Centre de Génétique Moléculaire UPR 2167 Université Paris 6

Section des Unités de recherche
Report from the visiting committee
Research unit : Centre de Génétique Moléculaire
UPR 2167
University of Paris 6
April 2008
Section des Unités de recherche
Report from the visiting committee
Research unit : Centre de Génétique Moléculaire
UPR 2167
University of Paris 6
April 2008
Report from the visiting committee
The research unit :
Name of the research unit : Centre de Génétique Moléculaire (CGM)
N° in case of renewal : UPR 2167
Head of the research unit: M. Lawrence Aggerbeck (former)
University or school :
University of Paris 6
Other institutions and research organization :
CNRS
Date(s) of the visit :
10th—12th March 2008
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Members of the visiting committee
Chairman of the commitee :
M. CHANDLER Michael, Toulouse
Other committee members:
M. SHERRATT David (absent due to illness), Oxford, UK - FRASER Peter, Cambridge, UK
M. CUPPEN Edwin, Utrecht, The Netherlands
M. GRANGE Thierry, Paris
M. RABILLOUD Thierry, Grenoble
M. KISS Tamàs, Toulouse
M. SCHWEISGUTH Francois, Paris
M. MONSAN Pierre , Toulouse
M. HOFLACK Bernard, Dresden, Germany
M. BASTIN Philippe, Paris
M. WERNER Michel, Gif-sur-Yvette
M. ARGENTINI Manuela, Strasbourg
CNU, CoNRS, CSS INSERM,
representatives :
représentant INRA, INRIA, IRD…..)
M. Bertrand DAIGNAN-FORNIER, Bordeaux, CoNRS representative
M. Michel VOLOVITCH, Paris, CNU representative
Observers
AERES scientific representative:
M. LASZLO Tora
University or school representative:
Ms. Catherine JESSUS, Université Paris 6
M. Jacques BITTOUN, Université de Paris Sud 11
Research organization representatives:
Ms. Martine DEFAIS, DSA CNRS
M. Miklos DE ZAMAROCZY, chargé de mission du CNRS
Ms. Michele SAUMON, Déléguée Régionale Ile de France-Sud
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Report from the visiting committee
1 z Short presentation of the research unit
Total number of lab members: 172 including
- Full time researchers: 59 (+ 4 emeritus faculty)
- Researchers with teaching duties: 18
- Postdoctoral Fellows: 30
- ITA and IATOS : 52
- Ph.D. students: 43, all with fellowship
Number of lab members with a HDR: 50, 28 are PhD advisors
Numbers of lab members who have been granted a PEDR: 1
Numbers of PhD students who have obtained their PhD since January 2004: 26
Average lenght of a PhD during the past 4 years; 3 years 11 months
Numbers of “publishing” lab members : 60 out of 77
2 z Preparation and execution of the visit
The committee visited the laboratory by March 10 to 12 2008. The visit was well prepared, with a thorough
and detailed document provided in advance. On site, the visit was properly organized, with presentations and
discussions with group leaders, technical and administrative staff, students and postdocs. The director gave
his presentations in front of the committee, but in the absence of the other members of the CGM. The
committee had time to discuss various issues and the execution of the visit was thus good. No committee visit
was organized to visit the different separate buildings of CGM.
3 z Overall appreciation of the activity of the research unit, of its
links with local, national and international partners
Historically, the Centre de Génétique Moléculaire (CGM) has been the flagship of French Genetics. It has
undergone a profound reorganisation since 2001, initiated by the previous director and, following his untimely
death, continued under the present director. This has been overseen in a prescient manner by the present
direction and actively supported by a scientific committee and a search committee.
The CGM has adopted a departmental structure and the director has overseen a reduction to 4 departments:
RNA; Genetics of Cellular Functions; Developmental Biology; and Functional Genomics and Biotechnology.
This has involved a rationalisation of the different research themes, a reorganisation of resources and the
creation of satellite laboratory space in three buildings in addition to the main center. The committee would
like to congratulate the present director for his role in the evolution of this large, complex and diverse CNRS
unit.
An indicator of the CGM activity is the publication output: 328 articles of which 253 were in 100-peer
reviewed journals with an average global impact factor of about 8. Although the absolute number of
publications has fallen, this has been largely compensated by an increase in the quality as revealed by the
impact factor of the journals: e.g. EMBO J., journals from the Cell and Nature press groups. International
recognition is also clear from the number of invited lectures (~122).
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The CGM is also active in teaching activities at all levels. In addition to the faculty members attached to the
Universities of Paris VI (3 MdC of which 1 HdR), Paris VII (1 MdC, 1 Pr2), Paris XI (8 MdC of which 1 HdR, 1 Pr2,
2 Pr1) and Versailles (1 MdC) other members of the CGM are actively involved in teaching in these and other
French universities. A large number of Masters students (M2) are undertaking their research projects within
the CGM and 26 PhD theses together with 9 Habilitations to Direct Research (HDR) have been completed over
this period. This should increase significantly in the near future as the number of PhD students has doubled
over the last 4 years.
4 z Specific appreciation team by team and/or project by
project
NOTE: two groups have recently joined the Institut Jacques Monod. These groups (Dynamics and Regulation of
Mitosis; Evolution and Development of the Metazoans) were not evaluated here but in the framework of the
AERES evaluation of the IJM. Since they have contributed to the activities of the CGM during the reporting
period, it seems reasonable to include their activities in the overall assessment of the CGM.
