sbml, sbgn and biomodels

SBML, SBGN and BioModels.net

Michael Hucka, Ph.D.Michael Hucka, Ph.D.Senior Research FellowSenior Research Fellow

Co-Director, Biological Network Modeling Co-Director, Biological Network Modeling CenterCenter

California Institute of TechnologyCalifornia Institute of TechnologyPasadena, California, USAPasadena, California, USA

SBML = Systems Biology Markup Language

Computational modeling becoming more prominent (again?)Computational modeling becoming more prominent (again?) Many software tools are available & more are being developedMany software tools are available & more are being developed More papers involve computational modelingMore papers involve computational modeling

Clearly need a Clearly need a common formatcommon format for exchanging models for exchanging models Allows exchange and publication of modelsAllows exchange and publication of models

o Among collaborators, in journals, on web sites, etc.Among collaborators, in journals, on web sites, etc. Removes opportunities for translation errorsRemoves opportunities for translation errors Allows resources to build on each other’s workAllows resources to build on each other’s work Helps the scientific processHelps the scientific process Helps encourage computational modelingHelps encourage computational modeling

SBML project an effort to define and evolve such a formatSBML project an effort to define and evolve such a format

SBML: A Lingua Franca

A machine-readable format for representing computational A machine-readable format for representing computational models of biochemical networksmodels of biochemical networks Defined in UML-like diagrams & XML SchemaDefined in UML-like diagrams & XML Schema

o Primarily targeted at XML, but independent of itPrimarily targeted at XML, but independent of it Intended for software tools, Intended for software tools, not for humansnot for humans Best for exchange—an intersection, not a union, of featuresBest for exchange—an intersection, not a union, of features

o Not intended to replace application’s internal formatNot intended to replace application’s internal format Arose in a multi-group collaboration started in 2000 for the Arose in a multi-group collaboration started in 2000 for the

Kitano Symbiotic Systems project (Doyle & Kitano PIs)Kitano Symbiotic Systems project (Doyle & Kitano PIs) Influenced by metabolic simulation software (e.g., Gepasi)Influenced by metabolic simulation software (e.g., Gepasi) But today is being applied more broadly (e.g., signaling)But today is being applied more broadly (e.g., signaling)

Broad Acceptance of SBML

SBML has become the international de facto standardSBML has become the international de facto standard Supported by over 100 software systemsSupported by over 100 software systems

o SimulatorsSimulatorso DatabasesDatabaseso Analysis toolsAnalysis toolso Editing toolsEditing tools

Supported by several alliancesSupported by several allianceso DARPA Bio-SPICE, IECA, othersDARPA Bio-SPICE, IECA, others

Supported by journalsSupported by journalso ““NatureNature journals and journals and Molecular Systems Molecular Systems

BiologyBiology support submissions involving support submissions involving SBML.”SBML.” [ [NatureNature, p.1, May 5, 2005], p.1, May 5, 2005]

Used in textbooks and university coursesUsed in textbooks and university courses

What Kind of Models?

Chemical reactions translated Chemical reactions translated to computable form:to computable form:

dd[mRNA[mRNAcytcyt]/dt = k]/dt = k11[mRNA[mRNAnucnuc] -] -

(V(Vm2m2[mRNA[mRNAcytcyt])/([mRNA])/([mRNAcytcyt] + K] + Km2m2))

Model can also include:Model can also include: CompartmentsCompartments Additional math formulasAdditional math formulas Discrete eventsDiscrete events

Structure of Models Expressed in SBML

o Beginning of SBML model definitionBeginning of SBML model definition• List of function definitionsList of function definitions• List of unit definitionsList of unit definitions• List of compartment typesList of compartment types• List of molecular species typesList of molecular species types• List of compartmentsList of compartments• List of speciesList of species• List of parametersList of parameters• List of initial assignmentsList of initial assignments• List of rulesList of rules• List of constraintsList of constraints• List of reactionsList of reactions• List of eventsList of events

o End of SBML model definitionEnd of SBML model definition




Molecules,Molecules,ions, etc.ions, etc.




Define locations Define locations where chemical where chemical are co-locatedare co-located




Processes—Processes—reactions,reactions,

translocation,translocation,modification,modification,

etc.etc.




