1. SBML, SBGN and BioModels.net Michael Hucka, Ph.D. Senior Research Fellow Co-Director, Biological Network Modeling Center California Institute of Technology Pasadena, California, USA

2. 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 developed  More papers involve computational modeling Clearly need a common format for exchanging models Clearly need a common format for exchanging models  Allows exchange and publication of models o Among collaborators, in journals, on web sites, etc.  Removes opportunities for translation errors  Allows resources to build on each other’s work  Helps the scientific process  Helps encourage computational modeling SBML project an effort to define and evolve such a format SBML project an effort to define and evolve such a format

3. SBML: A Lingua Franca A machine-readable format for representing computational models of biochemical networks A machine-readable format for representing computational models of biochemical networks  Defined in UML-like diagrams & XML Schema o Primarily targeted at XML, but independent of it  Intended for software tools, not for humans  Best for exchange—an intersection, not a union, of features o Not intended to replace application’s internal format Arose in a multi-group collaboration started in 2000 for the Kitano Symbiotic Systems project (Doyle & Kitano PIs) Arose in a multi-group collaboration started in 2000 for the Kitano Symbiotic Systems project (Doyle & Kitano PIs)  Influenced by metabolic simulation software (e.g., Gepasi)  But today is being applied more broadly (e.g., signaling)

4. Broad Acceptance of SBML SBML has become the international de facto standard SBML has become the international de facto standard  Supported by over 100 software systems o Simulators o Databases o Analysis tools o Editing tools  Supported by several alliances o DARPA Bio-SPICE, IECA, others  Supported by journals o “Nature journals and Molecular Systems Biology support submissions involving SBML.” [Nature, p.1, May 5, 2005]  Used in textbooks and university courses

5. What Kind of Models? Chemical reactions translated to computable form: Chemical reactions translated to computable form: d [mRNA cyt ]/dt = k 1 [mRNA nuc ] - (V m2 [mRNA cyt ])/([mRNA cyt ] + K m2 ) (V m2 [mRNA cyt ])/([mRNA cyt ] + K m2 ) Model can also include: Model can also include:  Compartments  Additional math formulas  Discrete events

6. Structure of Models Expressed in SBML o Beginning of SBML model definition List of function definitions List of function definitions List of unit definitions List of unit definitions List of compartment types List of compartment types List of molecular species types List of molecular species types List of compartments List of compartments List of species List of species List of parameters List of parameters List of initial assignments List of initial assignments List of rules List of rules List of constraints List of constraints List of reactions List of reactions List of events List of events o End of SBML model definition

7. Structure of Models Expressed in SBML o Beginning of SBML model definition List of function definitions List of function definitions List of unit definitions List of unit definitions List of compartment types List of compartment types List of molecular species types List of molecular species types List of compartments List of compartments List of species List of species List of parameters List of parameters List of initial assignments List of initial assignments List of rules List of rules List of constraints List of constraints List of reactions List of reactions List of events List of events o End of SBML model definition Molecules, ions, etc. Molecules,

8. Structure of Models Expressed in SBML o Beginning of SBML model definition List of function definitions List of function definitions List of unit definitions List of unit definitions List of compartment types List of compartment types List of molecular species types List of molecular species types List of compartments List of compartments List of species List of species List of parameters List of parameters List of initial assignments List of initial assignments List of rules List of rules List of constraints List of constraints List of reactions List of reactions List of events List of events o End of SBML model definition Define locations where chemical are co-located Define locations where chemical are co-located

9. Structure of Models Expressed in SBML o Beginning of SBML model definition List of function definitions List of function definitions List of unit definitions List of unit definitions List of compartment types List of compartment types List of molecular species types List of molecular species types List of compartments List of compartments List of species List of species List of parameters List of parameters List of initial assignments List of initial assignments List of rules List of rules List of constraints List of constraints List of reactions List of reactions List of events List of events o End of SBML model definition Processes—reactions,translocation,modification,etc.Processes—reactions,translocation,modification,etc.