Microbial infection of Drosophila
Over the 2004-08 period, this established group has made several very important contributions with high
international impact to understanding the response of Drosophila to bacterial infection. It has provided clear
evidence that the local response of the gut to oral infection is highly relevant. In particular, it has isolated in the
field and characterized in the lab a persistent non-pathogenic bacterium (Erwinia carotovora) and a novel
pathogenic bacterial species (Pseudomonas entomophila) that infect flies via ingestion. A single gene was
identified in E. caratovora which promotes persistence when introduced into gram negative but not gram positive
bacteria. The genome of P. entomophila was sequenced and annotated in collaboration with the French
Sequencing Center (Genoscope). In collaboration with a microbiology group of the CGM, 45 P. entomophila genes
required to infect and/or kill flies were identified. Another key achievement was the genome-wide expression
profiling of genes responding at the transcript level to infection. The function of several genes identified in this
microarray approach has been investigated. The team has also pursued the molecular characterization of the
signalling pathways that trigger antimicrobial peptide gene expression upon infection. Finally, this team has
played a pivotal role in the establishment of the Drosophila RNAi platform at the CGM. These various studies have
led to many publications in top-journals. Overall, the productivity and the quality of science by this team is
excellent. The group leader has high international visibility and has now moved his laboratory to the EPFL in
Lausanne (CH).
Growth and Metabolism in Drosophila
This team, composed of the PI, 2 postdoctoral fellows and 2 graduate students, was created at the CGM in
2005 and has received ANR funding. After a relatively long period of initial recruitment, the team has now
reached the critical size necessary to perform the large-scale genetic screens in Drosophila required by this
project. The research is centred on the physiology of lipid metabolism at the level of the whole organism using
genetics as an approach and Drosophila as a model system. This line of research, at the interface of Physiology
and Developmental Biology, is original and promising. The group has identified a gene involved in the regulation of
dS6K activity and is currently investigating the molecular mechanisms underlying this regulation. It has recently
initiated two ambitious large-scale RNAi screens to identify genes acting at the body level to regulate lipid
metabolism but it is too early to evaluate how fruitful these screens will be. Only a single collaborative paper has
been published over the 2004-08 period. It is therefore important that the interesting work on dS6K regulation be
published. The low productivity of the group during this period can be explained by the time necessary to set up a
new laboratory and initiate these ambitious projects.
Epithelial cells and Morphogenesis
This group, composed of the PI, an associate professor, a postdoctoral fellow and two graduate students,
introduced the C. elegans model into the Department of Development. At present, it is the only group using this
developmental system and providing its expertise to the CGM. The group has been well financed during the early
stages of its installation at the CGM and is currently supported by the ANR. A major contribution of the group has
been to highlight the function of LAP (LRR and PDZ domain) proteins in the establishment of epithelial cell
polarity. Another line of research has been initiated on the role of VPS proteins in endocytosis during development
and the relationships between endocytosis and autophagy. The scientific production could have been better.
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However, this probably reflects an extended lag phase required to set up the group, to establish the relevant
systems and to develop two related, but different lines of research. A promising point is that the group has
initiated a siRNA-based functional screen to identify genes regulating cell polarity in C. elegans. This could
provide the group with a more global view of this interesting, large biological question and put it in a privileged
position for the future. Depending on the limited resources available, the enthusiastic PI might be encouraged to
concentrate his forces on one given aspect of research at the present stage while recruiting additional
collaborators to increase the critical mass of his group necessary to investigate these two different lines of
research.
Cell-cell signalling and morphogenesis
This new group became part the CGM relatively recently (in 2005), as part of the CNRS ATIP programme. It
was subsequently joined by a young scientist, and now includes the PI (associate professor), a second associate
professor, one technical assistant and two PhD students (one defence is foreseen in early 2008). The team has
succeeded in attracting reasonable funding in addition to the ATIP financing. The scientific questions addressed by
the team (cell-cell signalling and morphogenesis in ovarian follicle formation in Drosophila) are perfectly in line
with the objectives of the Department of Development at the CGM, and the approaches are well thought out and
designed. The overall quality of the academic activity is good for a recently established group and the ongoing
projects are very promising. The productivity is quite satisfactory, taking into account that the two permanent
scientists in the group are teaching (they are Assistant professors in two different universities). The visit by the
committee confirmed that this group is very dynamic and it is clear that recently completed studies should be
published soon in good journals. The group needs to be reinforced by a post-doctoral researcher, and the team
leader is actively looking for such an addition. Given the recent achievements, and the quality of the projects,
the academic perspectives for the group are very high.
Yeast, a Model for Essential Functions in Eukaryotic Cells
This relatively large group works on both on mitochondrial functions (translation, assembly of protein
complexes, inhibition by drugs) and asymmetric division using yeast (S. cerevisae and/or S. pombe) as model
organisms. It is composed of the PI (DR2 CNRS), 5 tenured scientists (one assistant professor), 3 technical
assistants, and 5 doctoral students and is structured in three relatively independent but closely interacting subgroups. The mitochondrial translation sub-group took an important decision to work on S. pombe, whose
mitochondria are more similar to those of humans compared to S. cerevisae. This has led to interesting
discoveries, including the mitochondrial DNA loss in vitro, mimicking several human genetic diseases. The group
has several collaborators abroad, especially for analysis of patients suffering from mitochondria-related diseases
and interesting data have been obtained on the termination factor Hs-mtRF1a. Biolistic transformation of
mitochondria has been achieved in yeast and in Chlamydomonas, a different model organism, resulting in a high
profile publication. In a second theme a number of proteins important for assembly of mitochondrial respiratory
complexes have been characterised, including homologues of proteins known to be involved in human diseases.
