 Introduction History and geographical location of the unit

The CBS is located on the renovated "Navacelles" INSERM site where it moved in 2005 to occupy ~2000 m2 with some additional facilities in the nearby building. Since the last renewal, the unit has performed a profound change in its organization with the creation of two departments (Structural Biology and Single Molecular Biophysics), each hosting 5 and 3 research teams, instead of 3 thematic areas. This new organization, which is driven by a recent mobility of the staff, is aimed at a better coherence and visibility as well at sharing scientific and technical culture across the two departments.

Management team

Following the departure of the former director Cathy ROYER in September 2013, Mr Christian ROUMESTAND has been appointed director of the CBS for the current term and the next period and is assisted by Mr Pierre-Emmanuel MILHIET as deputy director. A managing committee with the directors and the team leaders has been launched recently and completes the management organization.

AERES nomenclature

SVE1_LS1, SVE1_LS2, ST2 and ST4

Unit workforce

Unit workforce

2  Overall assessment of the interdisciplinary unit Under the leadership of former directors, the CBS has occupied a unique place with the integration of structural biology and biophysics approaches within the same lab using state-of-the-art complementary instrumentation, creating a leadership position to develop interdisciplinary projects at the forefront of integrative structural biology. This remarkable achievement was accompanied by a profound reorganization in two departments with the emergence of young teams and a novel emphasis in synthetic biology. In this context, the CBS has addressed weaknesses reported during the last AERES evaluation. The different projects can be classified into six main biological themes or research axes that bring complementary skills and can be viewed as transverse across the different teams, e.g. infectious disease, structure-function and dynamic of intrinsically disordered proteins, structure and dynamic of biological membranes, regulation of gene expression, molecular motors, synthetic biology with emphasis on in-house collaboration between teams. Besides, the CBS has to cope with the departure of a prominent scientist that largely contributed to the development of biophysics and recruitment of talented researchers. Hence, the new management team must carefully preserve the equilibrium between the two main structural biology and biophysics disciplines. o Ensure adequacy between permanent staff and the number of main thematic areas, especially for those lacking financial support.

 Detailed assessments

Assessment of scientific quality and outputs

For the 2008-2013 period, lab members have published more than 200 publications in international journals, of which about half originating in CBS (first and/or last author). 27 publications are in Journals with an IF > 7 (of which 1 PloS Biology, 2 NSMB, 2 J Cell Biol, 3 JACS, 9 PNAS, 1 EMBO J, 8 NAR, 1 Science Signaling and 2 EMBO Rep) and about 20 as internal collaborations. In addition, 6 patents were filed during this period. The CBS has a very good production. Given the stunning expertise, complementary skills and state-of-the-art technology facilities, the CBS has clearly the means to further increase the visibility of some of its research themes by focusing on integrated studies across teams in an interdisciplinary context with a potential for high-impact publications in leading journals.

Assessment of the unit's academic reputation and appeal

The CBS is the flagship of an interdisciplinary discipline at the forefront of structural biology and biophysics in the Montpellier region and belongs to the French leaders in these fields. This successful implementation of technologies has been recognized with the partnership of CBS in two major French infrastructure projects (FRISBI, FBI). CBS holds a special position in combining specific interdisciplinary competences and skills and, as such, occupies an important place in collaborative national and international networks. Local collaborations have also been emphasized and a significant number of publications (>15) results from these interactions. A total of 55 research grants were obtained by the lab members, of which 18 from the ANR, 6 from industrial collaborations, 4 from EU programs and 3 from private foundations. Moreover, the CBS has demonstrated an impressive capacity to attract and recruit staff. 1 PI has been involved in the creation of a start-up and 5 PIs benefited from highly competitive European (2 ERC starting) and French (3 ATIP-Avenir, 1 ANR Chaire excellence and 2 Region-LR) programs. A young researcher was awarded the CNRS bronze medal.

The lab has hosted 17 Postdoctoral fellows (8 being international) and 5 temporary technical staff that illustrates the very good capacity of the lab to sustain competitive scientific activity, a recommendation from the previous evaluation report.

While most PIs are regularly invited to conferences and seminars abroad and in France, attendance to international conferences as invited speakers is not uniformly distributed among teams to promote a global lab visibility. In this context, one may cite the higher visibility of the super-resolution microscopy domain.

Assessment of the unit's interaction with the social, economic and cultural environment

The CBS ocupies a unique place in belonging to two national infrastructures with the aim to allow external users to access these advanced technologies. The CBS also promotes interactions with local start-ups and has a key role to deliver attractive educational and community-based programmes in structural biology and biophysics.

Assessment of the unit's organization and life

The laboratory life includes shared leadership, the regular meeting of consultation boards as well as regular scientific meetings for students. Meetings with the staff during the visit have highlighted the very good spirit of the lab and all the staff adheres to the restructuration and future project. Meeting with the affiliated institutions has emphasized the quite unique place of the CBS which in turn is strongly supported.

Assessment of the unit's involvement in training through research

During the past period, the CBS research staff consisted of one professor and three assistant professors ensuring their teaching duties, and the CNRS/INSERM scientists were also actively participating to teaching. All teams were active in recruiting PhD students (11 theses defended over the period and 9 PhD ongoing at the time of the visit) despite a decrease in graduate students. Overall, the CBS contributes significantly to educational activities as demonstrated by the creation of 2 Master programs. The CBS has organized several workshops, thematic schools and meetings and participates actively to the animation of the campus in training young scientists.

Assessment of the strategy and the five-year plan

The CBS wishes to develop 6 main research themes transverse to the 8 teams integrating molecular and structural biology, bioinformatics and biophysics, and consolidate its visibility by promoting local synergy. Transfer and mobility of personnel have led to reorganize the 3 research axis in two departments with 5 and 3 teams. The first theme on infectious diseases will investigate several aspects of viral transmission and will pursue on the mechanisms of Mycobacterium tuberculosis virulence. The second will address intrinsically disordered proteins in the context of pathologies and will be reinforced by an emerging team. The third will be dedicated to biological membranes and their components. The fourth will focus on the regulation of gene expression in the cancer context. The fifth will be dedicated to molecular motors by integrating a Labex project while a sixth theme will be initiated on the engineering of bacterial sensors by a second emerging team. While the CBS has clearly the potential to tackle this ambitious research plan, development of a strong federative project rather than too much diversity could increase its visibility. Emergence of two new teams will also demand some consideration to adapt the size and scientific objectives as opportunities still exist for some regrouping within the lab depending on the success of the teams. The strategy for the future will also consider developing new methodological approaches and reinforcing atomic force microscopy, a wish of CBS to continue implementation of integrated approaches across teams by acquiring complementary skills to address biological questions. The development of molecular and cell biology facilities to strengthen functional studies will be also considered. In this context, the demand for new space in a neighboring building to pursue a very successful attractiveness policy appears highly urgent and justified. Assessment of scientific quality and outputs

Team 1 consists of 6 permanent researchers with very complementary expertise in structural biology in general, including NMR, X-ray crystallography, SAXS and biochemistry. The research is concentrated around the structural biology of infectious diseases and protein folding. They have in particular solved 15 structures of M. Tuberculosis (10 by NMR, 5 by X-ray), making a significant contribution to this field. This can be considered classical structural biology work. On the folding side, the team has expertise in high-pressure NMR, as one of the few labs worldwide where this particular technique is present. Using high-pressure NMR, they study various systems, reaveling their structural and energetics landscape. This is done in collaboration with other groups worldwide, among others a well known group at Johns Hopkins (Garcia-Moreno), indicating the international visibility of the team (also backup by invited lectures at international conferences). Clearly the team has a unique expertise in high-pressure NMR.

Over the last five years the team has published 35 papers, a number of which in high impact journals (PNAS, Proteins, Nature Structural & Molecular Biology, Nature). This gives an average of 7 per year, for a team of 6 researchers, which is good. One of the limitations to a higher productivity seems to be the number of post-docs and PhD students. This is however a general problem that the unit has to face.

Assessment of the team's academic reputation and appeal

The team is well known internationally and has been quite successful in raising funds with two ANR grants in the period assessed. Visibility as assessed by the number of invited lectures at international (17) and national (4) conferences is good. It is part of the French Integrated Structural Biology Infrastructure (FRISBI) and initiated the acquisition of an 800MHz NMR spectrometer in the coming years (pending a positive evaluation of FRISBI).

Next to the permanent research staff, the team counts 1 post-doc and 3 PhD students. The team leader is actively involved in teaching and developing new master programmes to attract more students to CBS.

