 Introduction History and geographical location of the unit

The "Genetic Stability and Oncogenesis Unit" (UMR8200) is located on the Gustave Roussy Cancer Campus at Villejuif. The unit belongs to the IFR 54, an Integrated Research Cancer Institute in Villejuif (IRCIV). The UMR 8200 includes 55 people including 25 permanent research staff (1 DRCE, 5DR, 7 CR, 2PUPH, 1 MCU, 1 PU emeritus and 8 ITA). The UMR 8200 is affiliated to the CNRS, Gustave Roussy Institute and the University of Paris Sud. The unit brings an added value having the DNA Repair expertise in the Institute. In 2010 the unit hosted 5 groups working on closely related topics connected to genetic instability. Team 3 has joined the unit in 2012 and an ATIP/AVENIR team will join the unit in 2014. For the next contract (2015)(2016)(2017)(2018)(2019), the research unit will be formed by 5 teams. Two teams result from the merging of pre-existing teams. The new teams have been evaluated by the AERES committee except the ATIP/AVENIR team.

The UMR 8200 objectives are to generate scientific progress in the mechanistic understanding of genome stability at multi-scale levels (molecular level, cell, organisms). The projects of the unit are remarkably focused on the mechanisms that govern genetic stability with a particular emphasis on DNA repair, DNA replication, mutagenesis, Homologous Recombination, and oxidative stress with outputs in rare diseases, diversification in B lymphocyte, and cancer. These objectives are supported by a scientific policy that entails independent research groups that constitute scientific units, transparent and collegial governance and shared resources.

The location of the UMR 8200 facilitates collaborations with the clinic departments of the IGR and translation of their fundamental knowledge in terms of clinics. This is demonstrated by the participation of the teams of the unit to the SIRIC (Integrated Cancer Research Sites) programme, the leader of Team 2 being the coordinator of the DNA repair axis.

Management team

The present director of the UMR 8200 is a world-recognized scientist in the field of translesion synthesis (TLS). She has a preeminent role in synergizing the activities of the teams and promoting the cross-fertilization between team activities and the cancer translational research. The management of the UMR 8200 relies on 2 main bodies. The steering committee is composed of the director and one or two members of the teams. The steering committee deals with scientific and organizational strategy and manages most of the decisions related to the scientific life of the Unit including recruitment of new teams, allocation of financial support and space, and day-to-day running of the Unit. The Laboratory Council (Conseil de Laboratoire) represents the unit with the appropriate proportion of technical staff, post-docs and PhD students. The CL meets twice a year and is informed about information and decisions. The CL gives advice on internal matters, equipment maintenance responsibilities, ITA promotion politics and safety rules. The Unit has no Scientific Advisory Board (SAB). The management of the unit appears satisfactory. The meeting with the different categories of staff revealed a consensual agreement about the management of the Unit. A particular attention should be given to the career development of the ITA, overall because they have overwork due the very low ratio of ITA in the Unit. Over the past few years the UMR 8200 has solidified its position with several highlight in the DNA repair field and PIs being recognized as leaders in their related respective field of research. The overall scientific level of this Unit is very good with many publications in high impact journals. The evaluation committee encourages all the teams of the UMR 8200 not only to maintain this level but to increase excellence and ambition even further by consolidating the internal synergy between the teams and develop international collaborations. The recruitment of an excellent ATIP/AVENIR team goes in this direction.

AERES

The Unit project is a synergistic project covering scientific goals focused on genetic stability and mobilizing a broad range of experimental methods and techniques. Remarkably, the unit project allows scientists of the different teams to combine their know-how and complementary expertise in cell biology, genetics, biochemistry and molecular biology in an effective manner.

The committee was also impressed about the interactions with teams involved in cancer diagnosis and treatments. These kinds of interactions are quite unique in France and represent a model for the evolution of cancer research. The financial situation of the UMR 8200 is good with an overall budject of more than 5 million euros (excluding salaries from permanent staff). The situation is less clear about the sources to improve or even maintain the scientific infrastructure. The committee recommends to further support the UMR 8200 infrastructure.

Weaknesses and threats related to the context

The team has a huge deficit in ITA staff. This Unit has been 15 years without a single recruitment of ITA, something that is not normal specially for a Unit with such scientific quality. Moreover, the unit has lost two positions due to internal mobilities (NOEMI) and 4 positions due to retirements

The UMR 8200 teams have the scientific quality and recognition to participate in European and international consortia. Some team leaders could even lead such activities.

It was not completely clear how the teams of the UMR 8200 access common services and facilities, including cutting edge technological platforms.

Recommendations

The team leaders of the UMR 8200 in close interaction with the experienced PIs, should carry on to develop a long-term vision about the added value of having their scientific expertise at the institute.

The Unit should increase its critical mass in a near future with the recruitment of at least 1 team to further increase the synergies that are already very efficiently exploited by the teams. A team with experience in Epigenetics would be an added value to the unit.

The Committee approves the merger of units that have been proposed for the next contract providing that it will not be just juxtaposing activities but rather a synergistic work on common scientific projects. The committee recommends that the newly merged teams share open space, scientific goals and animation, and financial support.

The committee encourages the UMR 8200 to participate in international activities. CR scientist from team 2 is encouraged to apply for an ERC for young investigators.

Although the research projects of the Unit should be kept dedicated to fundamental aspects, the Committee encourages the teams to answer to SIRIC calls.

A website for the team should be established in English to promote international recruitment.

 Detailed assessments Assessment of scientific quality and outputs

The laboratory has a world-recognized expertise in several aspects related to genome stability. Assessment of the scientific production of the laboratory shows a total of 137 publications in peer-reviewed scientific journals over the last 5 years, excluding clinical publications with more than 70 articles over the period. The average impact of the publications is very good since 30% of the papers have an IF between 15 and 7. They have some outstanding contributions in which the members of the Unit appear as last author that have been published in high-ranking scientific journals such as Nat Cell Biol, Mol Cell, PNAS, Cell reports. About half of all research articles are collaborative, and 13% of them include members from different units in Gustave Roussy, demonstrating scientific interactions in the Institute. Finally, results have been presented as posters or oral communications at the main national and international scientific meetings in the fields of DNA repair, DNA damage response, genome instability, reactive oxygen species (ROS) and thyroid tumorigenesis and Ig gene diversification in B lymphocyte. In total, members of the unit have been invited in 60 meetings between 1 st January 2010 and mid-2013 with 64% in international meetings.

Assessment of the unit's academic reputation and appeal

The academic reputation and visibility of the laboratory is underscored by some outstanding contributions with a fraction (3.5%) of the papers having an IF>15, the large number of invitations of several members of the lab to act as speakers at national and international meetings, and the fact that several lab members received different prizes (Prize LNCC, Prize Dandrimont-Bénicourt 2013, Prize Lavrentiev 2012). Moreover, recognized scientists have been recently recruited or joined the lab including one ATIP/Avenir team that will start in the unit in April 2014, further demonstrating the excellent unit's academic reputation. Finally, several members of the unit take an active part in the scientific expertise for funding organizations (INCA, ARC, LNNC).

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

There is a significant impact of work done at the Unit in particular on the health sector. The UMR8200 takes part in the recently funded "Integrated Cancer Center" (SIRIC) that has been set-up to stimulate integrated research from basic to applied science and collaboration between clinicians and academic researchers. In this program, the DNA Repair axis is coordinated by the leader of Team 2. DNA Repair has become one of the main research axes at Gustave Roussy. The development of predictive tests monitoring DNA Replication and repair will permit individualized treatment options of DNA-damaging drugs and radiotherapy. Such tests may be patentable and could be integrated in clinical trials based on pre-selection of patients.

In addition, the director of the unit is a member of the steering committee of the IRCIV as well as a member of Scientific Policy Committee at IGR that discusses the main scientific and clinical orientations of the Research in the Institute.

Assessment of the unit's organisation and life

The decision-making structures of the unit are well-organized, and each team is working in an autonomous manner. There is a strong cohesion between people working within the unit. Concerning financial aspects the Unit is in a rather favorable situation due to the efficient recruitment of grants. However, resources are limited to further improve the scientific infrastructure of the Unit.

Assessment of the unit's involvement in training through research

There is a strong and supportive relationship between PhD students, postdocs and senior researchers in the unit. Weekly lab meetings are organized so that the monitoring of the research activities of students/postdocs is efficient. Additionally, students/postdocs are encouraged to attend national and international meetings where they can present their work to the scientific community.

In addition to the teaching activities displayed by Professors/Assistant-Professors (840 h), 6 researchers of the unit participate in teaching (190 h/year) at the major universities of Ile-de-France, Pasteur Institute and the Ecole Normale Supérieure de Cachan. Of note 80 hours per year are delivered in Universities of the Republic of Kazakhstan by Team 4.

