The document discusses the Systems Biology Markup Language (SBML), a format for representing quantitative models in computational biology, emphasizing the need for effective sharing of models and reproducibility in simulations. It outlines the evolution of SBML, its specifications, and the community's ongoing efforts to develop interoperable standards and software tools. Key lessons learned from the SBML development process highlight the importance of stakeholder engagement, simplicity, and formal procedures.

1. SBML (the Systems Biology Markup Language)
Michael Hucka, Ph.D.
(On behalf of many people)
California Institute of Technology
Pasadena, California, USA
Tuesday, July 26, 2011 1

2. Roadmap
What is SBML?
What is the SBML community like today, and how did it get there?
Acknowledgments
Tuesday, July 26, 2011 2

3. SBML
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4. Subject matter: computational modeling
Data
Experiments
Models
Focus on mechanistic, computational models
• Preferrably not statistical or curve-fitting models, but dynamical
models expressing hypothesized physical & chemical mechanisms
- Equations refer to identifiable processes
- Parameters have physical interpretations
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5. Example: Tyson 1991 model of cell cycle
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6. Goal: reproducible and reusable models and simulations
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7. To achieve that, need effective means for sharing models
Not enough simply to publish lists of equations!
Need a software-independent format
• No single package answers all needs
• New techniques ( new tools) are developed continuously
• Different packages have different niche strengths
- Strengths are often complementary
Need to capture both
• Mathematical content of a model
• Semantic content of a model
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8. SBML = Systems Biology Markup Language
Format for representing quantitative models
• Defines object model + rules for its use
- Serialized to XML
Neutral with respect to modeling framework
• ODE vs. stochastic vs. ...
A lingua franca for software
But: not a procedural description
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9. Basic SBML concepts are simple
The reaction is central: a process occurring at a given rate
• Participants are pools of entities (species)
f ([A],[B],[P ],...)
na A + nb B − − − − − − → np P
−−−−−−
f (...)
nc C −−
−→ nd D + ne E + nf F
.
.
.
Models can further include:
• Other constants & variables • Unit definitions
• Compartments • Annotations
• Explicit math
• Discontinuous events
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10. Basic SBML concepts are simple
The reaction is central: a process occurring at a given rate
• Participants are pools of entities (species) Can be anything
conceptually
f ([A],[B],[P ],...)
na A + nb B − − − − − − → np P
−−−−−− compatible
f (...)
nc C −−
−→ nd D + ne E + nf F
.
.
.
Models can further include:
• Other constants & variables • Unit definitions
• Compartments • Annotations
• Explicit math
• Discontinuous events
Tuesday, July 26, 2011 9

