Medical Tourism - New Hope For Children With Fragrant Proportions

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1 Section des Unités de recherche Report from the visiting committee Research unit : Centre for pathophysiology and therapies of children s diseases UMR_S 676 University Paris 7 March 2008

2 Section des Unités de recherche Report from the visiting committee Research unit : Centre for pathophysiology and therapies of children s diseases UMR_S 676 University Paris 7 March 2008

3 Report from the visiting committee The research unit : Name of the research unit : Centre for pathophysiology and therapies of children s Requested label : UMR_S N in case of renewal : 676 Head of the research unit : M. Pierre GRESSENS University or school : Université Paris 7 Other institutions and research organization: INSERM Date(s) of the visit : March 6 th

4 Members of the visiting committee Chairman of the commitee : M. David EDWARDS, London, UK Other committee members : M. Jean-Pierre BOURGUIGNON, Liège, Belgique M. Laurent FAGNI, Montpellier Ms. Ursula FELDERHOFF-MÜSER, Berlin, Germany M. Eric HERLENIUS, Stockolm, Sweden M. Grégoire LAUVAU, Nice M. Sergio PAPA, Bari, Italy M. Robert TAYLOR, Newcastle, UK M. Michael TOSCHKE, London, UK CNU, CoNRS, CSS INSERM, représentant INRA, INRIA, IRD..) representatives : M. Jean-Louis BESSEREAU, CSS INSERM representative Several members of the CNU Paediatrics Committee, including the CNU Committee chairman, were contacted by AERES, but none was available for the day of the site visit. Observers AERES scientific representative : M. Bruno GASNIER University or school representative : Ms. Anne JANIN, University Paris 7 Research organization representative (s) : Ms. Danièle MURCIANO, INSERM representative 3

5 Report from the visiting committee 1 Short presentation of the research unit Total number of lab members : 100, including : 18 researchers with teaching duties 10 full time researchers 6 clinicians 22 engineers, technicians and administrative assistants 22 PhD students, all with funding: French Ministry fellowship: 8; international funding : 1 ; industry : 2 ; other funding : 11 9 postdoctoal fellows Number of HDR : 18 ; of HDR who are PhD students avisors : 16 Number of PhD students who have obtained their PhD : 13 Average length of a PhD during the past 4 years : 3.2 years (1 student did not pursue his PhD because of serious health problems) Number of lab members who have been granted a PEDR : 1 Number of publishing lab members among researchers with teaching duties and full time researchers : 27 out of 28 2 Preparation and execution of the visit The Committee was given clear guidance on the goals of the proposed Centre for Pathophysiology and Therapies of Children s Diseases: identification of new therapeutic targets; production of data immediately translatable to Public Health; development of interactions with industry; encouragement of start-ups; and reinforcement of interactions with clinical research. These aims place the institution clearly within the translational research field, sitting between fundamental research and pragmatic or operational research. The activity of the groups was assessed against these translational goals, and the proposed Centre evaluated as a Translational Centre. The quality of the written documents and of the oral presentations was high. There was comprehensive recording of publications and activity, and the research was clearly described. It would have been helpful to have a more systematic description of external peer-reviewed grant funding for each group, but this did not impede the review. In order to validate the Committees objectivity in assessment of scientific quality and productivity, following the visit and the assignment of scores, the Chairman carried out an approximate bibliometric analysis of the research teams, examining citation rates for their work overall and specifically during the review period, with the aim of capturing any serious difference between the Committee s assessments and the apparent impact of the published work. These bibliometrics did not form part of the Committee s discussions during the visit. 4

6 3 Overall appreciation of the activity of the research unit, of its links with local, national and international partners The overall accomplishment was impressive, with many groups being clearly of world class in their fields. While the number of papers in the highest impact general discovery journals was limited, this reflected the translational focus, and there were a large number of publications in the highest impact speciality journals. All groups appeared to have achieved success over the review period and there is a high level of international recognition of the work of the groups. Post hoc bibliometric analysis in general agreed with the Committee s recorded views. The table records an approximate estimate of the Hirsch Index for each team leader over their career to date and over the period This analysis confirmed that: (a) many teams were performing at an internationally competitive level; and (b) in general there was good agreement between the bibliometric data and the committees ranking (provided to AERES in a separate document). Team # Lifetime Hirsch Index Lifetime Papers > 300 citations Hirsch Index Papers > 40 citations Table : Bibliometric analysis for team leaders. The Hirsch index (a value which records the number of papers with citations greater than that value) is recorded as a measure of overall impact and productivity. The number of papers with more citations than an arbitrary level is also given. During the final review of the scores and the report the Committee made three small adjustments to the preliminary scores assigned during the visit. These scores are not included in this report as requested by AERES. Many groups had developed effective national and international collaborations, working with other worldleading groups across Europe and the world. There was integration within the Paris Diderot University system with other groups, particularly for essential proteomic facilites; these are of the first importance. The groups were all seen to be motivated and effective and declared support for the proposed Centre. In some fields, for example mitochondrial pathophysiology, it was apparent that collaboration and integration between groups already existed, and that the creation of a Centre might speed progress; others, for example epidemiology, this was less so. 5