Assessment of the strategy and the five-year plan

The committee very strongly supports the five-year research plan of the unit that consists in tackling different aspects of genome integrity maintenance from fundamental research to clinic translational and biotechnological developments, in a continuum of biological models from yeast (ATIP Team) to mammalian cells and including patients. The unit is currently implementing the human and organisational resources to succeed in this ambitious challenge. It will be important to maintain research excellence to promote the international visibility of the unit and further develop the links between the researchers of the unit with the international cutting edge research performed in the field. The committee encourages the recruitment of an epigenetic group to include the epigenome maintenance in the central topics of the unit. Finally, the committee commends the efforts of the director to stimulate the links between clinicians and the academic researchers working in the Unit. The Kannouche team's research program builds mainly on the team leader's expertise on Translesion Synthesis (TLS) DNA polymerases. Recruitment of TLS polymerases to replication forks as a bulky DNA lesion by-pass mechanism and TLS implications in genome stability maintenance are relevant and highly competitive topics. The team's research has been focused on analyzing the regulation of TLS polymerases (pol eta and pol iota), as well as on the mechanistic characterization of the TLS process and its impact on protecting genetic stability in higher eukaryotic cells in response to oxidative damage. The team provided insight into the function and fine regulation of the TLS polymerase pol eta, revealing its importance for the functionality of replication forks facing ultraviolet (UV) light-induced DNA lesions and uncovering the role of pol eta's ubiquitin-binding (UBZ) and PCNA interacting peptide (PIP) domains in controlling its association to replication forks. The team also analyzed Fbh1 helicase function in favouring TLS by suppressing Homologous Recombination (HR) via its recruitment to replication factories and subsequent degradation, in a mechanism dependent on Fbh1-PCNA interaction. The team uncovered a "noncanonical" function of pol eta in response to oxidative damage, by which it is recruited to oxidative lesions independently of DNA replication and through the action of the Msh2-Msh6 Base Excision Repair (BER) factors. Lastly, the team reported a novel role for the pol iota TLS polymerase in the repair of oxidative lesions.

The topics engaged by the team are original and have provided a significant advancement in the understanding of important aspects of TLS polymerases function and novel TLS mechanisms suppressing genetic instability. The publication record of the team for this period is very good, with papers published in prestigious journals like Molecular Cell, EMBO Journal, Nucleic Acids Research and Human Molecular Genetics, which received a significant number of citations.

The Genome Plasticity and B cells team experienced a change of leadership in 2010 in which a new researcher took charge replacing the previous leader. The team's research has focused on the DNA repair mechanisms generating immunoglobulin (Ig) gene diversity. This topic is relevant and has potential implications for human health.

A first interest of the team is the regulation of single-stranded-DNA-specific cytidine deaminase (AID), a factor essential for priming somatic hypermutation (SMH) and class switch recombination (CSR) at Ig genes. The unit reported the importance of subcellular distribution on AID stability and how it affects its degradation by the proteasome. A second research interest has been the role of TLS polymerases in somatic hypermutation. The team contributed to show that the TLS polymerase kappa can exert a backup role in this process by substituting polymerase eta when the latter is absent. Since its change in leadership the team has focused on studying a novel role of the cohesin complex subunit RAD21 in CSR, the impact of limiting polymerase eta availability on genomic stability and the role of the Fanconi Anemia pathway on CSR and SHM.

The topics tackled by the team are original and have the potential to contribute to advancing the current understanding of important aspects of human Ig genes diversity generation. The publication record of the team for this period is fair, likely limited by the reshaping of the team and the establishment of new research lines. The team has published in good journals like J Exp Research, J Clin Investigation, J Immunol, Curr Opin Immunol and DNA repair both primary and collaborative papers, which have overall received a significant number of citations. Work from the newly established research lines has been submitted or is in preparation for submission, but has not been published at the date of the evaluation.

Assessment of the unit's academic reputation and appeal

The TLS polymerases and Cancer team's reputation is very good, as judged by the quality of the journals in which its research was published and by the number of citations. The team has a high involvement in national collaborative projects, though participation in international projects is not described. The team leader has been invited speaker in several relevant meetings such as the Gordon Conference on Mammalian DNA repair 2013 and has received the Dandrimont-Bénicourt prize in 2013. The team leader acts as ad hoc reviewer for prestigious journals and belongs to the INAC and ERC (external) reviewing boards. Internationalization in terms of recruitment of foreign students is in place.

The Genome plasticity and B cells team's reputation is fair, based on the quality of the journals in which its research was published and the number of citations received. The team leader has been invited speaker in international meetings such as the Workshop on AID biology in 2013 and the 26 th annual symposium of the Protein Society in 2012. The team leader acts as reviewer of scientific papers and has participated in the organization of meetings.

Assessment of the unit's interaction with the social, economic and cultural environment TLS polymerases and Cancer team: Interaction with the social, economic and cultural environment is good, and has been established through the participation of the team leader (Ms Patricia KANNOUCHE) in consulting for a private laboratory, radio interviewing and participation in invited seminars at a company.

Genome plasticity and B cells team: Interaction with the social, economic and cultural environment was established through the participation of the team leader in the organization of scientific workshops in high schools and universities and by serving as consultant for the media.

Assessment of the unit's organisation and life

Judging from the unit's report and the site visit the team is very well organized with a precise scientific objective and clearly defined roles within the unit. The accessibility of the teams to the pooled resources, the scientific coordination structures and the incentivising of team emergence are coherent and well organized.

The teams are very well integrated at Institut Gustave Roussy and within the unit, and hold several collaborations at a national and international level.

Assessment of the unit's involvement in training through research TLS polymerases and Cancer team: During this period the team has a good training record including 5 PhD students, 6 Master students and 9 undergraduate students. Of these, 2 PhD students have contributed as main author and collaborative publications, indicative of a good training, and have moved to appropriate postdoctoral positions. The team leader took part in teaching in French universities and has been involved in thesis evaluation committees, attaining an adequate outreach at regional and national level. A research line aims at exploring the molecular mechanisms mediating UV-lesion bypass in human cells. The team will analyse the role of pol eta SUMOylation in its stability/processivity, as well as the role of SUMO conjugating enzymes potentially acting on pol eta and Rad18. The function of TLS factors in promoting lesion by-pass directly at replication forks will also be explored in an approach employing different techniques such as electron microscopy, iPOND and proteomic searches. Part of this research relies on collaborations with other groups and on methodologies recently implemented by the team. A second research line aims at exploring a possible role of TLS factors in promoting heterochromatic regions replication and will explore the importance of such mechanism by addressing the impact of Pol zeta defects on fork progression and on the maintenance of the epigenetic landscape.

Additional research lines will be carried out by an emeritus professor within the TLS polymerase group headed by Ms Patricia KANNOUCHE. Two research lines will be carried out in collaboration with the PK and Genome Plasticity groups, as a continuation of previous work. The objectives and methodological strategy to develop these research lines are not stated in the report. In addition, an emeritus professor in the team will carry out studies on the DNA repair-deficient syndromes xeroderma pigmentosum (XP) and Cockayne syndrome (CS). A link between historic slavery process on African populations and the propagation of XP-causing mutations will be explored and the identity of a putative mutation causing myeolodisplasy in XP patients will be sought through genetic analysis of different patients and cohorts. Research related to a mitochrondrial alterations in CS patients will be carried out, though objectives and strategies are not described.

The proposed research strategy is in general original and supported by strong preliminary evidence, thus reducing the inherent risk of exploring novel hypotheses. The proposed research is credible and reflects the team's capacity to adapt to novel findings and ideas emerging in the research field. The proposed research strategy is expected to maintain the team's good productivity.

Genome plasticity and B cells team:

There are two main lines in the future research plan and strategy. The first one emanates from the current team's research and aims at identifying factors and/or post-translational modifications driving mismatch repair (MMR) factors to mediate somatic hypermutation (SHM) at Ig V genes. The second one aims at exploring the interplay between AID and TET2 oxygenase in a putative epigenetic pathway suppressing haemopoietic malignancies. This strategy is original and has the potential to render interesting insights into the analysed processes. The proposed research is consistent with the team's experience and is overall credible. The group's future reputation will depend on the quality of the scientific output of these research lines, as well as on that of the work carried out since 2010.

Overall, the Ms Patricia KANNOUCHE's team proposed research reflects the team's capacity to adapt to novel findings and ideas emerging in the research field. The involvement of non-academic partners is not explicit in the research plan. The SWOT analysis is realistic and provides an accurate assessment for strategic decisions regarding future research directions. In general the five-year research plan is feasible and likely to contribute with important findings regarding TLS-related mechanisms preventing genetic instability.