Assessment of the unit's interaction with the social, economic and cultural environment

The team and in particular the team leader has been successful in acquiring grants with local companies and is being supported by four contracts with large pharma industries (Sanofi-Aventis and Nosopharm). The NMR platform (IBiSa, now part of FRISBI) is offered to local, national and international users. Further a new protein production platform has been set up. The team has a clear, interdisciplinary and also unique expertise in some areas (e.g. highpressure NMR).

Assessment of the team's involvement in training through research

With currently three PhD students, the teams clearly contribute to training through research. With the professor position of the team leader there is a clear connection with education. It seems however that the developments in the current study curricula do not prepare well students to perform research in structural biology and all associated biophysical techniques. The team (and actually the institute) has made effort to correct this by participating in and reshaping as much as possible the master programs ("Structural Biology and Drug Design" and "Molecular and Cellular Biophysics") and is now considering also the bachelor level. This is a clear involvement in education (which is needed in order to prepare and attract students).

Assessment of the strategy and the five-year plan

The strategy for the coming years is a logical continuation of the current research topics, with structural biology of infectious diseases and protein folding using high-pressure NMR (a rather unique expertise of the CBS). All projects show a good level of interdisciplinarity and there are good collaborations in place. In particular the research lines around phospho-regulation and latency are timely and merit increased efforts. The team should also work at increasing their scientific outputs and ambition levels. This is a young team whose PIs joined the CSB during the last three years. The research work concentrates on intrinsically disordered proteins using a combination of NMR, SAXS and computational modelling, an ideal combination to study such systems. The systems under study are various, including phosphorylation effects in various systems and the characterisation of GPCR tails. There is also an interest in developing new methodologies to study those systems.

The last two years at the CBS have been used to set-up the lab and all methods and establish collaborations on biological systems. In terms of productivity, the teams published 10 papers since 2012, which is a rather impressive output considering the short time at CSB. Prior to that, they have published 39 papers since 2008, including high ranking journals (PNAS, Nature 2012 and other Nature journals), which is demonstrating an excellent productivity. There is thus a high potential for this team to grow in the coming years. The team leader has been quite successful in raising funds with an ANR Chaires d'Excellence grant and an INSERM grant for a co-funded PhD student. In addition he also obtained an ATIP-Avenir 2011 grant (turned down in favor of the ANR grant).

The team is well visible and recognized internationally, with invited lectures at international meeting. The publication and citations records are already very good, showing a very promising growth.

Assessment of the team's academic reputation and appeal

Again, this is a young team starting at the CBS. The team leader is well recognized in his field, which is backed up at the national level by the ANR Chaire d'Excellence. Both PIs have been involved in the organization of international and national meetings.

Assessment of the team's interaction with the social, economic and cultural environment

There are activities and collaborations with external groups for SAXS analysis, one of the expertise area of the team. There is a good potential for valorization, also with respect to the NMR part and the GPCR project which should attract interest from industry.

Assessment of the team's involvement in training through research

The team has currently one PhD student. No other teaching activities reported at this stage.

Assessment of the strategy and the five-year plan

The three main research areas for the coming years focus in structural studies of disordered proteins or segments thereof in huntington disease and GPRCs, and methodological development in this area. These are highly medically relevant and timely topics. But there is also competition in this area. The team has a good network in place, but will have to find its "niche".

Conclusion

A young, dynamic and excellent team that recently joined the CBS with lots of potential for further growth. The research area is highly relevant and timely and expected to lead to excellent publication with a good potential for valorization

Assessment of scientific quality and outputs

There are several research projects, all well focused in the virology field and in collaboration with virologists and molecular biologists. The team solved several impressive structures, including the viral baseplates or their constituents, thus highlighting how phages inject their genome into bacteria. They also paved the way to understanding how viruses bind to their cellular receptors, and provided structural data on viral transmission. The team is now focusing its interest on pathogens with projects about HIV, influenza and chikungunya. Technically excellent, they will progress a step further, by setting-up methods for imaging at the cellular level, with the aim to bring data on how HIV spreads from cell to cell through tunneling nanotubes, or CHIKV assembly/disassembly. Of particular interest are the developments of new techniques such as the use of origami in cryoEM, or the phasing of X-ray data with negatively stained EM samples. Besides the dynamics and creativity of the persons involved, this underlines the power of the balance of expertise in this team truly devoted to multi-scale structural biology.

Assessment of the team's academic reputation and appeal

The scientific achievements of these last years (33 publications since 2008) and the high quality of the results illustrate the dynamics of this quite new team, and bode well for the future projects. The level of publication, and ranking of the team members in the author's list appears to be somewhat modest, suggesting a lack of leadership in the collaborative work. This may reflect some understatement of their input value as structural biologists, a problem frequently encountered in such multidisciplinary projects.

Assessment of the team's interaction with the social, economic and cultural environment

Interactions are strong with other teams of CBS, such as Team 5 in the Structural Biology Department, but also with the Biophysics Department, as with the active collaboration with Team 8 in the development of correlative EM. Involvement in the unit day-to day life is manifest with the role of one team member as CBS administrator of the informatics and webmaster. With its deep involvement in the technical platforms for EM and crystallography, Team 3 is instrumental in CBS cohesion. The links with the scientific community are strong, especially at the national/European level, as CBS is one out of the 5 centers of the French Infrastructure for Integrated Structural Biology (FRISBI), open to molecular and cell biologists from both academia and industry from France and Europe, and as such directly linked to and part of the European INSTRUCT Infrastructure. The team is locally involved in the platform IBISA, more precisely in the poles (1) Crystallography, bringing expertise in crystallization, and structure solving and (2) Electronic Microscopy. This type of activity is quite time demanding, and could outbalance the workforce of the current team.

Assessment of the team's involvement in training through research

This is a quite recent team (2008), which can now capitalize on the past efforts to setup and validate an in-house heavy instrumentation. This explains why there is only one student in the team, for the moment. However, the involvement of one team member who is teaching in the Master BioMed, should help to improve this situation in the future.

In addition, the team participates to training through research, as this constitutes the spirit of the FRISBI/INSTRUCT program.

Assessment of the strategy and the five-year plan

The future projects are focused on human pathogens such as HIV, influenza and chikungunya. The expertise in cryoEM and crystallography will be maintained at the highest level, along with the development of new methods in order to locate the viruses in the cells, and follow their functions, such as assembly or disassembly of particles at the highest resolution possible. Also the use of DNA origami presenting specific molecules is a new and promising avenue. Both the established and new focus and their expertise will help to increase the team visibility, and favour publication in more prominent positions and journals. On the whole, this is a strong project, which leans on cutting-edge technologies, and will generate new developments for the community. The project is of obvious interest for human health, with high probability to yield outstanding results. This team is newly formed and will focus on Synthetic Biology, making use of Bacillus subtilis as a chassis. The team leader has just been appointed after a stay in Drew Endy's lab, and no output for team 4 can be listed yet. The overall goal is to develop a programmable diagnostic platform for detection of biomarkers in clinical samples. The work is divided in three major parts: 1. Parts standardization and measurements for predictable gene expression in B. subtilis, 2. Engineering chimeric eSTK receptors and 3. Biomolecular computation for biomarker analyses. This program appears well balanced, innovative and relevant with good chances of high level publications.

Conclusion

Assessment of the team's involvement in training through research

Not evaluated

Assessment of the strategy and the five-year plan

The organization of the research into three main themes is promising. In the second subject there are good opportunities to collaborate within CBS e.g. with teams 1 and 5. The team will have to build further on the manpower and expertise in Bacillus (and perhaps other Gram-positives for expression) to obtain further funding to carry out these projects.

Conclusion

There are very good chances in this field. The work program is well-balanced. The team is uniquely positioned within CBS, giving excellent possibilities for collaborations in the structural field. The team needs to build on increasing its expertise on B. subtilis engineering. International grants like ERC or Horizon 2020 would be welcome, to extend the team with PhD students and postdocs.

Strengths and opportunities:

o o Seek international collaborations in synthetic biology with B. subtilis, but be complementary The team is well recognized for its multidisciplinary skills, which combine chemistry, biochemistry, bioinformatics and structural biology (X-ray crystallography and NMR). During the previous period, the team obtained original and major results essentially on two main themes that are regulation of nuclear receptors and development of drug candidates by fragment-based approaches. The team has also developed innovative in silico tools to predict protein structure.

