting area of research, the committee is concerned about a certain dispersion of research topics followed by this group, and also about the relevance of the applied research studies to identify more inhibitors of HIV-1 reverse transcriptase. The group appeared to have some interesting data suggesting a role for the HIV-1 vif protein during particle morphogenesis, but it did not become obvious that they had a clearly defined strategy to move beyond this stage. Instead, the authors seem to focus on trying to pursue the down-regulation of APOBEC-3G translation by binding of vif to its messenger RNA. Beyond what has already been established, namely that vif counteracts the editing effect of APOBEC-3G by targeting it for degradation, a clear line of research to sort out all the different effects that are attributed to vif was not evident. Moreover, the group is opening an additional, completely different research line, which is the study of the packaging of the genomic segments of influenza virus, and only had preliminary data to show on this. The recommendation of the committee for this group is to focus on one or two strong scientific issues such that they can make a significant impact in their field. The group has enough capacity to do so, provided an effort is made to avoid dispersion. Group Biophysique et biologie structurale : The committee has mixed feelings about this group that has a focus on biophysical methods (mostly X-ray crystallography) for the study of RNA structure, folding and interactions. Although the group is undoubtedly competent and quite productive (23 papers), the papers produced are not of sufficient impact to provide an international visibility to the group. This group has been focusing for years on X-ray method development, which was of course crucial for the UPR9002 unit as a whole. The committee sees today s challenges and perspectives for scientific achievements in X-ray crystallography more in structural biology questions than in the development of specialized techniques with some potential for future applications. At present, the group has been trying to focus on difficult structural biology projects and on the development of new biophysical methods (i.e. microfluidics). Here, the committee is afraid that the group might dissipate energy by pursuing too many directions. Also by relying too much on collaboration, the scientific impact of the group tends to be diluted. The recommendation of the committee is therefore to focus on one strong structural biological project and X-ray as the biophysical method, enabling the group to make significant scientific contributions and be competitive. Group Ingénierie et cristallogenèse des systèmes d aminoacylation : The committee understands the impact of the work of this group over the years, including important direct contributions to the wealth of structural information currently available on trna synthetases (aars) and trna/aars complexes, to the mechanisms of aars function and specificity, and also to RNA-protein interaction. This project has largely disseminated in the Institute. This group has also been among the few worldwide that tried to understand and rationalize the process of crystallogenesis of biological macromolecules. This latter line of research, on which the group will concentrate in the future, has not led to very high impact publications per se, but has had an enormous indirect impact on the wide community of X-ray crystallographers by showing the way to obtain and improve the quality of crystals of important macromolecules. Recent technological developments, using micro-fluidics, which have been patented and will soon be accessible to other labs, are successful examples of results with a large practical impact on the crystallization of difficult proteins, RNAs and RNA-protein complexes. Similar comments can be made for the counter diffusion strategy to grow better crystals. Paralleling its work, the group appears to have established good connections at the international level. The committee believes the new focused line of research of this group will give the chance for the emergence of a new leadership in this area during the next contractual period. Group ARNt mitochondriaux et pathologies : The group has a long history on studies of aminoacyl trna synthetases and has focused in recent years on the analysis of mutations in mammalian mitochondrial trna genes and their cognate synthetases. Many of these mutations can cause a variety of neurodegenerative disorders and other general or tissue-specific abnormalities. The molecular mechanisms underlying these defects are in no case known and their elucidation is of medical importance. The group has the expertise and a network of collaborations to help unravel the mysteries connected to mitochondrial pathology. In recent years, the group has begun to pursue a systems biology concept, analyzing the state and capacity of the mitochondrial 6

