SBML (the Systems Biology Markup Language), BioModels Database, and related resources

SBML (the Systems Biology Markup Language),
BioModels Database, and related resources

Michael Hucka, Ph.D.
(On behalf of many people)

California Institute of Technology
Pasadena, California, USA
Friday, July 15, 2011 2

Background and context
Overview of SBML
Survey of some software resources for SBML
Related efforts
Acknowledgements
Roadmap


Overview of SBML
Related efforts
Acknowledgements
Roadmap


Must weave solutions using different methods & tools


Need effective sharing of 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


Goal: reproducible and reusable models and simulations

Overview of SBML
Related efforts
Acknowledgements
Roadmap


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
• Not procedural


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


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


Some basics of SBML core model encoding

๏ Well-stirred compartments
c

n



c
protein A protein B

n

gene mRNAn mRNAc



๏ Reactions can involve any species anywhere
c
protein A protein B

n

gene mRNAn mRNAc



๏ Reactions can cross compartment boundaries
c
protein A protein B

n

gene mRNAn mRNAc



๏ Reaction/process rates can be (almost) arbitrary formulas
c
protein A f1(x) protein B

n

f5(x) f2(x)

gene f4(x) mRNAn f3(x) mRNAc



๏ “Rules”: equations expressing relationships in addition to reaction sys.
g1(x) c
g2(x) protein A f1(x) protein B
.
.
. n

f5(x) f2(x)




๏ “Events”: discontinuous actions triggered by system conditions
g1(x) c
g2(x) protein A f1(x) protein B
.
.
. n

f5(x) f2(x)


Event1: when (...condition...), Event2: when (...condition...), ...
do (...assignments...) do (...assignments...)


“This is identiﬁed by “This is an enzymatic
c
g1(x) GO id # ...” reaction with EC # ...”
g2(x)
. protein A f1(x) protein B
.
“This is a transport
. n
into the nucleus ...” “This compartment
represents the nucleus ...”
f5(x) f2(x)

“This event
represents ...”
Event1: when (...condition...), Event2: when (...condition...), ...
do (...assignments...) do (...assignments...)

Signaling pathway models Fernandez et al. (2006)
DARPP-32 Is a Robust Integrator
of Dopamine and Glutamate Signals
PLoS Computational Biology

BioModels Database model
#BIOMD0000000153

Scope of SBML is not limited to one kind of model

Signaling pathway models Hodgkin & Huxley (1952)
A quantitative description of
Conductance-based models membrane current and its

•
application to conduction and
“Rate rules” for temporal evolution excitation in nerve
of quantitative parameters J. Physiology 117:500–544

#BIOMD0000000020


Signaling pathway models Izhikevich EM. (2003)
Simple model of spiking neurons.
Conductance-based models IEEE Trans Neural Net.

• “Rate rules” for temporal evolution
of quantitative parameters
#BIOMD0000000127

Neural models

• “Events” for discontinuous changes
in quantitative parameters


Signaling pathway models Tham et al. (2008)
A pharmacodynamic model for
Conductance-based models the time course of tumor
shrinkage by gemcitabine +
carboplatin in non-small cell lung
cancer patients

Clin. Cancer Res. 14
Neural models BioModels Database model

#BIOMD0000000234

Pharmacokinetic/dynamics models

• “Species” is not required to be a
biochemical entity


Signaling pathway models Munz et al. (2009 )

Conductance-based models When zombies attack!:
Mathematical modelling of an

outbreak of zombie infection
Infectious Disease Modelling
Research Progress, eds.
Tchuenche et al., p. 133–150
Neural models

#MODEL1008060001

Pharmacokinetic/dynamics models

• “Species” is not required to be a
biochemical entity
Infectious diseases


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)


What are SBML “Levels”?

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)


SBML continues to evolve


SBML Level 3—A modular SBML

Package Z

Package X Package Y

SBML Level 3 Core

A package adds constructs & capabilities
Models declare which packages they use
• Applications tell users which packages they support
Package development can be decoupled


Package Specification status
Graph layout Level 3 version defined; in review
Multicomponent species Level 3 version defined; in review
Hierarchical composition Level 3 specification under discussion
Groups Level 3 specification under discussion
Qualitative models Level 3 specification under discussion
Spatial geometry Level 3 specification under discussion
Arrays & sets Specification proposed
Distribution & ranges Specification proposed
Steady-state models Specification proposed
Graph rendering Specification proposed
Spatial diffusion Specification needed
Dynamic structures Specification needed


Multicomponent species Level 3 version species to represent:
Extends SBML deﬁned; in review
• Entities that can exist under
different states affecting their
Groups behaviors
Level 3 speciﬁcation under discussion
• Entities that are complexes of
other entities


Hierarchical composition Models composed of submodels
Level 3 speciﬁcation under discussion


Grouping model entities together,
for conceptual and annotation
purposes


Models in which entity variables are
Qualitative models Levelquantities; e.g., boolean models
not 3 speciﬁcation under discussion


2-D and 3-D geometry of physical
objects (compartments & species)


Example: Hierarchical Model Composition

Current SBML
Model “A”
Compartments ...
Species ...
Parameters ...
Reactions ...


