From the genetics of rare diseases to developmental biology, from epigenetics to genome dynamics and from bioinformatics to systems biology, the MMG explores all facets of the discipline through a translational approach that focuses on the patient. The teams are particularly interested in four main families of pathologies:
Within these four departments, 150 researchers, clinicians, engineers, post docs and students seek to improve our knowledge of these diseases by combining the exploration of patient cohorts and pathophysiological models using state-of-the-art technologies within five platforms. Closely associated with the Department of Medical Genetics of the Timone Hospital, the MMG is a joint research unit of Inserm and Aix-Marseille University. Led by Professor Nicolas LEVY, the centre is also one of the founding members of MARCHE, the University Hospital Federation dedicated to rare diseases of children and adolescents, certified by A*MIDEX, AP-HM and AVIESAN.Organisation chart
Diseases of the central nervous system affect hundreds of millions of people worldwide. They are a major public health concern and have a heavy economic and social impact. If neurodegenerative diseases are the most common, epilepsy, autism spectrum disorders or neuroendocrine diseases, which will be studied within the CNS/NET department, affect a large number of families too.
In close connection with the CNS mainly via the hypothalamus, the neuroendocrine system regulates a number of key functions via humoral mechanisms such as reproduction, response to stress, and metabolism, which connect them to more frequent diseases. At the beginning`of tHe guture five-year contract, the CNS/NET department will be composed of two teams requesting labelling by INSERM/AMU: Human Neurogenetics (led by Laurent Villard) and Differentiation and Proliferation of Neuroendocrine Tissues (led by Thierry Brue). Patients will be the starting point of all our projects. In this context, different members of the department have created large cohorts. Molecular diagnostics and search for new genes will be a major focus of the future department across multiple high-throughput sequencing projects. A major effort will also be made for the development of relevant models, which are still lacking in the field of epilepsy, autism spectrum disorders or neuroendocrine diseases. This includes animal models (mice, zebrafish and chickens) but also cellular models, especially specific iPS-derived human cell types or iPS derived from patients' cells. Access to the central nervous system for therapeutic approaches will also be a major focus of the department. The links between the various topics within the department are many. The study of the role of transcription factors is a common theme for the neuroendocrine proliferation/autism spectrum disorders topics. The study of intracellular signalling in CNS/NET diseases is another example, which will benefit from the complementary expertise of different groups. The permanent staff, belonging to the different hospital units involved in the department projects, will also be implicated and encouraged to meet regularly to share expertise and to stimulate new projects.
Team 1: Human Neurogenetics (Laurent VILLARD - DR2 INSERM)
Team 8: Differentiation and Proliferation of Neuroendocrine Tissues (Thierry BRUE - PUPH)
Inherited neuromuscular disorders form a large and heterogeneous group of genetic diseases causing progressive degeneration of the muscles and/or of the motor nerves that control movements. Most NMDs result in chronic long-term disability posing a significant burden to the patients, their families and public health care.
The objective of the NMD department is to combine basic research with the exploration of patients in order to identify the origin and primo-mechanism of diseases of the muscle (muscular dystrophies and rare myopathies) or peripheral nervous system (hereditary sensory and motor neuropathies), improve diagnostic procedures and interpretation, uncover underlying pathophysiological mechanisms and contribute to or launch clinical trials. The NMD department’s research areas cover studies on muscle and nerve structures and physiology, omics, epigenetics, disease modeling, bioinformatics and the development of reference databases for different diseases. All the projects carried by the three teams composing the department (Epigenetics, Chromatin & Disease Modeling; Translational Neuromyology and Bioinformatics and Genetics) rely on a tight network of associated clinicians and hospital services.
Team 5: Epigenetics, Chromatin and Disease Modeling (Frédérique MAGDINIER - DR2 INSERM)
Team 3: Translational Neuromyology (Marc BARTOLI - CR1 CNRS)
Team 6: Bioinformatics and Genetics (Christophe BEROUD - PUPH)
Cardiovascular disease - including heart attacks, congenital heart defects, and many other disorders - is the world’s leading cause of death. Since 2008, the UMR_S910 hosts research labs working to overcome cardiovascular disease. The department “Development and Pathophysiology of the cardiovascular system” will be composed of two teams requesting labeling by INSERM/AMU.