8 translation system in a wide variety of human tissues. Taking into account that this group is heavily involved in teaching at the University Louis Pasteur and engaged in international networking of this university, their scientific output and international visibility is very good. The committee recommends maintaining the level of present support. Group Evolution des machineries traductionnelles : The work of this group is based on oddities of the trna aminoacylation and modification machineries to find new mechanisms implicated in proteins synthesis. For this purpose the group analyses enzymes isolated from various organisms ranging from archaeas to model eukaryotes using biochemical and structural tools. The written production of this group is very good, especially if one considers that it is mostly composed of teachers. The committee would like to encourage the group to proceed in this direction. However, the committee also noticed that oral communication was limited and mostly restricted to France. The committee strongly recommends to this group to increase its visibility at the international level through oral communication at conferences and seminars in Europe, America and/or Asia. Group Evolution des systèmes d initiation de la traduction chez les eucaryotes : This is a new group that has become autonomous recently. Researchers of the group had been studying several aminoacyl trna synthetases. As a new independent group they recently initiated a new project on the non-conventional translation initiation mechanism responsible for the synthesis of histone H4 (in part derived from peculiarities in 3 end processing of mammalian histone mrna precursors). The still unpublished results obtained in the latter project are spectacularly interesting as they reveal the mechanism of a minimal protein synthesis system specialized to the efficient production of large amounts of histone proteins during DNA replication. The committee recommends focusing the work on the study of this unconventional translation initiation system because much can probably be learned about the regulatory aspects of protein synthesis. Given the limited size of the group, the committee expects that the work on trna synthetases will be finished soon to be able to concentrate a critical mass of researchers on the most promising project. It is expected that this new group should rapidly establish itself as a leader in this new area. The committee recommends that appropriate support is made available to this new group to stay competitive. Group Synthèse, fonction et pathologies des protéines à sélénocystéine : This group is pursuing several projects related to the mammalian machinery responsible for the synthesis of selenoproteins including the characterization of a transcription factor involved in trnasec synthesis, the characterization of a multiprotein complex binding to the SECIS element required for selenocysteine incorporation, and characterization of a human pathology linked to a defect in the production of a particular selenocysteine protein. The group also initiated a new project on the structure of HAR1, a rapidly evolving noncoding RNA in primates. Most of these subprojects are interesting and some have promising future potential. Yet, in general the research activities appear very diverse. The group s activities should be more focused in the future with more manpower dedicated to a limited number of promising projects. At present, the committee does not see a clear internationally visible research profile for this group. The committee recommends to build up new leadership(s) and to concentrate the work in one or several groups focussing on the topics with the highest potential. Group Bioinformatique, modélisation et simulation des acides nucléiques : The committee was very impressed by the high quality of the presentations, the results and the future plans of this group working on RNA structure, modeling, evolution and simulation. This is a well-established group with an excellent publication output (71 publications in four years) and high international reputation. The committee wants to stress that this group also provides also many services for the scientific community especially within the RNA Society. The projects proposed for the future are very ambitious and are likely to result in very important discoveries in the field of RNA structure and evolution. The recommendation of the committee is to continue with the same passion to maintain, and even strengthen, the leadership in the field of RNA modeling. An expansion of the group might have to be envisaged due to increasing competitiveness in this area of RNA structure analysis. If more resources were added, the group could extend its lines of research to include, for example, the analysis and modeling of protein-rna interactions. Another possibility for expansion could be the promotion or hiring of a highly talented group leader in this area. This would reinforce this type of research within the CNRS UPR9002 unit and help to prepare for the future. Group Recombination in the molecular evolution of HIV : This group has recently been recruited from the Pasteur Institute and moved to UPR9002 one month ago. It will thus only be fully assessed and graded at the next round of evaluation. Activities of this new team very nicely complement those of the new host institute. It brings new aspects on RNA-mediated evolution and recombination to the unit. The research 7