7 4 Specific appreciation team by team and/or project by project Team 1 : The group focuses on the mechanisms and functional consequences of perinatal brain injury, aiming to develop original strategies for neuroprotection in appropriate animal models. The team leader is a world leader in his field, and the productivity of the group is excellent; in the field of neonatal brain injury worldwide this successful and talented group can be regarded as key players. The group is undertaking translational research, aiming at early impact in clinical practice, following the highly plausible strategy of testing agents suitable for use in newborn infants; this largely means available drugs as regulatory issues make it unlikely that novel compounds can be tried initially in the newborn. The group has developed a number of effective strategies to investigate perinatal brain injury and have made notable contributions, for example identifying a neuroprotective compound (melatonin) which is going into clinical trial now through a European collaboration. There is substantial external funding and national and international collaborations have been formed and operated successfully. The group has coherent plans for the future, in line with international trends, and collaborates with other groups locally, leading a focus upon developmental brain damage that is of very high potential impact. The Committee rated the quality and productivity of the work very highly. However it was felt that the relevance of the work suffered from not having a clear route to phase I/II clinical trials. The Committee felt that the strategy being followed would be more effective if there was a clear relationship to a Clinical Research Facility undertaking these studies, either through developing a neonatal role for the Clinical Research Facility at Robert Debre in association with group 4, or through more formal links to translational and clinical researchers elsewhere. Team 2 : The group focuses on mitochondrial pathophysiology and the development of novel treatments for mitochondrial disease. The team leader is internationally recognized as an expert in mitochondrial medicine. He participates in international networks and has been funded by EU and National Grants. The team relocated to the Robert Debre Hospital from the Necker in 2005 and during the last three years have developed an exciting and coordinated programme. The small but talented team has several successful collaborations within the Inserm group. The work on mitochondrial pathophysiology has the potential to form a strategic theme for a Pediatric Research Centre, adding to work carried out with teams 1, 4 and 5. However the Committee noted the team leader s comment that research in his field is currently being developed across the world in Mitochondrial Medicine centres; it was not clear that the proposed Centre would fulfil this role completely, and the strategic needs of this research team need to be considered if a Centre is established. The Committee rated the quality and productivity of this team s research output very highly, noting innovative projects for allotopic expression of an alternative oxidase and the Harlequin mouse model of AIF deficiency. The group has been highly productive, including papers in high quality discovery journals and potentially valuable patents. This basic research was balanced by a view to translation as evidenced by the initiation of clinical trials of Pioglitazone in patients with Friedreich s ataxia. The team PI is poised to lead in this area at an international level through the excellent European and world-wide collaborations. Team 3 : Previous results of the team show that the peptide receptor sstr2a inhibits neurotransmission mediated by glutamate receptors and may control neuronal migration during brain development. The team now aims at studying membrane trafficking and intracellular signaling that could influence the receptor function and thus serve as therapeutic targets against neurodegenerative diseases. The group plans to study functional targeting of sstr2a in in vitro neuronal preparations, using a combination of innovative imaging technology, molecular electrophysiology and biochemistry. They will also test the neuroprotective effect of sstr2a in animal models of temporal lobe epilepsy, using brain injection of lentiviral expressing vector of the receptor. The overall project is coherent, quite original and of very high potential impact in the field. The work is basic research, but there is a potential for translational relevance in the understanding and treatment of epilepsy or 6