The scientific output of this team is excellent with 54 articles published in international journals of good quality (include NSMB, PNAS, Structure, NAR). This research topics also generated 5 patents, indicating that the conducted works are both scientifically excellent and socio-economically relevant. A significant proportion of the publications of the team were co-signed by external authors to the team or unit, reflecting the strength of collaborations. However, there appears to be an underrepresentation as last author of unit members on these publications.

Assessment of the team's academic reputation and appeal

The team has a good recognition, especially the two team leaders, with 10 participations as invited speaker. The team has been involved in the organization of one national meeting. The group has good national and international collaborations and is involved in different national and international collaborative networks (MobylNET IBISA, French Integrated Structural Biology Infrastructure (FRISBI), European ESFRI (EU-OPENSCREEN).

Assessment of the team's interaction with the social, economic and cultural environment

The team has demonstrated its ability to secure outside funding for most of their research at the national level, including 5 ANR grants. The research produced by the group has been valorized by 5 patents as well as two CIFRE grants with Oribase pharma. The team is also involved in the emergence of the AGV Discovery.

Assessment of the unit's involvement in training through research

One team's member participates strongly in teaching at the university, with 220 hours per year, and is co-head of the Master Biologie Structurale et Drug Design. One PI is member of the executive board of the doctoral school CBS2 and is involved in Master teaching for 10 hours per year. The team has currently 2 PhD students and 3 postdocs.

Assessment of the strategy and the five-year plan

The organization of the research into two main sub-groups, with one well-identified and well qualified PI for each, is consistent. The team plans not only to pursue their main projects but also to develop new integrated methodology for the structural characterization of ADMETox properties of chemicals, based on X-ray crystallography and structural bioinformatics. The existence, relevance and feasibility of the long-term projects are evident. The team has the manpower, the equipment, the expertise and the funding to carry out these projects. Their participation to the internal platform represents a long-standing commitment to improve local collaborations and productivity.

Conclusion

High quality work, expertise in the field, with nice methodological developments. Their interaction with the other teams is strong and they are able to secure funding for their projects.

Weaknesses and threats:

o Relatively low international visibility;

o Possible negative impact of the new start up activities on team productivity.

Recommendations:

o Maintain a good management of the research and valorization activities;

o Look for opportunities in Horizon 2020 and innovative medicine initiatives to increase visibility and funding. The team aims, on one hand, at developing novel single-molecule and super-resolution techniques; on the other hand, it applies these advanced techniques for the study of the transport and remodeling of DNA in bacteria and eukaryotes.

The development of new methodological approaches that allow the visualization of single molecules in living bacteria or higher eukaryotes, together with super-resolution techniques able to resolve sub-diffraction intracellular structures, puts the group activities at the forefront of biophysics research. Single molecule and super-resolution techniques have been constantly developing during the last few decades, leading to improved spatial and temporal resolution. Such technological developments have allowed deciphering important molecular mechanisms in biology, with particular regards to molecular motors function and nucleic acids structure and interaction with transcription factors and processing enzymes. The team activity, thus, fits in a rapidly developing area at the forefront of international biophysics research. The biophysics research deals with DNA structure and transport in bacteria, as well as higher-order chromatin structure in eukaryotic chromosomes, and how genetic material structure relates to transcription regulation in living cells. The physical mechanisms underlying gene activity and regulation are one of the key themes in current biophysics research.

The scientific output demonstrates excellent quality with publications during the last years in internationally renewed journals (NAR, Plos Biology, EMBO reports, etc).

Assessment of the team's academic reputation and appeal

The PI is well known at the international level, as demonstrated by several invited talks at international and national conferences and by his activity as reviewer for several national research agencies and scientific journals. Funded grants from the national funding agency as well as HFSO and a starting grant from ERC demonstrate the excellence of the team and the proposed research.

Assessment of the team's interaction with the social, economic and cultural environment

The PI is member of the France Bioimaging (FBI) Steering Committee; Labex EpigenMed and from France Bioimaging; GDR "Architecture et Dynamique Nucleaire" (ADN), and "Microscopie pour le vivant" (GDR2588); and has been involved in the organization of local workshops. The team has interactions with Andor technologies through an industrial contract and several national and international scientific collaborations.

Assessment of the team's involvement in training through research

The team has a very good involvement in training through research with two PhD students and four post-docs. The PI is also involved in the supervision of master's students, teaching in university courses and EMBO practical courses.

Assessment of the strategy and the five-year plan

The strategy of the team for the next five years develops through five main research projects. One of these projects deals with the higher-order architecture of the eukaryotic nucleus investigated at the single molecule level. This research is funded by an ERC starting grant, which should guarantee appropriate funding and promising results. Other two research projects involve the study of the bacterial chromosome architecture and the mechanism of DNA segregation in bacteria, studied by super-resolution microscopy. The fourth research line follows and extends previous studies of the team on DNA segregation in B. subtilis. Finally, a fifth research line deals with technological developments aimed at developing fast 3d super-resolution imaging.

The research plan is convincing, timely and deals with actual biophysical problems investigated with advanced techniques that promise to give new insight into unsolved biological questions. o Very good national and international network of collaborations and visibility.

Weaknesses and threats:

o Threats: Highly competitive field;

o No relevant weaknesses at the moment.

Recommendations:

o Maintain a good balance between the number of research lines and team size;

o Maintain a good balance between methodological development and science. The research follows from previous investigations by the team leader before arrival at the CBS where he developed an "optical torque wrench", which is able to apply and measure torque on microscopic nanofabricated particles.

During his postdoc period, the scientific output of the team leader was of high quality, with publications in toprated journals (Nature Physics, Nature Communications). The research topics are now funded by an ATIP-Avenir grant and a starting grant from ERC.

Assessment of the team's academic reputation and appeal

The PI is well known at the national and international level. He received an ATIP-Avenir grant and a starting grant from ERC, which indicates the excellence of the team leader and the proposed research.

Assessment of the team's interaction with the social, economic and cultural environment

The team leader has established collaborations with IEMN in Lille (France) for nanofabrication of the particles used in the angular optical tweezers, with the group of prof. Bertus Beaumont (TU Delft, The Netherlands), for molecular and cellular biology, and with Dr.Peter Galajda (Institute of Biophysics Cell Biophysics, Hungary) for motility assays in different conditions.

Assessment of the team's involvement in training through research

At present, one PhD student has been hired. Two postdocs will be hired in a near future.

Assessment of the strategy and the five-year plan

The scientific goals consist of three main research projects. 1) The development of novel technical advancements in optical manipulation, with a special focus on the application and measurement of torque. 2) The application of these novel techniques to the study of the flagelllar motor in E. coli. 3) The development of novel probes to expand near field scanning microscopy.

The research plan is well defined and scientifically solid. Although quite specific and focused on the development of techniques setup previously, the technological and methodological advancements might lead to developments with broad applicability and wide interest.

Weaknesses and threats:

o No relevant weaknesses at the moment.

Recommendations:

o Finding and appointment of skilled and multidisciplinary PD and PhD students is of utmost importance; o Extend the scientific outreach of the methodological development;

o Maintain a good balance between the number of research lines and team size. Assessment of scientific quality and outputs

Team 8 which will include 5 permanent researchers and 3 permanent ITAs for the next project, originates from the former team #2 "Biophysique des molecules uniques". The scientific accomplishments were achieved thanks to outstanding single molecule techniques developed by staff researchers (smFRET, PIE-FCCS, HS-AFM and superresolution). Moreover, each PI is conducting its own project of research and is contributing to other projects in a collaborative effort by providing complementary expertise.

Two main themes were investigated:

The structure and dynamics of membrane components They have investigated the structural dynamics of the extracellular domains of mGlu receptor by recording FRET at single molecular level (smFRET) in the presence of different ligands. This work was developed within the frame of collaboration at the local level for the biological model and international level for the methodological development.

In a long-standing collaboration with Eric Rubinstein at Villejuif, they have analyzed the membrane partition of tetraspanin by single molecule imaging. They have pursued this work through international collaborations by analyzing the role of tetraspanins for HIV-1 assembly and during infection.

The structure and dynamics of membrane microdomains were investigated using high-speed AFM within the frame of national and international collaborations.

The control of genetic expression in Bacillus subtilis

They have analyzed the repressor complexes both in vitro for the structural analysis (x-ray, SAXS, EM) and in vivo for the biological analysis (2-photons fluorescence fluctuation microscopy) in a network of internal (CBS), national and international collaborations. They have evidenced the competitive folding of anti-terminator and terminator hairpins upon anti-termination protein binding.