9 project is important because the high genetic diversity of HIV is fostered by its high recombination frequency (in addition to error prone replication). HIV is an excellent system for studying and understanding RNA-mediated recombination, because HIV is by far the best-studied retrovirus and because of the significance of the disease. The project is of great interest not only for understanding RNA recombination as a basic and yet not well-understood process, but because it may have specific applications. The group has a good potential to develop a long-term perspective and to link applied research with basic research. Yet, the committee suggests to this team to define and focus its strategic goals. The addition of this group will be beneficial to the whole UPR9002, and, with appropriate support, the committee expects the new group to develop fruitfully at its new location in the years to come. Group Aminoacylation des ARN de transfert eucaryotes: contrôle et pathogénicité : This new group was established five months ago, it will thus only be fully assessed and graded at the next cycle of evaluation. Members of this new group have a longstanding expertise and publication record on trna synthetases. The proposed project will involve analysis of the regulation of trna synthetases through alternatively spliced regions and a putative mechanism of trna import in Plasmodium falciparum. Both projects are original and may lead to surprising results. Obviously, given the recent date of formation of this group, only limited amounts of data have been accumulated so far. The committee would like to recommend to the group to validate quickly its hypotheses before engaging in potentially long and risky projects. The committee also recommends providing sufficient support for this group to allow it to prove its value as an independent and internationally visible group in the years to come. 5 Appreciation of resources and of the life of the research unit Overall, the unit appeared well organised with good sharing of resources, including technical assistant support, equipments and consumables. This extended beyond the administrative unit to the other units located in the same building and to the other institutes in Strasbourg and the surrounding area. The committee was pleased to see that efforts were taken to stimulate scientific discussions with neigboring institutions. As stated above, the general working atmosphere was good and technical and administrative personnels, students, post-docs, teachers and reseachers were generally pleased by the stimulating working atmosphere within the institute, which they recognized as a place of expertise to work on RNA, even if as everywhere, some small problems were apparent (only a minority of which were under the direct responsibility of the unit Director). The main issue noticed by the committee was the unusually high extent of inbreeding among the group leaders, who mostly originated from UPR9002 and the absence of an open strategy to recruit new group leaders. In summary, UPR9002 appears to provide a stimulating atmosphere to develop scientific projects in the area of RNA. The committee recommends to keep improving this situation. 6 Recommendations and advice Strong points : Internationaly recognized Institute in the RNA field. Strong teams world-wide leaders in their respective areas. Good apparent functioning of the institute. Good links to university and teaching. Weak points : Considerable inbreeding in the selection of new group leaders Recommendations : Implement a mechanism for selection of group leaders (with internal or external being selected competitively through the same process on open calls). This would give the director, and an appropriate selection committee, the opportunity to recruit the most promising candidates and provide the chance for both internal and external researchers to apply to such positions in open competition. It is, however, clear that internal promotions should be limited to the most promising projects and that staff members of the unit should also be encouraged to apply to 8

10 other institutes, where they would be able to disseminate the unique knowledge of UPR9002 on the analysis of RNA structure and function. Beyond group leaders, arrival of new outside collaborators should be stimulated at all levels: technicians, students, post-docs and permanent staff. Space made available by closure of groups (following retirement of a group leader or departure to another location) should be used to establish new teams rather than provide means for internal extension of already existing groups. Stimulate dissemination of institute knowledge through moving of researchers or teams to other institutions. 9

11

12 Architecture et Réactivité de l ARN Unité Propre de Recherche du CNRS n 9002 Conventionnée avec l'université Louis Pasteur de Strasbourg To the AERES Strasbourg, le 7/05/08 Prof. Eric WESTHOF Directeur AER_STBG1_032-UPR9002-PB-V1 Comments on the AERES evaluation report on the unit 9002 Architecture et Réactivité de l ARN All the members of the unit thank the Committee members and its President for the comments, analyses and constructive recommendations that they have reached following their site visit on February 19-21, We are pleased by the overall positive appreciations and we will endeavour to implement the recommendations during the next four years ( quadriennal ). Institut de Biologie Moléculaire et Cellulaire 15 rue René Descartes F Strasbourg Cedex Tél. : +33 (0) Fax : +33 (0) E.Westhof@ibmc.u-strasbg.fr Although we accept a very large majority of the points, some detailed responses regarding specific groups will be presented below. But, first, some general comments. We are extremely honoured and pleased to have been evaluated by a very international Committee. However, this led to several misunderstandings among the Committee members regarding the administrative, financial, and budgetary restrictive constraints imposed on our day-to-day management and which prevent us from long term views on personnel evolution as well as on scientific projects. Now, more precisely on the major issue raised by the Committee, namely the inbreeding of group leaders. Since the new directorship (January 2005), three groups were created ; two of them emerged from previous groups indeed and one resulted from the move to the unit of a researcher from the Pasteur Institute. The latter move is now almost fully accomplished (rooms remodelling, ATIP grant from the CNRS, possibility of obtaining a CNRS position). However, it took more than three years of discussions with our respective authorities to reach this present (extremely satisfactory and constructive) status. We are very thankful to the directorship of the Pasteur Institute and of the Scientific department Sciences de la vie of the CNRS for their support on this initiative. A researcher is retiring end of 2008 and a new group will be formed ; it will be led by a chargé de recherches from the CNRS coming from a neighbouring institute in Strasbourg. We are now submitting to various agencies for installation grants. Thus, in early 2009 (the beginning of the new quadriennal), four new groups will be in place, half of which led by scientists coming from outside the unit. Also, since 2005, we have had the recruitment of three CNRS technicians all

