The ERATO Systems Biology Workbench

1. The ERATO Systems Biology Workbench Hamid Bolouri ERATO Kitano Systems Biology Project California Institute of Technology & University of Hertfordshire, UK Project PIs: Hiroaki Kitano and John Doyle Software development team: Andrew Finney, Michael Hucka, Herbert Sauro Collaborators: Adam Arkin (BioSpice), Dennis Bray (StochSim), Igor Goryanin (DBsolve), Les Loew (VirtualCell), Pedro Mendes (Gepasi), Masaru Tomita (Ecell) Acknowledgements: Mark Borisuk, Eric Mjolsness, Tau-Mu Yi

3. Tool 7 Tool 6 Tool 5 Tool 2 Tool 4 Tool 1 Tool 3 Multistate reactions/stochastic Reaction/Diffusion Optimization Bifurcation analysis Visualization of networks Handle large systems Resource Sharing, Motivation Our goal: provide software infrastructure to enable sharing of simulation software (current and future) and collaboration between developers (and modelers!)

4. Ligand binding Motion +ATT -ATT flagellar motor R +CH 3 MCPs MCPs CW Signal transduction W W P P -CH 3 Motor A A ~ ~ B Y ~ P Z ATP ADP ATP P P B Y i i Example Workbench application: bacterial chemotaxis

8. Late signal from veg2 A-V model v10, April 4th, 2000 cb MVLbAS LiCl GSK-3 endomes  endomes mes  mes g frizzled mic  mic a2 late signal from ~ 7th cleavage micromeres veg1  veg2 mN nN nb a1 Maternal activator n1 mac / veg2  mic Endo-Mes-TXF Endo-only-TXF Zygotic Apical N Mes-TXF N-dependent-TXF Micromere id. factor Serrate Wnt8 A1 ? X t2 & & & & & OR & & & & OR & OR OTX Endo16 Mes Genes Endo- specific Genes Endo-mes Genes View from the genome, cb=cytoplasmic b, nb=nuclear b, mN=maternal N, nN=nuclear N, MVLbAS=maternal vegetally localised b catenin activating system

19. ERATO Systems Biology Workbench: driving principles • Integrate, don’t reinvent! • integrate existing simulators • use standard application integration methods • object oriented, XML, Java and related technologies • Accommodate future tools • minimize need for ad hoc solutions • object oriented, XML, Java and related technologies • XML & API standards for future contributors • Make sure contributors benefit • symmetric plug-in infrastructure • open source code infrastructure software • widen user-base, but protect IPR of contributors

23. Systems Biology Markup Language [SBML] • A common XML format for biochemical networks • Enables exchange of models between simulators • Developed in collaboration with BioSpice, DBsolve, Gepasi, Jarnac, Ecell, StochSim, VirtualCell • Available for public review since Sept 2000 at ftp://ftp.cds.caltech.edu/pub/caltech-erato/sbml/sbml.pdf • Proposed extensions due 2nd Quarter 2001

25. Example workbench plug-in modules • Data filtering and preparation • e.g. image processing, regression, clustering • Database support • e.g. web searching, storage management, translators, conflict resolution • Model description tools • scripts, languages, schematic tools • Model preprocessing • e.g. conserved quantities, redundancy removal • Maths language / maths description support • Equation solvers • e.g. ODE, DAE, PDE, stochastic • Analysis tools • e.g. 2/3/4D graphing, bifurcation, MCA • Optimization and parameter searching

26. Example potential plug-ins from DBsolve • Data filtering and preparation • regression to implicit and explicit algebraic equations • Database support • direct data import from WITT, MPW, KEGG • Model description tools • stoichiometric matrix • Model preprocessing • conserved quantities & redundancy removal • Maths language / maths description support • maths editor • Equation solvers • mixed ODE + NAE, LSODE • Analysis tools • 2D graphing, bifurcation, continuation, all steady states • Optimization and parameter searching • Hooke & Jeeves, Levenburg-Marquardt

27. Systems Biology Workbench - APIs • APIs provided by the Workbench for simulators • Will provide access to a spectrum of current tools • Integration into 3rd party simulators will require: • SBML output • One menu item associated with one external library call • Available Q1 2001 • Lower level APIs for optimization, bifurcation, time-based simulation and data display will follow, Q2 2001 • APIs provided by simulators to plug into Workbench • Existing collaborators • no API conformance, we will interface to given APIs • The minimum requirement: • Either parse SBML, parse equivalent documented format or provide a model construction API • Output some documented numeric format or structure • Future contributors to SBW • Standard API for independent development available Q2 2001

29. Systems Biology Workbench - APIs • APIs provided by the Workbench for simulators • Will provide access to a spectrum of current tools • Integration into 3rd party simulators will require: • SBML output • One menu item associated with one external library call • Available Q1 2001 • Lower level APIs for optimization, bifurcation, time-based simulation and data display will follow, Q2 2001 • APIs provided by simulators to plug into Workbench • Existing collaborators • no API conformance, we will interface to given APIs • The minimum requirement: • Either parse SBML, parse equivalent documented format or provide a model construction API • Output some documented numeric format or structure • Future contributors to SBW • Standard API for independent development available Q2 2001

32. Workbench Development Plan