User-definedUser-definedfunctions thatfunctions thatcan be calledcan be calledwithin mathwithin mathexpressionsexpressions




RedefinitionRedefinitionof built-inof built-in

default units,default units,or new unitsor new unitsdefined fromdefined from

base unitsbase units




Math equationsMath equations(for things that(for things that

can’t be expressedcan’t be expressedsimply as simply as reactions)reactions)




Assumptions aboutAssumptions aboutthe values of the values of

system variablessystem variables




DiscontinuousDiscontinuouschanges inchanges in

values of variablesvalues of variables

What Are SBML Levels?

SBML developed in stages or SBML developed in stages or LevelsLevels Level 1:Level 1: mostly basic compartmental modeling mostly basic compartmental modeling Level 2:Level 2: new features (but more complexity), such as: new features (but more complexity), such as:

o MathML instead of text strings for math expressionsMathML instead of text strings for math expressionso Support for user-defined functionsSupport for user-defined functionso Support for conditional eventsSupport for conditional events

Level 3:Level 3: under development; expect modular support for under development; expect modular support foro Multistate speciesMultistate specieso Model composition (submodels)Model composition (submodels)o DiagramsDiagramso Spatial featuresSpatial featureso … … and many moreand many more

Development Process

So far has been informalSo far has been informal Community of tool developers and researchersCommunity of tool developers and researchers

Mailing list: Mailing list: sbml-discuss@[email protected] (250+ people) (250+ people) Annual SBML Forum meeting (around ICSB) (~40 people)Annual SBML Forum meeting (around ICSB) (~40 people) Annual SBML Hackathon (~40 people)Annual SBML Hackathon (~40 people)

SBML Editors: Andrew Finney & Mike HuckaSBML Editors: Andrew Finney & Mike Hucka Reconcile proposals for changesReconcile proposals for changes Write final specificationWrite final specification Organize activities, moderate mailing list, write grants, etc.Organize activities, moderate mailing list, write grants, etc. Lead the “SBML Team”: Ben Bornstein, Bruce Shapiro, Sarah Lead the “SBML Team”: Ben Bornstein, Bruce Shapiro, Sarah

Keating, Ben Kovitz, Akira FunahashiKeating, Ben Kovitz, Akira Funahashi Process being revised this yearProcess being revised this year

http://www.sbw-sbml.org/erato



Software from the SBML Team

Embeddable software library for using SBMLEmbeddable software library for using SBML LibSBMLLibSBML

Interfaces to popular general math environmentsInterfaces to popular general math environments MathSBML (for Mathematica)MathSBML (for Mathematica) SBMLToolbox (for MATLAB)SBMLToolbox (for MATLAB)

Conversion toolsConversion tools KEGG2SBMLKEGG2SBML CellML2SBMLCellML2SBML

Web-based facilitiesWeb-based facilities Validation, visualization, example modelsValidation, visualization, example models

LibSBML

Library for manipulating data in SBML formatLibrary for manipulating data in SBML format An An embeddableembeddable library for application developers library for application developers Reads, writes, validates, converts SBMLReads, writes, validates, converts SBML

Written in portable ISO C and C++Written in portable ISO C and C++ Currently supports Linux, Windows, MacOS XCurrently supports Linux, Windows, MacOS X

APIs forAPIs for C, C++, Java, Lisp, Perl, Python, MATLAB C, C++, Java, Lisp, Perl, Python, MATLAB Fast, with a small runtime memory footprintFast, with a small runtime memory footprint Open-source under LGPL (thus commercial friendly)Open-source under LGPL (thus commercial friendly)

Related Efforts

Some similarity to CellML (Some similarity to CellML (www.cellml.orgwww.cellml.org)) SBML is somewhat closer to rep. used in simulatorsSBML is somewhat closer to rep. used in simulators CellML is somewhat more abstract and broaderCellML is somewhat more abstract and broader

o Based on modular componentsBased on modular components Both SBML and CellML teams are working togetherBoth SBML and CellML teams are working together

o Committed to bringing them closer togetherCommitted to bringing them closer togethero SBML Level 2 adopted features from CellMLSBML Level 2 adopted features from CellML