Example: Hierarchical Model Composition

Current SBML With model composition
Model “A” Model “A”
Compartments ... Compartments ...
Species ... Species ...
Parameters ... Parameters ...
Reactions ... Reactions ...

Model “B” Model “C”


More scenarios

Model “A”
Compartments ...
Species ...
Parameters ...
Reactions ...

Model “B” Model “B” Model “B”
Compartments ... Compartments ... Compartments ...
Species ... Species ... Species ...
Parameters ... Parameters ... Parameters ... ...
Reactions ... Reactions ... Reactions ...


More scenarios

Model “A”
Compartments ...
Species ...
Parameters ...
Reactions ...

Model “B” Model “C”
Model “D”
Compartments ...
Species ...
Parameters ...
Reactions ...


More scenarios

Separate ﬁles/resources
Model “A”
Compartments ... Model “B”
Species ... Compartments ...
Parameters ... Species ... Model “C”
Reactions ... Parameters ... Compartments ...
Reactions ... Species ...
Model “B” Parameters ...
Model “C” Reactions ...
Model “D”
Model “D”
Compartments ...
Think:
Species ... libraries of
Parameters ... well-tested
Reactions ... models


Links/references/replacements

Model “outer”
Model “inner”
S1 S2

Compartment “c” X1 X2

Compartment “q”


Links/references/replacements

Model “outer”
Model “inner”
S1 S2

Compartment “c” X1 X2

Compartment “q”

Implied model
Model “outer”

S1 S2 inner/X2
Compartment “c”


Overview of SBML
Related efforts
Acknowledgements
Roadmap


SBML.org


SBML Software Guide


SBML Software Guide

Find SBML software


SBML Software Guide

Some particularly full-featured, general simulation tools
COPASI: ODE & stochastic simulation, parameter scanning, powerful
plotting capabilities, much more
CellDesigner: graphical editing interface, SBGN support, SABIO-RK
integration, much more
iBioSim: special features for genetic circuit models for synthetic biology
Virtual Cell: web-based interface
roadRunner & SBW: .NET support, many tools in toolkit


Online SBML Validator



Validate SBML ﬁles


(demo)
(Demo)


How to keep in touch



Front-page news


Twitter & RSS feeds



Mailing lists/forums


Suggest subscribing to sbml-announce
(it’s very low volume)

SBML mailing lists & online forum interface

Software API libraries: libSBML & JSBML


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
๏ Written in portable C++
• Linux, Mac, Windows, FreeBSD
๏ APIs for C, C++, C#, Java,
Octave, Perl, Python, Ruby,
MATLAB (some via SWIG)
๏ Developed by Sarah Keating,
๏ Can use Expat, libxml2, or Frank Bergman, Ben Bornstein,
Xerces Akiya Jouraku, & Mike Hucka,
with substantial contributions
๏ Open-source under LGPL from many other people

JSBML
Pure Java implementation
API is highly compatible with libSBML
• Functionality is subset of libSBML functionality
Under active development
• Already in use in apps

• Help welcome!

Main developers:
Andreas Dräger
& Nicolas Rodriguez


BioModels Database


http://biomodels.net/biomodels


Features of BioModels Database
Stores & serves quantitative models of biological interest

• Free, public resource

• Models must be described in peer-reviewed publication(s)
All models are curated by hand to reproduce published results
Imports & exports models in several formats

• SBML, CellML, SciLab, XPP, BioPAX
Developed by Nicolas Le Novère’s group (EBI), funded by EBI & NIH
Today: 600+ models


(demo)


Overview of SBML
Related efforts
Acknowledgements
Roadmap


Growing community, greater challenges

Model Procedures Results

Representation
format SBRML

Minimal info
?
requirements

Semantics—
Mathematical

Other
annotations annotations annotations


Annotations add semantics and connections
Annotations can answer questions:
• “What exactly is this entity you call X?”
• “What other identities does this entity have?”

• “What exactly is the process represented by equation ‘e17’?”
• “What role does constant ‘k3’ play in equation ‘e17’?”

