ARC CPBIO
Process Calculi and Biology of Molecular
Networks
Action de
Recherche Coopérative INRIA
http://contraintes.inria.fr/cpbio
Year 2004, 2003, 2002
Genoscope
(contact: Vincent Schächter),
ModBio,
LORIA (contact: Alexander Bockmayr),
PPS,
CNRS (contact: Vincent Danos).
Position
In recent years, Biology clearly began a work of elucidation of
high level biological processes in terms of their biochemical bases at
the molecular scale. It is probably not necessary to describe here the
concrete applications and the perspectives of this research
(acceleration of the development cycle of drugs, new methods of
diagnosis, genic therapies, etc). In the end of the Nineties, the front
of research in Bioinformatics evolved, passing from the analysis of the
genomic sequence to the analysis of various data produced in mass by
technologies known as {\it post-genomic} (expression of ARN and
proteins, SNP and haplotypes, protein-protein interactions, 3D
structures, etc). This effort of disassembling per identification and
measurement of certain characteristics of the elementary components
(genes and proteins) starts to be used as a basis for the opposite
systematic effort: the reconstitution of the biological mechanisms in
which these components exhibit a function.
The complexity of the systems concerned makes everyone agree on the
need for a large parallel work around the symbolic notation of
biological processes and data. This is particularly true in network
biology (metabolic networks, extra and intracellular networks, networks
of genetic regulation) which interests us in this project. To give an
idea, it is estimated that 2.500 of the 10.000 kinds of proteins
present
in a cell concern tasks of information transfer. The scientific
community is still far from having all the keys for this operation, and
the language in which one could draw up the plans of this cellular
machinery remains to be defined.
Many works attempt to model and analyze biological processes. These
studies are structured by various modeling formalisms. Among the
diversity of approaches, our project focuses on process algebras as a
central subject. In 1998, R. Hofestädt (Bonn) and S. Thelen
(Magdeburg) used modified Petri nets for the representation of
metabolic
networks. In 1999, A. Regev and E Shapiro (Weizmann Institute) outlined
a surprising formalization of a cellular signaling pathway (the
RTK/MAPK
cascade) in the Pi-calculus of R. Milner, and showed how to describe
the
molecular "lego" which implements these tasks of communication in a
relatively readable way for the biologist. This reveals that an adapted
Pi-calculus could appear as an excellent tool for the description of
mesoscopic dynamics in biology.
In the requirements for a biological modeling language, an important
point and probably the least well perceived by a public of non computer
scientists, is that the language should allow a compositional or
modular
approach : as descriptions accumulate, and they accumulate very
quickly,
the model must be able to integrate the new data. One of the
consequences is that the model must remain open and must probably be
able to go up and down to a rather fine level of description (for
example molecular). Process calculi in the broad sense are particularly
well adapted to this task. Moreover the work of G. Berry and G. Boudol
on the Chemical Abstract Machine, that is used nowadays as an
intermediate language for process calculi, invoked already explicitly
the chemical metaphor.
More recently, the use of hybrid Petri nets (work of Matsuno et al..)
and of hybrid systems (works of Alur et al., and Ghosh and Tomlin)
appeared in biology. A. Bockmayr and A. Courtois rebuilt models using
hybrid concurrent constraint languages, that make it possible to
combine
discrete interactions and global dynamics with continuous time managed
by systems of differential equations. The impression that came out from
these last models is that the constraint languages with continuous time
provide an interesting framework and reliable algorithms to represent
multiscale dynamical systems.
Objective
The objective of the ARC CPBIO is to push forward a declarative and
compositional approach to a ``language of life''.
By working with the biologists of the ARC on well understood
biological models, we seek :
- to identify in the family of competitive models coming from
Functional Programming (Pi-calculus, Join-calculus and their
derivatives) 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;
- to provide, in close collaboration with biologists, a series of
examples of biomolecular processes transcribed in formal languages,
and a set of biological questions of interest about these
models;
- to design and apply to these examples formal
computational reasoning tools for the simulation, the analysis
and the querying of the models.
Results
The results achieved so far concern :
- on the one hand, our work on the mammalian cell cycle control
after Kohn's diagram, from the design of a core modeling language (M.
Chiaverini, V. Danos and C. Laneve), to the use of symbolic
model
checking methods for querying the temporal properties of the model (N.
Chabrier and F. Fages),
- on the other hand, the multiscale modeling of alternative
splicing regulation (D. Eveillard, D. Ropers, H. de Jong, C.
Branlant and A. Bockmayr).
Publications:
Modelling
and querying interaction networks in the biochemical
abstract machine BIOCHAM by François Fages, Sylvain
Soliman
and Nathalie Chabrier-Rivier. Journal of Biological Physics and
Chemistry 4(2), pp.64-73. October 2004.Preprint available as pdf.
The
Biochemical Abstract Machine BIOCHAM by Nathalie Chabrier,
François Fages and Sylvain Soliman.
Computational Methods in Systems Biology, CMSB'04, Paris, April 2004.
To appear in Lecture Notes in Bio-informatics, Springer-Verlag.
Modeling
and querying biochemical interaction networks, by Nathalie
Chabrier, Marc Chiaverini, Vincent Danos, François Fages. and
Vincent Schächter. Theoretical Computer Science 325:1, pp.25-44.
September 2004.
Multiscale modeling of alternative splicing regulation by
Eveillard,
Damien and Ropers, Delphine and de Jong, Hidde and Branlant, Christiane
and Bockmayr, Alexander. Computational Methods in Systems Biology,
CMSB'03, Rovereto, Italy, February 2003. Springer
LNCS 2602.75-87. © Springer-Verlag.
Symbolic
model checking of biochemical networks, by Nathalie
Chabrier and François Fages.
Computational Methods in Systems Biology, CMSB'03, Rovereto, Italy,
February 2003. Springer
LNCS 2602 149-162. © Springer-Verlag.
A
Core Modeling Language for the Working Molecular Biologist by Marc Chiaverini,
Vincent Danos. November 2002.
Using hybrid concurrent constraint programming to model dynamic
biological systems by Bockmayr, Alexander and Courtois,
Arnaud.
18th International Conference on Logic Programming, ICLP'02,
Copenhagen, July 2002. Springer,
LNCS 2401, 85-99. © Springer-Verlag
Software:
BIOCHAM a programming
environment for modeling biochemical systems, making simulations and
querying the model in temporal logic CTL.
CMBSlib a library of
computational models of biological systems.
Events:
Third International Workshop on Computational
Methods in
Systems Biology CMSB'05, co-located with ETAPS'05, Edinburgh,
Scotland, April 2005.
Second International Workshop on Computational Methods in
Systems Biology CMSB'04, Paris, France, March 2004.
First International Workshop on Computational
Methods in Systems Biology CMSB'03, Rovereto, Italy, March 2003.
Formal
Methods and Biological Reasoning workshop of the 3rd International
Conference on Systems Biology ICSB'02, Stockohlm, December 2002.
Teaching:
Cours de
bio-informatique formelle du Master Parisien de Recherche en
Informatique.