They have also investigated at a single bacterial level, the stochastic activity of metabolic gene promoters in order to understand the molecular bases of the transcriptional control mechanisms underlying bacterial adaptation to environmental changes (local and national collaboration).

Over the last period, the team has produced 51 publications (21 as corresponding authors, with 9 of them in high impact journals (IF>8) (4 in NAR, 2 in PNAS and one in JCB, Nat Struc Mol Biol and PlosBiol). One PI wa awarded by national (CNRS-bronze medal) and regional institutions.

Assessment of the team's academic reputation and appeal

The team has clearly established a good academic reputation in the field of biophotonics and AFM with national and international collaborations as testified by the number of articles published in collaboration. Visibility is also assessed by the number of invited lectures in international (21) and national (9) conferences.

During the last quadrennial, the team has attracted 9 students (3 from abroad) and 12 post-docs (8 from abroad). Two staff researchers (CR-CNRS & CR-INSERM) will join the team for the new quadrennial.

The team has secured their capacity to develop their scientific projects by a very efficient success in research funding (among them 11 ANR and 2 Investissement d'Avenir grants as partner of a LABEX and the France BioImaging Infrastructure) and two grants with private companies.

Assessment of the team's interaction with the social, economic and cultural environment Two contracts were signed with private companies. Dissemination of knowledge is assessed by the contribution of team members to the organization of summer schools (2), practical course (1 EMBO) and scientific congresses (5). Team members contribute to public outreach by participating to practical courses for high school teachers and by organizing regularly workshops for kids.

Assessment of the team's involvement in training through research

Staff members have contributed to supervise nine PhD students (four already got their diploma, five are still in training) and 12 post-docs (five are still present). The staff is active in teaching in Master BioMed, level 1 and 2, and in organizing national and international meetings and schools. One PI co-organized the EMBO Practical Course "Super resolution and advanced microscopies in living cell". Due to the leave of one staff member fervently implied in the oragnization of the teaching, the team should consider to capitalize this investment on the education/teaching components by spliting the free teaching duties between the team staff members.

Assessment of the strategy and the five-year plan

Following the recent reorganization of the department of single molecule biophysics, team #8 will pursue two main scientific themes and keep their methodological developments at the state-of-the-art.

The structure and dynamics of membrane components

Within the frame of their collaborative network at local, national and international levels, they will investigate:

-the structural dynamics of two reconstituted GPCRs (mGluR, GABA in lipid nanodiscs based on the single molecule techniques mastered by the team. The dynamics of oligomerization of the receptors will be analyzed in living neurons. This project will benefit from new fluorescent labeling techniques keeping minimal the steric perturbation due to fluorophore addition.

-the role of the lateral segregation of tetraspanins during viral infection and cell migration by single molecule approaches. They aim at performing epitope mapping and topographic analysis of HIV-1 budding. Similar approaches will be performed to map HCV receptors. This project will be contingent of challenging but realistic methodological development in which AFM and super-resolution techniques will be combined on the same setup.

The control of genetic expression in Bacillus subtilis

Following up on their previous work, they will analyze the mechanism of transcription termination by investigating the activation of antiterminators at the structural level by NMR and the molecular dynamics by smFRET.

The mechanism of the Rho-dependent termination will be deciphered by combining superresolution, magnetic tweezzers and fluorescence fluctutation using fluorescent single molecule techniques in solution and on living cells.

All of these projects will capitalize on the methodological developments mastered by the department of single molecule biophysics. The CBS directors would like to acknowledge all the members of the AERES committee for their evaluation. In general, we agree with the points taken up by the AERES committee, with the notable exception of what written for Team 3 (Team Leader: Patrick Bron): in our opinion, the committee quite rightly stressed some existing weaknesses of this "young "team (started in 2010), without addressing adequately the strengths (installation of a new technology in the lab involving heavy instrumentation, found raising, involvement in master courses…). These points are developed in detail below, as well as specific comments concerning the evaluation of Team 5 and 8. We added also a small remark concerning the "introduction" chapter that concerns the whole unit. Assessment of the unit's academic reputation and appeal, last paragraph. "In this context, one may cite the higher visibility of the super--resolution microscopy domain". I assume that the committee would say "advanced microscopy domain"? The "super--resolution" microscopy domain concerns essentially M. Nollmann (29 talks) in Team 6. During the period, E. Margeat and PE Milhiet also gave 16 and 42 talks respectively, on "advanced microscopies " (Atomic Force Microscopy, spFRET, Single particle tracking), which are not classified as "super--resolution".

Conclusion

--Team 3: We think that a number of important points concerning the « Multi--Scale structural Biology » (MSSB) team have been either missed or not sufficiently stressed in the AERES report. With this letter, we would like to address these points in order to present a clearer view of the MSSB team activities. As a matter of fact, the team was effectively created in 2010 (and not in 2008 as stated in the AERES report) and one of its major achievements has been the establishment at the CBS of a new experimental technique, namely the cryo--electron microscopy (cryo--EM), and the setup of the corresponding technically "heavy" instrumentation.

During the year 2009, Patrick Bron has installed cryo--EM and all associated equipment dedicated to this new technology. This installation represents a financial investment of more than 1.2 M Euros shared by INSERM and CPER Languedoc--Roussillon. In this context, it is worth noting that MSSB team started from scratch, and that in a very short time it has been able to optimize all steps of the cryoEM single--particle analysis method, allowing us to investigate biological complexes at high resolution by hybrid methods. This has led to the publication of a CryoEM three--dimensional reconstruction of a biological particle with the best resolution ever obtained using data entirely collected and processed by a French laboratory.

Installation of cryo--EM at the CBS was accomplished in tight partnership with INSERM and CNRS and one major condition imposed by both funders was to open this heavy instrument to the French scientific community through platform activities. Indeed, Patrick Bron was recruited as CR1 by one of the funding institutions (INSERM), whereas CNRS recruited a research engineer for the EM platform. Surprisingly, it appears in different places in the AERES report that platform activities in cryo--EM and X--ray crystallography (the two major techniques used by MSSB team) seem deleterious for the scientific reputation of the team and for leadership recognition. Instead, we consider that opening such technologies to the national scientific community is mandatory for the realization of larger interdisciplinary projects. Often at the expense, of course, of a "good" position in the authors list when the work is published… However, we would like to point out that, since the "Multi scale structural biology" group creation in 2010, we have published 23 articles: 9 of them have an impact factor superior to 9, in 6 of them we are either first or last author and corresponding author in 3.

Another positive point that should be mentioned is our capability to raise funds, as a result of our active policy in interacting with national organisms and private companies. Thus, from 2009, we have been able to raise more than 300 KE from various sources (ANR, PIR, PEPS, BUSR…). Moreover, the AERES report does not mention that we have developed a service contract with Sanofi Montpellier in partnership with INSERM Transfer.

Concerning the team's involvement in training through research, the AERES report suggests a relationship between the EM installation and the fact that we got only one PhD student over the evaluation period. The small number of PhD students is a general problem that concerns the whole structural biology community that fails to attract a sufficient number of students. This problem is probably more acute in Montpellier where the Science teaching in Biology is "historically" oriented toward Cell Biology… Nevertheless, we would like to stress that during the period of evaluation, the team hosted two post--doctoral students, one PhD student and 5 Master 2 students. In addition, a

oo

  Strengths and opportunities related to the context o Pioneering effort coupled to world-class expertise to develop strong interdisciplinary and complementary approaches in structural biology and biophysics within a same lab; o Excellent initiatives to attract young researchers; o Initiating timely and promising projects; o Developing innovative technologies linked to implementation and maintenance of state-of-the-art distributed facilities. Weaknesses and threats related to the context o Low participation in initiatives at the European level despite individual attractiveness; o Disparity in international leadership and visibility among research teams; o Large redistribution of employees and reorganization of teams may not be optimal and will have to be reevaluated internally after a few months; o Possible decrease in teaching duties might impact local visibility for students. Recommendations o Attention should be made to fully consolidate and integrate the emerging teams associated to new thematic areas; Attention should be given to avoid a division of the unit with the organization into two departments; o Develop a high-profile federative, interdisciplinary and cell biology-driven project across teams for high impact publications; Capitalize on the specific expertise in high-pressure NMR spectroscopy; o Reinforce the staff with teaching duties;

  Centre de Biologie Structurale, CBS, Nouvelle université de Montpellier, CNRS, INSERM, Mr Christian ROUMESTAND 10 4  Team-by-team analysis Team 1 : Biomolecular Structure, Function and Dynamics by NMR Name of team leader: Mr Christian ROUMESTAND

o

  Conclusion A well-established, complementary team of expert covering a variety of techniques in structural biology. Strengths and opportunities: o Unique expertise in high-pressure NMR; o Interdisciplinary of the team; o Good infrastructure in NMR (even better once the 800 MHz will be installed); o Good collaboration network (both national and international levels); o Transverse interactions with the other teams with strong impact on the unit cohesion; o Good links with big pharmaceutical companies. Weaknesses and threats: o Limited number of PhD students and post-docs for the team size; o International visibility/involvement in projects (EU); o Relatively low number of new research lines over the years. Recommendations: Look for opportunities in Horizon 2020 to increase visibility and funding; o Phospho-regulation and latency are timely research that merit increased efforts; o Keep working on the education/teaching components to attract mode students given the departure of a senior with teaching duties;o Maintain and possibly increase output and ambition level.

