The Lifeware research team

Lifeware is a project-team of Inria, located in the Paris-Rocquencourt research center. Created in January 2014 as a follow-up of the Contraintes project-team which ended in 2013, Lifeware 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 cell as computation, and on the use of concepts and tools from computer science to master the complexity of cell processes.

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. We contribute to the theory of biochemical computation, and develop since 2002 a modelling and analysis platform, the Biochemical Abstract Machine, BIOCHAM. The reaction rule-based language of this system allows us to reason about biochemical reaction networks at different levels of abstraction, in the stochastic, differential, discrete, logical and hybrid semantics of the reactions. We develop a variety of static analysis methods before going to simulations and dynamical analyses. We use quantitative temporal logics as a mean to formalize biological properties with imprecise data and to constrain model building.

A tight integration between dry lab and wet lab efforts is also essential for the success of the project. This is achieved through tight collaborations with biologists. Furthermore, we contribute, in collaboration with Pascal Hersen, MSC lab, 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 liveware (genetically modified living cells). The originality of this project thus also deals with the recourse to advanced microfluidic and synthetic biology technologies to perform accurate observations, modi cations 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 the Doctorate School Sciences Mathématiques de Paris Centre.

Finally, because of the importance of optimization techniques in our research, we keep some activity purely dedicated to optimization problems, in particular on constraint programming methods for computing with partial information systems and solving NP-hard static analysis problems, and on continuous optimization methods for dealing with continuous parameters.


Highlights


PhD Defense of David Fournier

November 27th 2014, University Paris-Diderot

Best student paper prize at CMSB'14, congratulations Pauline !

Pauline Traynard, François Fages, Sylvain Soliman. Trace Simplifications preserving Temporal Logic Formulae with Case Study in a Coupled Model of the Cell Cycle and the Circadian Clock (best student paper award). In CMSB'14: Proceedings of the twelth international conference on Computational Methods in Systems Biology, pages 114-128, Lecture Notes in BioInformatics. Springer-Verlag, 2014.

Exceptional PhD Defense of Xavier Duportet

November 14th 2014, Pasteur Institute

Release of Biocham 3.6

New release of Biocham with new features for hybrid simulation, improved SBML-3 interface and new version of biocham-web

Keynote talk at ECAI'14

Slides (pdf, with videos pptx), see also invited talk at ICDCIT'14:

François Fages. Cells as Machines: towards Deciphering Biochemical Programs in the Cell (Invited Talk). In Proc. 10th International Conference on Distributed Computing and Internet Technology ICDCIT'14, pages 50–67, volume 8337 of Lecture Notes in Computer Science. Springer-Verlag, 2014.

A paper accepted in TCS

François Fages, Steven Gay, Sylvain Soliman. Inferring Reaction Models from Ordinary Differential Equations. Theoretical Computer Science, 2014.

Laureate of the French Academy of Sciences

François Fages is very honoured to receive the Michel Monpetit prize 2014 of the French Academy of Sciences for his contributions to fundamental computer science (unification theory and constraint logic programming) and computational systems biology (modeling of biochemical networks and design and supervision of the implementation of the BIOCHAM software).

A paper accepted in Discrete Applied Mathematics

Steven Gay, François Fages, Thierry Martinez, Sylvain Soliman, Christine Solnon. On the subgraph Epimorphism Problem. Discrete Applied Mathematics, 162:214–228, 2014.

An article in the Bulletin of Mathematical Biology

refining the 10 years old result of C. Soulé on feedback circuits and multistationarity

Sylvain Soliman. A stronger necessary condition for the multistationarity of chemical reaction networks. Bulletin of Mathematical Biology, 75(11):2289–2303, 2013.

HDR defense of Grégory Batt

Grégory Batt brightly defended his ''Habilitation à Diriger des Recherches" (manuscript, slides,)

A paper accepted in PLoS Computational Biology

Szymon Stoma, Alexandre Donzé, François Bertaux, Oded Maler, Grégory Batt. STL-based analysis of TRAIL-induced apoptosis challenges the notion of type I/type II cell line classification. PLoS Computational Biology, 9(5):e1003056, 2013.

PhD Defense of Faten Nabli

July 10th 2013, Univ. Paris-Diderot

Release of Biocham-web in May 2013

Biocham-Web provides you access to the latest version of Biocham as a web service.

A paper accepted at CP 2012

Faten Nabli, François Fages, Thierry Martinez, Sylvain Soliman. A Boolean Model for Enumerating Minimal Siphons and Traps in Petri-nets. In Proceedings of CP'2012, 18th International Conference on Principles and Practice of Constraint Programming, pages 798–814, volume 7514 of Lecture Notes in Computer Science. Springer-Verlag, 2012. [ slides ] [ poster ]

A paper accepted in PNAS

Jannis Uhlendorf, Agnés Miermont, Thierry Delaveau, Gilles Charvin, François Fages and Samuel Bottani, Gregory Batt, Pascal Hersen. Long-term model predictive control of gene expression at the population and single-cell levels. Proceedings of the National Academy of Sciences USA, 109(35):14271–14276, 2012.

