Molecularbiologyhasuntilnowmainlyfocussedonindividualmolecules,on theirpropertiesasisolatedentitiesorascomplexesinverysimplemodelsystems. However,biologicalmoleculesinlivingsystemsparticipateinverycomplexn- works,includingregulatorynetworksforgeneexpression,intracellularmetabolic networksandbothintra-andintercellularcommunicationnetworks. Suchn- worksareinvolvedinthemaintenance(homeostasis)aswellasthedi?erentiation ofcellularsystemsofwhichwehaveaveryincompleteunderstanding. Nevertheless,theprogressinmolecularbiologyhasmadepossiblethedetailed descriptionofthecomponentsthatconstitutelivingsystems,notablygenesand proteins. Large-scalegenomesequencingmeansthatwecan(atleastinpr- ciple)delineateallmacromolecularcomponentsofagivencellularsystem,and microarrayexperimentsaswellaslarge-scaleproteomicswillsoongiveuslarge amountsofexperimentaldataongeneregulation,molecularinteractionsand cellularnetworks. Thechallengeofthe21stcenturywillbetounderstandhow theseindividualcomponentsintegrateintocomplexsystemsandthefunction andevolutionofthesesystems,thusscalingupfrommolecularbiologytos- temsbiology.
Bycombiningexperimentaldatawithadvancedformaltheories fromcomputerscience,"theformallanguageforbiologicalsystems"tospecify dynamicmodelsofinteractingmolecularentitieswouldbeessentialfor:(i)- derstandingthenormalbehaviourofcellularprocesses,andhowchangesmay a?ecttheprocessesandcausedisease-itmaybepossibletocorrelategenetic propertiesandsymptomsinnewandmoree?cientways,basedonanactual- derstandingofhowvariousprocessesinteract;(ii)providingpredictabilityand ?exibilitytoacademic,pharmaceutical,biotechnologyandmedicalresearchers studyinggeneorproteinfunctions. Inparticular,itmaysavetimebyreducing thenumberofexperimentsneeded,ifinadequatehypothesescanbeexcludedby computersimulation. Inresponsetothecallforpapers39weresubmittedtoCMSB2003. Allthe submittedpaperswerereviewedandtheprogrammecommittee(listedbelow) selected11high-qualitypapersforpublicationinthisvolume. Thecareofthe reviewersandoftheprogrammecommitteemembersinreviewingthepapers wassurelyvaluable. Afurther11paperswereselectedonlyforpresentationat theworkshopinordertostimulatediscussions(anabstractisincluded). AttheworkshopEhudShapiroandMichaelSterngavetwoinvited talks whosetopicsaredescribedinpapersincludedinthisvolume.
Theprogramme committeedecidedtoacceptforpublicationinthisvolumealsosomeposition papers that highlight the research trends in this new ?eld of computational methodsinsystemsbiology. Thereasonisthatbecausethisisthe?rstedition ofaworkshopinthisfast-growing?eldalargeviewofpotentialtopicsofresearch wasconsideredextremelyimportant. Rovereto,December2002 CorradoPriami ProgrammeCommitteeofCMSB 2003 CorradoPriami(Chair),UniversityofTrento(Italy), CharlesAu?ray,CNRS,Villejuif(France), CosimaBaldari,Universit'adiSiena(Italy), AlexanderBockmayr,Universit'eHenriPoincar'e(France), LucaCardelli,MicrosoftResearchCambridge(UK), VincentDanos,Universit'eParisVII(France), PierpaoloDegano,Universitad ' iPisa(Italy), Francois , Fages,INRIA,Rocquencourt(France), DrablosFinn,NorwegianUniversityofScienceandTechnology,Trondheim(N- way), MonikaHeiner,BrandenburgUniversityofTechnologyatCottbus(Germany), InaKoch,UniversityofAppliedSciencesBerlin,(Germany), JohnE.
Ladbury,UniversityCollegeLondon(UK), PatrickLincoln,SRI(USA), SatoruMiyano,UniversityofTokyo(Japan), GordonPlotkin,UniversityofEdinburgh(UK), SimonPlyte,PharmaciaCorporation(Italy), AvivRegev,WeizmannInstituteofScience(Israel), MagaliRoux-Rouqui'e,BSMIPasteurInstitute(France), VincentSchachter,HybrigenicsParis(France), MasaruTomita,KeioUniversity(Japan), AdelindeUhrmacher,UniversityofRostock(Germany), AlfonsoValencia,CNB-CSIC,CentroNacionaldeBiotecnologia(Spain), OlafWolkenhauer,UMIST,Manchester(UK) Local Organizing Committee Corrado Priami, Linda Brodo, Michela de Concini, Debora Schuch da Rosa Machado,andtheUniversityofTrentoEventsandMeetingsO?ce. List ofReferees F. Abascal,N. Chabrier,A. Cimatti,M. Curti,M. D. Devignes,S. Gnesi, J. Guijarro,K. Hafez,E. Klipp,C. Laneve,P. LopezRomero,F. Luccio, R. Marangoni,M. Padron,M. C. Pinotti,R. Rizzi,S. Tini. Acknowledgement TheworkshopwassponsoredandpartiallysupportedbytheUniversityofTrento, ComunediRovereto,APT,andtheEUprojectIST-32072-DEGAS. Table of Contents IInvitedPapers CellsasComputation...1 AmitaiRegevandEhudShapiro FormalModelingofC. elegansDevelopment:AScenario-BasedApproach ...4
Na'aman Kam,David Harel,Hillel Kugler, RamiMarelly, AmirPnueli, E. JaneAlbertHubbard, andMichael J. Stern IIRegularPapers Causal?-CalculusforBiochemicalModelling ...21 Michele Curti,Pierpaolo Degano, andCosima Tatiana Baldari GraphsforCoreMolecularBiology ...34 Vincent Danos and Cosimo Laneve ContributionofComputationalTreeLogic toBiologicalRegulatoryNetworks: ExamplefromPseudomonasAeruginosa...47 SabinePeresandJean-PaulComet ModelingCellularBehaviorwithHybridAutomata: BisimulationandCollapsing...57 Marco Antoniotti, Bhubaneswar Mishra, Carla Piazza, Alberto Policriti, andMarta Simeoni MultiscaleModelingofAlternativeSplicingRegulation...75 Damien Eveillard, Delphine Ropers,Hidde deJong,Christiane Branlant, andAlexanderBockmayr AMethodforEstimatingMetabolicFluxes fromIncompleteIsotopomerInformation...88 JuhoRousu,AriRantanen,HannuMaaheimo, Esa Pitk. anen, KatjaSaarela, andEsko Ukkonen DynamicBayesianNetworkandNonparametricRegression forNonlinearModelingofGeneNetworks fromTimeSeriesGeneExpressionData...104 SunYongKim, SeiyaImoto, andSatoru Miyano VIII Table ofContents DiscreteEventSimulationforaBetterUnderstanding ofMetaboliteChanneling-ASystemTheoreticApproach...1
14 Daniela Degenring,Mathias Rohl, .. andAdelinde M. Uhrmacher MathematicalModelingoftheIn?uenceofRKIP ontheERKSignalingPathway...127 Kwang-HyunCho, Sung-YoungShin, Hyun-WooKim,Olaf Wolkenhauer, Brian McFerran,and WalterKolch AMethodtoIdentifyEssentialEnzymesintheMetabolism: ApplicationtoEscherichia Coli...