Section: Application Domains
In-silico cell processes
In 2002 , we started a Collaborative Research Initiative ARC CPBIO on “Process Calculi and Biology of Molecular Networks”. By working on well understood biological models, we sought:
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to identify in the family of competitive models coming from the Theory of Concurrency and from Logic Programming (Constraint Logic Programming, Concurrent Constraint languages and their extensions to discrete and continuous time, TCC, HCC), the ingredients of a language for the modular and multi-scale representation of biological processes;
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to provide a series of examples of biomolecular processes transcribed in formal languages, and a set of biological questions of interest about these models;
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to design and apply to these examples formal computational reasoning tools for the simulation, the analysis and the querying of the models.
This work lead us to the design and implementation of the Biochemical Abstract Machine BIOCHAM that has the unique feature of providing formal languages corresponding to different qualitative and quantitative levels of abstraction for, on the one hand, modeling biomolecular interaction diagrams with reaction rules, and on the other hand, modeling the biological properties of the system in temporal logic. This double formalization of both the model and the biological properties of the system at hand has opened several new research avenues on the design and systematic validation of biological models.
In the 6th PCRD STREP project APrIL II (2004-2007) the focus was on probabilistic inductive logic programming for metabolic networks and we developed semi-automatic methods for model completion/revision from temporal logic specification of the system's behavior as observed in biological experiments. In the Network of Excellence REWERSE (2004-2008), the focus was on the application of the new Semantic Web technologies based on rules and constraints to bioinformatics. In this context, we developped type inference and abstract interpretation techniques to relate biological models at different levels of abstraction, providing a formal ground for reusing and combining models available on the web. In the ARC MOCA (2006-2007) on “MOdularity, Compositionality and Abstraction in gene and protein networks”, we studied with our partners the formal links between logical and numerical models of some parts of the cell cycle control, and modular decompositions based on control theory considerations [5] .
Currently, we develop these technologies and apply them to new biological questions which we investigate in partnerships with biologists in three projects. First, the EU STREP project TEMPO (2006-2009) on “temporal genomics for patient tailored chronotherapeutics”, coordinated by Francis Lévi INSERM Villejuif, where, in partnership with Jean Clairambault of the BANG project-team, we develop coupled models of the cell cycle, the circadian cycle and the effect of cytotoxic drugs in cancer therapies using BIOCHAM.
Second, the INRA AgroBi project INSIGHT , coordinated by Eric Reiter INRA Tours, where, in partnership with Frédérique Clément of the SISYPHE project-team, we develop models of FSH and GPCR signaling networks in mammalian cells. This research is now part of the AE REGATE coordinated by F. Clément SISYPHE.
Third, the AE COLAGE coordinated by Hughes Berry of the ALCHEMY project-team before his move to Lyon, with François Taddei, Ariel Lindner, INSERM Paris Necker, Hidde de Jong, Delphine Ropers, IBIS, J.L. Gouzé, and Madalena Chaves, COMORE, where we investigate the possibilities to control and reprogram growth and aging in bacteria E. coli using synthetic biology approaches.Along the same line of research, but in a different context, we collaborate with Pascal Hersen and Samuel Bottani, biophysicists at the Matière and Systèmes complexes lab, CNRS/Paris Diderot University, to design a prototypic platform and develop control software for the real-time control of gene expression in yeast.