8 excitotoxic injury and the team has published valuable research with Team 1; in the context of a Pediatric Research Centre, this needs to be considered strategically. The quality of publications of this group is good. The team looks quite strong in terms of resources and scientific expertise but is small and needs to maintain focus. A curent lack of substantal external grant funding may raise some questions over viability and the group needs to address this in the short term. Team 4 : This group has devoted considerable effort into developing a sophisticated suite of phenotyping tools for newborn rodents. The Committee felt that this facility was potentially of value to the Research Centre and could be widely applicable; it is possible that the new European regulations for paediatric drug testing might increase its usefulness. The group is currently generating a spin-out company based on this work. The Committee noted the success of this world leading technological development, and in engaging with the commercial world to develop the incubator company. However it had consumed much of the teams resources and that although the team had carried out some valuable work, for example with the PHOX2B mouse, as yet the research output was a little uneven. Further the committee noted a concern about the relation between the future company Phenopups and the scientific activity of the group. A spin-out company may provide technological development as well as external resources. Nonetheless, a clear distinction between company directed and research funded research is essential and may be difficult to achieve. It will be important to clarify this relationship, not least because the phenotyping technology will need continued development of the repertoire of tests if it is to be widely useful. Clear decisions on the allocation of resources is required and the group needs to decide how far it plans to focus on scientific questions or on the continued development of their technology. It was not clear to the Committee how far company workers could be distinguished from INSERM personnel; this requires detailed planning of staff allocation. Team 5 : This Avenir Research group grew from group 1, and represents a success for the Robert Debre research environment. The group will work on the role of oligodendrocytes in cerebral white injury, and identify neuroprotective targets aimed at preserving white matter structures. The Committee noted the enthusiasm and energy that the group leader had generated. The productivity and quality of scientific publications of the group is rated as good. The group has wide vision in plans for the future, which are all potentially of high impact. However the Committee noted that the wide focus of interests had a potential risk for the nascent group, particularly as the team leader works 50% of his time as a clinician. There is a case to focus the programme on a more restricted selection of molecular targets in the developing white matter in order to further succeed. The team leader s position as a working neonatologist has both advantanges and risks. He is in a position to provide links to clinical research, however his training is in laboratory science where he should focus, and his clinical duties could become a distraction. He is a talented researcher who could make a significant contribution to medical research, and careful thought needs to be given to supporting his laboratory to allow it to achieve its potential. Team 6 : This research team carries out epidemiologic studies with a focus on fetal programming and later metabolic diseases. They are working in a highly competitive field and are in competition with strong international groups. The Committee noted the success in developing and running running large-scale epidemiological longitudinal studies requiring a large amount of human and financial resource, and considerable time. These cohorts are valuable and need to be maintained. Parts of their work have been published in highly ranked international journals during the last four years and these publications have been well recognised on an international level. The two senior researchers are recognised internationally and have been invited to oral presentations at scientific meetings representing a healthy mixture between national and international meetings. There was some concern that the group s publications were not always of similar impact to some of their collaborators and competitors, but it was recognised that these large-scale studies now require large international networks and the group was playing an important part within the collective scientific effort. 7

9 The ongoing cohort studies represent a good basis for the future viability of the unit. Additionally the shortlisted EU project within the FP7 that is lead by researchers of the team optimally fits into the epidemiologic focus and offers a middle-term international perspective. This unit is the only one out of two units carrying out the major part of its research on humans within the Robert Debre Centre, and is thus relevant to a translational mission. However, the links between Team 6 and the other teams are limited due to the large difference in subject and methodology. The epidemiologic unit has access to the necessary Clinical Research Facility within the Hosptial and would be able to function on its own. It was not clear to the Committee that diabetes and endocrinology could be developed as a major theme for a Pediatric Reasearch Centre. It is possible that a more coherent strategy might be possible if the group considered using its cohorts or expertise to examine diseases being explored by Teams 1-3, 5 and 7; however this would require a major refocusing and would need careful consideration to avoid impairing the current research activity. Team 7 : This Avenir team is working at the edge of Neurosciences and Pediatric Endocrinology, with studies around the role of kisspeptin and GPR54 in puberty and reproduction. This topic appeared to be a breakthrough in the field where the team leader is recognised as a world-leader. In this context, the number of publications in highly ranked journals is impressive with respect to the size of the team. This group was established recently and is undertaking fundamental research. There has been a creative effort to create a better fit into the translational context of the research centre through the involvement of the team leader in the laboratory of clinical genetics and the recent integration of a staff scientist from Team 6 in Team 7. Unfortunately little was said about her work although she is clearly productive, and the success of this marriage cannot yet be assessed. We suggest that this group should be reassessed in the future to determine how effectively this structure is supporting their translational goals of the Institution. Team 8 : The leader of this team has published a seminal paper in 2001 linking Crohn diseases to the alteration of the gene encoding for NOD2, a protein involved in the detection of molecules from microbial origin that belong to the intracellular pattern recognition receptor family. The team leader is recognised as a world leader in this field, and his seminal paper has over 2000 citations in the literature. Building up on this important work, he has productively developed several clinically oriented projects over the past 4 years wich examine innovative routes to treament. The work is translational research of the highest level, with fundamental advances in understanding being rapidly moved towards clinical relevance. The different aims of the team are well defined and tight together. A lot of efforts have also been concentrated in setting up collaborative networks for clinical studies in France and Europe and it is likely that the outcome in terms of human and children health will be positive in the future. The team is very well funded and should therefore be secured over the coming years. The Committee noted the tremendous productivity of the team; their original paper in Nature was a major achievement that has received more than 2000 citations. During the current review period they have followed up this work with translational research for patient benefit rather than focusing on a more detailed deciphering the molecular mechanisms revealed by their earlier discoveries: and not surprisingly this has not led to further publications in Nature; however this is entirely within the translational research agenda. While this team clearly represents an added value to the general objectives of the center, its integration to the center is not obvious at first since most of the teams have a strong interest in neurologic-related disorders in children. Interactions and novel projects seem nevertheless to arise with other groups (team 5 and 7) which will certainly be positive in the next years. 8