• “What mathematical framework is being assumed?”
• “What organism is this in?”
• ... etc. ...
Multiple annotations on same entity are common


Systems Biology Ontology (SBO)
For semantics of a model’s math
Human- & program-accessible
• Browser interface

• Web services
Math formulas in MathML


<sbml ...>
...
<listOfSpecies>
<listOfSpecies>
<listOfParameters>
SBO:0000339
<listOfParameters>
<listOfReactions>
<listOfReactants>
</listOfReactants>
<listOfProducts>
</listOfProducts>
<math>
...
<math>
...
</sbml> “forward bimolecular rate constant, continuous case”


What is MIRIAM?
MIRIAM = “Minimum Information Requested In the Annotation of Models”
Addresses 2 general areas

Requirements for reference Scheme for encoding
correspondence annotations

Annotations for Annotations for
attributing model referring to external
creators & sources data resources

MIRIAM is not speciﬁc to SBML


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


Why worry about standard ways of writing annotations?
Structured, machine-readable annotations increase your model’s utility

• Allow more precise identiﬁcation of model components
- Understand model structure
- Compare models
- Integrate models
- Search models

• Adds a semantic layer—integrates knowledge into the model
- Understand the underlying biology
- Reuse models
- Convert models to other forms


Annotations permit inter-database linking


SBML deﬁnes a syntax for annotations

<species metaid="metaid_0000009" id="species_3" compartment="c_1">
<annotation>
<rdf:RDF xmlns:rdf="http://www.w3.org/1999/02/22-rdf-syntax-ns#"
xmlns:bqbiol="http://biomodels.net/biology-qualifiers/" >
<rdf:Description rdf:about="#metaid_0000009">
<bqbiol:is>
<rdf:Bag>
<rdf:li rdf:resource="urn:miriam:obo.chebi:CHEBI%3A15996"/>
<rdf:li rdf:resource="urn:miriam:kegg.compound:C00044"/>
</rdf:Bag>
</bqbiol:is>
</rdf:Description>
</rdf:RDF>
</annotation>
</species>



<annotation>
<bqbiol:is> Data references
<rdf:Bag>
</rdf:Bag>
</bqbiol:is>
</rdf:Description>
</rdf:RDF>
</annotation>
</species>



<annotation>
<bqbiol:is> Relationship qualiﬁer
<rdf:Bag>
</rdf:Bag>
</bqbiol:is>
</rdf:Description>
</rdf:RDF>
</annotation>
</species>


“Term #1.1.1.1 (alcohol dehydrogenase) in the Enzyme Commission’s
Enzyme Nomenclature database”
urn:miriam:ec-code:1.1.1.1

{
{
URN scheme established Chosen by the creator of the
by the MIRIAM project entry in MIRIAM Resources


MIRIAM Resources provides URI dictionary & resolver
http://www.ebi.ac.uk/miriam Community-maintained


MIRIAM identiﬁers now in use by many other projects

Data resources Application software
• BioModels Database (kinetic models) • ARCADIA
• PSI Consortium (protein interaction) • BioUML
• Reactome (pathways) • COPASI
• Pathway Commons (pathways) • libAnnotationSBML
• libSBML
• SABIO-RK (reaction kinetics)
• Saint
• Yeast consensus model database
• SBML2BioPAX
• E-MeP (structural genomics) • SBML2LaTeX
• SBMLeditor
• semanticSBML
• Snazer
• SBW
• The Virtual Cell


Annotations enable many interesting possibilities

http://www.semanticsbml.org

Model Procedures Results

Representation
format SBRML

Minimal info
?
requirements

Semantics—
Mathematical

Other
annotations annotations annotations


<sbml ...>
...
<listOfSpecies>
?
<listOfSpecies>
<listOfParameters>
<listOfParameters>
<listOfReactions>
<listOfReactants>
<speciesReference species="S1" stoichiometry="2"
sboTerm="SBO:0000010" />
...

SED-ML = Simulation Experiment Description ML
Application-independent format
Captures procedures, algorithms,
parameter values

• Steps to go from model to output
libSedML project developing API library


Overview of SBML
Related efforts
Acknowledgements
Roadmap


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

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

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 listening!

SBML (the Systems Biology Markup Language), BioModels Database, and related resources

Recomendados

Recomendados

Más contenido relacionado

Destacado

Destacado (20)

Similar a SBML (the Systems Biology Markup Language), BioModels Database, and related resources

Similar a SBML (the Systems Biology Markup Language), BioModels Database, and related resources (8)

Más de Mike Hucka

Más de Mike Hucka (20)

Último

Último (20)

SBML (the Systems Biology Markup Language), BioModels Database, and related resources