Pierre Glaudes

Mr Patrick

History and geographical location of the unit

As a preliminary consideration the experts committee has been evaluating a process of merging the efforts of two separate INSERM units, one led by Mr Pierre BOUGNÈRES and Mr Patrick AUBOURG and the other one by Ms Judith MELKI to create a novel research unit denominated GenoSud. This project is supported by the idea that the integration of 3 research units will provide an added value for potentiating research development by increasing interdisciplinarity. The team 1 has mostly developed cutting edge gene therapy for metabolic and genetic disorders affecting central nervous system; the team 2 has developed epigenetic and environmental research in the field of autoimmune Type 1 diabetes of childhood onset, and the team 3 has a worldwide known experience in genotyping for the discovery of new genes and of new phenotypes. During the visit, the experts committee could perceive the strong support of the local institutions for the creation of this research unit. Université Paris-Sud is very supportive since this research unit represents a bridge between medical research and more fundamental research that will be performed in a project called "Université Paris-Saclay" merging 3 universities and Engineers Schools. In addition, another team is working on gene therapy at this campus, thus increasing the critical mass on this topic and the possibility of collaborations with the unit. The Faculty of Medicine is also very supportive since teams of this research unit are headed by Medical Professors who are fully integrated in the Faculty. They are also critical -especially team 3 -for the structuration of a genetic platform at the Hospital level. The MirCEN structure (70 % CEA, 30 % INSERM) hosts three research teams plus other academic and non-academic (pharma industry) laboratories. Despite formal links with Genethon, no strong research programme is established with this structure. MirCEN is very supportive of the creation of the research unit taking into account its strong activity on gene therapy and adeno associated viruses.

Management team

The unit is headed by Mr Patrick AUBOURG who obviously has the stature and has recognition from all team members. The management seems very good with regular meetings between heads of each research team and also between researchers.

AERES nomenclature

SVE1-LS5 Neurobiology

Unit workforce

Doctoral students 8

Theses defended 6

Postdoctoral students having spent at least 12 months in the unit 6

Number of Research Supervisor Qualifications (HDR) taken 13

Qualified research supervisors (with an HDR) or similar positions 4 4

2  Assessment of the unit

Strengths and opportunities related to the context

The experts committee has identified several strengths and opportunities that are listed below:

the creation of this research unit is undoubtedly a nice opportunity for both the research teams themselves, and the institutions (INSERM, CEA, Université Paris-Sud);

the strengths of each team: (I) expertises on gene therapy for team 1, epigenetics in type 1 diabetes for team 2, gene identification for team 3; (II) originality of the research projects, i.e. not performed in a concurrent research team in France;

the new unit merges three research teams that should bring an added value for potentiating research development by increasing interdisciplinarity;

complementary research between clinical paediatric endocrinology research performed at the hospital, genetic research performed also at the hospital and experimental gene therapy research performed in the MirCEN facilities;

the integration of the INSERM-CEA platform with 7 technicians and engineers for primate studies reinforces the feasibility of the projects elaborated by team 1 using monkeys.

Weaknesses and threats related to the context

The experts committee has identified several potential weaknesses that are listed below:

location of the research teams in two sites: the INSERM building of Kremlin-Bicêtre hospital and MIRCen Building of CEA Fontenay-aux-Roses. This does not facilitate the interaction between teams 1 and 2 on the one hand and team 3 on the other hand;

there is heterogeneity of the research themes amongst the three research teams;

possible lack of feasibility of the research programmes, especially on epigenetics and environment on large populations.

Recommendations

The experts committee has overall an excellent opinion about the project of the unit creation, with several prominent projects that will continue the outstanding scientific level of the researchers. The combination of the three teams will favour additional interactions and foster potential creativity.

 Detailed assessments Assessment of scientific quality and outputs

The three teams composing this new research are all well-recognized at the international level. Team 1 researchers are world-wide acknowledged, especially because of their pioneering gene therapy studies onleucodystrophies. The group leader of team 2 is a very well know physician and scientist, his career being devoted to paediatric endocrine disorders, especially type 1 diabetes. He was the head of the former INSERM unit 946 which is the basis of this new research unit. The group leader of team 3 is also a very well know scientist with a solid experience in molecular genetics, especially with the discovery new genes and functions responsible for motor neuron disease and axonopathies. Another researcher of that team has made very important contributions on the molecular genetics of inherited endocrine and bone disorders (acrodysostosis, hyper-hypo-parathyroidism in particular). Specifically, the team 1 has 36 publications (Science 2009; first and last author) related to the FIRST clinical trial using lentiviral vectors for a monogenetic disease (adrenoleukodystrophy -ADL). Participation in a second gene therapy trial of Beta-thalassemia patients using lentiviral vectors (Nature 2010). Journals of IF ≈10 : Am J Hum Genet, Blood, Brain, etc. It can be noted that one paper is in positive revision in Nature Medicine, two other papers in preparation to be submitted in top-ranked journals. In addition, the team has three patents. For team 2, if the analysis is restricted to the group working on the genetics and epigenetics of type 1 diabetes (T1D), they published 9 papers in which the group leader appears as a first or last author in the last 4 years, among them publications in PLoS One 2013, 2012, and Mol Cell 2012. However, one may note the low number of publications in top-ranked journals in this period. Finally, the team 3 has excellent publications (Hum Mol Genet 2013, 2012;Am J Hum Genet 2012;NEJM 2011) and the group leader, as well as other permanent researchers, participates to the organization of International Congresses (2009Congresses ( , 2010)). Altogether, the unit production, although not formed as a whole during the past 5 years, is rather excellent.

Assessment of the unit's academic reputation and appeal

As indicated below in more details, each team leader is well recognized. The head of the unit has pioneered HSC gene therapy with integrative lentiviral vector applied to adrenoleukodystrophy. He was also awarded Grand Prix de l'Académie des Sciences in 2010; a permanent researcher in team 1 also received an Award from the American Society of Human Genetics. They have been invited for conferences in well-known institutes (USA, Europe, Japan). The group leader of team 1 created the European Adrenomyeloneuropathy (AMN) consortium. More recent accomplishments have been made by another researcher of the team for advancing the preclinical gene therapy of inherited forms of Alzheimer disease. The group leader of team 2 is a well-recognized leader in diabetes and endocrine paediatric disorders. One researcher of the team is Emeritus Professor of Epidemiology and Statistics, member of the French Academy of Sciences, expert also in biomathematics, and has obtained several French prizes. They have regular invitations in international congresses, but no recent international awards. To note, one researcher was recently hired by the INSERM within the team. Finally, the group leader of team 3 is a very well-recognized international scientist in human genetics. She has discovered new genes and new functions responsible for motor neuron disease and axonopathies. Another researcher in the team is also internationally recognized and has recently contributed to elucidating the molecular mechanisms of acrodystosis. Their team has strong links with Patients association, through The National Reference Center for rare diseases. The researchers have been invited to two Gordon Conferences, and four post-docs have been recruited within the last 4 years. Altogether, the unit academic reputation is simply excellent.

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

The group leader of team 1, together with a permanent researcher of the team, are principal investigators of international projects (FP7 EU), 4 ANR, 2 PHRC. In addition, they have over 10 contracts in private financing (French and European associations, or networks). The group leader has created the European AMN consortium. The group leader of team 1 and 2 lead a clinical USA-Europ trial in Childhood Cerebral Adrenoleukodystrophy (CCALD) with a biotech company BlueBirdBio (USA) starting in 2013. They also share 3 patents and 6 private research contracts from patients Associations. They also develop a start-up company on gene therapy "AAVLIFE". The group leader of team 2 is the principal investigator of 2 ANR grants, a third one is hold by a researcher of the team. He is also partner of 4 PHRC grants, showing the dynamism of this group in translational research. This team interacts with patients associations on diabetes type 1 (DT1). Over the last 10 years, the team has recruited a large cohort of DT1 patients, allowing genetic and epidemiological research. Finally, member (Ms Alexandra BENACHI) of team 3 is leading a Reference Center for rare diseases, namely congenital diaphragmatic hernia with strong interactions with patients associations. She also participates to two ANR and two PHRC research programs. Altogether, the unit academic reputation is, once again, simply excellent.

Assessment of the unit's organisation and life

The research unit is set-up on two sites: Hôpital Kremlin-Bicêtre and MiRCEN at the CEA (Fontenay-aux-roses). They use usual laboratories and offices. Importantly, in order to ease the communication between sites they actively use video-conferences, with a global positive outcome. They also run classical lab meetings. The team 1 is working on two sites, i.e. Hôpital Kremlin-Bicêtre for the clinical and genetic human research and MiRCEN at CEA for the experimental studies, especially in primates. The CEA-INSERM MiRCEN provides a high quality environment for monkey research. The team 2 has its research activity mainly based at the Hôpital Kremlin-Bicêtre, where they developed strong and historical interactions with team 1. For instance, the group leader of team 2 is co-director of the CAH gene therapy program developed by team 1. The team 3 is somehow splitted in two sub-projects "team 3A and team 3B", both headed by well-recognized researchers on genetics and endocrine disorders. They are using the same genetic tools and genetic facility recently built at Hôpital Kremlin-Bicêtre. However, because of different kind of pathologies, they seem to act independently rather than in synergy. Both are working at the site of the Hôpital Kremlin-Bicêtre, in which interactions with team 1 & 2 will certainly be needed to improve integration along the years. Meetings with the students, technical personal and permanent researcher gave an overall positive outcome of the unit strength and planned-cohesion.