Native gel electrophoresis, used for global analyses of these protein complexes in normal and various mutant
yeasts, was also adapted to study primary cultures from patients suffering from mitochondrial pathologies. A third
part deals with resistance to drugs which target mitochondrial complex III in several pathogens (e.g. Plasmodium
and Pneumocystis). The yeast model has provided a better understanding of the mechanism of resistance by
reproducing some of the mutations affecting cytochrome b. The group is well integrated with regular lab
meetings and rich internal communications. The three subgroups clearly interact well together and with several
groups in France and abroad. This is reflected in the publication record where the CGM laboratory is the main
driver (10 papers) or collaborator (11 papers). The cell cycle work deals with the Ser/Thr kinase Cbk1p initially
discovered by this group. Some unpublished results were presented: in particular the identification of new Cbk1p
mutants showing attenuated phenotypes allowing a clearer dissection of the phenotype (discrimination between
cell polarity and cell division defects, with consequences on mating). This work has not progressed as rapidly as it
could due to logistical problems unrelated to the science resulting in only one publication. Given the strong
competition in the area, the group will close that subject and join the mitochondrial subgroup. The
decision to reorganise the group and eventually to nominate an alternative group leader is fully
supported by the committee.
Regulation of Transcription and Post-Translational Maturation
This group, established some time ago, is interested in protein import into yeast mitochondria, maturation
of mitochondrial c-type cytochromes and structural and functional analysis of heme regulatory protein. The group
leader is clearly a highly competent expert in yeast genetics with a wide understanding of the overall
experimental problems. Unfortunately the group has shrunk dramatically over the past few years to a single
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publishing researcher. Thus, unusual working and publishing strategies have been implemented. Consequently,
except for a publication with a doctoral student (in collaboration with an American group whose PI is the senior
author), the work and publications are made as collaborations with leading european teams in the field of
mitochondria biogenesis. The publication list is excellent both in quantity and quality with a significant number of
world class publications. However, almost all publications are co-authored and the PI has not occupied a position
of leading or senior author on any. On deeper detailed analysis of the contribution of the group to the research
consortium, it appears that the expertise of the group in yeast genetics on mitochondria is undoubtedly a
significant and probably essential contribution to the consortium, although this is difficult to measure precisely. In
view of the unusual structure of this group and an absence of critical mass, the committee suggests that it might
be fused with another CGM group with closely-related research interests. Although it is certainly not reasonable to
inhibit such productive collaborations with foreign laboratories, a better integration within CGM would be positive
and provide a greater benefit for the institute.
Senescence and longevity in Podospora anserina
The group has been studying senescence in the filamentous fungus Podospora anserina for a long period of
time and has acquired a solid reputation in this area. The results obtained have established a tight link between
mitochondrial respiratory chain assembly and longevity in Podospora, leading to the hypothesis that decreased
ATP and/or Reactive Oxygen Species (ROS) production could account for increased life-span in Podospora.
Experiments to test these hypotheses are currently underway. In parallel, taking advantage of genetics and recent
sequencing of the Podospora genome (in which the group was also involved), several suppressors of mitochondrial
defects were analyzed. This has led to the identification of a transcription factor involved in the induction of an
alternative oxidase gene. This is a small group including two University staff (one Professor, the group leader and
an assistant professor), one tenured scientist, a postdoctoral fellow and a graduate student. During the last four
year period, the group has published five research articles in solid international journals and a review (BBA). All
except one are signed by the PI as last author. Importantly this group has obtained a substantial EC grant
(Integrated Project FP6) covering the evaluated period. The experimental model is original and well suited to
genetic analysis. The group has several collaborations which facilitate more detailed biochemical analysis. The
work by this small group might profit from a greater focus on the most original aspects of the subject.
Biogenesis of Bioenergetic Complexes in the Facultative Photosynthetic Proteobacterium, Rubrivivax
gelatinosus
This group studies the interplay between photosynthesis and respiration using a combination of genetics,
biochemistry and biophysics. It is composed of the PI (Professor), an associate professor, 3 tenured scientists, one
of who arrived very recently, 2 technical assistants, a postdoctoral fellow and a graduate student. The PI has
been involved in this area for a number of years. The beta-protobacterium Rubrivivax gelatinosus is an interesting
model system since it is amenable to genetic analysis and can grow both under aerobically (respiration) and
anaerobically in the presence of light (photosynthesis). The major results in the past years have been: isolation
and characterisation of the photochemical reaction center and the demonstration that it is expressed from a large
operon probably acquired from an alpha-proteobacterium; the identification of a second Rieske protein; and
identification of a prokaryote (cbb3) and a mitochondrial type (aa3) oxidase. The group is also analysing the
regulation of the photosynthetic genes and has shown that the transcription regulator PspR, which is a repressor
in the alpha-proteobacteria, has both repressor and activator properties in R. gelatinosus. A related bi-functional
role was also noted for the FnrL regulator which controls respiration (by regulating hemN expression) and
photosynthesis (by regulating both hemN and bchE expression). These phenomena are presumably related to the
capacity of the bacterium to grow both photosynthetically and aerobically and provide the circuitry to respond
rapidly to environmental changes. The group has published moderately well in respected international journals
and is involved in two ANR-financed projects.