These groups are the two mains French teams working on cardiac biology. They have long-term achievement on cardiac development and a strong connection with several clinicians (cardiologist and pediatric-cardiologist) located at “La Timone” Hospital and another group working on cardiac development located at Luminy (R Kelly). Their researches have contributed to better understand the etiology of specific heart disease, and how to use that information to prevent adult heart disease. They also mapped molecules that direct the development of fetal hearts — unraveling how nature tells a cell to become a heart cell. Finding these molecules has profoundly changed our understanding of congenital heart defects, leading to our discovery of genetic causes of heart disease and paving the way toward preventing these conditions in the future. Importantly, members of this department train tomorrow’s cardiovascular physicians and researchers. Several members teach at the Aix Marseille University, where they train graduate students and postdoctoral fellows.
Team 4: Genetics & Development of Cardiac Defects (Stéphane ZAFFRAN - DR2 INSERM)
Team 7: Physiopathology of Cardiac Development (Michel PUCEAT - DR1 INSERM)
Aging is becoming both a demographic and a socio-economic challenge since it is a major risk factor for the development of age-related morbidities such as cancer, diabetes, cardiovascular disorders and neurodegenerative diseases. On the other hand, cancer is the second most frequent cause of death in the EU-28 developed countries, and the most frequent for people below 65 years of age.
In this context, the novel Aging, Prenylation and Cancer team we propose to create, will bring together several groups with distinct but tightly linked research axes either orientated on aging, cancer and the bioinformatics/systems’ biology implementation of scientific research. The involvement of aberrantly accumulated or activated prenylated proteins (with Farnesyl or Geranyl-geranyl) in genetically determined premature aging syndromes (PS, lipodystrophies, cancer, human physiological and pathological spermatogenesis) will serve as a focus and common denominator of our scientific research strategies. Our department/team substantially contributed to the identification of many PS which share the dysfunction of a prenylated protein, and several other PS have been discovered as being due to activating mutations in genes encoding permanently prenylated proteins of the RAS-MAPK pathways (e.g. in Costello or Noonan syndromes HRAS or K-RAS are mutated). All these lines of evidence underscore the tight links existing among these two intertwined research axes. The expertise of the new group that will join our team in mathematical modeling applied to systems’ biology, represents a novel and very promising research axis that will allow transversal links to be forged with the different groups of the Department, through mutually fostered research projects. The AgiPreC department will be composed of a unique team including 4 inter-connected axes, each of them being led by a recognized PI. It will be composed of 37 persons (not including PhD and Master students) in total, scientists, physicians and pharmacists with a clear ambition of developing therapeutic proofs of concepts to be further developed for clinical applications in rare and more common diseases associated with prenylation defects.