Assessment of the unit's involvement in training through research

The unit members are well-integrated into the teaching at the university, with a strong implication in fields such as gene therapy. Team 1 is heavily involved in research and training, e.g. biotherapy teaching program at the Human Genetics Magister of Universities Paris 5 and 7. They organized the Annual Congress of the European Society for genes and cell therapy in 2012. They co-direct the Therapeutic Innovation and Translational Research teaching program at the local doctoral school. This team participates to 6 masters, and along the last 4 years 3 thesis were obtained, 3 thesis on going, and 7 master students were trained. The participation of team 2 is relatively more modest although they had one thesis obtained and one ongoing. Team 3 participates to university teaching in 4 different masters, and during the last 4 years, they had one 1 thesis obtained and 2 ongoing. The meeting with the head of the representative of the doctoral school to which most students are affiliated (École Doctorale n°419 "Signalisations et Réseaux Intégratifs en Biologie") gave a very positive and enthusiastic impression of the unit implication in training.

Assessment of the strategy and the five-year plan

The project is overall original because it assembles together team 1 that is developing cutting edge therapies in the challenging field of neuroscience and particularly to tackle disorders of the central nervous system with team 2 and team 3 that has a solid background in the characterization of new genes and its functional implications. More specifically, team 1 considers that AAV-gene therapy will become a potent tool for the gene therapy of specific diseases, such as the ones they are currently considering. They will test a new lentiviral vector with improved transduction efficacy in ALD. The french gene therapy trial will be opened in New York in metachromatic leukodystrophy (MLD). Other programs will be launched such as the optimization of the intra-thecal delivery of AAV in monkeys in AMN, studies in large animal models and clinical trials in FA (Friedreich cardiomyopathy), and CAH (congenital adrenal hyperplasia), studies in small animal models in inherited AD, and HD (Huntington disease). Team 2 has an ambitious and program on epigenetics of type 1 diabetes with original strategies modelling the child's lifetime through a geographical approach and life-style questionnaires and measuring epigenetic changes as well as other epidemiological parameters (pregnancy-child). This team needs to be reinforced to get more chances to get significant original results. Team 3 projects mainly rely on the identification of genes and genetic variants with WES that will be completed by functional experiments in mouse and zebrafish models, as well as cellular models. This team has access to unique resource of orphan diseases.

Overall, the experts committee agrees that the coordination of this complex project is well led by a clinician/researcher with expertise in the development of cutting edges therapies, including gene therapy, because this represents the final step of the translational research pipeline. However, the diversity of projects and strategies may make difficult real efficient interactions between the teams.  Detailed assessments

Assessment of scientific quality and outputs

The team is world-wide acknowledged because of their pioneering gene therapy studies and clinical trials on two devastating leucodystrophies: cerebral adrenoleukodystrophy (ALD) and metachromatic leukodystrophy (MLD). Additional interests of this team are focused on inherited forms of Alzheimer disease (AD), Friedreich ataxiacardiomyopathy (FAC), Adrenomyeloneuropathy (AMN) and Congenital Adrenal Hyperplasia (21-OH-deficiency). ALD: the internationally pioneering work of this team on ALD gene therapy, allowed them to publish in Science in 2009 the first results of their gene therapy trial with lentiviral vectors. It is expected that further studies, mainly related with the analysis of the pattern of integrated copies of the LVs, will be published soon in good scientific journals. In addition to gene therapy, this team aims to elucidate genetic and epigenetic factors that modulate the ALD phenotype.

MLD: for MLD this team has developed a gene therapy approach based on the intracerebral injection of adeno-associated viral (AAV) vectors expressing arylsulfatase. The proof-of-concept observations in small animal models have been already published by this group, and data from large animal models will be submitted soon. Interestingly, a clinical trial has been opened very recently and is under evaluation to be opened in New York in collaboration with Mr Ronald CRYSTAL.

Inherited AD: because cholesterol regulates the production and clearance of Aß-peptides in neuronal cell lines and it is increased in the brain from AD patients, this team has proposed to enhance its degradation by the overexpression of the CYP46A1 gene. The proof-of-concept of the efficacy of this novel approach has been published by this team in 2010 using AAV vectors delivered to the brain of a mouse model of AD.

From a total of 36 papers published since 2009, this team has an outstanding publication record with 1 groundbreaking paper (Science 2009; first and last author) related to the FIRST clinical trial using lentiviral vectors for a monogenetic disease (ALD. In addition, this team participated in a second gene therapy trial of Beta-Thalasemia patients using lentiviral vectors Nature (2010). Overall, the experts committee evaluates the scientific quality and outputs asoutstanding.

Assessment of the unit's academic reputation and appeal

As a consequence of the pioneering gene therapy clinical trial on ALD patients, there has been a recognition of the team leaders in several different Academias. Mr Patrick AUBOURG: Grand Prix de l'Académie des Sciences in 2010; Ms Nathalie CARTIER: American Society of Human Genetics, among other awards. Concerning national and international grants, the team has funding from France, from the European Commission (FP7) and also from US companies. Most of them are led by the group leader and one of the team researchers. One researcher of the team was the President of the 2012 meeting of the European Society for Cell and Gene Therapy. Many other distinctions were made to members of the team, including 3 student awards. The team members gave several lectures as invited speaker at the international level (17 presentations in meetings, 9 lectures in US, EU and Japan). The team members are members of several scientific committees and the group leader is in the editorial board of Gene Therapy Journal.

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

Clinicians working in the laboratory are involved in the care of the patients and families at the National Rare Disease Center for Leucodystrophies, a part of the clinical Neuropaediatric unit headed by the team leader. The team will expand this LV-HSC gene therapy approach of CCALD in a new US-Europe Phase III trial starting end of 2013 and plan to use a more potent LV vector provided by the biotech company BlueBirdBio (USA).They have created a start-up AAVLife to speed up preclinical steps towards a clinical trials in 2016 for FRDA cardiomyopathy (Inserm-Transfert and Inserm-Transfert-Initiave). The team plans to establish the necessary collaborations with biotechs and academic labs to be able to use improved AAV vectors at a GLP level in large animals. The team has obtained 6 grants from patients Associations. The group leader has obtained industrial partnerships with BlueBirdBio. The team has also obtained three patents related to the treatment of diseases mentioned above. All these activities reflect a strong commitment of the team with the Social and Economic environment.

Assessment of the unit's organisation and life

A potent gene therapy group has been already installed at the MIRCEN Institute at CEA-Fontenay to facilitate the studies performed with monkeys housed in CEA-INSERM, and collaborations with the neuroscience equipment of the MIRCEN Institute and the heart surgery facility of CCML. These strategic decisions to combine clinical units, research units and platforms should result in the development of optimized gene therapy of the neural diseases considered by the authors. It is of significance that this team will interact with the other two teams of the unit in the CEA-INSERM platform.

Assessment of the strategy and the five-year plan

This team has considered that AAV-gene therapy will become a very efficient and safe tool for the gene therapy of specific diseases, such as the neural diseases they are currently considering in their preclinical and clinical work. The decision of moving from the hematopoetic lentiviral gene therapy approach to a direct CNS administration of therapeutic AAV vectors constitutes a very relevant decission which hopefully will keep this team as international leaders in the definition of the most efficient approaches for the treatment of neural diseases. The team also aims that Université Paris-Sud and School-of-Medicine should be Reference Centers in this respect.

Plan for the specific gene therapy approaches in the following years:

-ALD: the team plan to expand the LV-HSC gene therapy approach of ALD in a new US-Europe Phase III trial using a more potent LV vector provided by BlueBirdBio. Because of limitations of current LV vectors used for the gene therapy of ALD patients only modest transduce of CD34+ cells have been achieved. A new LV with improved transduction efficacy will be investigated first in experimental studies;

-MLD: the gene therapy trial already opened in France will be also proposed to be opened in New York;

-AMN: the team plans to optimize the intra-thecal delivery of AAV in monkeys to define the vector dose to be used in AMN patients, with the final purpose of conducting a clinical trial in France and in the US;

-FA: aims will be focused on the treatment of myocardium since a high proportion of these patients die from cardiac failure. Frataxin-AAV vectors will be proposed for these gene therapy studies which will be conducted in collaboration. Studies in large animal models and clinical trials will be conducted in the near future;

-CAH: affected women in adult life due have a very severe and chronic virilisation. Preliminary results have shown that intra-adrenal injection of AAV vector carrying the gene that encodes the hydroxylase enzyme deficient in CAH patients corrects the phenotype in a mouse model of disease. Once the studies will be conducted in large animal models, clinical trials would be proposed; -Inherited AD: the team will investigate the effects of intracerebral injection of AAVs expressing the CYP46A1 in mouse models of the disease. Because intracerebro-ventricular injection of AAV2 vector has a limited diffusion capacity, new AAV serotypes with improved properties will be used in mouse and monkey models;

-HD: based on recent evidences suggesting that cholesterol homeostasis is impaired in HD, the authors observed a down regulated expression of CYP46A1 both in mouse and human HD. From a collaboration with neuroscientists in Paris (CNRS, Université Paris 6) they observed that the re-restored expression of this gene in a mouse model of the disease improved the characteristic motor deficits. In this collaborative effort, the implications of the overexpression of CYP46A1 on the phenotype of HD mice will be further investigated.