BioPAX (BioPAX (www.biopax.orgwww.biopax.org)) A common exchange format for databases of pathwaysA common exchange format for databases of pathways SBML & BioPAX are complementary, not competingSBML & BioPAX are complementary, not competing SBML and BioPAX teams working together to define linkages SBML and BioPAX teams working together to define linkages

between SBML and BioPAX representationsbetween SBML and BioPAX representations

Background

Human communication enhanced by diagramsHuman communication enhanced by diagrams No current standard for network diagrams in biologyNo current standard for network diagrams in biology

No consistency between authorsNo consistency between authors No consistency between papersNo consistency between papers No consistency betweenNo consistency between

publicationspublications A standard would be goodA standard would be good

Readers would need toReaders would need tolearn fewer notationslearn fewer notations

Easier to compare diagramsEasier to compare diagrams Could develop software toolsCould develop software tools

Value of Standard Notations

Well known in engineering fieldsWell known in engineering fields E.g.: electronic circuit diagrams,E.g.: electronic circuit diagrams,

UML for softwareUML for software Standardized (e.g., IEEE)Standardized (e.g., IEEE) Taught in textbooksTaught in textbooks Supported by softwareSupported by software

Automated verificationAutomated verification Generation of modelsGeneration of models

Why not apply this lesson, and standardize a notation for Why not apply this lesson, and standardize a notation for cellular networks?cellular networks?

Process Diagram Notation Elements

Kitano et al., Nature Biotech, 23(8):961, 2005

Starting Points: Process Diagram Notation

Systems Biology Graphical Notation

New project to develop a standard notationNew project to develop a standard notation Begun in late 2005 by KitanoBegun in late 2005 by Kitano

Others: Hucka (US), Le Novere (UK)Others: Hucka (US), Le Novere (UK) Borrowing SBML model of developmentBorrowing SBML model of development

Kick off workshop held Feb. 2006Kick off workshop held Feb. 2006o 30 people involved in existing software and notations30 people involved in existing software and notations

Working towards a first proposalWorking towards a first proposal Will introduce a community-based development processWill introduce a community-based development process

Current Directions for SBGN

Integrating Kitano Integrating Kitano Process Diagram NotationProcess Diagram Notation with Kurt with Kurt Kohn’s Kohn’s Molecular Interaction MapMolecular Interaction Map notation notation

SBGN-2 Workshop on Oct. 7, 2006, in Tokyo, JapanSBGN-2 Workshop on Oct. 7, 2006, in Tokyo, Japan 2 days before ICSB 2006 in Yokohama, Japan2 days before ICSB 2006 in Yokohama, Japan

BioModels.net

Background

SBML successful as glueSBML successful as glue Coalescing a communitiy of modelersCoalescing a communitiy of modelers Allowing interchange where none existed beforeAllowing interchange where none existed before

o Between software & researchers at many different levelsBetween software & researchers at many different levels SBML not without problemsSBML not without problems

But that community is committed to working them outBut that community is committed to working them out

Agreement on format opens new possibilities

Can think about answering FAQ:Can think about answering FAQ: ““Is there a database of models somewhere?”Is there a database of models somewhere?”

Discussions with SBML Team (esp. Andrew Finney) and Discussions with SBML Team (esp. Andrew Finney) and Nicolas Le NovNicolas Le Novèère team lead to ideas:re team lead to ideas: Could develop a database using XML technologyCould develop a database using XML technology

o Le NovLe Novèère at EBI had experience alreadyre at EBI had experience already But early realization was that database is not enoughBut early realization was that database is not enough

o Need curate the modelsNeed curate the modelso Need annotate with references to other data sourcesNeed annotate with references to other data sources

Why do the search issues arise?

SBML provides syntaxSBML provides syntax

SBML model doesn’t encode semanticsSBML model doesn’t encode semantics

UnregulatedUnregulated

Low info contentLow info content

BioModels Database: the driving force

The vision: The vision: Free global database of curated & annotated published modelsFree global database of curated & annotated published models

The prerequisites:The prerequisites: Guidelines for curating modelsGuidelines for curating models Controlled vocabulary for computational modelsControlled vocabulary for computational models

SBO

MIRIAM

BMDB

BioModels Database Aims to be the Swiss-Prot of quantitative modelingAims to be the Swiss-Prot of quantitative modeling Stores & serves Stores & serves quantitativequantitative models of biomed. interest models of biomed. interest