Genetics of Cellular Dynamics in Paramecium
This group, composed of the PI (DR2), 3 additional tenured scientists, an emeritus scientist, a technical
assistant and 2 graduate students. It has produced original and exciting research on the genome of Paramecium in
collaboration with the Genoscope and three other French laboratories. The amenity of this organism to RNAi
makes it a potent model for functional studies and solid data on basal body organisation and duplication have
already been obtained using this approach. The results provide a framework for further development of this
organism both in the genomics (gene organisation and expression) and cell biology (composition and function of
cilia) domains. In addition to its contribution to determining the nucleotide sequence of the vegetative
macronucleus and demonstrating the presence of several whole genome duplications, the group has also
constructed an extremely useful and powerful dedicated Paramecium data base which includes features now used
by Flybase. The re-organisation of the team which took place a few years ago has been entirely successful as
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reflected in the excellent publications in top journals. The development of a new genome project aiming at
determining the sequence of the germ line nucleus promises to reveal more exciting features of this organism
with importance for other organisms. New projects on cilia structure and functions are already on-going,
although a clear positioning in this competitive field will be required in the near future. The group has been
successful in attracting financing from several national funding sources.
Programmed Genome Rearrangement: Mechanism and Regulation
This group was initiated recently (2006) in the CGM under the CNRS ATIP programme and is composed of
the PI (CR1), a temporary technical assistant, a postdoctoral fellow and a graduate student. It is developing a
programme to investigate genome re-arrangements during nuclear maturation (the development of the vegetative
macronucleus from the germline micronucleus) in the ciliate Paramecium. Recently this group has obtained
extremely exciting results concerning the excision of specific DNA sequences (the IES, transposable elements and
other repeated sequences) and has identified some of the principle enzymes involved. This offers interesting
perspectives for analysis of the repair of double-strand breaks as many such events take place during, and are an
intimate part of, nuclear development. Despite the small size of the group, several elegant data sets have been
obtained and should give rise to high quality publications. This enthusiastic young team interacts efficiently with
the other Paramecium laboratory of the campus as well as with other collaborators in France and abroad. The
dynamism of the team and its leader holds much promise for the future. This group has been successful in
attracting funding from national sources.
Bacterial Genome Stability
This small group, composed at present of the PI, two graduate students, a postdoc and a technician arrived
in 2006. The research topic concerns the way(s) in which bacteria overcome premature replication fork arrest, a
relatively frequent and potentially lethal event. The PI has made most of the key contributions to understanding
this and has had a major international impact. This has resulted in many invitations to prestigious international
conferences, a series of major publications in excellent journals, the Silver medal of the CNRS and the
Bettencourt Schueller Foundation prize. The work has pinpointed a strong coupling between the replication and
recombination processes in the model bacterium Escherichia coli and has implications both for other bacteria,
archaea and eukaryotes. Present studies are directed at understanding how a replication block induced by binding
of the terminator protein Tus to an ectopic site is processed. In particular, how the repair helicase UvrD is
involved in this by “clearing” Tus and also the RecA protein. In addition, the group is dissecting the role of the
RuvAB motor proteins in reversing and rescuing stalled replication forks. The studies use very powerful and
elegant genetics and, more recently biochemical approaches are being introduced. The group has been successful
in attracting funding from national sources.
Chromosome Segregation and Cell Division
This is a relatively newly formed, energetic and dynamic research group studying novel mechanisms of
chromosome segregation in E. coli and integration of phage genomes into pathogenic strains of Vibrio cholerae. It
is composed of the PI (CR1), a tenured scientist, a technical assistant, two postdoctoral students and 3 graduate
students. The PI was awarded an ATIP and arrived at the CGM during the course of this award. The work ranges
from highly mechanistic studies using exciting single molecule approaches to understand molecular function, to
the elucidation of specific protein and DNA sequences involved in novel recombination pathways. This group is
among internationally recognized leading groups in these areas and is making influential contributions to these
fields, with importance to applied and fundamental studies in these areas. They have been highly productive in
the last four years, publishing several important papers in high-impact journals with admirable participation by all
members of the team. They appear to be in a good position to consolidate and build upon their strengths, and to
continue their excellent work in future publications. This group should be commended for maintaining an
excellent research and publication track record during disruptions caused by building renovations and for their
exciting future research plans and prospects. Potential weaknesses arise in the imminent departure of a few
members of the group, but a recent successful appointment to CR by one of the team members and planned
recruitment of new team members should help to maintain continuity and increase the strength of the group. The
group has been successful in attracting national and European funding (a EMBO young investigator award).
Conformation and dynamics of the E. coli chromosome
This moderate-size group is composed of two scientists (one recruited in 2004), 1 research engineer, 1
post-doctoral fellow, and 4 PhD students (several shared with another group). The scientific interests are twofold: E. coli chromosome dynamics and bacteria-fly interactions. Both subjects are perfectly integrated into the
scientific policy of the CGM, are highly relevant for our fundamental understanding of life while having possible
applications, and have been conducted very efficiently. Quality and productivity are very good with 11
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manuscripts in good to very good journals (including one review) of which 7 were signed by the team leader as
last author. The most notable contribution of the group: the ongoing project on macrodomains, chromosome
dynamics and stability is remarkably original and very promising. The group leader has proposed and established a
new concept of chromosomal organization in E. coli that can be considered as a major contribution. The second
line of investigation (host-pathogen interaction) may decrease in importance in the next four-year period, due to
the departure of the collaborating fly group from CGM. This collaboration was nevertheless very fruitful and its
discontinuation should not hamper the productivity of the group since its first and main project is of exceptional
interest and will be run by a coherent and expert team. The group has been successful in attraction funding from
national sources.