Taken together, a very ambitious strategy of high quality experimental and clinical research has been planned by the team for the next 5 years of work.

Conclusion  Strengths and opportunities:

This team is one of the pioneering international leaders for the gene therapy of neural diseases. So far they have used LVs in their clinical trials, and now they are planning to move towards the use of AAV vectors for the treatment of different neural disorders, both genetic and acquired. This team investigates the safety and efficacy of different gene therapy strategies in relevant animal models, progressing towards the development of clinical trials.

The long-term experience in bringing this kind of therapies to the clinic lets no doubt that this multi-disease program is very ambitious, but also realistic.

 Weaknesses and threats:

The complexity and the large number of diseases to be considered in the next years would imply a risk of diluting the efforts among all these objectives.

Because the CNS administration of AAV vectors constitutes a new gene therapy approach in the clinics, this impliesnew risks related with the administration route and the toxicity of the vector. However this risk seems to be very well evaluated by the team, based on the very pertinent toxicity studies conducted in relevant animal models.

 Recommendations:

Continue with the very well-coordinated preclinical and clinical work in selected neural diseases; prevent delays in the publication of the very relevant work already conducted in both the preclinical and clinical gene therapy studies to maintain the novelty of these results.  Detailed assessments

Assessment of scientific quality and outputs

The team head is a very well know physician and scientist, his career being devoted to paediatric endocrine disorders, especially type 1 diabetes. The group leader was the head of the former INSERM unit 946 composed of two teams. During the last 4 years, the group leader's unit has published well. If we restrict the analysis to his group working on the genetics and epigenetics of type 1 diabetes (T1D), they published 9 papers in which the group leader appears as a first or last author in the last 4 years, among them publications in PLoS One 2013, 2012, and Mol Cell 2012. However, one may note the lack of publication in top-ranked journals in this period. The group has performed an original work on epigenetics in type 1 diabetes. A strong effort has been made setting-up ahome-mademethylome array especially by a young researcher in the team. This has allowed to study CG methylation marks in the INS and IL2RA genes showing the possible importance of epigenetic changes at these genes in T1D. A whole methylome approach is now performed. Whereas this approach could lead to original findings, the demonstration of marginal and multiple epigenetic effects on T1D will probably require large populations and replication studies in order to be better published. The large cohorts initiated by the group leader and a researcher will help in that regard. Overall, the scientific quality and outputs should be considered as excellent.

Assessment of the unit's academic reputation and appeal

There is no doubt on the international reputation and appeal of the group leader in diabetes and endocrine paediatric disorders. One researcher of the team is Emeritus Professor of Epidemiology and Statistics, member of the French Academy of Sciences, expert also in biomathematics, and has obtained several French prizes. There is no doubt also that both the group leader and researchers of the team can synergize to propose new original protocols and strategies on epigenetics of diabetes. Both have been invited to give some international lectures. This is the last 5-year contract position headed by the group leader and no middle-aged researcher working in epidemiology and biostatistics is part of the group, one being more a molecular biologist and geneticist. This relative weakness may hamper the production of innovative results in the near future. No foreign post-doc has been attracted by the group in the last years. Overall, the academic reputation and appeal was considered as fully satisfactory.

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

The group leader is the head of a Pediatric and Endocrinology Department at the Hôpital Kremlin-Bicêtre (Paris). The team has a strong clinical research activity. The group leader is the principal investigator of 2 ANR grants, a third one is headed by a researcher now in another team. Four PHRC grants, showing the dynamism of this group in translational research. The group leader has also fostered interaction with patients associations on diabetes type 1 (DT1). Over the last 10 years, the team has recruited a large cohort (n = 7000) of DT1 patients, allowing genetic epidemiological research. Interaction with this population through auto-questionnaires investigating lifestyle and environment exposures, allowing the study of gene-environment interaction and modelling the child's lifetime through a geographical approach. The team has industrial contract with NovoNordisk (epidemiology of childhood T1D). This activity is simply excellent.

Assessment of the unit's organisation and life

The team has been assembled recently, focusing on the Epigenetic program of the group leader former INSERM unit. The activity of this research group is mainly based at the Hôpital Kremlin-Bicêtre since their move from the Hôpital St Vincent de Paul (Paris Descartes) in 2012. There have been long-term interactions with the team 1 and its group leader. For instance, the group leader of team 2 is co-director of the CAH gene therapy program developed by team 1. Clinical and genetic interactions with team 3 should be facilitated by the presence of a researcher both in teams 2 and 3. It will be critical to organize weekly meetings between the different teams to ensure a real research unit's life.

Assessment of the unit's involvement in training through research

During the last 4 years the team has been involved in teaching with: 1 thesis obtained, 1 thesis ongoing, and 3 post-doctoral fellows. The participation in training at university is through the participation to a Master.

Assessment of the strategy and the five-year plan

The activities of the team will be focused on epigenetic research, more specifically with studies of CG methylation of DNA, with the objective of finding methylation marks associated with T1D and gene-environment interactions (response to a stress or a treatment). At the epidemiological level, this an original project trying to modelize the child's lifetime through a geographical approach and life-style questionnaires and to measure epigenetic changes as well as other epidemiological parameters (pregnancy-child). At the cellular levels, experiments are conducted to measure epigenetic changes by glucose exposure in several cell lines. First interesting preliminary data have been obtained. Measurement of epigenetic marks and methylome in blood white cells from T1D patients will be of interest but will have also the limitation of the tissue specificity of epigenetic changes. However, this sophisticated epigenetic research program appears somewhat isolated -not in terms of research theory or conception but rather in the connection with other large similar cohorts. A more active search for collaborations within this field would probably be fruitful on the long-term.

Conclusion  Strengths and opportunities:

Innovative research program on epigenetics of type 1 diabetes.

Recruitment of a large cohort (n > 6000) of subjects witt T1D with a large number of environmental variables allowing gene environment interaction studies.

In house set-up of a small epigenetic platform allowing methylome array technology.

Interesting set up of cellular assay: methylome of BTC3 cells exposed to hyperglycemia.

Original research on the relationship between psychosocial maternal factors and childhood obesity through epigenetic marks (EpiChild program).

Ambitious program (Epimood) aiming at an integrative translational analysis between epigenetic marks, physiology and maternal behaviour for understanding early maternal neglect and mood disorders.

Complementary approaches and close collaborations with team 1.

Genetic collaborations to develop with team 3.

 Weaknesses and threats:

Recent move to the Université Hôpital Bicêtre. Thus local collaborations and networking probably need to be reinforced.

Relatively small research team lacking permanent researchers that would enhance the productivity. Need for at least one Engineer in Bioinformatics. In the unit, relative isolation on the field of epigenetics.

Epigenetics is becoming a higly competitive field requiring complete and innovative results for being published in high impact journals. Each research program seems itself ambitious and sometimes overambitious (Epimood for example) for this little research team.

Interesting preliminary results on epigenetic profile performed on white blood cells in young T1D patients but performed on a too small series (n = 10 cases and 10 controls) requiring replication.

Problems of the risk of spurious findings when looking at epigenetic marks at the whole genome level requiring multiple large data sets.

 Recommendations:

Taking into account the size of the team, one would recommend focusing on two or three major programs, too much diversity being at risk to not be efficient. This team needs to recruit an Engineer in bio-informatics as well as another full-time researcher to be more efficient.  Detailed assessments

Assessment of scientific quality and outputs

The team leader is a very well know scientist with a solid experience in genotyping and in molecular genetics. She has dedicated most of her research carrier to discover new genes and new functions responsible for motor neuron disease and axonopathies. Her scientific production is outstanding and she is very well known internationally. The team will take advantage from this project to empower the collection of well assessed and defined rare clinical phenotypes (collaboration with team 1) with unknown genetic background and to develop functional studies in cells, mouse models, or zebrafish (collaboration within the team 3 and with team 2). Indeed, this team is composed of two subgroups, the one headed by the group leader mainly working on motor neuron diseases, the second one being headed by permanent researchers mainly working rare inherited diseases of mineral and bone metabolism. Both subgroups have been successful independently in the past years.

It is clear that the main activities for genotyping in search of new genes represented by team 3 is quite a challenging and competitive area that will have advantage by a close interaction with groups that develop functional studies by modelling disease mechanisms. The impression reading this proposal is that the strategy and framework of this proposal goes in the right direction.

Assessment of the unit's academic reputation and appeal

Reading the summary of teaching activities in Université Paris 11, and the quality of the post-docs working in the team, the experts committee has the impression that this is a very active and appealing team with a high level of excellence. The scientific production in terms of publications is very good. Moreover the international reputation of the group leader is undoubtedly outstanding beyond her discovery of the SMN gene. The group leader and her team well understand that the simple genetic characterization of new genes in the field of rare diseases needs the integration of both the development of functional studies to have insights on the pathogenesis and very efficient interactions with international networks in order to collect additional patients and families to obtain a higher impact. Reading this project about the accomplishments so far gives a strong impression of a research unit that has a very good international interaction and reputation.

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

The team has produced one patent: methods for predicting, treating and modelling hormone resistance. Overall the team has obtained 7 grants by several agencies (ANR, PHRC, CRC, ERM, AFM) related to motor neuron disease, molecular signatures and function of B lynphocytes, molecular genetic definition of arthrogriposis, and genetic bases of Diaphragmatic hernia. The team has established a very good national network to collect patients with arthrogriposis, Diaphragmatic herni. Moreover, several international collaborations have been established particularly for motor neuron disease, spastic paraplegia and endocrinological disorders of the bone.