10. Structure of Models Expressed in SBML o Beginning of SBML model definition List of function definitions List of function definitions List of unit definitions List of unit definitions List of compartment types List of compartment types List of molecular species types List of molecular species types List of compartments List of compartments List of species List of species List of parameters List of parameters List of initial assignments List of initial assignments List of rules List of rules List of constraints List of constraints List of reactions List of reactions List of events List of events o End of SBML model definition User-defined functions that can be called within math expressions

11. Structure of Models Expressed in SBML o Beginning of SBML model definition List of function definitions List of function definitions List of unit definitions List of unit definitions List of compartment types List of compartment types List of molecular species types List of molecular species types List of compartments List of compartments List of species List of species List of parameters List of parameters List of initial assignments List of initial assignments List of rules List of rules List of constraints List of constraints List of reactions List of reactions List of events List of events o End of SBML model definition Redefinition of built-in default units, or new units defined from base units

12. Structure of Models Expressed in SBML o Beginning of SBML model definition List of function definitions List of function definitions List of unit definitions List of unit definitions List of compartment types List of compartment types List of molecular species types List of molecular species types List of compartments List of compartments List of species List of species List of parameters List of parameters List of initial assignments List of initial assignments List of rules List of rules List of constraints List of constraints List of reactions List of reactions List of events List of events o End of SBML model definition Math equations (for things that can’t be expressed simply as reactions) Math equations (for things that can’t be expressed simply as reactions)

13. Structure of Models Expressed in SBML o Beginning of SBML model definition List of function definitions List of function definitions List of unit definitions List of unit definitions List of compartment types List of compartment types List of molecular species types List of molecular species types List of compartments List of compartments List of species List of species List of parameters List of parameters List of initial assignments List of initial assignments List of rules List of rules List of constraints List of constraints List of reactions List of reactions List of events List of events o End of SBML model definition Assumptions about the values of system variables Assumptions about the values of system variables

14. Structure of Models Expressed in SBML o Beginning of SBML model definition List of function definitions List of function definitions List of unit definitions List of unit definitions List of compartment types List of compartment types List of molecular species types List of molecular species types List of compartments List of compartments List of species List of species List of parameters List of parameters List of initial assignments List of initial assignments List of rules List of rules List of constraints List of constraints List of reactions List of reactions List of events List of events o End of SBML model definition Discontinuous changes in values of variables Discontinuous changes in values of variables

15. What Are SBML Levels? SBML developed in stages or Levels SBML developed in stages or Levels  Level 1: mostly basic compartmental modeling  Level 2: new features (but more complexity), such as: o MathML instead of text strings for math expressions o Support for user-defined functions o Support for conditional events  Level 3: under development; expect modular support for o Multistate species o Model composition (submodels) o Diagrams o Spatial features o … and many more

16. Development Process So far has been informal So far has been informal Community of tool developers and researchers Community of tool developers and researchers  Mailing list: sbml-discuss@caltech.edu (250+ people)  Annual SBML Forum meeting (around ICSB) (~40 people)  Annual SBML Hackathon (~40 people) SBML Editors: Andrew Finney & Mike Hucka SBML Editors: Andrew Finney & Mike Hucka  Reconcile proposals for changes  Write final specification  Organize activities, moderate mailing list, write grants, etc.  Lead the “SBML Team”: Ben Bornstein, Bruce Shapiro, Sarah Keating, Ben Kovitz, Akira Funahashi Process being revised this year Process being revised this year

17. Software from the SBML Team Embeddable software library for using SBML Embeddable software library for using SBML  LibSBML Interfaces to popular general math environments Interfaces to popular general math environments  MathSBML (for Mathematica)  SBMLToolbox (for MATLAB) Conversion tools Conversion tools  KEGG2SBML  CellML2SBML Web-based facilities Web-based facilities  Validation, visualization, example models

18. LibSBML Library for manipulating data in SBML format Library for manipulating data in SBML format  An embeddable library for application developers  Reads, writes, validates, converts SBML Written in portable ISO C and C++ Written in portable ISO C and C++  Currently supports Linux, Windows, MacOS X APIs for C, C++, Java, Lisp, Perl, Python, MATLAB APIs for C, C++, Java, Lisp, Perl, Python, MATLAB Fast, with a small runtime memory footprint Fast, with a small runtime memory footprint Open-source under LGPL (thus commercial friendly) Open-source under LGPL (thus commercial friendly)

19. Related Efforts Some similarity to CellML ( www.cellml.org ) Some similarity to CellML ( www.cellml.org )  SBML is somewhat closer to rep. used in simulators  CellML is somewhat more abstract and broader o Based on modular components  Both SBML and CellML teams are working together o Committed to bringing them closer together o SBML Level 2 adopted features from CellML BioPAX ( www.biopax.org ) BioPAX ( www.biopax.org )  A common exchange format for databases of pathways  SBML & BioPAX are complementary, not competing  SBML and BioPAX teams working together to define linkages between SBML and BioPAX representations

