BioProMo

The scientific activities of this theme aim to implement, study, intensify and optimize the production of metabolites by microbial or cellular means in bioreactors, with applications in healthcare (monoclonal antibodies, antifungals, antibiotics, human cell secretomes) or energy (bioH2, bioCH4), but also to develop innovative processes for the production of human cells in bioreactors (MSC, immune cells). Understanding and controlling these complex cultures (cell heterogeneity and kinetics, monitoring, control and piloting, breakthrough bioprocesses) form the scientific basis of this theme.

In the healthcare application sector, activities focus on the joint development or technological and methodological consolidation of innovative sensors for on-line monitoring of CHO cell cultures, human immune cells, MSCs and their secretomes. These generic developments will then enable them to be used as tools for monitoring and steering bioreactor cultures. At the same time, the intensification of bioproduction processes is being studied through new culture strategies (culture modes, piloting, separator/bioreactor coupling), notably for (i) the production of specialized metabolites such as antibiotics by Streptomyces, (ii) the synthesis of antifungal compounds by microbial consortia or species isolated from consortia, (iii) the expansion of MSCs and the production of their secretome, (iv) the production of antibodies by CHO cells. In addition, new scientific fields are being explored, such as the study of the coupling of culture conditions (hydrodynamic and biochemical) on the production of characterized secretomes (cytokines, extracellular vesicles, microRNAs) from MSCs. The team's research activities in the field of bioenergy applications aim to produce biomethane by coupling hydrogen production by pure cultures or microbial consortia with biological methanation by hydrogen-trophic methanogens from communities already established in methanization.

The team is interested in methodological developments applied to new systems, integrating the production of new biocatalysts, the characterization of reaction processes and the design of new high-performance, selective processes for obtaining structurally controlled biomolecules. The originality of the approach is to study the biocatalyst, the reaction medium and the process at different scales, combining experimental and numerical methods.

Work on enzymes involves their engineering, production, characterization and immobilization on innovative supports. New experimental methodological couplings are implemented: i) the functionalization of biopolymers by coupled mechanical (extrusion)/enzymatic processes, ii) the functionalization of amino acids by coupled microbial/enzymatic processes, iii) the design of bioactive lipid vectors by a dual approach of enzymatic functionalization and physicochemical formulation, iv) the development of chemo-enzymatic processes to obtain phenolic platform molecules, v) the functionalization of photoactivatable molecules (for photodynamic therapy) and nanoparticles or nanoclusters (silica, chitosan, gold,. .) with entities that specifically target receptors overexpressed on cancer cells and neovessels. At the bioreactor scale, it is particularly interesting to study the impact of the process on the activity and stability of biocatalysts by coupling enzymatic and structural studies. At the biocatalyst scale, enzyme/substrate interactions are studied in molecular models to establish enzyme structure/function relationships. The structure/activity relationships of synthesized molecules are established by a dual experimental and modeling approach. With regard to metal-chelating peptides, functionality (ability to complex a metal ion)/bioactivity (e.g. antioxidant, antimicrobial activity) relationships are further investigated and extrapolated through the study of different biocatalysts, protein resources and metals (e.g. Cu2+) with a view to various applications in nutrition, cosmetics and health.

The objectives are to develop and use advanced numerical approaches integrating the modeling of multi-physical and chemical mechanisms, from the atomic scale to the scale of the bioproduction process, in close interaction with themes 1 and 2.

At the molecular level, the numerical approach developed in connection with enzymatic processes (Theme 2) focuses on the study of solvation of substrates and biocatalysts in reaction media, the selectivity and stability of enzymes, and the prediction of the structure and functions of new enzymes. This scale also provides information for mesoscopic modeling of the solvation of substrates and free or immobilized enzymes in eutectic or organic media.

At intracellular and inter-species levels, metabolic modeling using FBA (Flux Balance Analysis) contributes to a better understanding of these inter-microorganism interactions and the evolution of intracellular flux distribution in CHO cell cultures. These intracellular models can be integrated into multi-scale extra/intra-cellular models, with or without hybridization with AI methods, to ultimately improve optimal control laws for bioreactors, particularly cell culture (CHO, CSM) (digital twins for the bioprocesses studied in theme 1). On a larger scale, hydrodynamic and biokinetic models need to be integrated. For this, an automatic compartmentalization approach is being developed, based on numerical CFD flow simulations. Work on rapid hydrodynamic simulation and the compartmentalization of large bioreactors using AI tools are scientific strategies currently under development.

Finally, on the scale of the entire bioproduction process, the technico-economic and environmental analysis of the various innovative bioproduction technological solutions is carried out upstream of the design of real production lines (MSC expansion or and extracellular vesicle production).