Genome Analysis
This group is composed of the PI (DR2), 5 graduate students and three technical assistants (two of whom
are temporary). It is interested in the global organization and function of eukaryotic genomes. Several themes are
being investigated. These include: an analysis of mutational asymmetries associated with transcription and
replication and the use of the resulting sequence asymmetries to model eukaryotic replication and to detect
replication origins. Analyses have also been carried out to determine gene organization in replication domains and
to understand how replication and transcription might be coordinated. Over the years, this group has evolved
from an experimental group into a purely bioinformatics one. As such, it has developed unique expertise and is
publishing well in specialized journals. Integration with experimental research for validation of computationally
derived hypothesis is very important and although such collaboration is present, it relies on the collaboration with
a single group. Strengthening collaborations within and outside the CGM would be extremely rewarding. The group
has successfully taken up several smaller projects that are not directly associated with the main research
question. These projects were performed largely as a service because the bioinformatic expertise needed is rare
and was lacking in the primary research groups. It is highly likely that the demand for bioinformatic analyses and
solutions will continue to increase, not only at the national and international levels, but also within the CGM. The
committee advises to define a clear institute-wide strategy to address the bioinformatic needs in the near future.
The group has attracted funding from both national and European sources.
Regulation of transcription and ubiquitylation in yeast
This group has a strong historical background in sulfur metabolism and its regulation in yeast. During the
evaluated period, the group has contributed important work on regulation of assembly of the SCFMet30 ubiquitin
ligase complex by a small molecule: cadmium. A very interesting regulation of methionine transport by a
ubiquitin-dependent mechanism has also been revealed. Finally, transcriptional studies have been carried out and
the temporal sequence of coactivator recruitment on the Met4 transcription factor has been established. During
the last four year period, the group has had to deal with a much diminished presence of the group leader who has
been deeply involved in creating a Biotech Company. The main consequence of this was that the group was
managed, on an everyday basis, by a junior scientist. Despite this unusual and difficult situation, the group has
been very productive, both quantitatively and qualitatively, during the period with research publications in
excellent international journals, a review and methods article as well as obtaining several grants. It is composed
of the tenured scientist (CR1) as acting PI, a technical assistant, two postdoctoral fellows and a graduate student
(not including the PI). The experimental model is original. It has proved to be very fruitful and has a great
potential. However, because of the specific situation described above, the structure of the group should be
reconsidered. The junior scientist in charge of the team and who recently obtained a “Young Researcher ANR
grant”, cannot simply inherit this position and must apply in a competitive manner to become a group leader
either in the Institute or elsewhere. The group has been successful in attracting funding from national sources.
Chromatin and Transcription – Repression Mechanism
After a successful post-doctoral training period in the Mellor laboratory at the University of Oxford, the PI
started his independent research at the RNA Department of CGM in October 2005. He started his work with one
PhD student. Later, a technical assistant and three post-doctoral scientists joined his young group. It is composed
of the PI (CR1) three postdoctoral fellows and a graduate student. The PI has initiated a very ambitious research
program to learn about the potential function of non-coding regulatory RNAs in S. cerevisiae. Understanding the
complex world of eukaryotic regulatory RNAs represents a timely and fascinating field of modern molecular
biology. During the past two years, this young group has already demonstrated that silencing of the yeast Ty1
transposon is mediated by a short-lived antisense regulatory RNA. This was a significant contribution to the RNA
regulatory field, since RNA-dependent transcription regulation had not been reported earlier in yeast. More recent
results of the group point to the possibility that non-coding RNAs may play a general regulatory role in yeast gene
expression and at the same time, they also open up novel, attractive directions for the future research. The
outstanding achievements of the laboratory demonstrate that this young group has the capacity to conduct
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internationally highly competitive research. Funding has been obtained from both national and international (a
career development award from the HSFP) sources.
Genetic Regulation in Salmonella and its phages
This small group has been a pioneer in the analysis of prophages gifsy1 and gifsy2 involved in Salmonella
pathogenicity. It is composed of the PI (DR2), a tenured scientist, a technical assistant and a shared graduate
student. Recent, and as yet unpublished, results on the regulation of induction of these prophages indicate a
tiered two-level control mechanism involving an anti-repressor whose expression is regulated by the host SOS
master control protein LexA, which interacts with the phage repressor (GtgR) resulting in induction. This aspect is
now being carried out only as a collaborative effort with other groups. The scientific interest of this team has
shifted over the last four years to the study of gene regulation by small non-coding Salmonella RNAs (ncRNA). This
is supported by ANR funding. This new line of research fits well within the research themes developed within the
RNA Department. Several potential systems have been identified using lacZ fusions which respond to inactivation
of the ncRNA chaperone Hfq. Two well-defined systems are being used to study the molecular mechanisms
whereby small RNAs inhibit gene expression. One of these is a newly identified outer membrane protein, OmpZ.
The genetic and molecular biology approaches employed in this project are relatively standard and well-mastered
by the investigators. They should therefore produce solid results. This research could, however, be more
ambitious in its goals and innovative in its approaches, for example by combining the strong genetic approaches
with in vitro biochemical methods. Considering the small size of the team, the productivity is good. The group has
recently received a grant from the ANR.
RNA metabolism in eukaryotes
This team consists of 4 permanent scientists and one doctoral student. Its main lines of investigation are: I.