Assessment of the unit's organisation and life

Team 3 has been assembled just one year ago in 2013 merging together the INSERM unit led by the group leader with another INSERM unit. Moreover the group leader has moved from Genopole to join the Hôpital Kremlin-Bicêtre and creates team 3 to mostly dedicate energy to advanced genomic activities such as mastering exome and NGS genomics, including bioinformatics. Moving to the Hôpital Kremlin-Bicêtre and to the Université Paris-Sud, and coming together with the other teams will allow the group leader to come closer to clinical activities and to clinicians in order to better tackle the activity of genotype-phenotype correlation for genetic syndromes with unknown genetic background. It will be critical for team 3 to organize annual interviews with engineers and technicians.

Assessment of the unit's involvement in training through research

The team has at least 2 PhDs and 1 Post Doc. Moreover researchers, including the group leader, are actively giving teaching courses for Masters. By the fact that the group leader has moved to the Hôpital Kremlin-Bicêtre and the Université Paris-Sud, teaching courses could potentially be implemented.

Assessment of the strategy and the five-year plan

It is clear that the activities of the team will be focused on the discovery of new genes in the field of rare diseases by the application of NGS methodologies. It is conceivable that in a 5-year plan the simple molecular genetic characterization for new genes or new genotype -phenotype correlation discoveries will turn to be obsolete.

Thus the project to put together team 3 with the other 2 teams that integrate activities/expertise that have an early history and a more extended future, such as epigenetics/environment and gene therapy applied to genetic disorders, seems to be fairly strategic. Thus the weakness of the potentially limited activity of simply accelerating the results of genomic sequencing for the discovery of new disease genes will be compensated not only by the integration and facilitated communication with the other 2 teams but also by the additional role of team 3 in the study of microRNA and RNA microarray analysis.

Conclusion  Strengths and opportunities:

The team is led by a worldwide well-known scientist and geneticist, mostly since her discovery of the gene responsible for Spinal Muscular Atrophy, one of the most frequent recessive autosomal disorders. Furthermore, the group leader and her team are very active in discovering new genes every year.

Moving from Genopole to an university Hospital will surely improve the number of collaborations with clinicians to cover areas regarding the phenotype of rare disorders that are covered by this team.

The team will have the advantages of having a well-equipped laboratory for genomic investigations and advantages by merging with the other teams for the development of functional models.

 Weaknesses and threats:

Genotyping for new disease genes is becoming more and more challenging for publishing competitive and high impact papers. Thus on one side this team will have to make an effort in increasing international networks for collecting additional patients and on the other they should implement the development of the different branches of functional genomics.

 Recommendations:

Increase and implement the national and international network to improve and speed up the validation of novel disease genes. Besides developing genotyping activity to discover new disease genes, implement the area of functional genomics because there is a risk that genotyping for new disease genes with become obsolete in the next 5 years. For this period, these genotyping activities could profit from a formal collaboration between Université Paris-Sud, INSERM, CEA and the Institut de Génomique / CNG at Evry with very strong massive sequencing capabilities with -among others -Whole Exome Studies and Whole Genome Studies.

It is essential to acknowledge that the team sub-organization, i.e. parts 3a and 3b, requires planning for functional and interaction studies, for example with zebrafish experiments and functional studies in cells and mice. The next 5 years will show if the sub-organization of the team will benefit from the experience and knowledge and expertise in gene therapy and epigenetics of team 1 and team 2. Team 2. Les experts de l'AERES ont noté à juste titre un certain degré de disproportion entre la diversité des sujets abordés dans la recherche en épigénétique humaine et la dimension modeste de l'équipe 2. Il est tout à fait vrai que la mise au point de techniques d'étude de loci candidats mais aussi du methylome entier a ouvert plusieurs champs de recherche dans lesquels l'équipe n°2 s'est engagée. P. Bougnères et D. Fradin sont tout à fait conscients qu'après l'étape technologique, il va leurs falloir concentrer leur recherche sur 2 ou 3 champs bien circonscrits. Ceci est également vrai de la recherche environnementale conduite dans l'équipe. En 2014, les champs scientifiques abordés se sont plus précisément concentrés.

INSERM UNITE 986

Les experts ont recommandés le recrutement d'un ingénieur en bio-informatique comme support essentiel au travail de cette équipe. On peut souligner qu'un tel recrutement est évidemment le bien venu et aurait aussi beaucoup d'intérêt pour l'équipe 3, grosse utilisatrice de bio-informatique. La recommandation des experts de l'AERES va donc faire l'objet d'une demande de recrutement.

Team 3. L'équipe 3 a récemment rejoint l'unité constituée par P. Aubourg et P. Bougnères. Les experts de l'AERES s'interrogent sur sa capacité à maintenir un haut niveau de découvertes originales dans la compétition internationale pour ce qui est du recrutement de patients rares et de la génomique fonctionnelle des mutations et des gènes. Ils saluent l'efficacité de l'équipe 3 dans la découverte des mutations de nouveaux gènes. Il est important de leurs répondre qu'aussi bien dans le champ des pathologies abordées par J. Melki que dans celui de C. Silve, des recrutements, réseaux nationaux de médecins, associations de patients, connexions internationales ont été efficacement mises en place par les 2 chercheuses. Ce volet associé à la maitrise des nouvelles technologiques de la génomique y compris bioinformatiques nous semblent être de très bons atouts. Pour ce qui est de la génomique fonctionnelle, l'équipe 3 bénéficie d'une bonne maitrise des systèmes cellulaires d'expression comme d'excellentes collaborations pour les modèles souris et zebrafish. Récemment réunies en une seule équipe, J. Melki et C. Silve ont trouvé un très bonne espace de partage de techniques et de projets.

Bien cordialement

Patrick Aubourg

  Other professors (Emeritus Professor, on-contract Professor, etc.) N5: Other researchers from Institutions(Emeritus Research Director, Postdoctoral students, visitors, etc.)

N3:

  Permanent EPST or EPIC researchers and similar positions 3 3 Other permanent staff (without research duties) 2 2 N4: Otherprofessors (PREM, ECC, etc.) PU-PH, PR, MCF, PH N5: Other EPST or EPIC researchers (DREM, Postdoctoral students, visitors

  Assessment of the unit's involvement in training through researchThe team participates in the Biotherapy teaching program at the Human Genetics Magister of Universities Paris 5, Paris 7, and is involved in the Therapeutic Innovation and Translational Research program. Both the group leader and one researcher teach in biotherapy and neuroscience in 6 masters. Three thesis were presented during the last 3 years, and three others are currently undergoing. The team is thus very well implicated in the training of young researchers, i.e. 6 PhD students, 7 Master students, and 4 post-docs. Taken together the training track of the team can be considered extremely positive.

  Other professors (PREM, ECC, etc.) N5: Other EPST or EPIC researchers (DREM, Postdoctoral students, visitors, etc.

  Other permanent staff (without research duties) N4: Other professors (PREM, ECC, etc.) N5: Other EPST or EPIC researchers (DREM, Postdoctoral students, visitors, etc.spent at least 12 months in the unit Number of Research Supervisor Qualifications (HDR) taken 5 Qualified research supervisors (with an HDR) or similar positions 1 1

  Les experts de l'AERES ont analysé dans le détail les projets de recherche de la structure en création (unité mixte INSERM-CEA-Paris11) et l'organisation mise en place pour les mener à bien. Ils ont souligné que la réunion des 3 équipes (P. Aubourg, P. Bougnères, J. Melki) composait un ensemble ambitieux avec une diversité de projets. Le comité a exprimé l'importance de développer les interactions entre les équipes, chacune poursuivant un programme original et spécifique. Ces interactions se sont développées en 2014 au lendemain de la réunion effective des 3 équipes dans un même projet. Les séminaires, réunions de travail, échange de techniques, partage d'expériences sont fédérés par le fait que l'ensemble des équipes emploient des techniques de génétiques moléculaires et s'intéressent au contrôle de l'expression des gènes. Certains programmes sont déjà partagés entre P. Aubourg et P. Bougnères (thérapie génique du bloc en 21 hydroxylase), J. Melki et P. Bougnères (identification de gènes de maladies endocriniennes), J. Melki et P. Aubourg (identification de gènes de maladies neuropédiatriques). Ce qui réunit les 3 équipes est aussi la dimension médicale pédiatrique autour de maladies génétiques de l'enfant. Les 3 chefs d'équipe s'entendent bien et partagent leur vision du futur de l'unité à moyen terme. L'organisation en 2 sites obéit à des impératifs scientifiques. Le site de MIRCen-CEA permet en effet aux équipes de réaliser des projets de recherche (thérapie génique et épigénétique) dans le modèle de primate nonhumain et de bénéficier pour cela d'un environnement technologique unique. C'est pour cette raison que la structure s'est constituée avec mixité INSERM et CEA, et une participation active à la vie scientifique et technique de la plateforme MIRCen (Directeur : P. Hantraye). Les 3 chefs d'équipe, mais aussi plusieurs chercheurs participent activement à l'enseignement universitaire, scientifique et médical. L'organisation en 2 sites n'est pas à nos yeux et dans la vie quotidienne un obstacle significatif à la vie scientifique de l'unité. Chercheurs et techniciens s'échangent entre les 2 lieux qui se trouvent ainsi associés dans les mêmes projets. Il s'agit donc ainsi d'une complémentarité que les chefs d'équipe et le directeur de l'unité s'attachent à développer à son meilleur niveau. La présence de l'unité à MIRCen enrichit son champ scientifique et l'accès à la plateforme enrichit le champ technologique de toute l'unité.Commentaires spécifiquesTeam 1. L'équipe 1 s'est engagée dans un programme très ambitieux de thérapie génique adressée à plusieurs maladies. Les experts se sont interrogés sur le risque de dilution des efforts et de l'énergie en raison du nombre qu'ils leur a parut élevé de pathologies abordées. Notre réponse à cette crainte est que l'équipe 1 a développé ces dernières années des approches génériques d'utilisation des virus AAV sur le plan scientifique, technique et réglementaire, ainsi que des partenariats chirurgicaux (coeur-cerveau) très solides. Mis dans un pot commun, ces réalisations permettent d'aborder d'affilée plusieurs maladies à condition d'approprier les outils et les choix des pathologies, ce qui a constitué le fondement de notre stratégie : une plateforme médicale, scientifique, réglementaire et technique applicable à un sous-groupe de maladies bien choisies. Il est également important d'indiquer que l'application des progrès accomplis aux patients s'appuie sur un partenariat actif avec 2 sociétés de biotechnologies, dont l'une a été crée spécifiquement dans cet objectif.