13 coming from outside the unit. Furthermore, since 2005, two researchers left the unit for the IGBMC in Illkirch, one for starting a new group and another one to join a group where the need for RNA expertise was crucial. Such movements towards the outside are extremely difficult to plan and depend strongly on personal motivations and situations. Furthermore, it takes a long time to gather a critical mass of researchers with diverse expertises on RNA ranging from chemistry, biochemistry, molecular biology to cell biology and bioinformatics. The maintenance of such a RNA center is a necessity in Europe and we do host many visitors and short term fellows, a presence which guarantees the teaching and dissemination of our knowledge. We will strengthen this international presence in the future. In any case, following the advice from the Committee, we will set up, with the agreement of all group leaders, an international advisory board for further and continuous in-depth scientific evaluations and recommendations along such lines in order to prepare the next evaluation. Finally, a short note on point 1 : among the three non-publishing members, one has left the unit and one is retiring at the end of The third one is totally devoted to teaching responsibilities at the Université Louis Pasteur and participates actively to the research attractivity of the unit towards students. Group Réplication des virus à ARN et des rétrotransposons The team believes that academic teams have a major role to play in drug discovery, when, as it is doing, they explore new mechanisms of inhibition, rather than competing with major pharmaceutical companies for high throughput screening. Although most of the research in this area is still unpublished, the team has identified several molecules with interesting antiviral activities that demonstrate the validity on the concepts it is exploring. Concerning Vif, which the team demonstrated to be an RNA chaperone, an important part of the projects indeed aims at elucidating its role in viral assembly by studying its interactions with the genomic RNA and Gag, the main players of viral assembly. However, as the action of Vif is only apparent in non permissive cells, the mechanisms by which this protein counteracts the antiviral factors APOBEC3G/3F have also to be taken into account, including the poorly understood inhibition of APOBEC3G/3F translation by Vif. Finally, the project on the packaging of influenza virus will greatly benefit from the conceptual and methodological expertise the team gained in dimerization and packaging of HIV-1 RNA. Thus, even though the research topics are, in the team s mind, less dispersed than perceived by the committee, efforts will me made to follow its recommendations. Group Biophysique et biologie structurale Our team has mixed feelings about the comments raised by the committee. On the one hand, we agree with the fact that there is a danger of dispersion and that no papers have been published in the last four years in very-high-impactfactor journals. On the other hand, however, we do not understand why the committee focused his comments on our crystallographic methodological work

14 and even not mentioned our long-lasting and financially supported HIV-related work. We would like to recall the following facts: there is not a single word about our crystallographic methodological work in the leading section Summary of results and perspectives of our report, only one half-page paragraph is devoted to this aspect in the body of the 5- page report, among 16 peer-reviewed papers, 7 are related to HIV-1 studies and only 3 to crystallographic methods. Group Synthèse, fonction et pathologies des protéines à sélénocystéine The team thanks the Committee for the careful evaluation of the group. The PI would like to clarify a couple of issues. First, the team is aware that less heterogeneity should be present in the group. Following the drop of the selenoprotein N project (see below), there are clearly two major directions of research that will be pursued, one on the mechanism of selenoprotein synthesis, the other on the transcriptional activator Staf. The first project led to a recent publication in J. Cell Biol, in the framework of an ANR programme, in which we found that snrna, snorna and selenoprotein mrna assembly follows the same pathway, using chaperones (HSP90) and co-chaperones. It is the first time that a class of mrna is found to be assembled in a multi-subunit RNAprotein complex that requires chaperoning. This finding unifies the three categories of RNA. Other developments on these aspects should emerge soon. The project on Staf led us to discover that Staf is one of the most widespread transcription factors in the mammalian genome. Besides, bi-directional transcription of genes involving Staf in the human genome has been identified, with Staf promoters in the 3 UTR of mrnas in several cases, possibly indicating antisense transcription. The ongoing project is to detect Staf binding sites genome wide by a computational approach, followed by validation of selected hits by a wet lab approach. Secondly, at the end of the presentation by the PI, a former member of the group presented projects to be pursued when he returns to Strasbourg as an independent group leader. Although given right afterwards, there was no link between the two. The project he was directing previously in the team, selenoprotein N-induced pathologies, although successful will gradually come to an end and will be abandoned.

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