2 N3:N4:

 2 Permanent professors and similar positions N2: Permanent EPST or EPIC researchers and similar positions 2 Other permanent staff (without research duties) 1 1 Other professors (PREM, ECC, etc.) N5: Other EPST or EPIC researchers (DREM, Postdoctoral students, visitorsspent at least 12 months in the unit Number of Research Supervisor Qualifications (HDR) taken Qualified research supervisors (with an HDR) or similar positions  Detailed assessments Assessment of scientific quality and outputs

oo

  Young and highly dynamic team o Excellent potential for growing o Relevant and timely research topics o Already impressive output considering the short period at CBS o Good international network and visibility Weaknesses and threats: o Critical mass o Highly competitive field Recommendations: Keep getting grants to increase the group size o Define a niche and avoid overlap with other competing groups Team 3 : Multiscale Structural Biology Name of team leader: Mr Patrick BRON Workforce Permanent professors and similar positions N2: Permanent EPST or EPIC researchers and similar positions 2 2 N3: Other permanent staff (without research duties) N4: Other professors (PREM, ECC, etc.) N5: Other EPST or EPIC researchers (DREM, Postdoctoral students, visitors, etc.students having spent at least 12 months in the unit Number of Research Supervisor Qualifications (HDR) taken Qualified research supervisors (with an HDR) or similar positions 1   Detailed assessments

oo

  Excellent expertise in electron microscopy and instrumentation; o Well-balanced team composition with complementary expertise; o High number of collaborations; o Pro-active in the methodological development of hybrid methods; o Promising new research line in virus visualization in cells. Weaknesses and threats o Lack of visible leadership in the collaborative projects; o Lack of international visibility in the field; o Small size of the team; o Saturation of the operational microscope. Recommendations o Establish and ensure a stronger leadership in collaborative projects; o Ensure funding to attract and recruit; o Capitalize on the new promising research lines and interactions with the single molecule biophysics department; Invest in a routine microscope. Permanent professors and similar positions N2: Permanent EPST or EPIC researchers and similar positions N3: Other permanent staff (without research duties) N4: Other professors (PREM, ECC, etc.) N5: Other EPST or EPIC researchers (DREM, Postdoctoral students, visitorsspent at least 12 months in the unit Number of Research Supervisor Qualifications (HDR) taken Qualified research supervisors (with an HDR) or similar positions Centre de Biologie Structurale, CBS, Nouvelle université de Montpellier, CNRS, INSERM, Mr Christian ROUMESTAND 20  Detailed assessments Assessment of scientific quality and outputs

N4:

  Structures and screening of therapeutic and environmental targetsName of team leader: Mr William BOURGUET and Mr Gilles LABESSE Other permanent staff (without research duties) 3 3 Other professors (PREM, ECC, etc.) N5: Other EPST or EPIC researchers (DREM, Postdoctoral students, visitors

o

  Excellent productivity and funding; o Complementary expertise in timely and relevant topics for drug design; o Excellent valorization; o Development of methodological tools well embedded at the national and European level.

1 N3:N4:

 1 Permanent professors and similar positions N2: Permanent EPST or EPIC researchers and similar positions 1 Other permanent staff (without research duties) 1 1 Other professors (PREM, ECC, etc.) N5: Other EPST or EPIC researchers (DREM, Postdoctoral students, visitors

o

  Outstanding young and highly dynamic team with excellent potential for growing; o Excellent productivity and quality of scientific output; o Relevant and timely research topics; o Development of advanced single molecule and super-resolution techniques; o Very good collaboration network within CBS; o Excellent funding sources;

1 N3:

 1 Angular dynamics and manipulation at the single-molecule level Name of team leader: Mr Francesco PEDACI Workforce Permanent professors and similar positions N2: Permanent EPST or EPIC researchers and similar positions 1 Other permanent staff (without research duties) N4: Other professors (PREM, ECC, etc.) N5: Other EPST or EPIC researchers (DREM, Postdoctoral students, visitorsspent at least 12 months in the unit Number of Research Supervisor Qualifications (HDR) taken Qualified research supervisors (with an HDR) or similar positions  Detailed assessments Assessment of scientific quality and outputs The team just established at CBS in January 2013. The group aims at developing novel single-molecule techniques for the manipulation of rotary motors and the measurement of torque in macromolecular biological complexes.

o

  Young team leader with excellent potential for growing; o Methodological development of innovative single molecule manipulation techniques; o Excellent funding sources; o Very good collaborative network.

5 N3:N4:

 5 Structure and Dynamics of Nucleoproteic and Membrane AssembliesName of team leader: Mr Emmanuel MARGEAT and Mr Pierre-Emmanuel MILHIET Workforce Permanent professors and similar positions N2: Permanent EPST or EPIC researchers and similar positions 4 Other permanent staff (without research duties) 3 3 Other professors (PREM, ECC, etc.) N5: Other EPST or EPIC researchers (DREM, Postdoctoral students, visitors

oo

  Excellent quality of the scientific output o A unique interdisciplinary team mastering broad expertise in single molecule imaging and AFM o A very good balance between biology and methodology o Good scientific network at national and international level o Excellent funding strategy o Very active in teaching and spreading knowledge Weaknesses and threats: o A broad range of biological projects might impact team visibility o Broadness of the topics and size of the team might impact team cohesion Recommendations: Identify one flagship project to unify the team or consider splitting the team o Capitalize on the past realization to reinforce international visibility o Maintain an involvement in educational/teaching activities to secure student attractiveness 6  Supervising bodies' general comments Centre de Biochimie Structurale -U1054/UMR 5048 29, rue de Navacelles -34090 Montpellier

Workforce Team workforce Number as at 30/06/2013 Number as at 01/01/2015 N1: Permanent professors

	and similar positions	1	1
	N2: Permanent EPST or EPIC researchers and similar positions	2(3)	2(3)
	N3: Other permanent staff (without research duties)	2	2
	N4: Other professors (PREM, ECC, etc.)
	N5: Other EPST or EPIC researchers (DREM, Postdoctoral students, visitors, etc.)	1	1
	N6: Other contractual staff (without research duties)	1	1
	TOTAL N1 to N6	7(8)	7(8)

Team workforce Number as at 30/06/2013 Number as at 01/01/2015

	Doctoral students	4
	Theses defended
	Postdoctoral students having spent at least 12 months in the unit	1
	Number of Research Supervisor Qualifications (HDR) taken

 Detailed assessments

  Very promising and dynamic young group leader

	o Already excellent scientific network
	o Good opportunities to extend Synthetic Biology (SynBio) work in B. subtilis
	o Embedding in CBS gives unique opportunities (most synbio is not embedded in Structural Biology
	Departments!)
	o Opportunities to be involved in teaching SynBio internationally or locally
	Weaknesses and threats:
	o Continue to attract enough funding in a very competitive area
	o Finding and appointment of skilled and multidisciplinary PD and PhD students is of utmost importance
	Recommendations:
	o Ensure good integration and support within CBS (good start already with ESTPK work )

Qualified research supervisors (with an HDR) or similar positions

 Conduct of the visit Centre de Biologie Structurale, CBS, Nouvelle université de Montpellier, CNRS, INSERM, Mr Christian ROUMESTAND

Centre de Biologie Structurale, CBS, Nouvelle université de Montpellier, CNRS, INSERM, Mr Christian ROUMESTAND

member of the team (Stefano Trapani) is assistant professor at the University of Montpellier II and responsible of several teaching units in different master courses.