	GENOMIQUE, FACTEURS ENVIRONNEMENTAUX ET BIOTHERAPIE
	DES MALADIES ENDOCRINIENNES ET NEUROLOGIQUES
	Site de l'Hôpital de Bicêtre
	Bâtiment Grégory Pincus -Secteur Marron -1er étage
	80, rue du Général Leclerc
	94276 LE KREMLIN BICETRE Cedex
	Téléphone: 01 49 59 53 96
	Télécopie : 01 49 59 19 59
	e-mail	: patrick.aubourg@inserm.fr	Le 19 Mai 2014
	Observations sur le rapport d'évaluation de l'AERES

,

-Mr. Didier HOUSSIN, president -Mr

Specific premises visited:

The experts committee had a dedicated time to visit the laboratory of MirCEN and the CEA-INSERM platform comprising a fully-equiped space for monkey breeding and experimentation, brain imaging studies and neurostructural correlates.

Conduct or programme of visit: • meeting with all students/postdocs;

• meeting with all ITAs;

• meeting with all permanent researchers (without team leaders and unit director).


Pierre Glaudes

Through its director, who is also a professor at Collège de France, it is affiliated to the Institut de Biologie of the Collège de France, which also provides some permanent funding.

The unit was started as part of the Service Hospitalier Frédéric Joliot in Orsay, and then moved to the NeuroSpin facility, headed by Mr Denis LE BIHAN on the nearby Saclay campus, when this facility was opened in January 2007.

The Cognitive Neuroimaging Unit is the only life science core unit of NeuroSpin, which is almost entirely comprised of non-CEA researchers, most of whom are cognitive neuroscientists (the remaining staff are primarily physicists and computer scientists). Its primary role is to apply the remarkable brain imaging tools available at NeuroSpin to specific questions in cognitive neuroscience.

Management group

Doctoral students 15

Theses defended 9

Postdoctoral students having spent at least 12 months in the unit* 9

Number of Research Supervisor Qualifications (HDR) taken 2

Qualified research supervisors (with an HDR) or similar positions 4 5

2  Assessment of the unit

Strengths and opportunities related to the context

This is a coherent unit composed of 4 excellent to outstanding groups:

-group 1: Neuroimaging of Human Cognitive Architectures (directed by Mr Stanislas DEHAENE, professor at Collège de France): to analyze, in the healthy subject, the architecture of cerebral networks involved in cognitive functions that are particularly developed in humans, including syntax in the linguistic and mathematical domains, access to consciousness, and introspection; -group 2: Neuroimaging of Language and Symbols (directed by Mr Christophe PALLIER, DR2 CNRS): to analyze the neural bases of language and symbol processing, including the semantic processing of words and numbers; -group 3: Neuroimaging of Development (directed by Ms Ghislaine DEHAENE-LAMBERTZ, DR1 CNRS): to examine human cognitive development in infants and children, both at the structural and functional levels, and to develop new imaging techniques adapted to human infants; -group 4: Magnetoencephalography and Brain dynamics (directed by Ms Virginie VAN WASSENHOVE, CEA): to evaluate the processing of multisensory information, its temporal organization and particularly the representation of temporal information in the human brain, using magnetoencephalography (MEG) as a principal method.

It works in a technologically ideal environment with excellent facilities that will in due course include some of the most powerful magnets used in human brain research, supported by an animal team, a clinical facility and outstanding physical and technological engineering expertise.

The doctoral students and post-docs have an excellent esprit de corps and clearly interact well across groups a well as within. There is little isolationism and an understanding of the need for inter-disciplinarity There is a high degree of awareness about the external proselytisation of the unit's work which has high social importance in many ways. There are well managed interactions with the press, the educational community, popular science organisations and the local community. This activity intertwines with the scientific work and represents a refreshing public face of science that is paid for by the population and is to be congratulated.

The scientific output is outstanding and there seem no reasons to think it will not continue.

Weaknesses and threats related to the context

The site is remarkable (the "Notre Dame of Neuroimaging"). However it is isolated for both working staff and volunteers or patients. The strict CEA security rules at times interfere with working hours for the scientists and indeed seem to make group 3's and the Translational Unit's work more tedious than necessary.

There is a large number of temporary scientists associated with UNICOG -this could be perceived as a weakness but the experts committee feels this is in fact a major advantage giving a throughput of smart young scientists who can subsequently find work elsewhere thus raising the reputation of France in the field.

The management of NeuroSpin is clearly a major task -it seems that regular meeting of the heads of units with the director could benefit all in diminishing the administrative workload and giving opportunity for high-level interaction between the major units. There are significant outstanding administrative and managerial issues that make work difficult -for example, no access to computing from home or external collaborative sites; inability to scan 24 hours for 7 days in the week. Space is also becoming an issue -there are no plans in place yet to accommodate the people that will work in NeuroSpin for the Human Brain Project. The deployment of super-computing dedicated to the work requires planning too.

The links with the clinical community are sparse, which is remarkable given the quality of the work. A senior scientist left (Mr Andreas KLEINSCHMIDT) because an appropriate senior clinical position could not be found at the Salpétrière (a similar historical situation to that of Mr Denis LE BIHAN some years ago). There should be better coordination with that community through high level links to complement those that have developed with Mr Laurent COHEN and Mr Lionel NACCACHE.

The MRI Physics group of NeuroSpin that is developing the high performance magnets and other technologies is complemented by a Computational Science group that is perhaps too focused on abstract issues of image analysis -a component of this group's work could be associated with real-life problems as perceived from the angle of life sciences or cognition as opposed to the primary viewpoint of mathematics or algorithmics.

In terms of novel initiatives, the unit feels strongly that a non-human primate group should become established at NeuroSpin through the stabilisation of Mr Béchir JARRAYA. The experts committee agrees and urges steps to be taken to promote such a development. One of the UNICOG groups is relatively young with an appointment made to its leadership this year. The intellectual quality of the proposed programme in group 4 suggests that this was a wise appointment.

Finally, it is clear that the constant escalation of the internal costs of scans is beginning to be deleterious to work by the unit. A formal accord is needed stipulating how many free pilot studies are given to preparation of grants or for the testing of new collaborative groups.

Recommendations

The work of the unit should be supported fully and equally for all of its 4 constituent groups.

Plans need to be made for the accommodation of the HBP (Human Brain Project) Cognitive Architectures subproject.

High level communication with management, computation and physics needs to be made regular to promote interdisciplinary interaction in NeuroSpin at a higher level still than at present. The CEA needs to rapidly provide procedures that maintain security whilst providing an appropriate academic environment at NeuroSpin for UNICOG. This should not be outside the competence of the world's foremost security experts.

 Detailed assessments Assessment of scientific quality and outputs

Outstanding -world class (cognition) and in many ways, world leading in certain aspects (development).

Two groups are slightly further ahead than the remaining two, but both the latter have recently been formed or had new leadership. The experts committee is satisfied that the output in terms of numbers of publications, quality of journals and numbers of written outputs for general public consumption is first class.

Assessment of the unit's academic reputation and appeal

In a straw poll about 70 % of students and almost 100 % of post-docs came to NeuroSpin because of the reputation of UNICOG and its leader. The international collaborations are numerous and of high quality with people at the leading edge of the field which is also evidence for the unit's reputation scientifically.

Assessment of the unit's interaction with the social, economic and cultural environment This is outstanding with activity that goes from online lectures from the Collège de France to proposals to interactions with teachers for texts and methods to help dyslexic children read. Of note also is the major contribution to the Cogmaster programme run from the ENS/EHESS.

Assessment of the unit's organisation and life

The relationships between scientists are excellent, the unit is "woman friendly" and the staffs appreciates the flat structure and the disposition of working places that often give opportunities to interact between as well as within groups.

Assessment of the unit's involvement in training through research

PhD students have their own mentors -there is no dual mentorship programme in place to deal with tensions and other personal issues. This is common practice now -principal supervisor and mentor (or co-supervisor). However, the école doctorale system in place in France may represent another way of guiding students that is equally effective. There are many opportunities to learn how to present at international meetings and the use of English for these occasions is supported. The students expressed a desire for a retreat(s) where they could meet in more social circumstances to talk about what they are doing and to familiarise themselves with the bigger scientific picture of the unit.