Conclusion

 Strengths and opportunities:

The team has displayed a very good research record and presents very interesting future research prospects. The unit organization and researchers training are excellent. The research strategy is coherent. In most cases supported by preliminary evidence and promising. The implementation of new methodologies and the rearrangement of the team members are expected to enhance the competitiveness of the research team.

 Weaknesses and threats:

No major weaknesses are apparent.

 Recommendations:

The internationalization of the team by participation in collaborative networks or by recruiting foreign postdoctoral research would boost the team's reputation. This team is led by Mr Filippo ROSSELLI but contains two scientists with Emeritus who are still scientifically active and published very good papers in the last years. The focus of the team is consequently diverse, each exPI bringing unique expertise in the final pool (i.e. Homologous recombination and Nucleotide excision repair). However the main topic stays the topic of the PI, Mr Filippo ROSSELLI, who is an expert in the FANC/BRCA pathway with many recent achievements in excellent journals. Recently, the group has reported the involvement of FANC in preventing the segregation of defective chromosome, in collaboration with the Bloom protein. They also discovered that the FANC pathway was activated after exposure to UVC. This team is not only performing fundamental science but also tries to use its knowledge in DNA repair to address questions about SNP in DNA repair genes and risk of cancer that may be important in the future to predict cancer outcome. For such projects they use their location a the IGR to interact with Physicians and recolt tumour samples.

The publication record of the lab is excellent, with two papers published in Nature Cell biology and one in Molecular Cell. The PIs also published many papers in the last years as co-authors in collaboration with excellent teams (see below).

Assessment of the unit's academic reputation and appeal

The team's reputation is excellent. Their work is published in very good journals such as Nature Cell Biology or Molecular Cell. Members of the team include highly cited scientists who are regularly invited to conferences. Altogether, the 3 PI were invited to 43 international and national meetings. The team has a high involvement in national collaborative projects.

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

An expert in nucleotide excision repair in the team speaks regularly in media to explain the disease harbored by the so called « children of the moon ». He is recognized as the French expert for these disorders. He participated to several radio/TV programs. Mr Filippo ROSSELLI is a member of the scientific board of the Ligue Nationale contre le Cancer. Also, Mr Filippo ROSSELLI and his team members participate to the annual meeting of the French XP and FA parents association.

Assessment of the unit's organisation and life

The team is well organized with weekly lab meetings and seminars and fruitful interactions with other groups within the unit as evidenced by joint publications. The students and postdocs of the group expressed a high degree of satisfaction and common interest in the social well-being of the group.

Assessment of the unit's involvement in training through research

The team currently has three graduate student and two postdocs.

Assessment of the strategy and the five-year plan

Due to the departure of the emeritus it seems that the projects of the lab will be focused only on the FANC pathway as a direct link with what the team has done these last years. Consequently, the proposed research strategy is in general supported by strong published work, thus reducing the inherent risk of exploring novel hypotheses. The proposed research is credible and reflects the team's capacity to adapt to novel findings and ideas emerging in the research field. The proposed research strategy is expected to maintain the team's good productivity, with respect to the "threats" described below. Questions remain about the desire of the unit to create a team with one CR from Rosselli lab. If this lab looses the two emeritus and the CR, it is likely that they will not be able to compete at the international level.

Conclusion  Strengths and opportunities:

Very good record and equally good prospects. The research program is logical and appealing. The future directions are straightforward and promising.

 Weaknesses and threats:

Possibility to loose the CR who did the two last big papers of the lab as well as the two recognized Emeritus of the group.

 Recommendations:

The impact of the creation of a new team with the CR as PI should be considered relatively to the consequence for the Rosselli team. The CR is in an excellent position to apply for an ERC starting grant. Mr Bernard LOPEZ (BL) joined the UMR8200 unit in 2012. The primary scientific focus of the team is the regulation and coordination of homologous recombination with DNA replication, end-joining pathways (NHEJ and A-EJ) and mitosis. The team has recently been joined by experts to investigate endogenous sources of DNA replication stress such as reactive oxygen species (ROS) and their implications for radiocarcinogenesis and thyroid cancer.

BL and his team members are internationally recognized for their important contributions to our understanding of the choice of repair pathway for DNA double-strand breaks and the contribution from DNA repair factors such as MRE11, KU80, XRCC4, BRCA1, CtIP, RAD51, TdT and BLM. For example, a recent high-profile paper in Nature Structural and Molecular Biology demonstrated the role of the MRE11 nuclease in alternative NHEJ (presently 128 citations). Several regulatory mechanisms have been elucidated in the reporting period ; most importantly those of AKT1 and Bcl-2, which were shown to inhibit homologous recombination by sequestering BRCA1 and RAD51 in the cytoplasm. Another important finding from BL's lab is the demonstration that homologous recombination is required during unchallenged DNA replication. The members of the 'Reactive oxygen species and Radiocarcinogenesis' team which joins the team are internationally recognized for their long-lasting, innovative and knowledgeable expertise in the identification and characterization of NADPH oxidases and the interactions of oxidative stress with genomic deregulation and carcinogenesis, particularly radiocarcinogenesis, in the thyroid cell/tissue model. The team has also made the important finding that the increased ROS observed after radiotherapy persists for much longer (days) than can be explained by a direct consequence of ionizing radiation.

BL has engaged in several fruitful national and international collaborations e.g. to demonstrate the importance of nucleoporin 153 in DNA double-strand break repair.

The team is exceptionally well balanced between basic and translational research with close ties to clinicians. The strength in this area is supported by access to patients, and tissue samples there from, with various types/stages of thyroid cancer for which IGR is one of the preeminent referral centers in Europe.

The publication record of the lab is outstanding, with many papers in leading journals like Molecular Cell, Oncogene, Cancer Research, Nature Structural and Molecular Biology, and New England Journal of Medicine.

Assessment of the unit's academic reputation and appeal

The team's reputation is excellent. Their work is published in high-impact international journals and frequently cited. BL has many strong collaborators. He coordinates several collaborative research projects and networks and both he and his senior team members are frequently invited to meetings and for individual seminars. He is very well known and highly respected in the DNA repair community.

BL has served on many national and international scientific advisory boards and grant evaluation committees including the ERC. BL has organized two scientific meetings in the reporting period.

Assessment of the unit's interaction with the social, economic and cultural environment BL has contributed to a patent and collaborates with the Paris-based company Cellectis. A senior group member has headed 12 clinical trials on thyroid cancer patients.

Assessment of the unit's organisation and life

The team is well organized with weekly lab meetings and seminars and fruitful interactions with other groups within the unit as evidenced by joint publications. The students and postdocs of the group expressed a high degree of satisfaction and common interest in the social well-being of the group.

Assessment of the unit's involvement in training through research

The team currently has five PhD students and four postdocs. The high quality of publications by past PhD students is evidence that the training provided to graduate students is excellent. BL has served on 15 thesis juries and 6 HDR juries.

Assessment of the strategy and the five-year plan

The proposed research is highly feasible and likely to be a scientific and organizational success, because BL has assembled a team of complementary expertise and BL has managerial experience as deputy director of the UMR217 CEA/CNRS. The scientific focus of the team will be DNA replication stress and cancerogenesis with a strong translational element. The project is highly feasible because of the outstanding qualifications, complementary experience of the team members, and state-of-the-art core facilities available at the institute.

The proposed research project is timely and ambitious, because it focuses on sources of endogenous replication stress, which are more physiologically relevant but also inherently more difficult to study compared to the high levels of replication stress often studied by treatment with exogenous genotoxic agents and replication inhibitors. The team will take a genetic approaches to study RNA/DNA hybrids by expressing RnaseH in HR-deficient cells and to study ROS by inactivation of the NADPH-oxidase.

The proposed methods are well supported by core facilities of the institute such as DNA combing, mouse labs, 2D-gel electrophoresis and microscopy. These facilities should be maintained and kept up-to-date to support the research of the team.

Senior group members with clinical experience add a strong translational aspect to the team.

Conclusion

 Strengths and opportunities:

Outstanding track record and equally good prospects. The research program is logical and appealing. The future directions are straightforward and promising.

 Weaknesses and threats:

Attention should be paid to increase international recruitment.

Insufficient technician support.

No significant international (EU, HFSP, NIH) funding.

 Recommendations:

Support for a full time technician for the team would make the team more efficient.

The team should be in a strong position to apply of EU funding.  Detailed assessments

Assessment of scientific quality and outputs

This group uses E. coli, yeast and human cells to determine the molecular mechanisms that underlie DNA repair after oxidative damage. Complex DNA damages that represent a small fraction of DNA lesions, play however an important biological role as they lead to the death of the cell. The group is one of the research leaders in these processes of DNA repair and have demonstrated, among other crucial results, the role the human apurinic/apyrimidinic nuclease in nucleotide incision repair and have constructed several mutants of this enzyme that were crystallized. As DNA repair is central to cancer treatment, by chemo-as well as by radiation therapy, the work of the group fits well with the unit. The group has been extremely productive with 26 primary research publications with a constantly improving quality in the high impact factor of the journals (Mol Cell, NAR, PNAS, Oncogene). Overall, the group's track record is very good.

