Section: Overall Objectives

Overall Objectives

This project aims at developing formal methods and experimental settings for understanding the cell machinery and establishing formal paradigms in cell biology. It is based on the vision of cells as machines, biochemical reaction systems as programs, and on the use of concepts and tools from computer science to master the complexity of cell processes. While for the biologist, as well as for the mathematician, the size of the biological networks and the number of elementary interactions constitute a complexity barrier, for the computer scientist the difficulty is not that much in the size of the networks than in the unconventional nature of biochemical computation. Unlike most programs, biochemical reaction systems involve transitions that are stochastic rather than deterministic, continuous-time rather than discrete-time, poorly localized in compartments instead of well-structured in modules, and created by evolution instead of by rational design. It is our belief however that some form of modularity is required by an evolutionary system to survive, and that the elucidation of these modules in biochemical computation is now a key to apply engineering methods in cell biology on a large scale.

Concretely, we keep developping a theory of biochemical computation and a prototype implementation in the Biochemical Abstract Machine BIOCHAM , a modeling and analysis platform for systems biology. The reaction rule-based language used in this system allows us to reason about biochemical reaction networks at different levels of abstraction, in either the stochastic, differential, discrete, logical or hybrid semantics of the reactions. This allows us to develop and apply a variety of static analysis methods, before going to simulations and dynamic analyses, for which we use quantitative temporal logics as a mean to formalize biological properties with imprecise data, constrain model building and calibrate models in high dimension by optimization methods.

A tight integration between dry lab and wet lab efforts is also essential for the success of the project. In collaboration with Pascal Hersen, MSC lab, we contribute to the development of an experimental platform for the closed-loop control of intracellular processes. This platform combines hardware (microfluidic device and microscope), software (cell tracking and model-based predictive control algorithms) and genetically modified living cells. It is used to investigate the possibilities to externalize the control of intracellular processes for systems and synthetic biology applications.

This project addresses fundamental research issues in computer science on the interplay between structure and dynamics in large interaction networks, and on the mixing of continuous and discrete computation. Many static analysis problems of biological networks are NP-hard. The recourse to constraint logic programming (CLP) to model and solve them, is our secret weapon, which probably explains our capability to experiment ideas in computational systems biology in very short time, by implementing them in CLP, integrating them as new components in our modeling platform BIOCHAM , and evaluating them directly on a large scale in systems biology model repositories such as biomodels.net .

The originality of this project also deals with the recourse to advanced micro-fluidic and synthetic biology technologies to perform accurate observations, modifications and real-time control at both single cell and cell population levels. For this to work, collaborations with top international leaders of these techniques have been established and consolidated with student exchange programs, especially in the framework of the Doctorate School “Frontiers in Life Sciences” to which we are affiliated, in addition to “Sciences Mathématiques de Paris-Centre”.