Assessment of the strategy and the five-year plan

The 5-year plan is thorough, builds on the past, suggests new avenues and was considered scientifically exciting. The main initiatives relate to opportunities provided by the restructuring into 4 groups. Secondly, the technological advantages promised by the 7T and 11.5T magnets and by an established non-human primate physiology team that will provide mechanisms at the physiological level to complement those being elaborated by the MEG group seem to constitute a very coherent methodological blueprint.

The consciousness programme that will become more important in Mr Stanislas DEHAENE's project (group 1) is well validated with a prominent output already including consciousness signatures with EEG techniques that could be ready soon for clinical use (The procedure for obtaining a patent has commenced, which is to be applauded).

The strengthening of group 2 by two permanent engineers opens up new perspectives for the Linguistic work. The proposals here may be very taxing at the level of spatial resolution. This group is likely to use the 7T machine soon and possibly quite intensively.

Group 3 is world leading and not just because it is easier to do such studies in France nor because the field is small. Many theories of mental disease currently depend on knowing what happens during the development of the brain. This group is doing an amazing amount of descriptive work, mainly because the field is not scoped yet. Out of the results are merging new hypotheses that suggest a very productive period ahead. The cross-talk between non-human primate and infant brain investigation may be especially fruitful.

Group 4 is very neuroscience driven -indeed to the experts committee it seemed that much of the proposal for the next five years was very innovative for the MEG field. The ability to look out of the box was much admired and the rationale for the plan in terms of multisensory integration and interfacing with internal representations suggested that the risky nature of this work was well justified and worthy of support.

We were not provided with the Annual Report of NeuroSpin and so are unable to comment on the internal distribution of resources and on plans for the future in this regard.

In summary, an oustanding unit with excellent groups, an integrated and justified plan for the next 5 years and a workforce that seems enthusiastic, competent and proud of their discoveries.  Detailed assessments

 Group-by-Group analysis

Assessment of scientific quality and outputs

From a basic research perspective group 1 is undoubtedly one of the leading cognitive neuroscience groups in the world. This is shown by the breadth and importance of the intellectual problems on which they have made advances, and by the high quality of the journals in which their many findings have been published.

Mr Stanislas DEHAENE and his collaborators have made many discoveries in a wide range of fields, but in particular on number processing, word processing (particularly with Mr Laurent COHEN) and consciousness (particularly with Mr Jean-Pierre CHANGEUX). Of greatest impact has probably been the work on consciousness, where he and his collaborators have honed the first proper scientific theory, in the field in that the theory is both realised (in part) in a computational model and has been tested by his group in a wide variety of empirical contexts.

In all three areas we have seen a partial move in the last five years from the establishment of the empirical plausibility of Mr Stanislas DEHAENE's theories to their application in a variety of contexts. Thus his group have applied his theories to the neural changes occurring when one learns to read, to the processes occurring when one carries out mental arithmetic and to methods to monitor consciousness in those who are unable to speak or act. Findings have appeared in Science (4 papers), PNAS (5 papers), Neuron (1paper) and Current Biology (1 paper) and many other journals (85 in total). At a time when most cognitive neuroscientists are specialists in one or possibly two related cognitive domains and tend to use well tried experimental paradigms or ill-controlled ones, what is perhaps most remarkable is the ability of Mr Stanislas DEHAENE to launch novel and very well designed experiments in a variety of cognitive domains. In this respect his intellectual fertility and flexibility is probably greater than that of any other cognitive neuroscientist currently active.

Assessment of the unit's academic reputation and appeal

From a basic research perspective group 1 is undoubtedly viewed as one of the leading cognitive neuroscience groups in the world. This is shown by the honours awarded to Mr Stanislas DEHAENE, who is only 48, was the second winner of the Heineken Prize for Cognitive Science awarded in 2008 by the Dutch Academy of Sciences and has since received many academic honours including election to the Collège de France and the awarding of an honorary degree this year at the University of Lisbon. He has also been selected to lead the Cognitive Architectures pillar of the European FET "Human Brain Project".

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

Especially given the parallel research productivity, this has been excellent with preparation of a major permanent exhibit on the human brain at Cité des Sciences, authorship of two popular books on different aspects of cognition, and participation in TV and radio shows. Moreover software games and a website have been produced to help dyscalculic children, and a new consciousness monitoring method developed.

Assessment of the unit's organisation and life

There were no suggestions on the site visit that there were any problems in the relations within the group.

Assessment of the unit's involvement in training through research

This appears to be good with 8 Collège de France courses available on-line, contributions to the Cogmaster course at the ENS and a variety of courses given abroad.

Assessment of the strategy and the five-year plan

Of the three proposed lines of work for group 1, the work on consciousness is in part an extension of the types of studies previously carried out. However a major application is the development of EEG paradigms for assessing patients in apparent vegetative state. This would be clinically very useful since the main current methods employ fMRI, a much more expensive and less transportable technology. One surprising lacuna is that nothing is said on paper about the source of the patients; it is difficult to see how the research program could succeed without a steady reliable source. However it became apparent on the site visit that the collaborations with Mr Lionel NACCACHE and Mr Laurent COHEN at the Salpetriere, which will be an important source of such patients, are clearly very solid, so in practice this should not cause a problem.

The work on literacy/mathematics and education is again an extension, but a considerable one, of existing work on the effects on the brain of learning to read and so-called cultural recycling; in this respect one of the aims is to look at the brains of people with extensive training in mathematics when carrying out different types of mathematical/arithmetic operations. Investigation of this latter cognitive domain is potentially very fruitful.

What is really novel is the proposed work on the brain bases of recursion. This is particularly exciting, as it will look at recursion outside as well as within the domain of language. Outside language, recursion has hardly been experimentally investigated at all. Yet it is an important element in many of the greatest human achievements such as mathematics. In addition this is a process that is probably not possible to study in animals.

Conclusion  Strengths and opportunities:

The great intellectual fertility and flexibility of Mr Stanislas DEHAENE's scientific style.

The possibility of exploring a range of novel problems of wide significance and depth using highly creative and appropriately rigorous methods.

 Weaknesses and threats:

Mr Stanislas DEHAENE having to spend an increasing amount of his time not on science but on scientific management. This danger is being exacerbated by the need to prepare an increasing number of grant proposals for the unit in part due to the greater cost of scanning.

 Recommendations:

The group should be provided as smoothly as possible with the support necessary to carry out their planned excellent program of research.

In summary, a group led most ably by one of the leading cognitive neuroscientists in the world, currently producing research of great originality and importance to his field.  Detailed assessments

Assessment of scientific quality and outputs

The group has contributed mostly to the basic understanding of the brain structure-function mapping of language processing. A central question here was whether the brain actually relies on abstract constructs originating from theoretical liguistics (such as syntactic trees) to process sentences. Although the theoretical framework that serves to tie the different studies together is rather qualitative and vague, it has enabled a great diversity of work that clearly stands out in terms of originality and breadth. Also, the methodological know-how in imaging neuroscience clearly meets the standards of the international community (e.g., the use of repetition-suppression paradigms in fMRI).

One of the most original study addresses the comparison of brain responses to vocal utterances across primate species (humans and monkeys). This naturally lends itself to an evolutionary perspective on the functional segregation of the language network. More precisely, it complements group 1's "neuronal recycling hypothesis", which essentially states that the human language subnetwork engaged in reading borrowed brain computational resources that were well-suited to process language but were selected to serve a different purpose. Major achievements of the group also include the identification of language processing bottlenecks (e.g., time scales, conscious access), which consitute a distinguished contribution to the field. Note that most of these studies were published in high-impact international academic journals (e.g., PNAS, J. Neurosci., Neuroimage, etc). Taken together, this explains the high national and international visibility of the group leader (Mr Christophe PALLIER 's h-index=33).

Assessment of the unit's academic reputation and appeal

The reputation of the group regarding language processing in the brain has enabled tight collaborations with international groups that share related interests. For example, a series of studies on biliguism has been successfully conducted with colleagues from the University Pompeu Fabra in Barcelona (Spain). Another example is the study on subliminal speech priming, which was conducted in collaboration with the Catholic University of Leuven (Belgium).

In terms of academic reputation, the group leader has been invited to give seminars at UCLA, Vitoria, Barcelona, Taipei, Leipzig. He chaired the Journée "l'aire de Broca: 150 ans après" at the Pitié-Salpétrière hospital in Paris, and was a keynote speaker in two international workshops.

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

Outside its main research stream, the most salient contribution of the group is its contribution to the French Lexicon Project, an open database of lexicon decision times for 40000 words obtained across 1000 participants.

In addition, the group leader was invited to give lectures to language school teachers. Mr Christophe PALLIER also took part in multiple extra-scientific public debates about scientific, philosophical and ethical issues of neuroscientific research within the local environment of the institute.

Assessment of the unit's organisation and life

The group has a well-defined central focus, namely: language processing in the brain. This is a vast theme of research, which the group leader has chosen to address from many different perspective over the past few years. This could have incurred a cost in terms of scientific coherency, but the overall impression contradicts this idea, for two reasons. First, most studies are nurtured from theoretical linguistics, which provides conceptual guidance for both experimental design and results interpretation. Second, the relative dispersion of group 2's research interests serves the overall consistency of the research unit, through the many collaborative links it shares with the other groups. The latter point is also important for enabling the successful pooling of scientific, human, financial and material resources (e.g., joint group meetings, IT, co-application on grants, MRI scanners, etc) across the institute.