Assessment of the unit's academic reputation and appeal

Beside the leader, who is DR2 CNRS, there is only one permanent researcher (CR1 CNRS) in the group. The group's visibility is good and the leader received many invitations to speak at international meetings. He is editor of a Kazakhstan-based journal and has secured on a constant basis excellent collaborations with 5 national and 10 international laboratories. Several grants, not detailed (Charities, government or industry) have been secured during the period.

Assessment of the unit's interaction with the social, economic and cultural environment Although the group is small, there are several Television interviews mentioned, a public lecture and two journal interviews, which is good.

Assessment of the unit's organisation and life

The team looks well organized with good interactions within the team

Assessment of the unit's involvement in training through research

Excellent, for such a small group, it has/had trained 7 PhD students and several undergraduates.

Assessment of the strategy and the five-year plan

The team leader has secured or proposes to secure three grants for the next period, along which the team will develop its projects. These projects propose to extend the work that has already been conducted and are briefly described below. Two are under the responsibility of the team-leader, the third being headed by another permanent researcher of the team. It seems surprising to see such a small team already proposing to split into two sub-groups.

The projects are well described and combination of expertise of the team leader and his collaborator, and use of techniques well in hand all predict success.

Conclusion  Strengths and opportunities:

The projects are clearly outlined with solid background and prospects combined with good collaborations. The team leader is well considered and this work is necessary to understand DNA repair at the molecular level, which again, however fundamental, is really important in the light of cancer radio-and chemotherapies.

 Weaknesses and threats:

The projects that are described as grant applications do not allow understanding the overall strategy of the group.

 Recommendations:

The team should remain as one team.

2 

 2 spent at least 12 months in the unit 2 Number of Research Supervisor Qualifications (HDR) taken Qualified research supervisors (with an HDR) or similar positions 1 1 Detailed assessments Assessment of scientific quality and outputs

  Genome plasticity and B cells team: During this period the team has a fair training record including a PhD student, as well as master students and undergraduate students. The PhD student is currently in the 3 rd year and has not yet contributed with publications. The team members took part in teaching in French and UK universities.Assessment of the strategy and the five-year plan TLS polymerases and Cancer team: The future research plan and strategy are consistent with the team expertise and suppose a coherent expansion towards open questions in the function of TLS mechanisms.

N4:

  Other permanent staff (without research duties) 2 1 Other professors (PREM, ECC, etc.) 1 N5: Other EPST or EPIC researchers (DREM, Postdoctoral students, visitors

  and Cancer Name of team leader : Mr Bernard LOPEZ Workforce : Fusion between Mr Bernard LOPEZ's team and Mr C. DUPUY's team for the next contract Other permanent staff (without research duties) 1 N4: Other professors (PREM, ECC, etc.

2 N3:

 2 Permanent professors and similar positions N2: Permanent EPST or EPIC researchers and similar positions 2 Other permanent staff (without research duties) N4: Other professors (PREM, ECC, etc.) N5: Other EPST or EPIC researchers (DREM, Postdoctoral students, \visitorsco-supervision with foreign universities (Universities from Kazakhstan, Russia and Poland).

  Committee and of AERES to the lab 09h05-09h35 Presentation of the lab, achievements and projects (discussion included): Ms Patricia KANNOUCHE Presentation of the teams (time includes questions) lab personnel (in parallel)

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

	Unit workforce 2
	N1: Permanent professors and similar positions	4	4
	N2: Permanent researchers from Institutions and similar positions	11	10
	N3: Other permanent staff (without research duties)	9	6
	N4: Other professors (Emeritus Professor, on-contract Professor, etc.)	1	2
	N5: Other researchers from Institutions (Emeritus Research Director, Postdoctoral students, visitors, etc.)	9	8
	N6: Other contractual staff (without research duties)	2	4
	TOTAL N1 to N6	36	34
	Unit workforce	Number as at 30/06/2013	Number as at 01/01/2015
	Doctoral students	13
	Theses defended	18
	Postdoctoral students having spent at least 12 months in the unit*	16
	Number of Research Supervisor Qualifications (HDR) taken
	nomenclature SVE1_LS2; SVE1_LS1; SVE1_LS4; SVE1_LS6 Qualified research supervisors (with an HDR) or similar positions	11 6

 Assessment of the unit Strengths and opportunities related to the context

  Mr Frédéric COIN, expert of the committee, could not attend the site visit.

	14h00-14h30	Technicians
		Audience: Committee members, AERES delegate
		PhD students and post-docs
		Audience: Committee members, AERES delegate
		Scientists
		Audience: Committee members, AERES delegate, without team leaders
	14h30-14h45	Meeting with a representative of the graduate school
		Audience: Committee members, AERES delegate
	14h45-15h00	Meeting with the management team
		Audience: Committee members, AERES delegate
	15h00-15h30	Meeting with the representatives of the governing bodies:
		Audience: Committee members, AERES delegate
	15h30-17h45	Closed-door meeting
		Audience: Committee members, AERES delegate
	Specific points to be mentioned:

 Team-by-team analysis

On behalf of my colleagues, I would like to thank the committee members for the very positive evaluation and for the constructive remarks. We very much appreciated that the committee strongly supports the five-year research plan of the unit. We are also grateful for approving the merge of teams that have been proposed for the next contract.

We do think that some criticisms will help us to get better in our scientific output as well as in our international visibility. However, since this report is going to be made public we feel it necessary to correct some misunderstandings.

Management

"The Unit has no Scientific Advisory Board (SAB)". Indeed, our unit has not its own SAB but its activities are evaluated every two years by the Gustave Roussy's International SAB.

Weaknesses and threats

"The unit has a huge deficit in ITA staff."

We completely agree with this statement. We asked our institutions every year to support our unit by providing technical staff, without success up until now. This situation becomes a real threat for the unit to meet its missions and scientific objectives.

Recommendations

-"The committee encourages the UMR 8200 to participate in international activities." This recommendation is quite surprising since in the report, the committee recognized the involvement of several teams in international collaborations (e.g. "The teams are very well integrated at Institut Gustave Roussy, and hold several collaborations at a national and international level.", "BL has engaged in several fruitful national and international collaborations"….).

-"CR scientist from team 2 is encouraged to apply for an ERC for young investigators". This action is currently underway.

-We note that the recruitment of a team with experience in Epigenetics would be an added value to the unit.

Team-by-team responses:

TEAM 1: "TLS Polymerases and Cancer"

We would like to thank the AERES committee members for the positive feedback and the relevant comments they gave us to improve our project. In addition to the elements highlighted in the evaluation report, we wish to clarify one misunderstanding. The group leader of the "Genome Plasticity and B cells" team did not replace a previous PI but rather has set up a new team in 2010. Therefore, two sentences have to be modified as follows:

-P9, 4th paragraph, line 1: Instead of "The Genome Plasticity and B cells team experienced a change of leadership in 2010 in which a new researcher took charge replacing the previous leader", we should read:

The Genome Plasticity and B cells team is a new team formed by the group leader in 2010.

-p9, 5th paragraph, line 6: Instead of … "since its change in leadership"…, we should read: since its establishment, the team has focused… TEAM 2: "FANC/BRCA Pathways and Cancers"" We wish to thank the committee members for the extremely positive assessment of the past 5-year activities of the team.

For the future, the team will loose only one of the Emeritus (and not both), who will integrate the team of the Unit director. In light of her excellent CV, the committee suggested the application of one of the CR of the team for an ERC grant. We agree and thank the committee for the suggestion and support. Obviously, if the CR will obtain an ERC starting grant, it will be impossible to maintain the same position than now in the organization chart of the team. With an ERC starting grant, to be « independent » seems mandatory. But this will not imply that we will not continue to work in a strongly coordinated and collaborative manner. Moreover, we hope to reinforce the team by the recruitment of a new CR or MCU. One of the post-docs that presently works in the team is, in our opinion, in an excellent position to obtain a permanent position.

TEAM 3: "Recombination/Repair and Cancer"" We thank the committee members for their positive evaluation of our team. We are pleased that the visiting committee has appreciated the high quality of the research that is performed by our team. Below we wish to address the weaknesses and threats perceived by the committee and comment on the suggestions made by it:

1-"Attention should be paid to increase international recruitment." We suppose this should be a mistake. Indeed: In conclusion, we received students and post-docs from different continents (Europe, Africa, Asia, US). This is probably one of the best ratio we can find in France (and in many other countries).