--Team 5:

We would like to bring to the attention of the AERES committee the fact that two important research themes which confer both originality and visibility to our team have not been mentioned in its report:

In 2010 Team 5 has launched an innovative research project which tackles major public health and environmental issues related to the deleterious interference of environmental pollutants with the endocrine system of humans and animals. More specifically, the team uses a unique combination of leading--edge structural, biophysical, bioinformatics, cell--based and in vivo technologies to better understand, and in turn better predict, how a given chemical (or a mixture of chemicals) found in our daily environment (e.g. bisphenol--A, pesticide, phthalate,…) can substitutes for natural hormones and deregulate the normal function of their intracellular receptors. Commonly referred to as endocrine disruptors, these compounds are highly suspected to produce a range of developmental, reproductive, neoplastic, or metabolic diseases. Due to its originality and international recognition, this project benefits from excellent funding [2 ANR, 2 Plan Cancer Inserm, 1 PNRPE (Programme National de Recherche sur les Perturbateurs Endocriniens) and 1 ANSES (Agence Nationale de SEcurité Sanitaire de l'alimentation, de l'environnement et du Travail)], scientific output [PNAS, EMBO R., 2 EHP (a leading journal in the field of environmental sciences), 1 Toxicol Sciences, 1 book chapter and two reviews)] and visibility (7 invited communications in national and international conferences over the 2010--2013 period). As a result we are now part of an international consortium, in charge of the structural aspects, which recently applied to the Horizon 2020 call SFS--12 through the project SFERA (Safety of Food via combined Exposure and Risk Assessment).

In tight connection with the above theme, Team 5 also engaged a long--term program related to drug-design by developing a novel approach combining bio--compatible chemistry and in situ diffraction. This is providing the CBS with a unique expertise in the growing and highly--competitive field of Structure--Based Drug Design. This specific position has been recognized at the national level (by selecting the CBS to develop these techniques within the infrastructure FRISBI) and it also led to the creation of the start-up AGV--discovery.

Lastly, it is mentioned in the paragraph "Assessment of scientific quality and outputs" that: "There appears to be an underrepresentation as last author of unit members on these publications." We may agree with this comment. However, it would be worth noticing that this is rather well balanced by the number of patents (5) and our significant and fruitful involvement in platform activities (development and services in both bioinformatics and X--ray crystallography). Accordingly some papers are not yet published due to pending patent applications while in the context of a platform work we favor our collaborators as last author (e.g.: 7 such publications in bioinformatics and 4 in X--ray crystallography).

--Team 8

We would like to argument that the biological topics are not as broad as pointed by the committee. We mainly addressed two main topics i) Regulation of gene expression and ii) Structure and Dynamics of Membrane Assemblies, which are both currently very active in terms of publications and funding attractiveness. Gathering the different people of Team 8 is also based on a network of collaborations covering shared methodological developments (TIRF single molecule setup, advanced data analysis, two--photon FCCS), human resources (Caroline Clerte and Patrice Dosset --engineers) and biological topics (tetraspanins, GPCRs, transcription termination). This led to several common publications in high impact factor journals (JCB, Traffic, EMBO Reports, Molecular Microbiology, NAR, Ann NY Acad Science). We really think that our internal collaboration within the team is a key element to maintain our ability to tackle major biological problems using the advanced biophysical methods that we develop together.


 Introduction History and geographical location of the unit

The laboratory of Biochemistry of the École Polytechnique was created in 1975 to study the molecular bases and mechanisms of translation of the genetic message into proteins, using and developing the techniques and methods of biochemistry, molecular biology, analytical chemistry, structural analysis and bioinformatics. Beside bacteria, yeast and mammals, in the past ten years archaea also became an important model organism. The importance of bacteria remains essentially as targets for antibacterial action. Now the studies of translation mechanisms in eukaryotes constitute the major project. Beyond their interest for basic research, these central processes have in the past few years been clearly identified as important therapeutic targets. New directions of research have been explored, notably toward fields corresponding to patent social requests (ie. selenium toxicity). Following the recruitment in 2003 of a new investigator the "Structural bioinformatics" theme has been initiated. In 2012 the translation related project has been reinforced by to the recruitment of a young investigator who is in charge of the 5 th theme concerning translation termination and mRNA decay.

The laboratory is part of the research section of École Polytechnique in Palaiseau (plateau de Saclay) near other prestigious research centers (Orsay University, CNRS campus of Gif, CEA-Saclay…). The ongoing process of integration of these institutions within a single campus is a unique opportunity. The proximity of the synchrotron Soleil and the associated developments is an additional asset.

Management team

Mr Yves MECHULAM, the director of the laboratory, is assisted by a referent for Communication and Training (formation), and a person in charge of "Safety and working conditions" and PCR (competent person for radioprotection).

The scientists responsible for research themes are systematically consulted before any important decision

AERES nomenclature

SVE1_LS1

Unit workforce

Unit workforce (full time equivalents) 2  Overall assessment of the interdisciplinary unit

Strengths and opportunities related to the context

The projects on the archaeal translation machinery and on the relationship between translation and mRNA decay in eukaryotes are of very high quality with a promising future. The related publications have long-lasting impact and high visibility.The highlight of the last period is the structure of the ternary initiation complex aIF2-GDPNP-Met-tRNA. The work is highly original; the results were unexpected and led the field towards new concepts. The work on selenium cytotoxicity has had a great impact in the field. Over the last period the "Computational studies" theme was highly productive. The team must be commended for the quality of the atmosphere. Recent strategic movements towards hybrid structural approaches in combination with biophysics are very promising and will further increase the drawing power of the unit.

Weaknesses and threats related to the context "Selenium toxicity" does not fit in the general issues studied by the unit.

The CRISPR project starts in a highly competitive field without visible advantages.

Recommendations

More focus and a better integration between computational and experimental approaches would strengthten the unit research capability and revigorate the applied aspects of the research.

.

 Detailed assessments

Assessment of scientific quality and outputs

The unit has a particular strength in structural studies in translation initiation. The publications coming from the group have long-lasting impact and high visibility. The recruitment of a successful young PI in the related topic "Coupling between translation termination and mRNA decay in eukaryotes" strengthens this research domain. Recent strategic movement towards hybrid structural approaches in combination with biophysics is very promising and will further increase the drawing power of the theme and the unit.

The team has produced some really good work in the field of selenium cytotoxicity, work that has a great impact in the field. If the group expands the model systems beyond yeast and create networks with complementary expertise outside of the unit, the team may be very successful.

The bioinformatics group is well recognized in the field (invitations in international meetings and reviews) and was highly productive during the past period.

Assessment of the unit's academic reputation and appeal

The unit has established numerous collaborations with other academic laboratories as well as companies.

The laboratory is involved in FRISBI (south-Paris node), the french infrastructure for integrated structural biology, as well as in the national research program GDR "Archées". The unit's head, chair of the Biology department at EP, is a member of Soleil SAB.

Several BIOC members have international recognition.

Assessment of the unit's interaction with the social, economic and cultural environment

The laboratory is active in the social and cultural area. It participates on a regular basis to actions aimed at raising awareness to Science (i.e., « Journée Portes Ouvertes »).

The members of the unit are evidently highly focused on basic research. However, in a few areas interactions with other (commercial) partners could potentially lead to the development of novel antibacterials and should be considered.

Two collaborative studies with industrial partners show the unit's potential (NANOBIOSENSORS ANR project with THALES Research and ANR project PROTICAD with Kineo-CAM, a company developing computer-aided motion tools, recently bought by SIEMENS).

Assessment of the unit's organisation and life

The unit works as a single team/laboratory with 4/5 themes of research. The operating mode is by "Assemblée Générale" (general assembly) rather than with an elected "Conseil de laboratoire". All unit members can therefore express their opinion on important questions, such as for instance the role of the laboratory in the construction of a biology institute at École Polytechnique. This assembly votes the modifications of the "Règlement Intérieur" and meets at least once a year, for information and discussions around safety issues. All equipment is made available to all laboratory members.

The scientists responsible for research themes are systematically consulted before any important decision.

The themes could easily overlap with the concept of teams but the committee could observe a general agreement with the present organisation and, thanks to the management, a good atmosphere within the unit.

The laboratory has 11 ITAs (engineers, technicians, administrators), 9 from École Polytechnique and 2 from CNRS. During the meeting with the committee members, the ITAs expressed their satisfaction with the mode of operation of the laboratory, which promotes their polyvalence and implication in research projects. Working conditions and relationships with the direction are appreciated. Concerns were expressed regarding career developments (limited opportunities to change job level) and the creation of platforms in the X-Bio project, which will decrease the involvement of ITAs in research projects. The distribution of work between platforms and projects should be discussed with the direction.