20. SBGN

21. Background Human communication enhanced by diagrams Human communication enhanced by diagrams No current standard for network diagrams in biology No current standard for network diagrams in biology  No consistency between authors  No consistency between papers  No consistency between publications A standard would be good A standard would be good  Readers would need to learn fewer notations  Easier to compare diagrams  Could develop software tools

22. Value of Standard Notations Well known in engineering fields Well known in engineering fields  E.g.: electronic circuit diagrams, UML for software Standardized (e.g., IEEE) Standardized (e.g., IEEE) Taught in textbooks Taught in textbooks Supported by software Supported by software  Automated verification  Generation of models Why not apply this lesson, and standardize a notation for cellular networks? Why not apply this lesson, and standardize a notation for cellular networks?

23. Process Diagram Notation Elements Kitano et al., Nature Biotech, 23(8):961, 2005

24. Starting Points: Process Diagram Notation

25. Systems Biology Graphical Notation New project to develop a standard notation New project to develop a standard notation Begun in late 2005 by Kitano Begun in late 2005 by Kitano  Others: Hucka (US), Le Novere (UK) Borrowing SBML model of development Borrowing SBML model of development  Kick off workshop held Feb. 2006 o 30 people involved in existing software and notations  Working towards a first proposal  Will introduce a community-based development process

26. Current Directions for SBGN Integrating Kitano Process Diagram Notation with Kurt Kohn’s Molecular Interaction Map notation Integrating Kitano Process Diagram Notation with Kurt Kohn’s Molecular Interaction Map notation SBGN-2 Workshop on Oct. 7, 2006, in Tokyo, Japan SBGN-2 Workshop on Oct. 7, 2006, in Tokyo, Japan  2 days before ICSB 2006 in Yokohama, Japan

27. BioModels.net

28. Background SBML successful as glue SBML successful as glue  Coalescing a communitiy of modelers  Allowing interchange where none existed before o Between software & researchers at many different levels SBML not without problems SBML not without problems  But that community is committed to working them out

29. Agreement on format opens new possibilities Can think about answering FAQ: Can think about answering FAQ:  “Is there a database of models somewhere?” Discussions with SBML Team (esp. Andrew Finney) and Nicolas Le Nov è re team lead to ideas: Discussions with SBML Team (esp. Andrew Finney) and Nicolas Le Nov è re team lead to ideas:  Could develop a database using XML technology o Le Nov è re at EBI had experience already  But early realization was that database is not enough o Need curate the models o Need annotate with references to other data sources

30. Why do the search issues arise? SBML provides syntax SBML provides syntax SBML model doesn’t encode semantics SBML model doesn’t encode semantics UnregulatedUnregulated Low info content

31. BioModels Database: the driving force The vision: The vision:  Free global database of curated & annotated published models The prerequisites: The prerequisites:  Guidelines for curating models  Controlled vocabulary for computational models SBO MIRIAM BMDB

32. BioModels Database Aims to be the Swiss-Prot of quantitative modeling Aims to be the Swiss-Prot of quantitative modeling Stores & serves quantitative models of biomed. interest Stores & serves quantitative models of biomed. interest  Only models described in peer-reviewed scientific literature Models are curated by humans: computer software checks syntax, humans check semantics Models are curated by humans: computer software checks syntax, humans check semantics Models are simulated to check correspondence to reference Models are simulated to check correspondence to reference Model components are annotated to improve identification and retrieval Model components are annotated to improve identification and retrieval Accepted in SBML and CellML formats, served in several (SBML, XPP, CellML, diagram; more coming) Accepted in SBML and CellML formats, served in several (SBML, XPP, CellML, diagram; more coming)

33. www.ebi.ac.uk/biomodels

34. Search

35. Annotation Sources From Nicolas Le Novère @ EBI

36. 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 curators  Individuals from modeling community  Authors of papers  JWS Online (has links to journals) Nature/EMBO Molecular Systems Biology author guidelines recommend depositing models into BioModels Database Nature/EMBO Molecular Systems Biology author guidelines recommend depositing models into BioModels Database

37. MIRIAM

38. SBO = Systems Biology Ontology Occupy a space currently not filled by other ontologies Occupy a space currently not filled by other ontologies Primarily for describing rate laws and constituents Primarily for describing rate laws and constituents  Classification of rate laws o “Henri-Michaelis-Menten”, “reversible mass action”, etc. o Each term includes a MathML function defining the rate expression  CV for the roles of reaction participants o “substrate”, “catalyst”, “competitive inhibitor”, etc.  CV for the roles of parameters in quantitative models o “Hill coefficient”, etc.