2-"No significant international (EU, HFSP, NIH) funding". We thank the committee to estimate that the quality of the laboratory makes it eligible for international funding. As we have been very successful in collecting funds (even with competitive calls) for the team to work in better than decent conditions, it would be counter-productive to waste time and energy with calls for non-necessary applications. This is not an exceptional and particular situation, but represents the common situation for most of the laboratories. Consequently, we believe that this should be removed from the weaknesses or threats section, especially because this point is raised in the recommendation section (and should stay here).

3-"Insufficient technician support".

We fully agree with the committee and this is actually the main threat of the laboratory.

Specific comments from C. Dupuy's group: Concerning "Assessment of the unit's academic reputation and appeal" and "Assessment of the unit's interaction with the social economic and cultural environment" the assessment of the "ROS and radiocarcinogenesis" team is not mentioned : organization of international congress and meetings, invited speakers in international meeting , reviewer of scientific papers, participation in training course.

TEAM 4: "DNA Repair"" We are pleased to see that our team has been positively considered by the AERES committee in terms of scientific quality and outputs, reputation and appeal, social interactions, group organization, involvement in training and long term strategy. It is remarkable that the AERES committee emphasized that, regardless of the small size of the team (only 2 tenure staff), it has demonstrated excellent achievements in terms of productivity, academic reputation and student training. However, despite all these achievements, the AERES committee does not recommend to provide any support to the team in the form of recruitment of full time technician or engineer.

Based on the fact that the size of the team is very small, the AERES committee recommends to not split it into two groups. This is apparently a misunderstanding as we didn't propose to split the team but rather to develop a new research theme: study of the role of DNA repair in epigenetic regulation. This theme has been orally presented to the committee by the CR1 researcher who has his own funds and small group of post-docs and students and this fact was not mentioned in the report.

Once again, we thank the members of the AERES Committee.


 Introduction History and geographical location of the unit

The proposed unit is an extension and a restructuration of the UMR S_757 (that was endorsed by both the Université Paris-Sud and the INSERM). There will be two teams participating in the present project. All Team 1 members will come from UMR S_757. Team 2 will include members from different origins. Two will come from UMR S_757, one will move from UPR2301 (CNRS) and the last one from UMR8619 (CNRS-UPS). Teams will be located at the same place as the UMR S_757, i.e., and will occupy 1200 m 2 in a building (number 443) located in the Campus of the Université Paris-Sud, city of Orsay.

Management team

The proposed Unit will be directed by Mr Laurent COMBETTES; Team 1 will be directed by Mr Laurent COMBETTES and Mr Thierry TORDJMANN and Team 2 by Mr Oliver NÜSSE and Ms Cécile BOUTON. 2  Overall assessment of the interdisciplinary unit

AERES nomenclature

SVE1_LS4; SVE1_LS3

Unit workforce

Unit workforce

The proposed unit is an extension and a restructuration of the UMR S_757. Overall there will be a significant reinforcement of the UMR S_757 that was already strong. The future unit will be unique as it will concentrate most of the local forces in the field of biology, these forces being appointed by the Université Paris-Sud, INSERM and CNRS. In other words, the "revised" UMR S_757 will be a model of "multi-organisms" integration. The integrative research project of the "revised" UMR S_757 will combine multi-disciplinary expertise including biochemistry, molecular biology cell biology, imaging, animal models, and clinic. This should foster new approaches in basic and translational research. The restructuration into two teams is logical. Team 1 will include "historical" components of UMR S_757 and will pursue research in the field of liver physiology and pathophysiology, which was the major theme of this Unit. Team 2 will include two researchers interested in inflammation (immunopathology) and oxidative stress who were already working at the UMR S_757 and newcomers who are experts in the field of metalloproteases and nitrosative stress. The extension and restructuration of the UMR S_757 should be viewed as a first significant step of a larger reorganization of biology laboratories in the south of Paris under the umbrella of the Institute for Research on Medication and Innovative Therapies (IRMIT). This reorganization develops in the context of the creation in 2014 of the new Campus Paris-Saclay that will involve about 25 institutions of research and higher education (including Grandes Ecoles such Ecole Polytechnique).

Strengths and opportunities related to the context

The project will cover a large spectrum of activities from basic to clinical research creating opportunities for innovation.

The project of Team 1 will continue to explore liver regeneration (a major theme of UMR S_757) but also will develop bridges to inflammation (via its interest in bile acid effects) and hence will benefit from the expertise of Team 2 in this field. Interestingly Team 2 which is mainly involved in basic research on mechanisms of cell stresses and immunopathology will find a field of application by collaborating with Team 1 in studies on mechanisms of liver injury and degerulation of liver reparation.

Unit members, in particular its Leader are very involved in the Campus Paris-Saclay initiative. The Unit should benefit from the multidisciplinarity of the IRMIT. The Unit will have the opportunity to develop further beneficial collaborations with researchers in physics and biophysics working at the Campus Paris-Saclay.

Weaknesses and threats related to the context

The document entitled "Internal Rules" included in the project is not detailed; in particular it does not take into account the division into two teams and does not define the role of the Internal Council of the Unit.

An engineer appointed by the CNRS has been working for a long time with a group which is currently outside the UMR S_757. This group will participate in the future Team 2 and the engineer wishes to move with researchers. There is no information on whether or not this engineer will be able to move.

Four engineers or technicians who are currently at UMR S_757 will retire during the next period.

Recommendations

The Comittee strongly supports the presented project.

Internal Rules should be more clearly described.

 Detailed assessments

Assessment of scientific quality and outputs

There are excellent scientific quality and outputs. Members of the future Unit have published 167 peer-reviewed articles during the last period. Among these there are original articles not only in high impact factor specialty Journals (e.g., Hepatology with IF = 12) but also very good "generalist" Journals such as Nature Communications, PNAS, or JBC. Scientific results have been presented as oral presentations or posters in national/international meetings or workshops. The scientific production of each Team will be detailed below.

Assessment of the unit's academic reputation and appeal

Academic reputation and appeal are very good to excellent. There are very efficient translational collaborations with clinicians and physicists and chemists. Important grants were obtained from this collaborative work. Unit members are involved in projects that have been selected in the context of the "Investments for the Future" (Equipex Morphoscope) or in the Clinical Consortium DHU "Hepatinov". The team members are principal investigators or participate in different national basic science networks (9 ANR). A clinician is in charge of the National Reference Center on biliary atresia. Unit members are expert reviewers for a large number of scientific journals and agencies (AERES, ANR, INSERM, etc..). Senior researchers have been regularly invited to give lectures at national or international levels.

In term of appeal for young researchers 9 post-Doc have been trained and 8 established investigators with University, INSERM or CNRS permanent positions joined recently the unit.

Assessment of the unit's interaction with the social, economic and cultural environment Interactions with the social, economic and cultural environment are very good. The Unit leader Mr Laurent COMBETTES is significantly involved in the process of reorganization of biology laboratories of the south of Paris as well as that of integration of biology in the new multidisciplinary Université Paris-Orsay. This will allow the Unit to play a crucial role in the emergence of interdisciplinary research projects.

Clinicians participate in French TV or radio programs (France 5, France 2, Le Figaro). One Unit member is among the Scientific Committee of a Center organizing conferences and seminars about the evolution of research and its place in the Society. There is strong involvement in dissemination of knowledge at the undergraduate degree levels.

Assessment of the unit's organisation and life

The Unit project includes 44 persons: 7 established investigators from the INSERM (2) and CNRS (5), 13 established investigators from the University (including Medical School), 1 clinician without university position, 9 technicians and Engineers, 1 technician with a temporary position, 10 students (7 PhD, 3 Master 2) and 3 post-docs. The Unit will be organized into two Teams and such an organization is coherent with the scientific projects and objectives of the Unit. The arrival of several researchers was of great help to the setup of two Teams. All members of Team 1 were previously members of the UMR S_757. Team 2 will be composed of ex-UMR S_757 members and new comers from outside. The fact that Team 2 is a "composite" will favor the integration of new comers.

The Unit will benefit from large surfaces localized in a building at Campus of the Université Paris-Sud (Orsay). The clinical research will be carried out in 2 different Hospitals (Pediatric and Adult Liver Units at Hôpital Kremlin-Bicêtre and Hôpital Paul Brousse, respectively). It could be argued that a dichotomized organization of the Unit into teams and the different geographical locations may represent a limit to the scientific interactions of the teams. However, this risk will be limited by the fact that the team projects have been designed to induce multidisciplinary collaboration between the two teams.

In the context of the new Campus Paris-Orsay and reorganization of biology laboratory (IRMIT, see supra), it is planed that the Unit will occupy a new building along with laboratories from the Faculty of Pharmacy (currently at Châtenay-Malabry) and from the Chemistry department in Orsay. The new building will be located about 2 km from the current location and should be operational at the end of the decade. This reorganization will be a unique opportunity to promote interdisciplinary research on innovative therapies.

