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Presentation given on the first day of COMBINE 2013 in Paris, France, on September 16, 2013.
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Recent developments in the world of SBML (the Systems Biology Markup Language)
Michael Hucka, Ph.D.Department of Computing + Mathematical Sciences
California Institute of TechnologyPasadena, CA, USA
COMBINE 2013, Paris, September 2013
Email: [email protected] Twitter: @mhucka
Outli
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Background and motivation
About SBML
Recent developments
Acknowledgements
Outli
ne
Background and motivation
About SBML
Recent developments
Acknowledgements
“ The nature of systems biology”Bruggeman & Westerhoff,
Trends Microbiol. 15 (2007).
Large-scale integrative models are growing
Many models have traditionally been published this way
Problems:
• Errors in printing
• Missing information
• Outright errors
• Dependencies onimplementation
• Can be a hugeeffort to recreate
Is it enough to communicate the model in a paper?
Is it enough to make your (software X) code available?It’s vital for good science:
• Someone with access to the same software can try to run it, understand it, verify the results, etc.
• Opinion: you should always do this in any case
Is it enough to make your (software X) code available?It’s vital for good science—
• Someone with access to the same software can try to run it, understand it, verify the results, etc.
• Opinion: you should always do this in any case
But it’s still not ideal for communication of scientific results:
• Doesn’t necessarily encode biological semantics of the model
• What if they don’t have access to the same software?
• What if they don’t want to use that software?
• What if they want to use a different conceptual framework?
• And how will people be able to relate the model to other work?
Different tools ⇒ different interfaces & languages
Outli
ne
Background and motivation
About SBML
Recent developments
Acknowledgements
SBML: a lingua fra
nca
for software
Format for representing computational models of biological processes
• Data structures + usage principles + serialization to XML
• (Mostly) Declarative, not procedural—not a scripting language
Neutral with respect to modeling framework
• E.g., ODE, stochastic systems, etc.
Important: software reads/writes SBML, not humans <Beginning of SBML model definition>
List of function definitionsList of unit definitionsList of compartments
List of molecular speciesList of parameters
List of rulesList of reactions
List of events<End of SBML model definition>
SBML = Systems Biology Markup Language
The raw SBML (as XML)
The raw SBML (as XML)
Don’t work with it directly! Let software do it.
The process is central
• Literally called “reaction” (not necessarily biochemical)
• Participants are pools of entities of the same kind (“species”)
• Species are located in containers (“compartments”)
Models can further include:
• Other constants & variables
• Discontinuous events
Core SBML concepts are fairly simple
• Unit definitions
• Annotations
• Other, explicit math
na1 A nb1 B+ nc1Cf1(...)
na2 A nd2 D+ ne2Ef2(...)
...nc3 C nf3Ff3(...) + ng3G
Core SBML constructs support many types of models
Typical ODE models (e.g., cell differentiation)
Conductance-based models (e.g., Hodgin-Huxley)
Typically do not use SBML “reaction” construct,but instead use “rate rules” construct
Neural models (e.g., spiking neurons)
Typically use “events” for discontinuous changes
Pharmacokinetic/dynamics models
“Species” are not required to be biochemical entities
Infectious diseases BioModels Database model#MODEL1008060001
BioModels Database model#BIOMD0000000451
BioModels Database model#BIOMD0000000020
BioModels Database model#BIOMD0000000127
BioModels Database model#BIOMD0000000234
Example of model type Example model
List originally by Nicolas Le Novére
Many examples of SBML and software resources are available
Accepted by dozens of journals *
100’s of software tools available today
• Libraries: libSBML, JSBML
• 250+ listed in SBML Software Guide †
1000’s of models available in SBML format today
• ... in public databases, e.g., BioModels Database, Reactome
• ... as supplementary data to published papers
• ... in private repositories
* http://sbml.org/Documents/Publications_known_to_accept_submissions_in_SBML_format† http://sbml.org/SBML_Software_Guide
National Institute of General Medical Sciences (USA) European Molecular Biology Laboratory (EMBL)JST ERATO Kitano Symbiotic Systems Project (Japan) (to 2003)JST ERATO-SORST Program (Japan)ELIXIR (UK)Beckman Institute, Caltech (USA)Keio University (Japan)International Joint Research Program of NEDO (Japan)Japanese Ministry of AgricultureJapanese Ministry of Educ., Culture, Sports, Science and Tech.BBSRC (UK)National Science Foundation (USA)DARPA IPTO Bio-SPICE Bio-Computation Program (USA)Air Force Office of Scientific Research (USA)STRI, University of Hertfordshire (UK)Molecular Sciences Institute (USA)
SBML funding sources over the past 13+ years
Outli
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Background and motivation
About SBML
Recent developments
Acknowledgements
Recent developments in software tools by the SBML Team
New features in the SBML Test SuiteSBML Test Suite = conformance-testing system for SBML software
• Part 1: corpus of test models & expected numerical results
- 1200+ cases, all tagged by features tested
• Part 2: software facilities
- Online assessment system
- New: standalone test runner
- New: online database of results
http://sbml.org/Software/SBML_Test_Suite
New standalone SBML Test Suite RunnerRuns an SBML-compatible application through the test suite cases
Written in Java + SWT — installers available for Mac OS, Windows, Linux
New database of SBML Test Suite resultsDeveloped by Frank Bergmann
New database of SBML Test Suite resultsDeveloped by Frank Bergmann
New database of SBML Test Suite resultsDeveloped by Frank Bergmann
Example: RoadRunner
Recent developments in SBML
Evolution of SBML continuesToday: SBML Level 3
• Level 3 Core provides framework for common models
• Level 3 packages add additional constructs to the Core
Level 3 package What it enablesHierarchical model composition Models containing submodels ✔
Flux balance constraints Constraint-based models ✔
Qualitative models Petri net models, Boolean models ✔
Graph layout Diagrams of models ✔
Multicomponent/state species Entities w/ structure; also rule-based models draft
Spatial Nonhomogeneous spatial models draft
Graph rendering Diagrams of models draft
Groups Arbitrary grouping of components draft
Distributions Numerical values as statistical distributions in dev
Arrays & sets Arrays or sets of entities in dev
Dynamic structures Creation & destruction of components in dev
Annotations Richer annotation syntax
Status
SBML Level 3 package: Hierarchical Model CompositionDefines syntax for composing models from other models (or fragments)
Nicknamed ‘comp’
Developed by Lucian Smith, Mike Hucka, Stefan Hoops, Chris Myers, Andrew Finney, Martin Ginkel, Ion Moraru, Wolfram Liebermeister
Species ...Compartments ...