Assessment of the unit's involvement in training through research

The unit is strongly involved in teaching at École Polytechnique (EP).

Three CNRS researchers are part-time teachers of EP. The unit hosts three EP lecturers in Bioinformatics (teaching and experimental training). The laboratory plays also a key role in biology experimental training by providing teachers and giving students access to the lab equipment. A unit member is in charge (with a member of the Informatics department) of the third year program on "Bioinformatics". The unit's head is in charge of the third year program "Biology". Three courses, "Computational Biology", "Experimental training in genetical engineering" and "Project in computational biology", are taught by members of BIOC. BIOC is also deeply involved in an experimental teaching program for second-year students.

The unit contributes to two Master 2 programs anchored to the Saclay campus: "Engineering of Biomolecules" and "Bioinformatics and Biostatistics".

BIOC is involved in a recently launched national network for teaching Integrative Structural Biology to PhD students and young researchers. This network constitutes the teaching part of the French Initiative for Integrated Structural Biology.

In the 2008-2013 period, the laboratory has hosted a total of 31 students for research internships.

The important development of biology in the academic cursus of EP should favor the recruitment of more PhD students from EP in BIOC. In view of the quality of the EP students this opportunity is of strategic importance for both the unit and the school.

Students are members of ED n°447, a Doctoral School hosted by both École Polytechnique and ENSTA Paris Tech (École Nationale Supérieure de Techniques Avancées). This school is multidisciplinary and Biology is an active part of it.

Assessment of the strategy and the five-year plan

The research of the laboratory is deeply anchored in biological questions, with strong interfaces with informatics. The fusion of bioinformatics and experimental biology projects goes in the right direction. The combination of hybrid structural approaches with biophysical and computational methods is another extremely valuable development.

An important challenge arises from the planned expansion of biology at EP with the operation "Biology and Interfaces" which will result in the creation of the X-Bio (for cross-disciplinary biology) Institute. This institute will federate the facilities and the programs of the BIOC and the LOB (Laboratory of Optics and Biosciences from the Physics department). New teams will be recruited in the field of Cell Biology in order to reinforce the biology core and reach a critical mass in integrated biology. The institute aims at giving EP an international visibility in biology. It is integrated in the development of the Saclay campus where other biology institutes are being set up.

The project is appealing and deserves a high priority. The BIOC is rightfully at the heart of the program but there appears to be significant uncertainty regarding the impact of the LOB on the BIOC research priorities. It is imperative that the mode of working and the areas of collaboration between the two units are clarified. This theme will be fused with bioinformatics from 1/1/15.

 Strengths and opportunities:

A number of interesting and promising lines of research have been pursued in this area. However, there is a feeling of incoherence about this theme. The projects on D-aminoacyl-tRNA deacylase in blue algae and the one on 16S-rRNA methylases were effectively abandoned because there was apparently no interest in exploring the potential for these lines of work to serve as platforms for the development of antibacterials. Section 1.5 of the scientific report indicates that there was a short-term commitment to research on potential biosensors. This area of work has also been terminated.

The potential for exploitation of the methionyl-tRNA synthetase mutants to enable in vivo incorporation of non-canonical amino acids into proteins is apparently not a priority. Although the research collaborators in California may have been the initial drivers for this project, this does not rule out further development of this area by BIOC. Given that the Director indicated that synthetic biology is a developing interest within the unit, the team might want to revisit the discussion of this area. Section 1.5 indicates that there was a short-term commitment to research on potential biosensors. This area of work has also been terminated with two publications in Biosens Bioelectron (2009) and Opt express (2010).

 Weaknesses and threats:

Potential applications of the theme's results have not been further investigated due to a lack of interest.

 Recommendations:

Two promising projects could potentially form the basis for novel drug targeting work, peptidyl-tRNA hydrolase and methionyl-tRNA synthetase. Research that has practical uses can also be intellectually challenging and exciting, and therefore the decision to deprioritize these projects should be reconsidered. The fusion with theme 3 provides such an opportunity.

Theme 2:

Toxicity of selenium Manager's name:

 Overall opinion of the theme :

The theme was established in 2007. The quality of the work is excellent and, despite a limited production (5 published papers in JBC, FEBS J, Plos One), the constellations work has had a major impact on the field.

The reputation of the team is good, based on the good but limited production. However the focus of the theme does not fit in the general issues studied by the unit. The team is isolated in the present environment and this isolation may harm the ability to progress. There are no natural points of connection between this theme and the rest of the unit.

The drawing power would increase drastically if the team broadens the field of research by creating network and expanding the models under study beyond solely yeast.

 Strengths and opportunities :

The team has produced some really good work in the field of selenium cytotoxicity, work that has a great impact in the field. The team may be very successful if they continue this work and expand the model systems beyond yeast and create networks with complementary expertise outside of the unit.

 Weaknesses and threats :

The group is isolated in the unit and there seems to be no really firm ideas of how to proceed and develop the successful work that has been produced so far. The presentation did not give any vision for how to expand the research in models beyond yeast and no networks or collaborations were mentioned. The risk is that the lack of a strategy will severely prevent a successful continuation of the selenium research.

 Recommendations :

The drawing power would increase drastically if the team broadens the field of research by creating network and expanding the models beyond solely yeast.

Theme 3:

Computational studies Manager's name:

TOTAL

The theme focus is on the development and refinement of computational methods for the design of proteins (sequence-space exploration). The sophisticated procedure, based on the accurate evaluation of free energies of binding, allows sequences that fit for a given feature to be generated and ranked. The method is made freely available to the community as the Proteus software. Applications dealt with problems related to drug design or enzyme-substrate recognition in amino-acyl-t-RNA synthetases.

The bioinformatics project for the next period will consist mainly of pursuing the present developments. The applications on the elucidation of allosteric mechanisms of translational GTPases and the design of aminoacyl/tRNAsynthetases specificity will be continued.

 Overall opinion of the theme :

During the past period, the theme was highly productive (~30 papers, ie. J Mol Biol, JACS, J Compt Chem, Biochemistry, Plos One ...). However the degree of integration between computational and experimental work was found to be lower than expected. The team appeared not to be collaborating with colleagues within the unit on a number of projects where such collaboration might be advantageous. A stronger alignment of this team with the research objectives of the other parts of the unit would bring dividends for all concerned. The fusion of the theme with the previous protein engineering project provides such an opportunity.

 Strengths and opportunities :

The theme leader is well recognized in the field (invitations in international meetings and reviews). Two young researchers were recently recruited and the theme benefits from a strong support from EP which provides PhD and post-doc fellowships. The theme is also implicated in teaching and looks attractive for master students.

 Weaknesses and threats :

The spectrum of applications is rather large and not much connected to the topics and experimental studies conducted in the unit.

 Recommendations :

A focus on fewer projects driven by the data provided by the experimental groups will be beneficial to both sides. It would also help to further assess the methodology. The fusion of the theme with the protein engineering theme is a move in the good direction. The availability and the visibility of the methods would be greatly improved by the development of web services.

Theme 4:

Supramolecular assemblies in initiation of translation Manager's name: The topic is timely and internationally highly competitive. In recent years, the team has made a number of important steps towards solving the structures of macromolecular complexes in translation initiation and understanding their function. The highlight of the last period is the paper in Nature Structural and Molecular Biology, which reports the structure of the ternary initiation complex aIF2-GDPNP-Met-tRNA. The work is highly original; the results were unexpected and led the field towards new concepts for the mechanisms of recognition in initiation complexes.

While crystallography remains a strong focus, the team continues to develop hybrid approaches towards large macromolecular complexes. In particular, they have established a very valuable collaboration on cryo-electron microscopy with a group in Strasbourg who belongs to the outstanding specialists in that field, which opens a new exciting route towards solving the structures of the ribosome complexes in translation initiation. This is a very challenging goal at the forefront of the field. Furthermore, the translation initiation team has joint interests with the computational studies group on the GTPase mechanisms of translation factors, which is another very exciting direction. Finally, the team has invested a considerable effort in establishing a toolbox of biochemical and biophysical approaches to study translation initiation in archaea, which brings them in a worldwide unique position to probe the function-structural relationships. In summary, the productivity and the scientific quality of the team in the field of translation initiation is excellent with a strong position for further innovative work in the next period.