The document entitled "Internal Rules" included in the project is not detailed enough; in particular it does not take into account the division into two teams and the fact the 6 engineers or technicians will compose a "pool" shared by the unit Teams. In addition, the document does not define the role of the Internal Council of the Unit in the overall management of the Unit. Nevertheless it is important to note that the functioning of the UMR S_757 is harmonious; during private interviews with the Visit Committee, every member of personel expressed their entire satisfaction with working in this Unit. Since the UMR S_757 is the back bone of the future Unit there is not doubt that the harmony will be preserved and excellent. Regarding technical support, Team 1 will have four engineers or technicians. The issue regarding the presence of an engineer in Team 2 has been mentioned earlier. Six other engineers or technicians will be dedicated to different tasks (such as administration, biochemistry, imaging, cell culture, flux cytometry) and will be shared by the two Teams. A full-time personel in charge of flux cytometry has been recruited very recently via the University. As mentioned before, four persons involved in the technical support of the Unit will retire during the next period.

Assessment of the strategy and the five-year plan

The strategy for the next 5 years will use interdisciplinary approaches covering a large spectrum from basic to clinical research to create opportunities for therapeutic innovation. As mentioned earlier the Unit will be composed of two Teams; the project of Team 1 is entitled "Biliary Homeostasis and Liver repair" and the one of Team 2 "Inflammation, Metallo-Proteins and Redox Systems". Each Team will both develop its own projects based on past history and specific interdisciplinary expertise and collaborate with the other Team through integrative projects. For example:

a) The project regarding the role of purinergic receptors in liver regeneration is common to the two Teams; b) A completely new project on infantile liver disease due to mutations in the gene called tRNA 5methylaminomethyl-2-thiouridylate methyltransferase (TRMU, a protein coding gene) has been created by combining clinical expertise from members of Team 1 with biochemical skills from new members of Team 2; and c) The phenotypic polarization of macrophages will be addressed in mouse models of liver disease as well as in vitro studies of redox biology.

Overall, this is an ambitious and exciting project that appears feasible based on the competence and excellence of the two teams. It is important to underline that a part of Unit project has been already evaluated positively and granted through different frameworks.

10 4  Team-by-team analysis Assessment of scientific quality and outputs

Team 1 has excellent scientific quality and outputs. The success of Team 1 is the result of a long-lasting history of involvement in research in the field of "liver science". Major points include:

1) The development of cell lines expressing polarity of hepatocytes and allowing to address questions raised in liver physiology;

2) The demonstration of the role of calcium signaling in liver regeneration;

3) First demonstration of the role of purinergic signaling (in particular P2X4 and P2X7 receptors) and the beneficial role of the bile acids receptor TGR5 in liver regeneration;

4) The first demonstration of the potential therapeutic interest of a new drug in patients with mutations of BSEP (also known as ABCB11) which cause Progressive Familial Intrahepatic Cholestasis (PFIC2).

Team 1 has an excellent publication track record since it published 120 original articles, including publications produced by the Team itself in Gastroenterology (IF=12.2, n=1); Hepatology (IF=12, n=5); Nature Communication (IF=10, n=1); J Hepatol (IF=9.8, n=5). Moreover Team 1 did 56 oral presentations in national/international meetings or workshops.

Assessment of the unit's academic reputation and appeal

Team 1 has a very good to excellent academic reputation and appeal. It has developed efficient translational collaborations with clinicians and physicists and chemists and important grants were obtained from this collaborative work. It was involved in the co-organization of a workshop on Cellular Biology (130 participants). The two "historical" Team leaders Mr Laurent COMBETTES (calcium signaling) and Mr Thierry TORDJMANN (liver regeneration) are renowned scientists; two scientists who joined the UMR S_757 in 2008 are both renowned pediatricians specialized in liver diseases. The team has been enriched by the arrival in 2012 of an expert in cilia biology.

Mr Laurent COMBETTES and Mr Thierry TORDJMANN are involved in "Morphoscope" (created on December 2011), which aims to establish state-of-the art facilities for optical imaging and image analysis of living systems. It is funded by a major grant (MORPHOSCOPE2, 9 million euros) from the National Agency for Research (ANR) which has been selected for the second round of national "Equipement of Excellence (EQUIPEX)", part of the operation "Investments for the Future" set up by the French Ministry of Research. It will integrate cutting-edge technology in photonic microscopy and computational analysis dedicated to in vivo multiscale investigations in integrative biology, based on the expertise of its core developing partners. This unique platform with emphasis on technology development and innovation will be located at Ecole Polytechnique (one of the funding members of the Campus Paris-Saclay initiative).

Members of Team 1 are already involved the Clinical Consortium DHU "Hepatinov". This DHU has been created in January 2013 under the umbrella of the Assisitance Publique Hôpitaux de Paris. It gathers a large number of clinicians and researchers who are working in partnership with SMEs with the objectives of developing new diagnostic and therapeutic approaches for liver diseases. Members of Team 1 are involved in "Hepatinov" in two ways: first as basic researchers and second as clinicians of the Department of Pediatric Hepatology and Pediatric Liver Transplantation at Bicêtre University Hospital (a tertiary care center for pediatric liver diseases including genetic cholestasis) which is headed by a university hospital professor member of the team.

Teams members are involved in networks awarded by the ANR (Mr Thierry TORDJMANN PI of one completed project and of another one which is ongoing; another scientist is co-investigator of one completed project). The team includes a university hospital professor who is responsible for the French national reference centre for biliary atresia.

Team members are expert reviewers for scientific journals and national agencies (AERES, ANR, INSERM etc..)

In term of appeal of young researchers two post-docs have been trained and two established investigators with University permanent position joined recently the Team.

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

The interaction with the social, economic and cultural environment is very good. Pediatricians are involved in multifaceted relationships (with the Agence of Biomedicine; patients families and Family patients associations) related to their involvement in the management of severe liver disease and liver transplantation. Mr Emmanuel Jacquemin often participates to TV and radio programs (France 5, France 2) and gives press interviews (Le Figaro).

Assessment of the unit's organisation and life

The team's organization and life is excellent.

The team project includes 19 persons: 3 established investigators from the INSERM (2) and CNRS (1), 6 established investigators from the University (including Medical School), 1 clinician without university position, 4 engineers and technicians, 4 students (1 PhD, 3 Master 2) and 1 post-doc. In addition, as mentioned earlier, Team 1 will have technical support from 6 engineers or technicians who compose a "pool" shared by the two Unit Teams.

The team structure is appropriate regarding the underlying scientific strategy. Although there have been successive waves of retirements, this is in part compensated by the recruitment of young MCFs. It should be emphasized that the relationships between researchers and technical personels are excellent due to an "intrinsic" culture of dialog.

Assessment of the unit's involvement in training through research

The involvement in training through research is excellent. All team members are very involved in teaching and tutoring.

Since 2008 20 students were trained in the team. Five PhD theses were completed over the period. One of the scientists is involved in the council of the department of biology; she is also assistant vice-president of teaching; finally she is member of the national commission (CNU section 65, cellular biology) in charge of teaching and research personnel.

Assessment of the strategy and the five-year plan

The strategy and five-year plan are excellent. The scientific objectives of Team 1 are in continuity with past findings and address the following three points.

1) The Role of purinergic and bile acid signaling in liver repair and biliary homeostasis. The general objective is to determine the impact on liver regeneration of the purinergic signaling through P2X4 and P2X7 receptors on the one hand, and bile acid signaling through the TGR5 receptor on the other hand. The project is very original and capitalizes on available mice models to study liver ATP and bile acid signaling. This project will be led by Mr Thierry TORDJMANN and involve two engineers, one post-doc (to be recruited), one PhD student; one Master 2. Interestingly the project will benefit from the expertise of Team 2 members and clinical connections with "in-Team" Pediatricians and hepatologists from the Centre Hépato-Biliaire (experts for liver diseases in adults).

2) Progressive Familial Intrahepatic Cholestasis type 2 (PFIC2): pathophysiology and treatment. This project will be divided into two parts. The first part of the project is entitled "Specific pharmacotherapy for PFIC2". A polarized hepatocellular line isolated in the UMR S_757 (Can-10 cells) will be used to study the consequences of missense mutations identified in patients. This part of the project will also use stable clones expressing different Bsep mutants.

In these models, a library of chemical compounds will be screened in collaboration with UMR 8076 CNRS-Université Paris Sud -BioCIS and the Innovation Thérapeutique LabEx LERMIT. The second part of the project is entitled "Anti-BSEP alloimmunization after liver transplantation for PCFIC2: Screening, natural history and identification of antigenic target". Overall, this project will benefit from an available prospective and well-annotated patients cohort indispensable for high-quality translational medical research.