10 5 Appreciation of resources and of the life of the research unit Resources : (a) Institutional : The resources available to the groups are in general appropriate, but the small size of the Centre makes it impossible to provide all resources on site. It will never be possible to maintain all the most up-todate equipment needed for advanced science in one institution, particularly a small one. Links to other centres locally are important, and the Protemomics facility at Bichat Hospital seems an appropriate model, although it was noted that the use made of this by the groups was generally small. Access to clinical resources and a Clinical Research Facility is important but currently underused. The Committee felt that there is a significant deficit in the provision of data management and informatics resources. The Centre does not appear to have effective informatics suppport, either at the level of data curation or at the level of bioinformatics. There is statistical support but this seems to be under-achieving, and there was little evidence of input into experimentation- for example there was not evidence of adaptive designs in animal studies. (b) Individual groups : The Committee felt that levels of resource were in general appropriate, but that there was a case for strengthening some groups. Mitochondrial pathophysiology appears to be a developing theme across the centre. It might be appropriate to develop a formal strategy to support Team 2 to pursue this further. Team 3 is attempting complex work and needs to develop external funding sources. Some interim funding may allow this group to succeed. Group 5 needs support to develop : The team leader s position as clinical scientist is valuable to the institution but it is not possible to run a laboratory while active 50% of the time as a neonatologist- a famously arduous medical speciality. The team leader needs support to maintain and develop his laboratory. It is recommend to re-evaluate the group within a certain time frame. Life of the research unit : The teams at the Robert Debre Centre have an excellent track record in training both scientific and medical students, as evidenced by the number of successful PhD theses awarded in recent years. It is evident from talking to students, engineers and post-doctoral scientists alike, that they feel very much a part of the ongoing research programme of the centre, and that their opinions are both valued and represented at the level of important decision-making committees (e.g. Council). Given the PhD programme of the Centre is required to integrate with different disciplines from several Universities, there exists a remarkable degree of integration at this level, which is a real strength of the training programme. Students and post-doctoral scientists organise a monthly lecture series to keep abreast of scientific and technological developments, whilst there is clear evidence of structures built into the programme to ensure student progression is monitored and checked during postgraduate training. Morevover, there is a proven track record of successful PhD students being able to develop their careers and latterly of new groups growing out of existing research groups. The committee felt that there is an imbalance within the institution in that a centre with 100 staff only appears to possess 9 post-doctoral scientists amongst the 8 groups. This must cause significant problems in planning strategically to develop research goals and new projects. The Director has made it clear that this issue has already been appreciated and addressed and a number of new appointments are in the pipeline. One issue we would raise from the discussions with this group is that whilst many of the engineers find working at the Centre both highly enjoyable and scientifically-stimulating, they feel collectively that there is little recognition at Institute level for their contribution to successful research programmes. Whilst we would want to bring this to the attention of the Director, we do not believe this detracts from an excellent post-graduate training programme for both Masters and Doctoral students. 9