Team 2: Aging, Prenylation and Cancer (Nicolas LEVY - PUPH)
In 2012, Nobel Prize honoured ground-breaking works by Prs Gurdon and Yamanaka on cell plasticity (Gurdon et al., 1958; Takahashi and Yamanaka, 2006). Pr Yamanaka showed that reprogramming of somatic cells can be achieved in human cells by viral transfer of 3 to 4 transcription factors normally expressed in embryonic stem cell and involved in the maintenance of the pluripotent phenotype. The subsequent derivation of pluripotent stem cells called iPSC (induced Pluripotent Stem Cell) opened the door to the elaboration of in vitro models of human diseases. Those new models allow addressing cellular impact of given genetic backgrounds in numerous independent tissues obtained by in vitro differentiation. In the future, it is believed that cell therapies could be based on autologous iPSC derived on demand from the patient himself. Thus, to date, iPSCs represent considerable promise as a novel tool for modeling human disease and for drug discovery thanks to their capacity of self-renewal and differentiation. In this context, UMR_S910, has imported the iPSC technology to address the physiopathology of genetic diseases, its core competency, by taking advantage of its constant collaboration with hospitals to obtain unique samples and accompanying medical records, including from patients with atypical form of diseases. The hiPSCs facility has been founded in 2011 by B. Binetruy and F. Magdinier in order to produce hiPSCs from primary cells from patients affected with genetic diseases explored by the different teams of U910. So far, we have developed and validated hiPSCs clones for at least 8 different rare genetic diseases. Several independent hiPSCs lines are derived for a given patient. At least 10 clones are isolated and maintained for 10 passages for stabilization. To avoid inter clone variability, two clones are selected and fully characterized. In addition, we have reprogrammed non-mutated cells available to all end-users as controls. The HiPSCs facility is now coordinated by F. Magdinier (DR2 INSERM) and involves three persons, Claire El Yazidi (Technician, INSERM), Morgane Thomas (Engineer, AFM contract) and Emilie Pellier (Engineer, AFM contract). The goal of the facility personnel is to perform cell reprogramming, isolation, characterization and quality control of the hiPSCs clones and form users. The facility personnel is also involved in the technological development: adaptation to new techniques of reprogramming, development of Crispr/Cas9 genome editing, optimization of differentiation protocols. The CRISPR/Cas9 technology offers the major interest to study the effects of a given mutation in a homogenous background, representing a powerful complementary approach to the study of patients-derived hiPSCs. The hiPSCs core facility has received several grants, from Association Française contre les Myopathies (AFM), Fondation pour la Recherche M.dicale (FRM) and Fondation Aix Marseille University. The hiPSCs is associated to several research programs led by members of our research unit (AFM, ANR, A*Midex…) and has recently received a label from Aix Marseille University. The goal in the future is to open the facility to external users: training, on-demand reprogramming to external users (academics, Industry), production of differentiated cells for disease modeling, drug screening etc. The rarity of the different syndromes, the close connection with clinicians and center for biological resources and our capacity to handle hiPSCs production, characterization, differentiation and end-user training greatly facilitate the development of in vitro cellular models of rare disease, in particular for the exploration of tissues which are not otherwise accessible. This unique situation gathering clinical management of patients and technological tools availability, led us to set a new facility to make our knowhow available to collaborative laboratories. This structure will render the access to reprogramming technique much easier for scientific community. Our overall goal is to benefit patients and open new perspectives for the exploration of patho-mechanisms of these different diseases, identification of biomarkers and development of therapeutic strategies.
The mission of the Imaging core facility (ICF) applied to the exploration of small animal is to enable research teams of the UMR_S 910 unit to access the most advanced imaging technologies. It contributes to the histological exploration of patient cells as well as animal models and to better understand the rare genetic diseases. The use of equipment is carried out by a common system of online booking. Currently, the core facility is equipped of an ApoTome microscope, an Axiozoom (VM16 fluorescent binocular) for large samples and several epifluorescent microscopes (straight or reverse). The preparation of tissues can also be done using cryostat, vibratome or microtome. All users are trained to use the equipment; no prior imaging experience is necessary.
This platform has been created at mid-2016 by the fusion of an existing transcriptomic platform and new equipment dedicated to Next Generation Sequencing. The missions of this core facility are to provide access to genomics to transcriptomics and epigenomics sequencing and analysis services to the research teams of the Research Unit, as well, in the near future, to projects external to our Research Unit. The aim of this platform is to support and boost the genomics projects developed by the research teams of the Research Unit, by providing scientific and technologic support both at the experimental design and at the analysis/interpretation steps. For this reason, two bioinformaticians dedicated to the analysis and interpretation of the generated data have been recruited. In terms of quality and certification, the platform will try to reach the highest standards, and to obtain the ISO certification.
The platform is placed under the scientific direction of Val.rie Delague, Inserm Research Director (DR2), who will also be the head of the “Pathomechanisms in neuromuscular disorders” group in the “Translational Neuromyology Group” in the new research unit. The staff will be composed of 6 persons, representing 4.5 FTEs: two part-time Research Engineers (50%), three part-time technicians (50%) and two full time Bioinformatician Engineers. The remaining half-time of the staff will be dedicated to research activities in research teams form the Unit.