The focus of the team on structure and function of translation initiation is at the core of the unit. The theme provides a focal point for a number of other projects and developments. It has a strong record in studies of gene expression and outstanding expertise which can be used as a platform for all members of the unit. The theme provides natural collaborations with computational studies, translation termination and mRNA stability and diverse protein biosynthesis and engineering projects.

Theme 5:

Coupling between translation termination and mRNA decay in eukaryotes Manager's name: This research theme is new to the unit. It is headed by a young CNRS research director who joined the unit in 2012 with an ATIP-Avenir support. The recruitment strategy was recommended by the previous visiting AERES Committee. The committee feels that this new theme is excellent and fits well into the global strategy of research of the laboratory. The PI has a strong background in biocrystallography and a recognized expertise in mRNA decay studies, as testified by his recent publication co-signed with a team leader at IGBMC (Strasbourg) in the top ranked Nat. Rev. Mol. Cell Biol. Ongoing research projects include molecular and structural studies of macromolecular complexes related to ribosome activity, such as the methyltransferase adaptor protein Trm112 in complex with its targets, and the regulation of mRNA decay at the level of decaping.

 Strengths and opportunities:

This research theme focuses on macromolecular complexes for which multiple structural approaches are needed. Locally, it benefits from the human and technical potential of the laboratory in protein expression, purification and crystal growth. The proximity of the French synchrotron SOLEIL ensures a privileged access to high quality SAXS and macromolecular crystallography beamlines. The presence within the laboratory of bioinformatics can be an asset to synergistically decipher specific protein-protein interactions, especially in the case of the adaptor Trm112. At the national and international level, the PI has developed tight collaborations with teams at the forefront of mRNA decay studies.

 Weaknesses and threats:

The PI has so far been successful in raising funds and postdoctoral grants but the limited size of the group could be a threat in this highly challenging field of research.

 Recommendations:

To seek reinforcing and stabilizing this promising research theme with the recruitment of another permanent staff member ( "Chargé de recherche" or "Maître de Conférences" or an engineer as one will reach retirement age).

Newly created theme:

CRISPR-dependent immunity of bacteria.

Manager's name: The CRISPR project has just started and the quality cannot be assessed. This is a highly competitive field.

4

   Theme-by-theme analysis Theme 1: Structure-function relationships of proteins involved in the translation of the genetic message Manager's name:

Number as at 30/06/2013 Number as at 01/01/2015

	N1: Permanent professors and similar positions	3	3
	N2: Permanent researchers from Institutions and similar positions	7	7
	N3: Other permanent staff (without research duties)	10.6	9.6
	N4: Other professors (Emeritus Professor, on-contract Professor, etc.)	1	1
	N5: Other researchers from Institutions (Emeritus Research Director, Postdoctoral students, visitors, etc.)	4	1
	N6: Other contractual staff (without research duties)
	TOTAL N1 to N6	25.6	21.6

Unit workforce Number as at 30/06/2013 Number as at 01/01/2015

	Doctoral students	6
	Theses defended	8
	Postdoctoral students having spent at least 12 months in the unit*	4
	Number of Research Supervisor Qualifications (HDR) taken	1
	Qualified research supervisors (with an HDR) or similar positions	5	5

Workforce Theme workforce in Full Time Equivalents

  Mr Yves MECHULAM and Mr Pierre PLATEAU

		As at	As at
		30/06/2013	01/01/2015
	FTE for permanent professors	1
	FTE for permanent EPST or EPIC researchers	1.5
	FTE of other permanent staff without research duties (IR, IE, PRAG, etc.)	2.4
	FTE for other professors (PREM, ECC, etc.)	0.5
	FTE for postdoctoral students having spent at least 12 months in the unit
	FTE for other EPST or EPIC researchers (DREM, etc.) excluding postdoctoral students
	FTE for other contractual staff without research duties
	FTE for doctoral students
	TOTAL	5.4

Workforce Theme workforce in Full Time Equivalents

	Mr Thomas SIMONSON
		As at	As at
		30/06/2013	01/01/2015
	FTE for permanent professors	1
	FTE for permanent EPST or EPIC researchers	2
	FTE of other permanent staff without research duties (IR, IE, PRAG, etc.)	1
	FTE for other professors (PREM, ECC, etc.)
	FTE for postdoctoral students having spent at least 12 months in the unit
	FTE for other EPST or EPIC researchers (DREM, etc.) excluding postdoctoral students
	FTE for other contractual staff without research duties
	FTE for doctoral students	1
	TOTAL	5
	From 1/1/15, this theme will be fused with "engineering" and become: "Macromolecular engineering:
	computational and experimental studies". Manager: Mr Thomas SIMONSON; co-managers: Mr Yves MECHULAM and Mr
	Pierre PLATEAU.

Workforce Theme workforce in Full Time Equivalents As at 30/06/2013 As at 01/01/2015

	FTE for permanent professors	1
	FTE for permanent EPST or EPIC researchers	2.5
	FTE of other permanent staff without research duties (IR, IE, PRAG, etc.)	1.5
	FTE for other professors (PREM, ECC, etc.)
	FTE for postdoctoral students having spent at least 12 months in the unit
	FTE for other EPST or EPIC researchers (DREM, etc.) excluding postdoctoral students
	FTE for other contractual staff without research duties
	FTE for doctoral students

  Ms Emmanuelle SCHMITT and Mr Yves MECHULAM

	Workforce
	Theme workforce in Full Time Equivalents	As at 30/06/2013	As at 01/01/2015
	FTE for permanent professors	1	1
	FTE for permanent EPST or EPIC researchers	1	1
	FTE of other permanent staff without research duties (IR, IE, PRAG, etc.)	0.9	1.3
	FTE for other professors (PREM, ECC, etc.)
	FTE for postdoctoral students having spent at least 12 months in the unit
	FTE for other EPST or EPIC researchers (DREM, etc.) excluding postdoctoral students
	FTE for other contractual staff without research duties
	FTE for doctoral students	1
	TOTAL	3.9	3.3

Workforce Theme workforce in Full Time Equivalents

	Mr Marc GRAILLE
		As at	As at
		30/06/2013	01/01/2015
	FTE for permanent professors
	FTE for permanent EPST or EPIC researchers	1	1
	FTE of other permanent staff without research duties
	(IR, IE, PRAG, etc.)
	FTE for other professors (PREM, ECC, etc.)
	FTE for postdoctoral students having spent at least 12 months in the unit
	FTE for other EPST or EPIC researchers (DREM, etc.) excluding postdoctoral students
	FTE for other contractual staff without research duties
	FTE for doctoral students	2
	TOTAL	3	1

 Detailed assessments

 Overall

opinion of the theme:

Workforce Theme workforce in Full Time Equivalents

	Mr Pierre PLATEAU
	As at	As at
	30/06/2013	01/01/2015
	FTE for permanent professors	1
	FTE for permanent EPST or EPIC researchers	1.5
	FTE of other permanent staff without research duties (IR, IE, PRAG, etc.)	1
	FTE for other professors (PREM, ECC, etc.)	1
	FTE for postdoctoral students having spent at least 12 months in the unit
	FTE for other EPST or EPIC researchers (DREM, etc.) excluding postdoctoral students
	FTE for other contractual staff without research duties
	FTE for doctoral students
	TOTAL	4.5

Bases moléculaires et régulation de la biosynthèse protéique, BIOC, EC Polytechnique, CNRS, Mr Yves MECHULAM

 Overall opinion of the theme:

For this theme the unit has a well-established reputation as a leader in the field. The publications coming from the group have long-lasting impact and high visibility. Recent strategic movement towards hybrid structural approaches in combination with biophysics is very promising and will further increase the drawing power of the theme.

 Strengths and opportunities:

The group solved some of the most challenging problems in establishing the biochemical and biophysical approaches in archaeal translation initiation. These methods, in combination with the hybrid structural approaches established in the lab, provide a strong basis for the future success of the theme. The theme is and will remain the core of the unit, providing numerous possibilities for collaboration and exchange in know-how and human resources. The position of the group within the unit and its international standing are very strong.

 Weaknesses and threats:

The only potential weakness lies in the absence of in-house cryo-EM facility for analysis of biological samples (presently this work is done in collaboration with Strasbourg). The group would have the necessary expertise. Here, a stronger commitment of the school to the focus on Biology would be desirable.

 Recommendations:

The theme should be strongly supported and further strengthened. In particular, the combination of hybrid structural approaches with biophysical and computational methods is extremely valuable in the context of the unit and the school as a whole and should be strongly supported.