11 6 Recommendations and advice Strong points : A number of productive and world-leading groups with a clear translational agenda The potential for some integration and focusing around strengths such as mitochondrial function, developmental brain injury and phenotypic characterisation. What needs to be improved : Informatics and Bioinformatics : Whether or not a formal Centre is declared, there is a need to develop some aspects of the scientific infrastructure quite urgently, in particular informatics and bioinformatics. While resources in general terms seem to be broadly appropriate, there is a risk to all the groups if this is not done. Clinical research and experimental medicine : There was no substantial portfolio of first in child/man experiments and the active Clinical Research Facility on site was used mainly by other research groups outside INSERM (with the exception of team 6 which does not undertake experimental medicine). There are several potential strengths within Robert Debre which could add value to the INSERM group: as well as the clinical research facility there is a respected imaging group who could contribute to clinical and experimental research.several groups appear to be developing experimental medicine links outside the Hopital Robert Debre; this may be appropriate but a stragegy is needed for human research either in-house or through formal collaboration if the translational goal is to be achieved. The number of post-doctoral researchers in the institution is remarkably small. This is a significant issue for the stability and effectiveness of the research teams and also for the career development of PhD students. This may reflect the institutional structure, but also the relatively low level of independent grant income. This issue needs to be addressed. Recommendations : The Research Teams : The Committee was supportive of the groups being reviewed, and felt that they made a significant contribution to medical science. As translational groups, they are an important and often under-resourced link in the pipeline between basic discovery science and pragmatic implementation research. The committee believes that whatever decision is taken concerning the formation of a specific Centre, the individual groups should be supported. A Centre for the Pathophysiology and Therapies of Children s Diseases The creation of a successful, formally constituted Centre would require considerable strategic planning. The current alignment of groups allows for some integration and added-value, but is not ideal. The proposed democratic governance structure would make it difficult for the Director to change the balance or structure of the Centre to achieve symbiosis and added value. While there is considerable opportunity to promote scientific collaboration and economic efficiency within the Robert Debre Inserm group, it is not clear to the committee that the proposed Centre would add significantly to this unless the Director is given considerably more opportunity to chose the strategic direction it should take. The Director needs to be empowered to make effective strategic decisions concerning the Centre and the direction of the research undertaken. However it appears to the Committee that, while there is already an efficient use of shared facilities and good value for money in the institutional investment, further integration of the groups will lead to improved scientific ouput and economies of scale, particularly in the context of a wider integration into the local research structure. The provision of shared technical staff and facilites is well managed and effective and provides a sound basis for the development of science within this INSERM unit. 10

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13 Institut national de la santé et de la recherche médicale Faculté de Médecine Paris, le 02/06/08 GENERAL COMMENTS Informatics and bioinformatics We are addressing this high priority issue along three lines: - By completing the on-going renovation of the network infrastructure, which will connect all users to a server and general network services: data storage, sharing and protection, calendar and event coordination; - By applying to hire a permanent engineer in bioinformatics from Inserm; - By developing the on-going collaboration with the local Centre for Clinical Epidemiology, allowing full access to a large array of bioinformatics resources. Clinical research and experimental medicine The link with the Clinical Research Facility (CRF) dedicated to paediatric research at Robert Debre Hospital will be strengthened. The formal incorporation of this important structure into the Research Centre was denied by Inserm for administrative reasons. Despite this technical restriction, most of the Teams have engaged in multiple clinical studies critically involving the CRF. The future will clearly see a further strengthening of this already established joint venture between the CRF and the Research Centre. The clinical imaging group is integrated in Team 1 and we are conducting together studies in mice and human foetuses and preterm neonates. In addition, we are currently establishing collaborations with Neurospin (CEA) in several experimental and clinical projects to further enhance our imaging capabilities. Postdoctoral researchers When we completed the application we had indeed eight postdoctoral fellows. Different teams applied for specific budgets to support the salary of postdoctoral positions and we are going to welcome five additional postdoctoral fellows within the two coming months (including one from Poland, one from India, one French scientist coming back from the USA and two French scientists who just completed their PhD). So we will have 13 postdoctoral fellows by the end of this year and are planning to further increase this number in the coming years. At the same time, we also plan to maintain good opportunities to train PhD students as we believe this is of paramount importance at the national level. UMR 676 Inserm-Paris 7 IFR 02 & IFRH Hôpital Robert Debré (AP-HP) 48 BD Sérurier Paris, France Tél Fax pierre.gressens@inserm.fr