Assessment of the unit's involvement in training through research

First, note that the group gathers three post-doctoral trainees and three PhD students, who benefit from weekly meetings chaired by the unit's group leaders.

The group leader is a member of the CogMaster pedagogic board (MSc in cognitive sciences @ École Normale Supérieure, Paris). Note that this is not the sole contribution of Mr Christophe PALLIER's contribution to the CogMaster, since he is also lecturing on neuroimaging data analysis.

Assessment of the strategy and the five-year plan

The group's research project aims at identifying the neural representations of atomic cognitive constructs, following a gradient of abstract complexity (beginning with words and numbers, and culminating in the syntactic structure of language). The three permanent researchers have slightly different interests (e.g., language vs number sense), but share similar methodological tools (fMRI, multivariate decoding techniques). Importantly, many research questions rely on the notion of hierarchical processing, e.g., the representation of a given word depends upon the syntactic context. Such hierarchical processing hypothesis appears at different scales (e.g., phonemes in a word, words in a sentence, etc). This relates to an overarching and transversal research question of the unit, namely: the representation of recursive structures (i.e. structures that are self-similar). This is one of the most original aspects of the unit's project, to which group 2 is likely to significantly contribute.

One has to acknowledge the fact that two new permanent researchers are joining the group, which brings along its own promises and risks. On the one hand, the scientific complementarity of the three permanent reearchers is evident from their respective research interests. For example, an exciting extension to the group's past expertise is clinical interest in dyscalculic children of one permanent investigator. First, this will bring additional neuropsychological insights steming from the nature of the pathological impairments to the number sense. Second, this will largely augment the group's contribution to translational research (cf. epidemiological study of dyscalculia and dyslexia, in collaboration with Dr. F. RAMUS). Also, the project on high-field (7T) fMRI of a another investigator is very appropriate, given the strong local deployment of MR physics resources. Last but not least, her involvement in the Human Brain Project holds great promises in terms of the group's international visibility. On the other hand, there is a risk of lack of convergence between the different research agendas. This is because this convergence relies on a central tenet, namely: the existence of a common brain structure for manipulating hierachical (recursive) structures of words and numbers. The critical point here is that it is yet unclear how the group will re-organize and adapt its strategic direction if this assumption happens to be unjustified.

In general though, the objectives are credible, both in scientific terms, and with regards to the human, financial and material resources that they require.

Conclusion  Strengths and opportunities:

-synergetic scientific expertises of the three main researchers; -opportunities for translational research; -novel research program based upon high-field MRI.

 Weaknesses and threats:

-no apparent knowledge in quantitative modelling of cognitive processes; -no apparent link with group 4 (electrophysiology); -diluted research program (language and number sense).

 Recommendations:

Engage in thorough collaborations with computational neuroscientists with adequate background on linguistics/number sense.

Promote local cutting-edge neuroimaging facilicities, in the aim of diversifying experimental methods (EEG/MEG platform, advanced data analysis, etc).

In conclusion, the group's past achievements are of high quality and its current research projects are ambitious, novel and timely. In addition, the group is likely to both strongly benefit from and contribute to the local scientific environment. In addition to its strong potential for translational research, these merits call for a very positive overall evaluation.  Detailed assessments

Assessment of scientific quality and outputs

The scientific quality and output of group 3 lead by Ms Ghislaine DEHAENE-LAMBERTZ is outstanding. This is reflected through its publication record with more than 35 peer-review publications, most of these in top scientific journals such as Science, PNAS or J. Neuroscience, as well as the numerous invitation that the group members have received from national and international organizations.

Clearly, the group led by Ms Ghislaine DEHAENE-LAMBERTZ has become an international leader in human cognitive development in infants and children, both at the structural and functional levels, as recognized by various prizes to group members.

Finally, the scientific quality of the group is also highlighted by the variety of public and private grants it has received in the last 5 years.

Assessment of the unit's academic reputation and appeal

Group 3 is one of the leader in the field of human development not only nationally but also internationally, rivaling with groups such as the one of Graffman at NIH or Stiles Davis at UCSD for example. It provides a rare center of excellence where both a structural and functional understanding of human brain development is being pushed through a combination of ingenious behavioral paradigms and new frontiers in brain imaging. The combination of such skills is rare on the international scene and places group 3 ahead of most human developmental center around the world.

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

The impact of the unit on society is already visible and will only increase in the next few years. The unit has already produced a number of books for parents and teachers, and is quite active in the dissemination of knowledge about human brain development and its consequences for best practices in education. Its conversion of academic content into educational games for dyspraxic children illustrates perfectly the dedication of this group to translating lab research into useful tools for society.

It is a source of information for the national and international press being sought out by French media. It has also very strong links with the medical community and in particular best practice in the treatment of pre-term infants. The planned atlas of the baby's brain and its functional organization will be a huge contribution for both the scientific community and society at large, with practical implications for domains as varied as health, education and parent-children relationships.

Assessment of the unit's organisation and life

Excellent access to a dynamic, rich and multidisciplinary environment, with international speakers series. Outstanding support of group member and smooth integration of the various skills and background needed to excel.

Assessment of the unit's involvement in training through research

Group 3 provides a very strong inter-disciplinary environment to its trainee, a key asset in a field that calls for skills as varied as excellence in experimental design and insights in ethological method to probe behavior all the way to knowledge of state of the art in machine learning and big data management. The group provides an ideal setting to training young researchers and future stars in the domain. This is reflected in the numbers of excellent PhD and postdoctoral fellow that have come through the units, as well as the very large network of fruitful collaborations the group has established.

Assessment of the strategy and the five-year plan

The five year plan is well thought out with clear objectives and reachable deliverable, while at the same time being quite ambitious. The breadth and depth of the international collaboration established over the years is commandable, with the group being now centrally positioned to being at the fore front of the development of new imaging techniques adapted to human infants.

Conclusion  Strengths and opportunities:

-pushing the limits of functional and structural approaches to brain development; -excellent group dynamics and collaborative work; -outstanding outreach.

 Weaknesses and threats:

Ease of access to MR facilities: this group is among the rare such groups in the world that can push forward the limits of functional brain imaging in infants and children. Yet access rules and CEA regulations make it very difficult for NeuroSpin to be a parent-and children-friendly environment.

Cost of access to MR facilities: it is well know that paediatric populations are difficult to scan as they cannot be as easily instructed to cooperate, stay still and be quiet. This type of research requires an experimenter be patient and seize the opportunity when the infant or child is ready to cooperate. These requirements are not well aligned with an MR cost structure based on booking precise scan slots ahead of time. This procedure requires more flexibility to be efficient, so that this research is not limited by unfair costing in relation to other groups.

 Recommendations:

It would seem advantageous for NeuroSpin to take advantage of its unique facilities, entirely dedicated to MR research and the proximity of such an outstanding group, to continue breaking new ground in paediatric functional MR imaging and enlarging our understanding of human brain development. The group was originally lead by Mr Andreas KLEINSCHMIDT who moved to Geneva in Spring 2012. Ms Virginie VAN WASSENHOVE, who joined the unit in 2008, officially became the new leader of the group in September 2012, and the only permanent researcher. This scientific assessment therefore does not include Mr Andreas KLEINSCHMIDT's production which was not performed in collaboration with the present members of the group. Group 4's activity had two facets: 1) Setting up and running the Magnetoencephalography (MEG) Lab since the end of 2008 with two INSERM research engineers dedicated to this activity not only at the group or unit level but also as part of the Neurospin facilities. This includes ensuring reliable recordings and deploying state-of-the-art methods for signal analysis and dynamic source reconstruction. This activity is transverse to the other groups since 4 papers using MEG have been published by group 1's members, and 2 by physicists from another CEA laboratory developpping new MEG instrumentation.

2) Developping a specific experimental research project aiming at evaluating the processing of multisensory information, its temporal organization and particularly the representation of temporal information in the human brain. The group leader has obtained in 2011 an ERC Starting Grant to understand the neural dynamics underlying the representation of time. Original results have been obtained on automaticity in multisensory processing and in temporal cognition, mostly based on behavioral and fMRI measures performed in collaboration with former group leader's host laboratories, and more recently with MEG recordings. This has lead to to a very good production: 12 papers, and 6 international conference proceedings, in journal such as Plos One (2), Philos Trans R Soc Lond B Biol Sci (3), Frontiers (3), and Neuropsychologia (1).

Assessment of the unit's academic reputation and appeal

From a technological and methodological point of view, the MEG Lab is well connected to national and international MEG community and is now attracting various MEG projects.

On the scientific side, group 4 is a young and emerging group. It is attracting PhD and post-doc students thanks to a succession of grants (Marie-Curie reintegration grant, ANR young researcher, and ERC starting grant). It is also involved in the european flagship Human Brain Project for the characterization of the brain architectures for time representation and manipluation.

The group leader has been invited to ~25 national or international conferences or seminars in reknown institutes (Montreal, MIT Boston, Konstanz, Tübingen). She is on the editorial board of Plos One, Frontiers in Auditory Cognitive Neuroscience, and Timing and Time Perception.

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

The group leader produced several interviews on internet media for the public at large. She also made a TED presentation in Paris on Time and the Brain.