Parameters ...Reactions ...
Model “A”Core SBML
Species ...Compartments ...
Parameters ...Reactions ...
Model “A”With hierarchical model composition
Species ...Compartments ...
Parameters ...Reactions ...
Model “B”
Species ...Compartments ...
Parameters ...Reactions ...
Model “C”
The ‘comp’ package supports multiple arrangements
Species ...Compartments ...
Parameters ...Reactions ...
Model “A”
Species ...Compartments ...
Parameters ...Reactions ...
Model “B”
Separate files (possibly in databases)
Species ...Compartments ...
Parameters ...Reactions ...
Model “C”
Model “C”
Model “D”
Species ...Compartments ...
Parameters ...Reactions ...
Model “D”
Model “B”
Substitutions and deletions of entities can
be defined
Results can be “flattened” to plain SBML Level 3 CoreImplemented in libSBML
Allows tools to read L3 + ‘comp’ models as if they were just plain L3
Species ...Compartments ...
Parameters ...Reactions ...
Model “A”
Species ...Compartments ...
Parameters ...Reactions ...
Model “B”
Species ...Compartments ...
Parameters ...Reactions ...
Model “C”
Model “C”
Model “D”
Species ...Compartments ...
Parameters ...Reactions ...
Model “D”
Model “B”Species ...Compartments ...
Parameters ...Reactions ...
Model “A”
SBML Level 3 CoreOriginal SBML Level 3 Core + SBML ‘comp’
Define syntax for constraint-based (e.g., flux-balance analysis) models
• E.g. problem: optimize a specific property subject to constraints on reaction fluxes and other parameters
Nicknamed ‘fbc’
Developed by Brett Olivier and Frank Bergmann
Implemented in libSBML & SBMLToolbox; supported in CMBPy, FAME, SBW
Converters available to/from CORBA Toolbox
SBML Level 3 package: Flux Balance Constraints
SBML Level 3 package: Qualitative ModelsSupports using discrete logical formalism – e.g., Boolean net, Petri, ...
Nicknamed ‘qual’
Adds data structures for:
• Qualitative species – assume discrete levels or states (e.g., 0 or 1)
- Unlike normal SBML species, which are quantities of stuff
• Transitions, with inputs, outputs and function terms
- Transition function terms evaluated at each time step
Developed by Claudine Chaouiya, Sarah Keating, Duncan Berenguier, Aurélien Naldi, Denis Thieffry, Tomáš Helikar, Nicolas Le Novère, Martijn van Iersel
Implemented in libSBML & JSBML; supported in GINsim, CellNOpt, Cell Collective
Paper under review – manuscript at http://arxiv.org/abs/1309.1910
SBML Level 3 package: LayoutDefines syntax for storing diagram layouts in SBML file
• Does not define the rendering of the diagram
- Rendering is the domain SBML Level 3 Rendering package
Nicknamed ‘layout’
Originally developed by Ralph Gauges, Ursula Rost, Sven Sahle, and Katja Wegner for SBML Level 2; updated for Level 3 by Frank Bergmann
Implemented in libSBML & JSBML; supported in COPASI, SBW, others
Outli
ne
Background and motivation
About SBML
Recent developments
Acknowledgements
Attendees at SBML 10th Anniversary Symposium, Edinburgh, 2010
Mike Hucka, Sarah Keating, Frank Bergmann, Lucian Smith, Andrew Finney, Herbert Sauro, Hamid Bolouri, Ben Bornstein, Maria Schilstra, Jo Matthews, Bruce Shapiro, Linda Taddeo, Akira Funahashi, Akiya Juraku, Ben Kovitz, Nicolas Rodriguez, Andreas Dräger
SBML & JSBML Team:
SBML Editors: Mike Hucka, Frank Bergmann, Sarah Keating, Nicolas Le Novère, Chris Myers, Lucian Smith, Stefan Hoops, Sven Sahle, James Schaff, Darren Wilkinson
And a huge thanks to many others in the SBML and COMBINE communitiesfor massive contributions to SBML development and continuing support
SBML is the product of a wonderful, dedicated community
I’d like your feedback!You can use this anonymous form:
http://tinyurl.com/mhuckafeedback