3) Ciliary proteins and cholangiocyte differentiation. During development and during regeneration after massive hepatocyte loss or during chronic liver injury, the differentiation of cell precursors in cholangiocytes and the subsequent organization of the ductal plate are conditioned by multiple signaling pathways in particular Notch, Hedgehog or TGFβ. Studying the role of cilia in bile duct formation is timely, very original and important for the overall team's project. An important step of the project is the optimization of culture conditions which will determine the ability to perform studies on the effects of mechanical stress, biochemical environment, hedgehog signaling as well as the influence of inactivation of ciliary proteins on the differentiation and organogenesis of cholangiocytes. The project includes the development of 2D or 3D micropatterns in collaboration with the Institut Curie and the University of Singapore, to identify the optimal conditions to obtain "functional" cholangiocytes.

The overall Team 1 project is feasible and addresses the question of mechanisms of liver regeneration/reparation in the context of societal issues related to liver transplantation which is the only available treatment of very severe acute or chronic liver diseases. However liver transplantation is costly and there is organ shortage which is associated with ethical issues related to justice and equity. Improved knowledge in this field is a prerequisite to the development of novel therapeutic approaches that are alternatives to or allow delaying liver transplantation. Logically Team 1 is a significant component of the DHU "Hepatinov".

Conclusion

 Strengths and opportunities:

The team has been developing a strong expertise for many years in the studied field and contributed to the knowledge in liver physiology and pathophysiology. The proposed project is very original and addresses the crucial question of improving knowledge of mechanisms of liver regeneration and reparation. This should help to address unmet medical needs in the field of therapies for liver diseases.

The team associates clinical and basic scientists, including full time researchers. This is an opportunity to pursue and develop strong translational studies.

 Weaknesses and threats:

Some engineers and technicians who play significant roles in the scientific activity of the team will retire during the next period.

 Recommendations:

The Committee welcomes and recognizes the high interest of the team's projects.

Detailed assessments

Team 2 will include 4 different groups. Two groups are already located at UMR S_757. One group will move from UPR2301 (CNRS). Another group will move from UMR 8619 (CNRS-Université Paris-Sud).

Assessment of scientific quality and outputs

Team 2 has very good scientific quality and output. The group of Mr Oliver NÜSSE is recognized for having produced significant methodological advances in ROS imaging; it has regular publications in good impact journals (J Leukoc Biol IF=4.6;Free Radic Biol Med IF=5.3). The group of Ms Cécile BOUTON has 27 publications (FEBS J IF=4.2; JBC=4.6) and 2 invited book chapters; a third group has 20 publications (JBC IF=4.6; Nitric Oxide IF=3.2).

Assessment of the unit's academic reputation and appeal

Team 2 has an excellent academic reputation and appeal. Mr Oliver NÜSSE has an excellent international reputation in the field of oxidases. The group of Ms Cécile BOUTON had invitations to 6 international meetings including 2 Gordon Conferences; Mr Jean KANNELOPOULOS gave 2 international lectures and Mr Olivier Guittet gave one; Mr Jean KANNELOPOULOS is member of PULMO-NET (Research training network-Marie Curie Actions). Two post-docs will participate in the team's project.

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

The interaction with the social, economic and cultural environment is very good to excellent. Mr Oliver NÜSSE is member of the Council of the "Centre d'Alembert" at Orsay. Ms Cécile BOUTON has given combined lectures and practical courses for general public and participated in Science Workshops for later years of primary school. Mr Franck Brouillard has participated in the creation of the Villebon-Georges Charpak Institute, a boarding high school, for students motivated by science and technologies. This academic project involves several big companies, including SNCF, Orange, Areva, Microsoft, Société Generale, Solucom. Several team members are involved in the review panels of national agencies/Institutions (e.g., ANR, AERES, INSERM, University) and international agencies (FNRS, Mardsen Fund (NZ), TEAM program evaluation).

Team members have shown their ability to raise funding (ANR, FRM). Mr Pierre BOBE has filled three international patents and one national patent; one international patent has been licensed; all are related to arsenic trioxide treatment.

Assessment of the unit's involvement in training through research

The involvement in training through research is excellent.

All team members are very involved in teaching and tutoring. They are involved in PhD supervision (7 current PhD students), teaching in post-graduate courses, Masters (1 and 2) and undergraduate degrees. Six PhD theses were completed over the period. Several members of the Unit are responsible for and/or involved in teaching programs. Mr Oliver NÜSSE is Co-director of the Doctoral school "Biosigne: Signalisations et réseaux integrative en biologie" (ED 419). Ms Cécile BOUTON is Co-Organizer of Post-graduate courses "Mitochondrion" PRES UniverSud Paris. Other team members teach in Master Biologie Santé, "Signalisation et Physiologie Cellulaire; Neurosciences" Université Paris-Sud; at "Omics in pharmacology and toxicology" Master degree, Université Paris-Descartes; in the new Institute "Georges-Charpak" at Palaiseau; at the Erasmus Mundus program in SERP chem. Mr Oliver NÜSSE is responsible for the flow cytometry platform of the institute, which is open for research and teaching from licence to PhD level. Mr Oliver Nüsse is also co-organizing and teaching the CNRS flow cytometry course in Gif/Orsay. A team member is member of the science council of the faculty of Sciences in Orsay.

Mr Oliver NÜSSE is a member of the council of the department of biology and is president of the commission (CCSU section 64-69) in charge of the teaching and research personnel in biology (promotion and recruitment) of the biology department.

Assessment of the strategy and the five-year plan

The strategy and five years plan are very good to excellent. Team 2 will combine expertise in cell redox mechanisms, iron metabolism and phagocyte biology as well as in autoimmune and auto-inflammatory diseases. The main goal is to get more insight into the cell redox phenomena and their link with inflammation and pathologies of the immune system, in the frame of hepatic fibrosis, liver regeneration and mitochondrial infantile diseases. The project will address the following points.

1) Production of ROS and RNS.

Studies will be divided into two parts.

The first part is entitled "Regulation of NADPH oxidase and ROS imaging". This very interesting project will investigate NOX2 at the cellular level (new signaling pathways) by exploring the role of phosphoinositide in NOX2 assembly. This implies the development of new tools for ROS and RNS imaging in collaboration with Team 1 and a group from the Laboratory of Physical Chemistry, LCP, Orsay. The model system of host-pathogen relationship is the interaction between phagocytes and Candida glabatra (an opportunistic pathogen) and will be extended to liver inflammation. Team 2 members involved will be Mr Oliver NÜSSE, two other scientists, one post-doc (FRM funding) and 3 PhD students.

The second part is entitled "Regulation of iNOS expression and macrophage phenotype by p73". The role of the antioxidant bZIP transcription factor NRF2 will also be addressed. There will be a collaboration with the Karolinska Institute in Stockholm. Part of the task will involve collaboration with Team 1 (mouse model of chronic inflammation of liver, macrophage polarization). The project involves 2 scientists and one PhD student.

2) Fundamental and pathophysiological studies on Fe-S proteins.

Ms Cécile BOUTON and another scientist will address the very interesting hypothesis that mitoNEET is part of a novel branch of the mitochondrial Fe-S export pathway to repair the [4Fe-4S] cluster of IRP-1, an important regulator of cellular iron homeostasis. Team 2 members involved are Ms Cécile BOUTON, 3 other scientists, one post-doc (to be recruited, ANR funding) and one engineer (if available, see infra) This project will combine expertise in Fe-S biochemistry and cell biology (Ms Cécile BOUTON and colleagues), genetics of human Fe-S deficiency (IGBMC, Illkirch), biochemistry and biophysics on metalloproteins (CEA Grenoble and Saclay, and ICSN Gif) and cell imaging (Team 1).

Ms Cécile BOUTON and colleagues will be also involved in a new project on infantile liver disease due to mutations in the gene called tRNA 5-methylaminomethyl-2-thiouridylate methyltransferase (TRMU, a protein coding gene). This project will be conducted in collaboration with Team 1.

3) New mouse models autoimmune and autoinflammatory diseases. This project will address the important question of the role of the death receptor Fas and P2X7 purinergic receptor in the development of autoimmune diseases with multiorgan injuries (including the liver) in relation to proliferative and autoreactive T-cell subsets. The project involves 2 scientists and 3 PhD students. This group recently developed a novel mouse strain (called B6/lpr-P2X7R KO) characterized by a deficiency in both Fas apoptotic pathway (lpr mutation) and P2X7 purinergic signaling pathway in normal C57BL/6 (B6) genetic background. These mice develop an autoimmune disease very similar to that observed in MLR/lpr mice (a paradigm for murine autoimmune disease which is due to a complex interaction between lpr mutation and MLR background). The project is very interesting: they will develop different strains of conditional KO mice, in which P2X7R expression is abolished in T lymphocytes, macrophages or dendritic cells only. These conditional KO mice will be then crossed with B6/lpr mice. These novel mouse strains raised on a B6 genetic background has much less complex genetic background than the MRL/lpr mice and will allow to identify more easily variations in gene expression involved in T-cell proliferation and autoreactivity. An ANR France-Taiwan (2014-2016) will support this project. 4) Targets of arsenic in the treatment of autoimmunity and inflammation.