14 TEAM 4 1. Scientific output Contrary to the report's assertion, the scientific output by Team 4 is not a little uneven. This output comprised numerous original papers, invited reviews, and a patent. The team displayed very high productivity, especially considering that it had a single full-time researcher. Original articles During the review period, Team 4 published 20 original articles reporting just the work on mouse models. The first or last author (generally both) were Team 4 members for all but one article. Most studies were published in good speciality journals and three appeared in PNAS. Of note, three PhD students and one post-doctoral fellow published their results as first authors in high-ranked journals: Development, Am J Respir Crit Care Med and, on two occasions, PNAS. One of these papers (PNAS 2003) was complimented in an Research Highlight in Nature Reviews Neuroscience in Another paper (ERJ 2007) was complimented in an accompanying editorial and two other papers (JAP 2003 and JAP 2004) were featured as Highlighted Topics. Details on the level of the journals that published our original papers on mouse studies are given below: Journal Year IF 2007 ISI category 2007 Rank in ISI category PNAS PNAS PNAS Multidisciplinary sciences 3/50 Am J Respir Crit Care Med ,091 Respiratory system 1/34 Development Developmental Biology 5/34 Eur Respir J Respiratory system 3/34 J Physiol (Lond) Physiology 9/78 Chest Respiratory system 6/34 Am J Physiol: Reg-I Am J Physiol: Reg-I Physiology 18/78 Neuroscience Neurosciences 63/200 Neuroscience J Appl Physiol J Appl Physiol J Appl Physiol Physiology 24/78 Behav Brain Res Behavioral sciences 6/42 Physiol Behav Behavioral sciences 19/42 Acta Physiol Scand Physiology 34/78 Respir Physiol Neurobiol Physiology 38/78 Pediatr Pulmonol Respiratory system 22/34 Team 4 contributed to over half the in vivo genetic mouse models of respiratory control disorders published worldwide. The team is taking part in a European Union-funded project (FP7) on paediatric drugs and acquired funds from the ANR, other agencies, and awards (as detailed below). In addition to the above mouse studies, the team published four human experimental studies, 16 clinical studies, ten book chapters and didactic articles. The scientific output of the emeritus research director who recently joined the team comprises 16 additional original papers, including a paper in Nature Genetics of which he is the last author. Invited reviews UMR 676 Inserm-Paris 7 IFR 02 & IFRH Hôpital Robert Debré (AP-HP) 48 BD Sérurier Paris, France Tél Fax pierre.gressens@inserm.fr

15 Team 4 published eight invited reviews in peer-reviewed journals (among the 13 review papers published worldwide on the topic), reflecting its high international standing in the field of genetic factors involved in respiratory control. The results obtained by Team 4 were presented as invited lectures at several international conferences and will be presented again at the next European Respiratory Society meeting in Patent A patent on original methods for phenotyping newborn mouse was recorded by the World International Property Organisation in Our valorisation project will be presented at the next European Research and Innovation Exhibition, as an invited conference, in Paris. 2. Ressources The statement in the report that technological developments consumed much of the team's resources is misleading, since it erroneously suggests that investments in new technologies left inadequate funds for research activities. During the review period, Team 4 earned both grants dedicated to valorisation programs and grants dedicated to the scientific program. The technological project consumed only those resources specifically allocated to it. For this reason, it is unwarranted to compare the overall team resources and the scientific output, as done in the report (However it had consumed much of the teams resources and that although the team had carried out some valuable work... as yet the research output was a little uneven.). Part of the technological program had no direct impact on research output (e.g., market research, industrialisation processes, obtaining proof of concept), Furthermore, technological resources were mainly attributed in 2007, i.e., at the end of the review period, which precluded any, even remote, impact on research output. GRANTS FOR THE VALORISATION PROJECT Ministère de la Recherche Contest OSEO k ANR Biotechnological projects k Université Diderot Award k GRANTS FOR THE SCIENTIFIC PROJECTS Inserm and Université Paris 7 Part of institutional support to U k /y Legs Poix Research grant k /y ANR Research grant (Rare Diseases) k /y AFSO Research grant ,7 k /y ANR Research grant (Neurosciences) k /y Fondation Garches Research grant k Ministère de la Recherche ACI (Cooperative project) ,3 k /y JFRN Award k ANR: Agence Nationale de la Recherche; AFSO: Association Française du Syndrome d'ondine; ACI: Aide Concertée Incitative: JFRN: Journées Françaises de Réanimation Néonatale. 3. Scientific questions versus technology The report emphasizes the need for clarifying the balance Team 4 plans to achieve between its work on scientific questions and the continued development of its technology. Team 4 is conducting a scientific project on postnatal developmental disorders, while pursuing efforts to design innovative tools for studying these disorders. The scientific component and the technological component go hand in hand, working symbiotically, as illustrated by the patent obtained by Team 4. Human resources are currently allocated as follows. Two PhDs are studying respiratory control disorders of genetic origin and two other PhDs are investigating the developmental consequences of intermittent hypoxia (in a model of apnoea of UMR 676 Inserm-Paris 7 IFR 02 & IFRH Hôpital Robert Debré (AP-HP) 48 BD Sérurier Paris, France Tél Fax pierre.gressens@inserm.fr

