Complex brain organoid model reproducing the glioblastoma tumor niche and its immune component for the development of personalized medicine
Glioblastoma, responsible for 3,500 annual deaths in France, is an extremely aggressive brain tumor that is resistant to current treatments. Clinical trials in immunotherapy have shown only transient effects, underscoring the importance of understanding resistance mechanisms and developing more targeted therapeutic strategies.
We have developed an innovative model of glioma stem cell invasion in immunocompetent and vascularized brain organoids derived from induced pluripotent stem cells (iPSCs) (Raguin et al., submitted). This model faithfully reproduces the glioblastoma tumor niche, including vascular co-option, reprogramming of microglia into tumor-associated macrophages, and tumor recurrence following radiotherapy.
The aim of this PhD project is to derive a universal brain organoid model for the transfer of glioma cells from patients and lymphocytes to optimize the immunotherapy approach (CAR-T cells).
The project involves creating a universal model of human brain organoids that are immunologically "silent" by suppressing the expression of the HLA class I/II system in iPSCs (CRISPR/CAS9 for the ß2M and CIITA genes). Additionally, it aims to elucidate the mechanisms of immunosuppression induced by irradiation, such as the reprogramming of microglial/macrophage cells and the involvement of senescence. Various approaches to make the tumor microenvironment more conducive to immunotherapy will be explored, including activating the type I interferon pathway through genetic modification or with cGAS/STING pathway agonists. Subsequently, the use of CAR-T cells targeting an antigen overexpressed by glioblastoma cells (CD276/B7-H3) will be studied. This model could be used in personalized medicine by co-cultivating patients' tumor cells, monocytes, and CAR-T cells.
This project offers innovative perspectives for the personalized treatment of glioblastoma via immunotherapy and could represent a major advancement in this therapeutic approach.
Biogas upgrading with an advanced Biorefinery for CO2 conversion
The use of renewable energy sources is a major challenge for the coming decades. One way of meeting the growing demand for energy is to valorize waste. Among the various strategies currently developed, the recovery of biogas from anaerobic digestion plants appears to be a promising approach. Biogas is composed mainly of methane, but also of unused CO2 (around 40%). The project proposed here is to reform biogas using a renewable biohydrogen source to convert the remaining CO2 into pure CH4. We propose to set up a stand-alone advanced biorefinery that will combine photoproduction of hydrogen from waste (e.g.: lactoserum) by the bacterium Rhodobacter capsulatus combined with the CO2 present in the biogas in a biomethanation unit containing a culture of Methanococcus maripaludis, a methanogenic archaea able to produce CH4 from CO2 and H2 only (according to the Sabatier reaction). The aim is to produce CH4 in an energy-efficient and environmentally-friendly way.
Multiplexed whole-body in vivo imaging monitoring of pathogen dissemination and immune responses dynamics in tuberculosis
This thesis is dedicated to set up a multiplexed medical imaging monitoring of pathogen colonization and associated immune responses dynamics at the whole body scale for various infectious diseases. This could provide an innovative and non-invasive tool to better understand dynamics links between immune responses and pathogen distribution throughout the body and potentially provide new biomarkers associated to several diseases. To tackle this issue this thesis would implement such strategy in tuberculosis disease. The main aim is to determine the relationship between Mycobacterium tuberculosis dissemination and associated immune responses across the whole body during the course of tuberculosis infection from early infection to latent or active tuberculosis thanks to innovative multiplexed imaging protocols. The goal of this study is to provide correlations in time and space between local bacterial burden and several immune cell infiltrations (activated macrophages and T lymphocytes subsets) occurring following infection and detected over time by imaging. These findings could then provide, with minimal invasiveness, predictive biomarkers on disease or local granuloma progression and may provide also valuable insight on potential immune targets for future preventive or curative strategies based on modulation of the immune system. To do so, this thesis would take advantage of the preclinical Non-human primate model of tuberculosis developed in France and on our in vivo imaging of pathogens and immune cells expertise in NHPs. Of note, deeper immune cell profiling in samples of interest (imaging guided) will be assessed by spatial or single-cell transcripomic technologies in tissue samples to provide additional readouts on TB pathophysiology and potential treatment efficacy.
Nitrogenase Active Site Assembly: What Distinguishes a Nitrogenase from a Scaffold
The challenges posed by climate change and soil degradation call for urgent solutions to reduce greenhouse gas emissions and reliance on nitrogen fertilizers while ensuring sufficient crop yields to feed a growing global population. A natural solution lies in the use of nitrogenase, a bacterial enzyme capable of converting atmospheric nitrogen into ammonia, which can be directly assimilated by plants. However, the biosynthesis of its metal cofactor, FeMo-co, is a complex process that requires the coordinated action of numerous proteins.
This PhD project aims to streamline this complex process by studying simplified nitrogenase systems found in certain organisms, which use fewer proteins, notably by combining multiple functions into single proteins. By conducting comparative structural and functional studies, we seek to understand how these simplified systems work and how they can be adapted for use in crops like cereals, potentially allowing large-scale cultivation without heavy nitrogen fertilizer use.
This project is a collaboration between leading teams at CEA’s Institute of Structural Biology and CSIC Madrid, specializing in metalloprotein structure-function analysis and the biochemistry and genetics of nitrogenase assembly. The successful candidate will work in a cutting-edge research environment, gaining international experience and valuable skills for a future career in academic research or R&D.
Optimization of gamma radiation detectors for medical imaging. Time-of-flight positron emission tomography
Positron emission tomography (PET) is a nuclear medical imaging technique widely used in oncology and neurobiology.
We're proposing you to contribute to the development of an ambitious, patented technology: ClearMind. This gamma photon detector uses a monolithic PbWO4 crystal, in which Cherenkov and scintillation photons are produced. These optical photons are converted into electrons by a photoelectric layer and multiplied in a MicroChannel plate. The induced electrical signals are amplified by gigahertz amplifiers and digitized by SAMPIC fast acquisition modules. The opposite side of the crystal will be fitted with a matrix of silicon photomultiplier (SiPM).
You will work in an advanced instrumentation laboratory in a particle physics environment .
The first step will be to optimize the "components" of ClearMind detectors, in order to achieve nominal performance. We'll be working on scintillating crystals, optical interfaces, photoelectric layers and associated fast photodetectors, and readout electronics.
We will then characterize the performance of the prototype detectors on our measurement benches.
The data acquired will be interpreted using in-house analysis software written in C++ and/or Python.
Finally, we will compare the physical behavior of our detectors to Monté-Carlo simulation software (Geant4/Gate).
A particular effort will be devoted to the development of ultra-fast scintillating crystals in the context of a European collaboration.