11. Example of model type Example model
Signaling pathway models BioModels Database model
#BIOMD0000000153
Conductance-based models
• “Rate rules” for temporal evolution
of quantitative parameters
BioModels Database model
#BIOMD0000000020
Neural models
• “Events” for discontinuous changes
in quantitative parameters
BioModels Database model
#BIOMD0000000127
Pharmacokinetic/dynamics models
• “Species” is not required to be a
biochemical entity
BioModels Database model
#BIOMD0000000234
Infectious diseases BioModels Database model
#MODEL1008060001
Scope of SBML is not limited to one kind of model
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12. 300+ curated & annotated models in BioModels Database
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13. SBML Software Guide
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14. SBML Software Guide
Find SBML software
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15. Number of software systems supporting SBML
300
229 as of July 14 ↓
200
100
0
2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011
(counted in middle of each year)
http://sbml.org/SBML_Software_Guide
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16. libSBML
Reads, writes, validates SBML Latest stable version: 5.0.0
• Hundreds of rules for helping http://sbml.org/Software/libSBML
to ensure correct SBML
Unit checking & conversion
Well-tested
Core is written in portable C++
Runs on Linux, Mac, Windows
APIs for C, C++, C#, Java,
Octave, Perl, Python, Ruby,
MATLAB (some via SWIG) Developed by Sarah Keating, Frank
Can use Expat, libxml2, or Xerces Bergmann, Ben Bornstein, Akiya
Jouraku, & Mike Hucka, with
Open-source under LGPL substantial contributions from many
other people
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17. Current state of SBML specifications
Specification document available from
http://sbml.org/Documents
Newest: Level 3 Version 1 Core
• Oct. 2010
About SBML “Levels”:
• Levels help manage significant restructuring of SBML architecture
• Levels coexist
- E.g., Level 2 models will remain valid and exist for a long time
• A Level is not solely a vertical change (i.e., more features)—there is
horizontal change too (i.e., changes to existing elements)
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18. What is the SBML community like today, and how did it get there?
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19. What happened in the beginning?
Circa 2000: Hamid Bolouri contacted groups having relevant software tools
• Organized workshops & set goal: develop interoperability
• Funding from Japanese agency JST (via Hiroaki Kitano & John Doyle)
• 3 core developers worked on software infrastructure at Caltech
Early years: focus on software infrastructure (SBW)
• SBML was a component, but not sole (or even primary) focus
Eventually: SBML turned out to be more popular
• 2 core developers remained (Finney & Hucka), focused on SBML
• More groups/software supported SBML
• Original dev. process was ad hoc, but involved constant feedback
- Hosted biannual workshops where intense discussions were held
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20. What happened when SBML gained users?
Implemented editorial board
• Bootstrapped with heavily-involved people (Hucka, Finney, Le Novère)
- After that, turned to community-based elections
• Editors are volunteers, serve for limited terms
Implemented electronic polling for major decisions & voting
Continued biannual meetings
• Split into forum meetings and hackathons
Developed a somewhat more formal process
• http://sbml.org/Documents/SBML_Development_Process
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21. SBML’s scope is widening to support more types of models
Package Z
Package X Package Y
SBML Level 3 Core
SBML Level 3 is designed around concept of modular additions
• A package adds constructs & capabilities
Models declare which packages they use
• Applications tell users which packages they support
Package development can be decoupled
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22. What’s happening now?
SBML Level 3 Package specification & software development is ongoing
Creation of COMBINE: Computational Modeling in Biology Network
• Goal: coordinate development of interoperable, non-overlapping
standards covering all aspects of modeling in biology
• http://co.mbine.org/
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23. Model Procedures Results
Representation
format SBRML
Minimal info
?
requirements
Semantics—
Mathematical
Other
annotations annotations annotations
Standards emerging for related but out-of-scope areas
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24. Some lessons about what think we got right
Start with actual stakeholders
• Address real needs, not perceived ones
Don’t include the kitchen sink
• Smaller & simpler easier to understand, describe, implement
Provide transparent & inclusive process
• Critical to legitimacy—people must see their ideas being considered
Engage people, constantly, in many ways
• Not just electronic forums, email, etc., but face-to-face
• Not getting responses? Find a new approach!
Have independent leaders/organizers/shepherds
• Avoid the appearance of bias or agenda
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25. Some lessons about what definitely got wrong
Inadequate testing before freezing/releasing
Not managing complexity creep
• Feature changes between SBML versions make support harder
Not formalizing the process sufficiently
• Need “Requests for Comments” procedures, voting procedures, etc.
• Only put most of this in place in recent years
Underestimating how much time it takes to do everything
• Also: democratic, open processes move slowly
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26. Roadmap
What is SBML?
What is the SBML community like today, and how did it get there?
Acknowledgments
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27. People on SBML Team & BioModels Team
SBML Team BioModels.net Team
Michael Hucka Nicolas Le Novère
Sarah Keating Camille Laibe
Frank Bergmann Nicolas Rodriguez
Lucian Smith Nick Juty
Nicolas Rodriguez Vijayalakshmi Chelliah
Linda Taddeo Michael Schubert
Akiya Joukarou Lukas Endler
Akira Funahashi Chen Li
Kimberley Begley Harish Dharuri
Bruce Shapiro Lu Li
Andrew Finney Enuo He
Ben Bornstein Mélanie Courtot
Ben Kovitz Alexander Broicher
Hamid Bolouri Arnaud Henry
Herbert Sauro Visionaries Marco Donizelli
Jo Matthews Hiroaki Kitano
Maria Schilstra John Doyle
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28. National Institute of General Medical Sciences (USA)
European Molecular Biology Laboratory (EMBL)
ELIXIR (UK)
Beckman Institute, Caltech (USA)
Keio University (Japan)
JST ERATO Kitano Symbiotic Systems Project (Japan) (to 2003)
National Science Foundation (USA)
International Joint Research Program of NEDO (Japan)
JST ERATO-SORST Program (Japan)
Japanese Ministry of Agriculture
Japanese Ministry of Educ., Culture, Sports, Science and Tech.
BBSRC (UK)
DARPA IPTO Bio-SPICE Bio-Computation Program (USA)
Air Force Office of Scientific Research (USA)
STRI, University of Hertfordshire (UK)
Molecular Sciences Institute (USA)
Agencies to thank for supporting SBML & BioModels.net
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29. Where to find out more
SBML http://sbml.org
libSBML & JSBML http://sbml.org/Software
BioModels Database http://biomodels.net/biomodels
MIRIAM http://biomodels.net/miriam
SED-ML http://biomodels.net/sed-ml
SBO http://biomodels.net/sbo
KiSAO http://www.ebi.ac.uk/compneur-srv/kisao/
TEDDY http://www.ebi.ac.uk/compneur-srv/teddy/
Thank you for your time!
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30. Extra slides
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31. Evolution of features took time & practical experience
Level 1 Level 2 Level 3
predefined math
user-defined functions user-defined functions
functions
text-string math notation MathML subset MathML subset
reserved namespaces for no reserved namespaces no reserved namespaces
annotations for annotations for annotations
no controlled annotation RDF-based controlled RDF-based controlled
scheme annotation scheme annotation scheme
no discrete events discrete events discrete events
default values defined default values defined no default values
monolithic monolithic modular
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32. Level 3 package Active? libSBML 5 implementation?
Graph layout ✓
Groups ✓
Spatial ✓
Flux balance constraints ✓
Hierarchical composition ✓ (in progress)
Multicomponent species ✓
Annotations ✓
Graph rendering ✓
Distribution & ranges ✓
Qualitative models ✓
Dynamic structures
Arrays & sets
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33. Model Entity
element referenced
relationship qualifier
(optional)
MIRIAM cross-references are simple triples
{ Data type
identifier
Data item
identifier
Annotation
qualifier }
(Required) (Required) (Optional)
Format:
URI chosen from Syntax & value space Controlled
agreed-upon list depends on data type vocabulary term
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