Assessment of the unit's organisation and life

Group 4 is clearly structured around the MEG facility. Thanks to two permanent engineers, this MEG platform is very well organized. State-of-the-art signal analysis softwares are made available to the users and, importantly, the development of new methodological tools is in progress (including real-time MEG).

Although, the group is still young, the general atmosphere was perceived as both friendly and effective, with a strong sense of inter-disciplinarity. The group 4 members are experienced in collaborating with other groups' members and external partners.

In addition, to further develop their expertise in MEG signal analysis, they will develop and/or adapt novel methodological approaches (e.g., decoding techniques, real-time analysis, functional connectivity, scale-free analysis, graph theory analysis). The two recently recruited INSERM engineers have an essential role for that objective, including supervising students.

Due to the very small size of the group in terms of permanent researchers, the plan appears rather ambitious. However, the group leader has secured excellent fundings to achieve her goals, including a participation to the FET Human Brain Project.

Conclusion

 Strengths and opportunities:

-to have set up the MEG Lab facilities at Neurospin and for the unit with dedicated permanent engineers; -opportunity to develop interactions with other groups or units taking advantage of the MEG expertise; -to have developped a novel research project on the representation of time in the brain, only poorly explored in other french research laboratories; -excellent fundings.

 Weaknesses and threats:

-small size of the group (only one permanent researcher); -running costs for the MEG platform requested by CEA seem to increase abruptly.

 Recommendations:

Collaborations with the other groups and external research groups should be increased for a better exploitation of the MEG facility.

A strategy for recruiting an additional researcher should be considered over the next 5 years to consolidate the cognitive neuroscience side of the group. Gilles BLOCH

  location of the unit The Cognitive Neuroimaging unit was created by INSERM in January 2002 and renewed in January 2006 and again in January 2010. It is a mixed unit affiliated to INSERM, the French Atomic Energy Commission (CEA, which provides the building and the brain imaging facilities) and Université Paris-Sud (which provides part of the funding).

N4:

  Other professors (PREM, ECC, etc.) N5: Other EPST or EPIC researchers (DREM, Postdoctoral students, visitorsspent at least 12 months in the unit 3 Number of Research Supervisor Qualifications (HDR) taken Qualified research supervisors (with an HDR) or similar positions 1 1

N4:

  Other professors (PREM, ECC, etc.) N5: Other EPST or EPIC researchers (DREM, Postdoctoral students, visitors, etc.spent at least 12 months in the unit 1 Number of Research Supervisor Qualifications (HDR) taken 1 Qualified research supervisors (with an HDR) or similar positions 1 2

N4:

  Other professors (PREM, ECC, etc.) N5: Other EPST or EPIC researchers (DREM, Postdoctoral students, visitors, etc.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

N4:

  Other professors (PREM, ECC, etc.) N5: Other EPST or EPIC researchers (DREM, Postdoctoral students, visitors, etc.

  GIF SUR YVETTE Cedex FRANCE Conduct or programme of visit: 08h45-09h00 Door closed meeting -Presentation of AERES to the experts committee by the Scientific Delegate (DS) 09h00-09h15 Presentation of the experts committee and of AERES to the unit by the DS 09h15-10h00 Presentation of the unit, scientific assessment and projects: UNICOG (including brief tour of the installations (Mr Stanislas DEHAENE)) Team presentations (including half time for discussion) the institutions (Mr Jacques BITTOUN-Paris Sud, Mr Gilles BLOCH-CEA and Mr Etienne HIRSCH-INSERM) Meeting with permanent and non-permanent staff 13h30-14h15 Three demonstrations by lab researchers and engineers: -Ms Jessica DUBOIS, Mr François LEROY and Ms Caroline HURON on children studies (anatomical and behavioral work) -Mr Marco BUIATTI, Ms Leila AZIZI-ROGEAU and Mr Sébastien MARTI on the MEG facility and MEG decoding -Ms Evelyn EGER and Ms Manuela PIAZZA on number decoding. 14h15 -14h45 Meeting with the technical staff Audience: members of the expert committee, DS and ITA representatives of the organisms Meeting with PhD students and post-docs and/or fixed-term contract researcher, engineers. Audience: members of the expert committee and DS 14h45-15h00 Meeting with the representative of the "École Doctorale ED3C": Ms Ghislaine DEHAENE Audience: members of the expert committee and DS 15h00-15h15 Break 15h15-15h45 Meeting with the head of the UMR Audience: members of the expert committee and DS 15h45-17h45 Door closed meeting Audience: members of the expert committee and DS Monsieur Pierre Glaudes Directeur de la section des unités de l'AERES 20 rue Vivienne 75002 Paris France Fontenay-aux-Roses, le 26 février 2014 Objet : Rapport AERES E2015-EV-0911101C-S2PUR150007888-004771-RT, Unité de NeuroImagerie Cognitive N/Réf. : DSV/DIR/2014-Monsieur le Directeur, Je vous remercie pour l'envoi du rapport d'évaluation de l'unité mixte de recherche NeuroImagerie Cognitive (UNICOG) dirigée par Monsieur Stanislas Dehaene, dont le CEA, l'Université Paris-Sud et l'Inserm exercent la tutelle. Le comité de visite a réalisé un remarquable travail d'évaluation et souligne la très grande qualité scientifique de cette unité. Le CEA se réjouit de l'appréciation portée par le Comité sur cette unité et prend bonne note de ses suggestions. UNICOG, localisée sur le site de Saclay, est partie prenante du centre de recherche NeuroSpin, dont le CEA assure également la tutelle scientifique. C'est à ce titre que je souhaite apporter quelques éléments d'éclairage à la remarque du Comité de visite concernant notamment l'accueil des enfants et de leurs parents sur le site de Saclay. La localisation de cette unité sur un site CEA induit certaines contraintes d'accès, propres à tous les sites du CEA, qui engendrent parfois des désagréments (horaires, autorisations, etc). Neurospin a été construit à l'extérieur de l'enceinte sécurisée du centre CEA Saclay afin de limiter au maximum ces contraintes. NeuroSpin est une installation d'imagerie de recherche de haut niveau, qui rassemble sur un même site des compétences exceptionnelles de méthodologistes de l'imagerie et du traitement de signal, et de neurobiologistes. La proximité de NeuroSpin avec les physiciens de Saclay permet le développement de technologies d'imagerie au meilleur niveau. Pour réaliser des protocoles de recherche chez les volontaires, et notamment chez l'enfant, Commissariat à l'énergie atomique et aux énergies alternatives Centre de Fontenay-aux-Roses l 18 route du Panorama l BP 6 92265 Fontenay-aux-Roses Cedex T. +33 (0)1 46 54 94 67 l F. +33 (0)1 46 54 78 48 gilles.bloch@cea.fr Etablissement public à caractère industriel et commercial l RCS Paris B 775 685 019 Direction des sciences du vivant Le Directeur NeuroSpin a été doté des locaux spécifiques, comme une salle de jeu pédiatrique et une salle de démonstration de l'IRM (maquette à taille réelle) afin de familiariser les volontaires avec les équipements. Quatre chambres, disposant chacune de deux lits, sont à disposition des familles et des enfants ainsi que des berceaux et lits à barreaux adaptés aux plus jeunes âges, viennent compléter ce dispositif d'accueil indispensable au bon déroulement des études. Le niveau de satisfaction des familles accueillies dans le cadre des protocoles réalisés à NeuroSpin est excellent. Je regrette donc que le Comité AERES n'ait pas eu le temps de visiter NeuroSpin et l'infrastructure d'accueil des enfants volontaires et de leur famille, afin de pouvoir apprécier à sa juste valeur l'environnement qui leur est offert. Je vous prie d'agréer, Monsieur le Directeur, l'expression de toute ma considération.

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

	Director of the unit: Mr Stanislas DEHAENE
	AERES nomenclature
	SVE1_LS5 (primary)
	SVE1_LS7 (secondary)
	Unit workforce
	and similar positions	1	1
	N2: Permanent researchers from Institutions and similar positions	13	14
	N3: Other permanent staff (without research duties)	2	2
	N4: Other professors (Emeritus Professor, on-contract Professor, etc.)
	N5: Other researchers from Institutions (Emeritus Research Director, Postdoctoral students, visitors, etc.)	17	12
	N6: Other contractual staff (without research duties)		1
	TOTAL N1 to N6	33	30

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

Assessment of the unit's involvement in training through research

The group leader is lecturing Advanced Cognitive Neuroscience Graduate course at École Normale Supérieure, Paris, and is a guest lecturer in various advanced courses (École Polytechnique, ENS Lyon, École des Oscillations). She obtained her habilitation to supervise research (HDR) in 2013. Two PhD students already defended their thesis in 2013, with several articles related to their work, and two will finish in 2014.

to the Decree of 3 november 2006 1 , -Mr. Didier HOUSSIN, president -Mr

Assessment of the strategy and the five-year plan

The strategy for the next 5 years focusses on time perception research and temporal dynamics, mostly using MEG recordings. It will largely correspond to the group leader's ERC starting grant and to an ANR Young Researcher grant recently obtained. This should definitely help the group to develop and expand over the next 5 years. Several, still poorly explored questions, will be adressed: are neural oscillations critical for the encoding of time ? Does time perception require an internal clock ? Is Time another mental magnitude such as space and numbers ? What are the neural basis of mental time travel ? How a multiscale representation of time is established in the human brain ? The design of experimental paradigms will capitalize on the expertise of the group on multisensory integration and interfacing with internal representations.