Structural-functional studies of a particular class of RNA helicases. II. Regulation of splicing of the tropomyosin
gene. III. Mechanisms underlying splicing misregulation in myotonic dystrophy type I disease. Project I is carried
out in collaboration with a foreign team by one scientist and the productivity is regular. The methodologies used
in projects II and III are mostly the purification of RNA-binding proteins, their characterization by mass
spectrometry and their functional analysis using transient transfection and RNAi in cultured cells. Project II is
carried out by two scientists and the group leader and has given rise to two good quality publications in the 4-year
period, one of which is from the thesis project of a PhD student. The productivity of this project is satisfactory
but it is not clear that it will be more successful in the future and its discontinuation should be considered.
Project III has been initiated recently within the frame of a national network involving 6 teams. It has great
potential in contributing to the understanding of a human genetic disease. The project is therefore potentially
very competitive although only a single doctoral student is involved at present. Reorientation of the activity of
the team within the framework of a collaborative project would undoubtedly be a good strategy to increase the
research output and visibility. A larger proportion of the work force of the lab should be allocated to attain the
critical mass required for a competitive scientific production. Significant progress would be facilitated by the use
of more diverse experimental approaches to circumvent the pitfalls of the biochemical strategy used. The
biochemical expertise of the team would be better exploited through internal and/or external collaborations than
by remaining isolated. Furthermore, a more active involvement of the staff scientists in the supervision of young
scientists is recommended. The group has attracted funding from the French AFM.
RNA, Informational Molecule and Tools
This is a highly productive established group, composed of the PI (DR2), a tenured scientist, a technical
assistant, 1 postdoctoral fellow, and 3 graduate students. The group is studying mRNP assembly, mRNA export and
the production, degradation and function of interesting examples of the plethora of non-coding RNAs produced in
the genome of eukaryotes. The team is highly collaborative and interactive both within the CGM and without,
with work focusing on highly original and interesting mechanisms of gene control. They have an excellent track
record of publications over the last four years with several influential papers in high-impact journals. This group is
among the international leaders in this area of research, both in terms of quality of output and the originality of
the concepts arising from their work and being put forth in their publications. The study of non-coding RNA
function is an emerging area of research that is growing very rapidly, and one that shows considerable promise for
future discoveries in gene and genome control. This group is well placed to capitalize on their pioneering work in
this field and the challenge now is to maintain or even accelerate their pace of discovery to stay ahead of the
large numbers of researchers world-wide who are turning their efforts to this area. Overall they should be
commended for their excellent output and for maintaining exciting and original lines of inquiry. Unfortunately for
the CGM and for this group in particular, some of the other excellent groups who clearly interacted or synergized
with this group will be leaving shortly. This group will undoubtedly be a central pillar in the rebuilding of the
department and hopefully an equally interactive and supportive group for the inspiration and development of
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younger group leaders who have recently entered the CGM. The group has had great success in attracting grants
to support their work from a variety of national and international sources.
Structure, Function and Evolution of Structured RNA
This group is composed of the PI (DR1), three tenured scientists (one of whom has recently received
funding from the CNRS ATIP programme), an associate professor and two graduate students. It has made
significant contributions in the past to the identification and analysis of group II introns. It is now composed of
several sub-teams that have had different levels of success. One main discovery is the identification of an internal
ribosome entry site localised downstream of the start codon in the HIV2 gag RNA sequence, with an extensive
characterisation at the structural level and a comparative analysis with RNAs from the same group of viruses. The
leader of this sub-team has recently had the opportunity to establish his own group and is leaving the laboratory.
The core work of the group remains the analysis of the structure and mechanism of group II intron mobility. This
has proved difficult but progress has been made in understanding the role of divalent metal ions in the folding and
catalytic processes and in the phylogenic relationships between group II introns from different species. The third
aspect of this group is the study of the genes which have “coevolved” with the dam gene in E. coli and role of
DAM methylation in the E. coli cell cycle. This is an area in which very little is known and the sub-team has
obtained some potentially interesting (unpublished) results on the link between cell division and initiation of
replication. It has been successful in attracting national funding.
Splicing and Degradation of Eukaryotic mRNAs
This highly productive group is composed of the PI (DR1), 3 tenured scientists, an associate professor, an
emeritus professor, 4 technical assistants (three financed by the EU), 3 postdoctoral fellows, and 3 graduate
students. One of the tenured scientists has recently been awarded funding in the CNRS ATIP programme to create
an independent group. During the past years, this group has provided a major driving force for the scientific
community of the CGM. As recognition of its important scientific the contributions, the group leader was recently
awarded the silver medal of the CNRS. This is a large group in which many members are financed from outside
resources, an indication of the capacity of the group leader to attract funding. The distinguished record of
important and solid contributions made by this laboratory has contributed significantly to the international
visibility of CGM. The major scientific interest of the group is in understanding the mechanism of mRNA
degradation that represents an important step of eukaryotic gene expression regulation. During the past four
years, the laboratory provided important insights into the mechanisms of nuclear and cytoplasmic mRNA
degradation. They identified novel cytoplasmic structures, called the P bodies, which provide the cytoplasmic
place for most mRNA decay processes in human cells. They identified human Caf1 and Pop2 as active
deadenylases and showed that Btg2 acts as a general activator of human mRNA deadenylation. In the context of a
collaborative work, the group described a novel polyadenylation/mRNA degradation pathway implicated in a new
quality control mechanism responsible for degradation of aberrant pol II transcripts in yeast nuclei. Finally, they
demonstrated that the Exon Junction Complex plays a crucial role in recognition of aberrant mRNA transcript in
yeast nonsense-mediated decay. The results of the laboratory have been published in top quality scientific
journals. The evaluation committee has no doubt that this research group will provide significant novel insights in
the future. This group has attracted a significant level of external funding. It was announced that the PI will be
moving from the CGM in 2009. The group has been very successful in attracting funding from national, European
(EU, ESF) and international (HFSP) sources.