16 prematurity). Two MDs are performing newborn mouse studies of experimental treatments of apnoea and resuscitation processes. The emeritus research director is investigating the impact of early neurological disorders on development. All collaborations with national or international groups (six in all) focus on mouse models of early developmental disorders. Two engineers are developing phenotyping resources and one post-doctoral fellow is managing the start-up project. 4. Relationship between team 4 and the future company The report mentions a risk of confusion between INSERM personnel and company employees. This risk is theoretical, as the company has not yet been created and the team has a single Inserm employee (the team leader). Nevertheless, we thoroughly examined the relation between the research centre and the future company. The use of offices and animal facilities will be under a lease agreement between the future company and the centre. The future start-up will use its own equipment. Intellectual property rights will be licensed to the future company via Inserm Transfert. The intellectual property rights have been discussed with Inserm-Transfert. All agreements will be formalised between Inserm-Transfert, University Paris 7 and the research centre when the company is launched. The participation of team personnel to the future company is strictly defined by French law, which leaves very little room for confusion. Article 19-1 of the Law of July 12, 1999, specifies the modalities of contracts between public research organisations and private companies, including specific contracts with newly created companies. Article 25-2 of the Law of July 12, 1999, specifies the modalities of participation of public research personnel in private companies. Research personnel, while remaining in the public sector, may contribute scientifically to a private company that valorises their research output for renewable 5-year periods. This activity must be compatible with their public employment and must account for less than 20% of their work time. A ceiling exists for the corresponding income. Two Team 4 members (the Inserm employee and one of the MDs) will contribute to Phenopups as scientific advisers within this regulatory framework. The future start-up will hire all its employees independently, and none of its employees will be involved in Team 4 activities. UMR 676 Inserm-Paris 7 IFR 02 & IFRH Hôpital Robert Debré (AP-HP) 48 BD Sérurier Paris, France Tél Fax pierre.gressens@inserm.fr

17 TEAM 5 The AVENIR Team 5 is dedicated to the investigation of white matter damage induced by perinatal oxidative stress. Thus, this topic is rather distinct from the aims of team 1 but benefits from the exceptional environment of the Research Centre at Robert Debré hospital. AERES committee noted that the too wide focus of interests of our group could be detrimental for a nascent team. We would like to precise that we plan to first investigate these targets in a pragmatic approach. We take advantage from the translational position of the leader to test a restricted number of innovative hypotheses potentially of high impact in deeply modifying the perinatal management of very preterm infants. The apparent heterogeneity of the scientific questions raised is due to the need for us to explore several unanswered hot topics in order to subsequently further explore only the most valuable or them. This effort into developing translational research should be supported by recruiting one full time researcher. This is probably the most critical issue for our group and we hope that Inserm will help us to succeed in this key task for the continuation of the team and the achievement of our potential. UMR 676 Inserm-Paris 7 IFR 02 & IFRH Hôpital Robert Debré (AP-HP) 48 BD Sérurier Paris, France Tél Fax pierre.gressens@inserm.fr

18 TEAMS 6 & 7 Regarding teams 6 and 7, the visiting committee raised specific points and made a general comment on the role of endocrinology and diabetes as part of the research center. We will fisrt address the specific points and then discuss the general comment. Specific points Team 6 There was some concern that the group s publications were not always of similar impact to some of their collaborators and competitors, but it was recognised that these large-scale studies now require large international networks and the group was playing an important part within the collective scientific effort Comparative bibliometry is difficult and we acknowledge the fact that our group's publication might not reach the same level as some of our competitor's; however, the publications of the group demonstrate a regular and consistent production in top subspecialty journals. In addition, we want to stress the fact that after a first set of publications pointing to the fetal origins of complex diseases in first rank journals by several groups including ours some years ago, further publications in the same area tend appear in top specialty journals rather than in top general journals. This phenomenon is true not only for our group but also for our competitors. The newly developed cohort with close monitoring of fetal growth is extremely original if not unique as of today. However, there is always some delay between the implementation of such a project and scientific production. Thanks to our original and unique tools, the group is actually embarked in an international collaborative network seeking support from 7FP in Team 7 There has been a creative effort to create a better fit into the translational context of the research centre through the involvement of the team leader in the laboratory of clinical genetics and the recent integration of a staff scientist from team 6 in Team 7. Unfortunately little was said about her work although she is clearly productive and the success of this marriage cannot yet be assessed. We suggest that this group should be reassessed in the future to determine how effectively this structure is supporting their translational goals of the institution. We would like to add some precision on the role of the University-Researcher who joined team 7 in This Medical Doctor is a full professor of developmental biology at Denis Diderot Medical School and the head of the national center for rare endocrine growth diseases. She is essential in translational and clinical research in pubertal diseases with emphasis on genetic and pathophysiological approaches. As stated elsewhere, the added value to team 7 of this University-Researcher with high expertise in Pediatric Endocrinology is essential and representative of the close interaction between the research center and the Endocrine unit of one of the largest Pediatric centers in Europe. We acknowledge the fact that the size of team 7 is limited and we are seeking a full time scientist to strengthen this team in Global Analysis on team 6 and 7. It was not clear to the Committee that diabetes and endocrinology could be developed as a major theme for a Pediatric Reasearch Centre. Members of teams 6 and 7 consider this statement unfounded for several reasons: The endocrinology and diabetes research teams (6 & 7) interact daily with the clinical department of the hospital which is one of the largest of its sort. This interaction is essential in the field of translational research and would not be possible elsewhere. The statement raises the issue of whether research in a Pediatric subspecialty area is better suited in a Pediatric center or in a center that is devoted to the area overall (endocrinology, gastro-enterology, ). We believe (as members of team 8) that there are Pediatric specificities to our approaches that are not UMR 676 Inserm-Paris 7 IFR 02 & IFRH Hôpital Robert Debré (AP-HP) 48 BD Sérurier Paris, France Tél Fax pierre.gressens@inserm.fr