39. Example of SBO Term in OBO Format From Nicolas Le Novère @ EBI

40. sboTerm Original proposal for links to rate law definitions was discussed at Bio-SPICE Hackathon early in 2005 Original proposal for links to rate law definitions was discussed at Bio-SPICE Hackathon early in 2005  Uses RDF inside elements Reception to original was lukewarm Reception to original was lukewarm  “Isn’t this like using a sledgehammer to kill a fly? Why don’t you just have a string attribute?” Response: new proposal for using a single attribute Response: new proposal for using a single attribute  Attribute is a URI pointing to an identifier in SBO  E.g.: …

41. Conclusion

42. 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

43. The People SBML SBML  John Doyle  Hiroaki Kitano  Hamid Bolouri  Herbert Sauro  Andrew Finney  Mike Hucka  Ben Bornstein  Bruce Shapiro  Ben Kovitz  Sarah Keating  Maria Schilstra  Akira Funahashi  Akiya Joukarou  Dozens of contributors over several years SBGN SBGN  Hiroaki Kitano  Akira Funahashi  Nicolas Le Novere  Mike Hucka BioModels Database BioModels DatabaseDevelopers:  Nicolas Le Novere  Marco Donizelli  Melanie Courtot  Lu Li  Arnaud Henry  Camille Laibe  Chen Li Curators:  Harish Dharuri  Nicolas Le Novere  Lu Li  Bruce Shapiro BioModels.net BioModels.net  EMBL-EBI (Le Novere)  SBML Team (Hucka)  KGI (Sauro)  SBI (SBI, Japan)

44. Where to Learn More SBML: http://sbml.org SBML: http://sbml.org SBGN: http://sbgn.org SBGN: http://sbgn.org BioModels.net: http://biomodels.net BioModels.net: http://biomodels.net Upcoming: Upcoming:  SBML Forum 2006 in Yokohama, Japan, after ICSB 2006  SBGN Workshop Oct. 7 before ICSB 2006 Thank you!

46. MIRIAM Reference Correspondence Model must be encoded in a public, standardized, machine- readable format (SBML, CellML, GENESIS, etc) Model must be encoded in a public, standardized, machine- readable format (SBML, CellML, GENESIS, etc) Model must comply with the encoding format Model must comply with the encoding format Model must be clearly related to a single reference description Model must be clearly related to a single reference description Encoded model structure must reflect the biological processes listed in the reference description Encoded model structure must reflect the biological processes listed in the reference description Model must be instantiated in a simulation: all quantitative attributes must be defined Model must be instantiated in a simulation: all quantitative attributes must be defined When instantiated, the model must be able to reproduce all results given in the reference description within some tolerance value When instantiated, the model must be able to reproduce all results given in the reference description within some tolerance value

47. MIRIAM: Attribute Annotation The model must be named The model must be named A citation must be provided A citation must be provided  Citation must be complete—a complete citation, a unique id, or an unambiguous URL  Should permit identifying authors of the model Name & contact info for the model creators must be provided Name & contact info for the model creators must be provided Date and time of creation and last modification should be provided. A history is useful but not required. Date and time of creation and last modification should be 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 cost” distribution

48. MIRIAM: External Resource Annotation The annotation must unambiguously relate a piece of knowledge to a model constituent The annotation must unambiguously relate a piece of knowledge to a model constituent The referenced info should be described using a triplet of {data type, identifier, qualifier} The referenced info should be described using a triplet of {data type, identifier, qualifier}  The data type should be written as a URI; LSID ok too  Optional qualifiers should refine the link between the model constituent and the piece of knowledge; e.g., “has a”, “is version of”, etc.

49. SBML Level 2 Version 2 Draft New data objects: species type, compartment type, constraints, initial assignment structures New data objects: species type, compartment type, constraints, initial assignment structures Dimensionless units Dimensionless units Mass units for substance (maybe) Mass units for substance (maybe) Using of reaction id in MathML expressions Using of reaction id in MathML expressions Removal of predefined annotation namespaces Removal of predefined annotation namespaces Removal of offsets field in unit definitions Removal of offsets field in unit definitions sboTerm on SBase sboTerm on SBase Consensus not yet 100%; goal is to finalize in ‘ 06 Consensus not yet 100%; goal is to finalize in ‘ 06