Institute of Technology SBML: Systems Biology Markup Language Michael Hucka, Andrew Finney Herbert Sauro, Hamid Bolouri Principal Investigators: John Doyle, Hiroaki Kitano JST/ERATO Kitano Systems Biology Project California Institute of Technology Pasadena, California, USA

Institute of Technology 2 Background and Motivation Problem: –Many software tools, few common exchange formats Difficult to exchange models between different analysis & simulation tools Difficult to take advantage of different tools A Solution (In Principle): –Define a common exchange language Use a simple, well-supported, textual substrate (XML) Add components that reflect the natural conceptual constructs used by modelers in the domain –We propose SBML: Systems Biology Markup Language

Institute of Technology 3 Scope of SBML Domain: biochemical network models S1S1 S2S2 S3S3 X0X0 X1X1 K 1 *X 0 - S 1 *K 2 S 3 /K i V max *S 1 K m +S 1 k 3 *S 2 k 4 *S 2 - k 5 *S 3 k 6 *S 3 k 7 *S 3 *S 1 2 X2X2

Institute of Technology 4 Aspects of SBML SBML is being defined incrementally –SBML Level 1 covers non-spatial biochemical models Intentionally kept simple for maximal compatibility –SBML Level 2 will extend Level 1 with more facilities But after we gain experience with SBML Level 1! Defined in abstract form (UML) + textual descriptions –Used to define XML encoding + XML Schema –But definition itself is independent of XML XML Schema empowers intelligent, extensible tools –Data verification, dynamic user interfaces Users do not write in XML — software tools do!

Institute of Technology 5 A model is described using a list of components: –Beginning of model definition »List of unit definitions (optional) »List of compartments »List of species »List of parameters (optional) »List of rules (optional) »List of reactions –End of model definition Each component has a specific structure Structure of Model Definitions in SBML

Institute of Technology 6 Preliminary Definitions Most elements inherit from a base type: SBase –Provides for annotations & notes on components Type for names: SName –Letters, digits, underscores: “K1”, “CamKII_P286” Formulas are expressed in text string form –“k4 * S5/(1 + k2)”, “hilli(S1, V, S5, h)” –Not MathML

Institute of Technology 7 “Compartment” =Bounded container in which species are located Fields: –name : SName –volume: floating-point number (optional, default = 1) –units: SName (optional) –outside: SName (optional) Example: … …

Institute of Technology 8 “Specie” =Entity (ion, molecule, etc.) that takes part in reactions Fields: –name: SName –compartment: SName –initialAmount: floating-point number –units: SName (optional) –boundaryCondition: boolean (default=“false”) –charge: integer (optional, no default) E.g.: … <specie name=“Glucose_6_p” compartment=“c1” initialAmount=“0.75”/> …

Institute of Technology 9 “Reaction” Fields: –name: SName –reactants: SpecieReference [1..*] –products: SpecieReference [1..*] –kineticLaw: KineticLaw (optional) –reversible: boolean (optional, default = “true”) –fast: boolean (optional, default = “false”) SpecieReference: –specie: SName –stoichiometry: integer (optional, default = “1”) –denominator: integer (optional, default = “1”) KineticLaw: –formula: text string –parameters: Parameter (optional, [0..*]) –timeUnits, substanceUnits: SName (optional)

Institute of Technology 10 “Reaction” Example … … X0X0 S1S1 k 1 *X 0

Institute of Technology 11 “Parameter” and “Rule” Parameter: (either in global list or reaction def.) –name: SName –value: floating-point number –units: SName (optional) Rule: additional constraints outside reaction def. –Possibilities: Algebraic rule Species concentration (scalar or rate of change) Compartment volume (scalar or rate of change) Parameter (set value) <specieConcentrationRule specie=“S2 formula=“k*t”/> <compartmentVolumeRule compartment=“A” type=“rate” formula=“0.10*t”/>

Institute of Technology 12 “UnitDefinition” Allows (a) redefining default units on quantities and (b) defining and naming new unit combinations –Predefined units are SI + 4 additions (liter, gram, dimensionless, item) –Combinations are [10 scale * unit exponent ] [10 scale * unit exponent ] … … …

Institute of Technology 13 Example S1S1 X2X2 X1X1 k 1 *X 0 k 2 *S 1 k 3 *S 1 X0X0