Only models described in peer-reviewed scientific literatureOnly models described in peer-reviewed scientific literature Models are Models are curated by humanscurated by humans: computer software checks : computer software checks

syntax, humans check semanticssyntax, humans check semantics Models are simulated to Models are simulated to check correspondence to referencecheck correspondence to reference Model components are Model components are annotatedannotated to improve identification and to improve identification and

retrievalretrieval Accepted in SBML and CellML formats, served in several Accepted in SBML and CellML formats, served in several

(SBML, XPP, CellML, diagram; more coming)(SBML, XPP, CellML, diagram; more coming)

www.ebi.ac.uk/biomodels

Search

Annotation Sources

From Nicolas Le Novère @ EBI

Model Sources

Seeded using small collections (e.g. from sbml.org)Seeded using small collections (e.g. from sbml.org) Now receiving models from Now receiving models from

BioModels Database curatorsBioModels Database curators Individuals from modeling communityIndividuals from modeling community Authors of papersAuthors of papers JWS Online (has links to journals)JWS Online (has links to journals)

Nature/EMBO Nature/EMBO Molecular Systems BiologyMolecular Systems Biology author guidelines author guidelines recommend depositing models into BioModels Databaserecommend depositing models into BioModels Database

MIRIAM

SBO = Systems Biology Ontology Occupy a space currently not filled by other ontologiesOccupy a space currently not filled by other ontologies Primarily for describing rate laws and constituentsPrimarily for describing rate laws and constituents

Classification of rate lawsClassification of rate lawso ““Henri-Michaelis-Menten”, “reversible mass action”, etc.Henri-Michaelis-Menten”, “reversible mass action”, etc.o Each term includes a MathML function defining the rate Each term includes a MathML function defining the rate

expression expression CV for the roles of reaction participantsCV for the roles of reaction participants

o ““substrate”, “catalyst”, “competitive inhibitor”, etc.substrate”, “catalyst”, “competitive inhibitor”, etc. CV for the roles of parameters in quantitative modelsCV for the roles of parameters in quantitative models

o ““Hill coefficient”, etc.Hill coefficient”, etc.

Example of SBO Term in OBO Format

From Nicolas Le Novère @ EBI

sboTerm

Original proposal for links to rate law definitions was Original proposal for links to rate law definitions was discussed at Bio-SPICE Hackathon early in 2005discussed at Bio-SPICE Hackathon early in 2005 Uses RDF inside <annotation> elementsUses RDF inside <annotation> elements

Reception to original was lukewarmReception to original was lukewarm ““Isn’t this like using a sledgehammer to kill a fly? Why don’t Isn’t this like using a sledgehammer to kill a fly? Why don’t

you just have a string attribute?”you just have a string attribute?” Response: Response: new proposalnew proposal for using a single attribute for using a single attribute

Attribute is a URI pointing to an identifier in SBOAttribute is a URI pointing to an identifier in SBO E.g.:E.g.:<kineticLaw <kineticLaw sboTerm=“http://biomodels.net/SBO/SBO#0001354”>sboTerm=“http://biomodels.net/SBO/SBO#0001354”>……

Conclusion

The Funding

NIH (USA) International Joint Research Program of NEDO

(Japan) ERATO Kitano Symbiotic Systems Project (Japan) ERATO-SORST Program of the Japan Science and

Technology Agency (Japan) Ministry of Agriculture (Japan) Ministry of Education, Culture, Sports, Science and

Technology (Japan) BBSRC e-Science Initiative (UK) DARPA IPTO Bio-Computation Program (USA) Air Force Office of Scientific Research (USA) For meetings: MathWorks, TERANODE, Oracle,

AstraZeneca

The People

SBMLSBML John DoyleJohn Doyle Hiroaki KitanoHiroaki Kitano Hamid BolouriHamid Bolouri Herbert SauroHerbert Sauro Andrew FinneyAndrew Finney Mike HuckaMike Hucka Ben BornsteinBen Bornstein Bruce ShapiroBruce Shapiro Ben KovitzBen Kovitz Sarah KeatingSarah Keating Maria SchilstraMaria Schilstra Akira FunahashiAkira Funahashi Akiya JoukarouAkiya Joukarou Dozens of Dozens of

contributors over contributors over several yearsseveral years

SBGNSBGN Hiroaki KitanoHiroaki Kitano Akira FunahashiAkira Funahashi Nicolas Le NovNicolas Le Novereere Mike HuckaMike Hucka