Selenoprotein Synthesis and Regulation in Mammals
This group arrived towards the end of 2007 with funding from the CNRS ATIP programme. It is composed of
the PI (CR1) and a graduate student. From the information made available to the committee, it appears clear that
the ongoing installation of this research group at the CGM can be viewed as a new start, and the committee
certainly supports this view. The PI has initiated projects to investigate the hypothesis that there is an intimate
relationship between the recoding machinery which results in Selenocysteine insertion and that of translation
termination using an siRNA approach to determine the role of a variety of translation factors. Different healthy
and cancerous mammalian cell models will be explored. It is also proposed to couple these studies to a
transcriptome analysis. As a newly established group, thus with limited resources, special attention must be paid
to the management of the research projects. The idea of an ongoing collaboration with an established American
research team, with which strong links already exist, is certainly a good one, in view of the limited resources in
such a starting group. However, it will be necessary to have projects in which the group will have the leadership,
in order to establish itself. Within this frame, it appeared clear to the committee that targeted projects should be
prioritized over more wide-scope projects, at least for the coming years. In conclusion, this research group is
really kicking off, and as such, is rather fragile, so that special attention and support should be given to it in order
to make this operation a success.
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Membrane Protein Engineering
This long established group composes the Biotechnology department of the CGM. The PI has many close
links with French industry and has been involved in some important developments. The major contribution of this
group has been the assembly of reaction pathways for steroid synthesis in yeast. This has been continued over a
period of more than 15 years and has resulted in patents (prior to the present reporting period) and an important
high profile article. The PI is clearly creative and has an abundance of projects in various stages of advancement
and on a variety of topics. There appears to be little scientific contact or dialogue with other members of the
institute and, in the absence of foreseeable further additions of groups to this department, the articulation of this
group within the CGM is unclear. This group probably needs a more appropriate support structure. It has a solid
publication record over this period and has one patent. It is well financed principally from industrial sources but
also by the EU and national programmes.
Bioinfome: Bioinformatics for Transcriptome and Proteome
This group is located close to the micro-array platform of the campus that specializes in the analysis of
transcriptomes from various species. It performs the statistical analyses of the data resulting from the
experiments of the platform and is implicated in the design of the experiments. In addition, the group performs
research in the field of transcriptome analysis, with the development, among other things, of tools for the
statistical analysis of DNA chip data and the analysis of scanner images. This activity has resulted in six
publications, including two in Bioinformatics for which the group is solely responsible. The scientific productivity
can thus be seen as good given that the group includes three university professors and lecturers that have
important teaching loads. The feeling of the reviewers is that even though the research in the past four years
period has been good and relevant to the activities of the platform, there is a danger of obsolescence.
Indeed, transcriptome analysis or the study of the genome-wide location of proteins by micro-arrays will almost
certainly be replaced, except in specific cases, by technologies involving high throughput sequencing. Thus,
instead of pursuing the development of methodologies aiming at the improvement of the analysis of micro-array
data, the group should probably direct its efforts towards these new technologies. Important decisions have to be
made in coordination with the CGM and the Gif Campus in the next year to retain the relevance of the research.
5 z Appreciation of resources and of the life of the research
unit
At present, the CGM is composed of 73 tenured scientists (57 researchers and 16 university faculty members with
significant teaching responsibilities), 44 graduate students, 30 postdoctoral fellows, 51 research assistants and 15
other contractual personnel including central services and administrative staff. It has directly recruited 8 tenured
scientists over this reporting period in addition to those arriving from elsewhere with tenured positions. The CGM
now has a strong non-francophone component, which is an indication of its dynamism and attractiveness. This also
creates an important international flavour to the CGM. There has been a major increase in the number of
postdoctoral fellows principally as a result of ANR funding but also an important increase in the number of
graduate students over the reporting period.
A clear strength of the CGM over the past few years has been its ability to attract a number of young energetic
group leaders: 5 of these were accompanied by finance from the CNRS ATIP programme for young scientists. The
contribution of these groups to the CGM is globally excellent. Another is leaving to take up an ATIP position in
another location as is required by this programme. Young group leaders have also been awarded a number of
prizes including two from the Fondation Bettencourt-Schueller, two CNRS silver medals and one EMBO young
investigator award. At the other end of the age spectrum, the Center has managed to retain several retired
members of its scientific staff in emeritus positions. These scientists continue to make real contributions to the
Center. The general disappearance of such senior scientists in the European system compared to the USA
represents a significant loss of potential and of past investment and reduces European competitivity.
The CGM has also shown significant success in attracting external funding. Twenty-one ANR grants were obtained
during this reporting period with a success rate of nearly 50%, significantly higher than the national average.
There has also been an equally important input from funding by charitable foundations. This capacity to attract
funding has coincided with gradual erosion in institutional funding which should be closely monitored by the CNRS
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since a continuation of this trend will significantly reduce competivity of the unit as a whole. A large proportion
of Institutional funding has been used in essential building renovations.