Institute of Technology 14 Example in SBML <specie name=“X0” compartment=“c1” boundaryCondition=“true” initialAmount=“1”/> <specie name=“S1” compartment=“c1” boundaryCondition=“false” initialAmount=“0”/> <specie name=“X1” compartment=“c1” boundaryCondition=“true” initialAmount=“0”/> <specie name=“X2” compartment=“c1” boundaryCondition=“true” initialAmount=“0.23”/>

Institute of Technology 15 Example in SBML <specie name=“X0” compartment=“c1” boundaryCondition=“true” initialAmount=“1”/> <specie name=“S1” compartment=“c1” boundaryCondition=“false” initialAmount=“0”/> <specie name=“X1” compartment=“c1” boundaryCondition=“true” initialAmount=“0”/> <specie name=“X2” compartment=“c1” boundaryCondition=“true” initialAmount=“0.23”/>

Institute of Technology 16 Example in SBML <specie name=“X0” compartment=“c1” boundaryCondition=“true” initialAmount=“1”/> <specie name=“S1” compartment=“c1” boundaryCondition=“false” initialAmount=“0”/> <specie name=“X1” compartment=“c1” boundaryCondition=“true” initialAmount=“0”/> <specie name=“X2” compartment=“c1” boundaryCondition=“true” initialAmount=“0.23”/>

Institute of Technology 17 Example in SBML <specie name=“X0” compartment=“c1” boundaryCondition=“true” initialAmount=“1”/> <specie name=“S1” compartment=“c1” boundaryCondition=“false” initialAmount=“0”/> <specie name=“X1” compartment=“c1” boundaryCondition=“true” initialAmount=“0”/> <specie name=“X2” compartment=“c1” boundaryCondition=“true” initialAmount=“0.23”/>

Institute of Technology 18 Example in SBML...

Institute of Technology 19 Example in SBML

Institute of Technology 20 Brief History of SBML Level 1 Apr. 2000: Proposed during 1st Workshop on Software Platforms for Molecular Biology (Caltech) May 2000: started with review of existing simulators Aug. 2000: First draft proposal issued Sep. 2000: Second draft proposal issued Nov. 2000: Further discussions over mailing list & during 2nd Workshop on Software Platforms (Tokyo) Dec. 2000: Revised version for final comments issued Mar. 2001: Final SBML Level 1 issued

Institute of Technology 21 Acknowlegments Level 1 developed with help from several groups: BioSpiceE-CellStochSim CellML GepasiVirtual Cell DBSolveJarnac Discussions with many people: Dennis Bray, Athel Cornish-Bowden, David Fell, Carl Firth, Warren Hedley, Martin Ginkel, Igor Goryanin, Jay Kaserger, Andreas Kremling, Nicolas Le Novere, Les Loew, Daniel Lucio, Pedro Mendes, Eric Mjolsness, Melanie Nelson, James Schaff, Bruce Shapiro, Tom Shimizu, Hugh Spence, Joerg Stelling, Kouichi Takahashi, Masaru Tomita, John Wagner Funding: Japan Science and Technology Corporation

Institute of Technology 22 We have finalized SBML Level 1 –Publicly available — anyone may use it –We may issue version updates to correct problems But future work will be on SBML Level 2 SBML Level 1 is being used as the common exchange format in the Systems Biology Workbench project The Status of SBML Level 2 Level 3? Level 1

Institute of Technology 23 The Future of SBML Features anticipated in Level 2: –Composition of models –Arrays of components –Connections –Geometry –Database support –Diagram support SBML Level 2 is in development; expect proposal within the year We want your help and input — please contact us and join the “sysbio” mailing list

Institute of Technology 24 Relationships to CellML TM SBML developed independently –Coming from a biochemistry direction –Oriented towards biochemical network models Goals: –Exchange models between simulation/analysis software –Simplicity, functionality –Conceptualization is oriented towards biochemical network models We are engaged in dialogue with CellML group –Bidirectional exchange of ideas –Both groups desire to maintain translatability

Institute of Technology 25 Availability Visit our web site for the SBML Level 1 spec: See our posters! Ask to see our demo of the Systems Biology Workbench! Talk to us!