BioModels DatabaseBioModels DatabaseDevelopers:Developers: Nicolas Le NovNicolas Le Novereere Marco DonizelliMarco Donizelli Melanie CourtotMelanie Courtot Lu LiLu Li Arnaud HenryArnaud Henry Camille LaibeCamille Laibe Chen LiChen Li

Curators:Curators: Harish DharuriHarish Dharuri Nicolas Le NovereNicolas Le Novere Lu LiLu Li Bruce ShapiroBruce Shapiro

BioModels.netBioModels.net EMBL-EBI (Le Novere)EMBL-EBI (Le Novere) SBML Team (Hucka)SBML Team (Hucka) KGI (Sauro)KGI (Sauro) SBI (SBI, Japan)SBI (SBI, Japan)

Where to Learn More

SBML: SBML: http://sbml.orghttp://sbml.org SBGN: http://sbgn.orgSBGN: http://sbgn.org BioModels.net: http://biomodels.netBioModels.net: http://biomodels.net

Upcoming:Upcoming: SBML Forum 2006 in Yokohama, Japan, after ICSB 2006SBML Forum 2006 in Yokohama, Japan, after ICSB 2006 SBGN Workshop Oct. 7 before ICSB 2006SBGN Workshop Oct. 7 before ICSB 2006

Thank you!Thank you!


MIRIAM Reference Correspondence

Model must be encoded in a public, standardized, machine-Model must be encoded in a public, standardized, machine-readable format (SBML, CellML, GENESIS, etc)readable format (SBML, CellML, GENESIS, etc)

Model must comply with the encoding formatModel must comply with the encoding format Model must be clearly related to a Model must be clearly related to a singlesingle reference description reference description Encoded model structure must reflect the biological processes Encoded model structure must reflect the biological processes

listed in the reference descriptionlisted in the reference description Model must be instantiated in a simulation: all quantitative Model must be instantiated in a simulation: all quantitative

attributes must be definedattributes must be defined When instantiated, the model must be able to reproduce all When instantiated, the model must be able to reproduce all

results given in the reference description within some results given in the reference description within some tolerance valuetolerance value

MIRIAM: Attribute Annotation

The model must be namedThe model must be named A citation must be providedA citation must be provided

Citation must be complete—a complete citation, a unique id, or Citation must be complete—a complete citation, a unique id, or an unambiguous URLan unambiguous URL

Should permit identifying authors of the modelShould permit identifying authors of the model Name & contact info for the model creators must be providedName & contact info for the model creators must be provided Date and time of creation and last modification should be Date and time of creation and last modification should be

provided. A history is useful but not required.provided. A history is useful but not required. Model must provide precise terms of distribution.Model must provide precise terms of distribution.

MIRIAM does not require “freedom of distribution” nor “no MIRIAM does not require “freedom of distribution” nor “no cost” distributioncost” distribution

MIRIAM: External Resource Annotation

The annotation must unambiguously relate a piece of The annotation must unambiguously relate a piece of knowledge to a model constituentknowledge to a model constituent

The referenced info should be described using a triplet of The referenced info should be described using a triplet of {data type, identifier, qualifier}{data type, identifier, qualifier} The data type should be written as a URI; LSID ok tooThe data type should be written as a URI; LSID ok too Optional qualifiers should refine the link between the model Optional qualifiers should refine the link between the model

constituent and the piece of knowledge; e.g., “has a”, “is version constituent and the piece of knowledge; e.g., “has a”, “is version of”, etc.of”, etc.

SBML Level 2 Version 2 Draft

New data objects: species type, compartment type, constraints, New data objects: species type, compartment type, constraints, initial assignment structures initial assignment structures

Dimensionless unitsDimensionless units Mass units for substance (maybe)Mass units for substance (maybe) Using of reaction id in MathML expressionsUsing of reaction id in MathML expressions Removal of predefined annotation namespacesRemoval of predefined annotation namespaces Removal of offsets field in unit definitionsRemoval of offsets field in unit definitions sboTermsboTerm on on SBaseSBase

Consensus not yet 100%; goal is to finalize in ‘06Consensus not yet 100%; goal is to finalize in ‘06

sbml, sbgn and biomodels

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