The services provided by the platform, include next generation sequencing (NGS), Sanger sequencing, qRT-PCR, CGH array and bioinformatics services. Transcriptome by DNA microarray is available, but will progressively be replaced by RNA-Seq. For NGS sequencing, the proposed services are the following: Genomics : whole exome, targeted exome, amplicon sequencing, any DNA-Seq technology which might be developed Transcriptomics : RNA-Seq (whole transcriptome or targeted transcriptome), Epigenomics : ChIP-Seq, High-Throughput bisulfite sequencing Bioinformatics: bioinformatics services will be proposed both in the experimental design and in the analysis and interpretation of the generated data. The analysis will include primary data analysis, but also, if needed, further analysis, such as variant search, CNV search or linkage analysis, depending on the researcher’s needs. The bioinformaticians from the platform will work in close connection with the Bioinformatics team (C. Béroud), in order to implement new analysis tools, which will be developed by this team.
The genomic platform is equipped with :
-Next Generation sequencing
One next generation sequencer NextSeq500, Illumina
One next generation sequencer MiniSeq, Illumina
One next generation sequencer Ion Torrent PGM (Personal Genome Machine), Life Technologies
One Applied Biosystems 3130x Capillary Sanger sequencer
A GeneChip microarray platform (Affymetrix)
Covaris M220 for DNA shearing:
Bioanalyseur 2100 (Agilent Technologies)
Nanodrop ND-1000 spectrophotometer (Thermo Scientific), QuBit fluorimeter (Invitrogen)
LC480 real time PCR system(Roche)
Surescan microarray scanner (Agilent)
Biomek 3000 (Beckman) for automatization of capture, amplicon sequencing and Q-RT-PCR
The Biological resources center, also part of the Department of Medical Genetics & Cell Biology, processes and maintains biological resources from patients with rare genetic diseases and their families. This structure is part of the Network of Biological Resource Centers (CRB) in Marseille and has proved to be an absolutely indispensable tool to develop the various research themes of the research unit (UMR). In the context of a novel laboratory, this CRB will be among the dedicated integrated platforms. This structure is almost entirely dedicated to process, manage and store human samples. It has in charge the DNA extractions from blood samples, generation of white cells from peripheral blood (PBMC), immortalization as lymphoblastoid cell lines (using EBV), management of the collections storage and cession of materials to researchers and/or hospital biologists. In addition, culture of fresh fibroblasts from patients is among its missions and tasks. To date, more than 25 000 patients samples have been processed and secured. Around 50% of these samples correspond to labelled collections for research purposes, i.e to perfectly characterized patients at the clinical level. Particular collections have been set up for neuromuscular disorders, heart disorders, premature aging syndromes and central nervous system, in the main scope of our research lab.
This structure is certified by Inserm and AP-HM
CRB authorisation number by the French ministry of research: AC 2011-1312
Authorization to export and import samples : N°IE-2013-710
In the last years, we established a new organization including a Management Committee, a Strategic
committee which defines the policy, strategy, communication and QMS, and a Scientific Committee which assesses new projects, assesses sample requests and write scientific reports.
Our Institutions have recognized the importance of this CRB as it is open to all AP-HM and university teams working in the field or having needs in the field of genetics and rare diseases with a view to:
1- developing translational research;
2- to valorize the AP-HM resources outside the institution;
3- To increase partnerships with private bodies - start ups - pharmas.
Our efforts, therefore, will go towards better interactions with the institution's media services to recruit and train dedicated staff, to obtain the necessary equipment and to have suitable spaces for implementing our activities. This implementation will be done in interaction with the GIPTIS project of which the CRB will be core component, serving all projects and teams. The scientific and strategic committees are drawing-up a list of thematic research priorities to be addressed to the institutions with the of obtaining the funding necessary for the creation of new sample collections. This project is part of the medical Project for our hospital (AP-HM).
The Biological Resources Center is labelled :