Recent developments in the world of SBML (the Systems Biology Markup Language)

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

http://cshlccb.wordpress.com/2012/08/03/michael-hucka-california-institute-of-technology-the-systems-biology-markup-language-sbml-model-databases-and-translation/




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Background and motivation

About SBML

Recent developments

Acknowledgements

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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

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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




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

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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

http://co.mbine.org

http://co.mbine.org

http://co.mbine.org

http://co.mbine.org

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



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



Model “A”With hierarchical model composition



Model “B”



Model “C”

The ‘comp’ package supports multiple arrangements



Model “A”



Model “B”

Separate files (possibly in databases)



Model “C”

Model “C”

Model “D”



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



Model “A”



Model “B”



Model “C”

Model “C”

Model “D”



Model “D”

Model “B”Species ...Compartments ...


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

http://arxiv.org/abs/1309.1910

http://arxiv.org/abs/1309.1910

http://co.mbine.org

http://co.mbine.org

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

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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