All members of Team 2 will take part in a common project to understand selectivity of arsenic trioxide treatment (in line with their previous studies). They will address gene expression, Fe-S cluster assembly, iron metabolism and NOX2 activity in selected T-cell lines. Each participant will contribute according to his/her technical and scientific skills.

Conclusion

 Strengths and opportunities:

The Team has been developing a strong expertise for many years in fields of NOX, ROS imaging, redox systems, metallo-proteins and murine models of auto-inflammatory diseases. Overall the team projects will address paradigmatic and poorly understood mechanisms underlying immunopathology (i.e., collateral tissue damage, including liver injury, caused by the immune system of the host). Team 2 will provide an "added value" to Team one, and vice-versa.

 Weaknesses and threats:

The overall 5-year program of Team 2 is broad and ambitious.

One of the incoming groups has worked for a long time with an engineer appointed by the CNRS. There is no information on whether or not this engineer will be able to follow the researchers in the new structure. The fact that some Team members might move to the new structure not accompanied by the engineer would weaken the group.



Recommendations:

The Committee recognizes the high interest of the Team's projects and the strong expertise of Team members to address important questions related to inflammation. The project is ambitious and the Team is encouraged to propose a more focused work plan.

  Assessment of the unit's involvement in training through research The Unit's involvement in training through research is excellent. The members of the Units teams have trained 15 PhD students and more than 20 Master students since 2008; 12 Master/PhD students are undergoing training. Past Master students were recruited from: M1 Erasmus University of Wrocław, Poland and Paris-Sud; M1 Biologie-Santé, Université Paris-Sud; M1 Surface, Electro, Radiation, and Photo Chemistry (Serp chem), Université Paris-Sud; M1 Biologie Informatique Université Paris-Diderot; M1 Biologie-Santé. Université Versailles St Quentin; M1 physiologie et physiopathologie, Université Pierre-et-Maire Curie; M2 signalisation et neuroscience, Université Paris-Sud; M2 Produits de Santé issus de la Biotechnologie, Universités Paris-Sud, Paris-Descartes and Paris-Diderot; M2 Dynamique cellulaire, microbiologie et biotechnologies, Université Paris-Sud; M2 Génome, Cellules, Développement, Evolution (GCDE), Université Paris-Sud; M2 Biologie Cellulaire Physiologie et Pathologies (BCPP), Université Paris-Diderot; M2 Sciences-Santé, Université de Picardie. Several members of the Unit are responsible for and/or involved in teaching programs: Co-direction of the Doctoral school "Biosigne: Signalisations et réseaux integrative en biologie" (ED 419); Organization of Post-graduate courses "Mitochondrion" PRES UniverSud Paris; Teaching in Master Biologie Santé, "Signalisation et Physiologie Cellulaire; Neurosciences" Université Paris-Sud; Teaching at "Omics in pharmacology and toxicology" Master degree, Université Paris-Descartes; Teaching at Master "Longevity and Aging", Université de Versailles-Saint Quentin; Coorganization of the 2nd year of biology (300 students); Responsibility for the "Magistère of Biology and Biotechnology" in Orsay; Responsible of PCSO (Préparation aux Cursus Scientifiques d'Orsay: a one year preparatory course for about 130 high school students who need to improve their science education before entering the regular licence program); Involvement in the new Institute "Georges-Charpak" at Palaiseau; Responsibility of the WIMS initiative in order to develop a distance education at the L1 level; Involvement in MOOC (massive open online courses) project in collaboration with the chemistry and physics of Paris-Sud; Teaching in the science and engineering program at Ecole Supérieure de Physique et de Chimie Industrielles de la Ville de Paris (ESPCI ParisTech); Responsibility for program and course of Cell Biology at ESPCI ParisTech; Program Manager for the "Scientific Projects in interface with biology" and in charge of the relations with biotechnology companies for ESPCI ParisTech; Responsibility for the implementation of programs for the biology License at PSL (Paris Sciences et Lettres); Teaching in the Erasmus Mundus program in SERP chem.; Responsibility for the flow cytometry platform of the institute, which is open for research and teaching from license to PhD level; Teaching and co-organizing the CNRS flow cytometry course in Gif/Orsay. Unit members participate in several University Councils and Committees related to teaching.

  Biliary homeostasis and liver repairName of team leader: Mr Laurent COMBETTES and Mr Thierry TORDJMANN Workforce Other professors (PREM, ECC, etc.) N5: Other EPST or EPIC researchers (DREM, Postdoctoral students, visitors

  Team members are responsible for or involved in teaching programs: 2nd year of biology (300 students); "Magistère of Biology and Biotechnology" in Orsay; PCSO (Préparation aux Cursus Scientifiques d'Orsay: a one year preparatory course for about 130 high school students who need to improve their science education before entering the regular license program); responsibility of the WIMS initiative in order to develop a distance education at the L1 level in the new Institute "Georges-Charpak" at Palaiseau and Boris MOOC (massive open online courses) project in collaboration with the chemistry and physics of Paris-Sud; teaching in the science and engineering program at Ecole Supérieure de Physique et de Chimie Industrielles de la Ville de Paris (ESPCI ParisTech); responsibility of the program and course of Cell Biology at ESPCI ParisTech; Program Manager for the "Scientific Projects in interface with biology" and in charge of the relations with biotechnology companies for ESPCI ParisTech; responsibility of the implementation of programs for the biology License at PSL (Paris Sciences et Lettres).

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

	Doctoral students	6
	Theses defended	9
	Postdoctoral students having spent at least 12 months in the unit*	2
	Number of Research Supervisor Qualifications (HDR) taken	3
	Qualified research supervisors (with an HDR) or similar positions	12	13
		Number as at	Number as at
		30/06/2013	01/01/2015
	N1: Permanent professors and similar positions	11	13
	N2: Permanent researchers from Institutions and similar positions	2	5
	N3: Other permanent staff (without research duties)	8	8
	N4: Other professors (Emeritus Professor, on-contract Professor, etc.)		1
	N5: Other researchers from Institutions (Emeritus Research Director, Postdoctoral students, visitors, etc.)	2	4
	N6: Other contractual staff (without research duties)	1	1
	TOTAL N1 to N6	24	32
			5

We thank the AERES committee for its evaluation work and the report which was sent to us. We welcome the very positive feedback on our ongoing and future projects and on the new lab structure. We sincerely thank the committee for its support, and we wish to respond to some points raised by the expert committee.

Concerning the "Internal Rules" which should be more clearly described: the policy of the lab has always been to promote the participation of everyone. Thus, the laboratory council brings together ALL members of the unit. This strengthens group cohesion and everyone's adhesion to the project and until now, this enables to share all laboratory resources both technical and financial. We agree that the new structure of the laboratory will render this policy more difficult. This is why we chose co-directions for both teams, which will promote exchanges among the two teams and between the teams, and will enable our new colleagues being integrated more easily and quickly into the lab.

Concerning the new team 2, we agree that the project is ambitious and that it would merit to be a bit more focused. However, we would like to point out that the project of team 2 is based and evolves from the ongoing projects of the different groups who will join the team. These projects are supported by various grants (ANR, FRM, DIM, CSC…). Based on this background, we have defined 3 priorities: 1) Regulation and consequences of ROS and RNS production in phagocytes 2) Functional characterisation of Fe-S proteins, especially mitoNEET 3) New mouse models of autoimmune and autoinflammatory diseases. All three projects are related to the adaptive cellular response to inflammation and redox imbalance. Once all members of team 2 will be in the same building, the intersection between these priorities will be naturally reinforced by daily interaction, joint team meetings and shared expertise, promoting thus a more focused work.

Regarding the technicians, we are well aware that a majority of them will go soon into retirement. We are confident that our institutions will pay attention to this crucial issue and compensate for these departures. A position has just been assigned to our laboratory by the University Paris-Sud; the person will be recruited this spring and will be in our lab starting from the next academic year. Concerning the engineer appointed by the CNRS, as four new members are CNRS scientists, an accreditation by CNRS will be requested. Endorsement by CNRS will be decisive to allow the CNRS engineer to follow the team with whom she works for a long time.

Yours faithfully L. Combettes