*News: The Lifeware group has now moved to Inria Saclay - Ile de France*

## The Lifeware research team

Lifeware is a project-team of Inria, located in Saclay - Ecole Polytechnique Campus (formerly in Paris-Rocquencourt until January 2016). Created in January 2014 as a follow-up of the Contraintes project-team, 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.

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.

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 formalise biological behaviours 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, modications 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.

## Highlights

### A paper accepted in Biosystems

Pauline Traynard, Céline Feillet, Sylvain Soliman, Franck Delaunay, François Fages. Model-based Investigation of the Circadian Clock and Cell Cycle Coupling in Mouse Embryonic Fibroblasts: Prediction of RevErb-alpha Up-Regulation during Mitosis. *Biosystems*, 2016.

### A paper accepted at ECCB'16

Pauline Traynard, Adrien Fauré, François Fages, Denis Thieffry. Logical model specification aided by model- checking techniques: application to the mammalian cell cycle regulation. *Bioinformatics*, 32(17):i772-i780, 2016.

### A paper accepted at CMSB'16

François Fages, Thierry Martinez, David Rosenblueth, Sylvain Soliman. Influence Systems vs Reaction Systems. In *CMSB'16: Proceedings of the fourteenth international conference on Computational Methods in Systems Biology*, pages 98–115, volume 9859 of *Lecture Notes in BioInformatics*. Springer-Verlag, 2016.

### PhD Thesis defense of François Bertaux

Wednesday June 15th at Inria Paris.

### A paper accepted in PLoS Computational Biology

A. Llamosi, A.M. Gonzales-Vargas, E. Cinquemani , G. Ferrari-Trecate, P. Hersen, G. Batt. What Population Reveals about Individual Cell Identity: Single-Cell Parameter Estimation of Models of Gene Expression in Yeast. *PLOS Computational Biology*, 9(12), 2016.

### PhD Thesis defense of Pauline Traynard

Tuesday May 10th at ENS.

### PhD Theses season

Artemis Llamosi on Tuesday 15 December and Thierry Martinez on Thursday 17 December will defend their PhD thesis !

### A paper accepted in PLoS ONE

Tai-Yin Chiu, Hui-Ju K. Chiang, Ruei-Yang Huang , Jie-Hong R. Jiang, François Fages. Synthesizing Configurable Biochemical Implementation of Linear Systems from Their Transfer Function Specifications. *PLoS ONE*, 10(9), 2015.

### PhD Defense of Steven Gay

May 26, 2015, University Paris-DIderot.

### A paper accepted in ACM TOMACS

Hui-Ju Chiang, François Fages, Jie-Hong Jiang, Sylvain Soliman. Hybrid Simulations of Heterogeneous Biochemical Models in SBML. *ACM Transactions on Modeling and Computer Simulation (TOMACS)*, 25(2):14:1–14:22, 2015. [ preprint ]

### A paper accepted in Constraints

Faten Nabli, Thierry Martinez, François Fages, Sylvain Soliman. On Enumerating Minimal Siphons in Petri nets using CLP and SAT solvers: Theoretical and Practical Complexity. *Constraints*, 21(2):251–276, 2016. [ preprint ]

### Xavier Duportet laureate of Doctors-Entrepreneurs awards

for his PhageX project, the antibiotics of the future, congrats !!!

### A paper accepted in PLoS Computational Biology

F. Bertaux, S. Stoma, D. Drasdo, G. Batt. Modeling dynamics of cell-to-cell variability in TRAIL-induced apoptosis explains fractional killing and predicts reversible resistance. *PLoS Computational Biology*, 10(10):e1003893, 2014.

### A paper accepted in Algorihms for Molecular Biology

Sylvain Soliman, François Fages, Ovidiu Radulescu. A constraint solving approach to model reduction by tropical equilibration. *Algorithms for Molecular Biology*, 9(24), 2014.

### 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. [ preprint ] [ slides ]

### 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, pptx), see also invited talk paper 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. [ preprint ]

### A paper accepted in TCS

François Fages, Steven Gay, Sylvain Soliman. Inferring Reaction Systems from Ordinary Differential Equations. *Theoretical Computer Science*, 599:64–78, 2015. [ preprint ]

### 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).

Slides (pdf, pptx) and talk in French at College de France.

### 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. [ preprint ]

### HDR defense of Grégory Batt

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

### 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. [ preprint ]

### 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. [ preprint ] [ 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(ℝ_{lin}) in January 2012

FO-CTL(ℝ_{lin}) 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. [ preprint ]

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. [ preprint ]

### 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. [ preprint ]

### 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. [ preprint ]

### 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. [ preprint ]

### 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. [ preprint ]

### 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. [ preprint ]

### A paper accepted in TCS

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

### 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 tutorial paper at SFM 2008

François Fages, Sylvain Soliman. Formal Cell Biology in BIOCHAM. In *8th Int. School on Formal Methods for the Design of Computer, Communication and Software Systems: Computational Systems Biology SFM'08*, pages 54–80, volume 5016 of *Lecture Notes in Computer Science*. Springer-Verlag, 2008. [ preprint ]

### 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. [ preprint ]

### 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.