A paper accepted in MolSysBiol, with Robert Lefkowitz, Nobel Prize in Chemistry 2012

Domitille Heitzler, Guillaume Durand, Nathalie Gallay, Aurélien Rizk, Seungkirl Ahn, Jihee Kim, Jonathan D. Violin, Laurence Dupuy and Christophe Gauthier, Vincent Piketty, Pascale Crépieux, Anne Poupon, Frédérique Clément, François Fages, Robert J. Lefkowitz, Eric Reiter. Competing G protein-coupled receptor kinases balance G protein and β-arrestin signaling. Molecular Systems Biology, 8(590), 2012.

A paper accepted in Algorithms for Molecular Biology

Sylvain Soliman. Invariants and Other Structural Properties of Biochemical Models as a Constraint Satisfaction Problem. Algorithms for Molecular Biology, 7(15), 2012.

Release of FO-CTL(ℝlin) in January 2012

FO-CTL(ℝlin) is a constraint solver for full First-Order Computation Tree Logic formulae with linear arithmetic over the reals in constrained transition systems (CTS). CTS are transition systems where both states and transitions are described with constraints.

Two papers accepted in TCS

Aurélien Rizk, Grégory Batt, François Fages, Sylvain Soliman. Continuous Valuations of Temporal Logic Specifications with applications to Parameter Optimization and Robustness Measures. Theoretical Computer Science, 412(26):2827–2839, 2011.

Elisabetta De Maria, François Fages, Aurélien Rizk, Sylvain Soliman. Design, Optimization, and Predictions of a Coupled Model of the Cell Cycle, Circadian Clock, DNA Repair System, Irinotecan Metabolism and Exposure Control under Temporal Logic Constraints. Theoretical Computer Science, 412(21):2108–2127, 2011.

A paper accepted at PPDP 2010

Thierry Martinez. Semantics-preserving translations between Linear Concurrent Constraint Programming and Constraint Handling Rules. In Proceedings of PPDP'10, International Conference on Principles and Practice of Declarative Programming, Edinburgh, UK, pages 57–66. ACM, 2010.

Release of Biocham 3 in June 2010

Biocham 3 is now available including a new SBGN graphical editor, new methods for model reduction, parameter optimization and robustness analyses w.r.t. temporal logic specifications.

A paper accepted at ECCB 2010 and in Bioinformatics

Steven Gay, Sylvain Soliman, François Fages. A Graphical Method for Reducing and Relating Models in Systems Biology. Bioinformatics, 26(18):i575–i581, 2010.

A paper accepted at CP 2009

François Fages, Aurélien Rizk. From Model-Checking to Temporal Logic Constraint Solving. In Proceedings of CP'2009, 15th International Conference on Principles and Practice of Constraint Programming, pages 319–334, Lecture Notes in Computer Science. Springer-Verlag, 2009.

A paper accepted in JTB

Sriram Krishnamachari, Sylvain Soliman, François Fages. Dynamics of the interlocked positive feedback loops explaining the robust epigenetic switching in Candida albicans. Journal of Theoretical Biology, 258(1):71–88, 2009.

A paper accepted at ISMB 2009 and in Bioinformatics

Aurélien Rizk, Grégory Batt, François Fages, Sylvain Soliman. A general computational method for robustness analysis with applications to synthetic gene networks. Bioinformatics, 12(25):il69–il78, 2009.

Release of Rules2CP and PKML in April 2009

Rules2CP is a general purpose rule-based modeling language for constraint programming. It aims at making constraint programming technology easier to use by non-programmers, by modeling combinatorial optimization problems with logical rules and elementary data structures. The Packing Knowledge Modeling Language (PKML) is a Rules2CP library dedicated to industrial bin packing problems.

A paper accepted in TCS

François Fages, Aurélien Rizk. On Temporal Logic Constraint Solving for the Analysis of Numerical Data Time series. Theoretical Computer Science, 408(1):55–65, 2008.

A paper in a book chapter

François Fages, Sylvain Soliman. Model Revision from Temporal Logic Properties in Systems Biology. In Probabilistic Inductive Logic Programming, pages 287–304, volume 4911 of Lecture Notes in Computer Science. Springer-Verlag, 2008.

A paper accepted in TCS

François Fages, Sylvain Soliman. Abstract Interpretation and Types for Systems Biology. Theoretical Computer Science, 403(1):52–70, 2008.

Release of CHRat in July 2008

The CHRat language is a modular version of the Constraint Handling Rules language CHR, called CHRat for modular CHR with ask and tell. Any constraint defined in a CHRat component can be reused both in rules and guards in another CHRat component to define new constraint solvers.

Release of Biocham 2.7 in April 2008

Biocham 2.7 releases a powerful parameter search procedure with respect to temporal logic quantitative properties, a stochastic simulator and an inference system for conservation laws.

A paper accepted at FMSB 2008

François Fages, Sylvain Soliman. From reaction models to influence graphs and back: a theorem. In Proceedings of Formal Methods in Systems Biology FMSB'08, Lecture Notes in Computer Science. Springer-Verlag, 2008.

IGEM 2007 foundational research prize

For its first participation to the iGEM 2007 competition organised by the MIT on synthetic biology, the French team with Aurélien Rizk was finalist and won the first prize of foundational research using Biocham.