Although this was certainly a wise decision to reduce the number of departments in the CGM, at the present time
the RNA department will be temporarily weakened by the probable departure of one of the major groups and the
Functional Genomics and Biotechnology department has not significantly evolved and still accommodates only
one group. The Developmental Biology department has also been severely reduced by the departure of three
teams. Restructuring is an ongoing and evolving process. It must take into account mobility of constituent groups,
the arrival of new groups and retirement of various personnel. The number of academic staff has remained
remarkably constant over this reporting period. The departure of several groups and the arrival of others have
created the possibility to better define the contours of the departments. For example, several of the newly
arrived groups study genome stability in various organisms and these would form a nucleus for a new department.
Some reduction of the contour of the institute around its more coherent aspects could also facilitate the overall
organisation. Several possible changes in contour are under discussion while waiting for the nomination of a new
director.
Discussion with tenured staff, technical and administrative staff, postdoctoral and doctoral students was
revealing. This indicated a large degree of cohesion and interaction within these groups and a general
contentment in the way in which the Institute functions at “ground level”. However, the increase in research staff
(the number of postdoctoral fellows and PhD students has increased by factors of 3 and 2 respectively without a
concomitant increase in technical support staff) is placing a strain on the general services of the CGM. One major
hindrance to the daily life of the CGM was generally felt to be its geographic dispersion and the necessity for
renovation. It is estimated that only 60% of essential renovations have been accomplished so far. The committee
is aware that the cost of renovations is probably far higher than the construction of new facilities and building
new facilities might be more appropriate for ensuring current and future scientific needs and to comply with
complex evolving health and security regulations.
Finally, one pressing concern within the Center is the nomination of a new Director after the retirement of the
present director at the end of 2008. This has proved problematic and is not related to the attractiveness (or lack)
of the CGM but rather to the present evolutive and therefore uncertain situation of French research resources and
salaries and overall structure. Various possibilities would be to extend the search internationally, to modify the
governance structure by increasing the responsibilities of the department heads or to build a more collegiate
system of direction. The appropriateness of these choices should obviously be discussed by the CGM community in
relation to the proposed restructuring of the Gif campus and in an attempt to facilitate and simplify the work of a
future Director.
6 z Recommendations and advice
— Strong points :
—
o
A clear strength of the CGM over the past few years has been its ability to attract a relatively
large number of young energetic group leaders who are, in turn, attracting bright new recruits.
o
The number of non-francophone researchers is also quite high and helps give an international
flavour.
o
The CGM has also shown significant success in attracting external funding at both the national
and international level.
o
This has also been associated with other types of recognition such as 2 CNRS silver medals, an
EMBO young investigator award, an HSFP award and numerous ATIP attributions.
o
Different groups in the unit have had important international impacts in the area of mRNA
stability, replication, chromosome organisation and segregation, recombination and bacterial
pathogens.
Weak points :
o Institutional funding: There has been a gradual erosion in institutional funding which should be
closely monitored by the CNRS since a continuation of this trend will significantly reduce competivity
of the unit as a whole.
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o Technical and Administrative Staff: The increase in research staff (the number of postdoctoral
fellows and PhD students has increased by factors of 3 and 2 respectively without a concomitant
increase in technical support staff) is placing a strain on the general services of the CGM.
o
The depart of several groups from the CGM has been unfortunate and is some cause for concern.
— Recommendations :
o Renovations: A large proportion of Institutional funding has been used in essential building
renovations. It is estimated that 40% of essential repairs remain to be undertaken. Funding for this
might be integrated into a campus-wide policy. The committee is aware that the cost of renovations
is probably far higher than the construction of new facilities and might be more appropriate for
ensuring current and future scientific needs and to comply with complex evolving health and security
regulations.
o Departmental structure: The departure of several groups and the arrival of others have created
the possibility to better define the contours of the departments. For example, several of the newly
arrived groups study genome stability in various organisms and these would form a nucleus for a new
department. Several possible changes in contour are under discussion while waiting for the
nomination of a new director. Particular points to consider would be:
ƒ
The Developmental Biology department which has been severely reduced by the
departure of three teams has now reached a critical size. Restructuring this
department is now essential.
ƒ
The single group which constitutes the present department of Functional Genomics
and Biotechnology is localised in the Institute de Chimie des Substances Naturelles.
Although this seems a natural thematic choice for this group, the geographical
location does not facilitate interactions with the rest of the CGM. This group
probably needs a more appropriate support structure.
The committee feels that the reflections already taking place represent a constructive point of
departure.
o Governance: Various possibilities for attracting a new director would be to extend the search
internationally, to modify the governance structure by increasing the responsibilities of the
department heads or to build a more collegiate system of direction. Perhaps more responsibilities for
decision-making should be accorded to department heads and individual PIs. If more responsibilities
for decision-making were accorded to department heads and individual PIs, this would capitalize on
the energy and vision of several of the younger staff scientists and give an added value to the
Institute both in terms of reactivity and attractiveness. However, the choice of department chairs
becomes important since they might be required to shoulder significant responsibilities. Junior
tenured staff who are attempting to set up their own groups would not be appropriate in these roles.
The appropriateness of these choices should obviously be discussed by the CGM community in
relation to the proposed restructuring of the Gif campus and in an attempt to facilitate and simplify
the work of a future Director.
o The Gif Campus: Preliminary discussions are underway between the Directors of the different
Institutes on the Gif campus with a view to building a campus-wide organisation and policy. This
should be encouraged since it will certainly increase the strength of the individual units.
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