19 compatible with an adult environment and that remaining in a Pediatric environment is the only place where this research can be successfully developed. Over the past 20 years, the endocrinology and diabetes research in pediatrics at Robert Debré hospital has raised to be considered among the top of the specialty in Europe. The scientific production, the originality of the topics and the overall quality of research clearly demonstrated the pertinence of our strategy. We acknowledge the fact that group 6 has evolved a great deal in the past four years. Four years ago, endocrinology and diabetes research onsite was limited to team 6 with one Inserm researcher and one University-researcher. Teams 6 & 7 now comprise one Inserm researcher and four University-researchers. Team 7 interacts with several of the neuroscience teams. Team 6 has expanded with the arrival of a Universityresearcher developing the theme of epidemiology in Endocrine diseases and is coordinating a large FP7-granted project (as highlighted by the committee). This evolution shows that indeed endocrinology and diabetes research is an important and active component of our research center and that future years should further demonstrate its good health. UMR 676 Inserm-Paris 7 IFR 02 & IFRH Hôpital Robert Debré (AP-HP) 48 BD Sérurier Paris, France Tél Fax pierre.gressens@inserm.fr

20 TEAM 8 Team 8 focuses on the understanding of Crohn's Disease mechanisms and treatment. Crohns' Disease is a gastrointestinal disorder and it is not related with disorders of the brain investigated by other teams. For this reason, its project may be seen out of the scope of the research centre. It is true that several groups in the current research centre are working on paediatric neurology to date (mainly Teams 1, 3 and 4) and that this topic is a leading one. However, the research centre proposed here is not defined by the field of neurosciences only. For example, Teams 6 and 7 are involved in research on endocrine or metabolic disorders, Team 2 works on mitochondrial diseases, Team 4 has developed a research on pup physiology which explores much more than neurological disorders, etc... Finally, it is expected that additional groups will joint the research centre in the next years and it is unlikely that the majority of them will focus on neurosciences only. Indeed, the research centre is defined by a translational research on paediatric disorders. These two key words are applying to our research and we thus consider being a full part of Robert Debré research centre. We are aware that scientific interactions are important within a centre and the lack of common works between team 8 and other teams has been noted. We agree that the interface projects between other groups are limited to date. The recent creation of our INSERM unit (in January 2007) and the limited number of researchers in the team did not give us the opportunity to develop new interface projects until now. However, two new projects have emerged recently. They have not been discussed in details during the presentation because of time limitations. These projects are the following: 1) Puberty of Crohn's Disease patients. Puberty is known to be delayed in Crohn's Disease patients but only limited investigations have been done on this subject to date. We have developed a preliminary project with Team 7 to explore this question with the department of paediatric gastroenterology. It is a direct consequence of a recent work performed in collaboration with J. Cosnes at Saint Antoine hospital on the final height of paediatric Crohn's disease patients (manuscript in preparation). 2) Effect of NOD2 on the stress induced gut inflammation. Neonatal stress has been shown to increase the gut permeability and to induce a gut inflammation. These parameters are also increased in Crohn's Disease. A postdoctoral fellow in the group is currently working on the inflammation and permeability in NOD2 knock out mice (NOD2 is a susceptibility gene for Crohns' Disease). However, he is also expert in the field of neonatal intestinal immune response to stress during. We have thus decided to explore the role of NOD2 in neonates. This work will be done in collaboration with Team 4 taking advantage of its expertise in physiology and stress. This research may have consequences for children disorders, mainly necrotising enterocolitis and infant colitis. These diseases are taken in charge respectively by the departments of neonatology (Team 5) and gastroenterology. Paris, June 2 nd, 2008 Pierre Gressens Director UMR 676 Inserm-Paris 7 University UMR 676 Inserm-Paris 7 IFR 02 & IFRH Hôpital Robert Debré (AP-HP) 48 BD Sérurier Paris, France Tél Fax pierre.gressens@inserm.fr