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 TechnologyPasadena, California, USA

2Friday, July 15, 2011

Background and context

Overview of SBML

Survey of some software resources for SBML

Related efforts

Acknowledgements

Roa

dmap



Overview of SBML


Related efforts

Acknowledgements

Roa

dmap


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 simulations7Friday, July 15, 2011


Overview of SBML


Related efforts

Acknowledgements

Roa

dmap


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

SBML = Systems Biology Markup Language


The reaction is central: a process occurring at a given rate

• Participants are pools of entities (species)

Models can further include:

• Other constants & variables

• Compartments

• Explicit math

• Discontinuous events

Basic SBML concepts are simple

naA + nbBf([A],[B],[P ],...)−−−−−−−−−−−−→npP

ncCf(...)−−−→ ndD + neE + nfF

...

• Unit definitions

• Annotations


The reaction is central: a process occurring at a given rate

• Participants are pools of entities (species)

Models can further include:

• Other constants & variables

• Compartments

• Explicit math

• Discontinuous events

Basic SBML concepts are simple

naA + nbBf([A],[B],[P ],...)−−−−−−−−−−−−→npP

ncCf(...)−−−→ ndD + neE + nfF

...

Can be anything conceptually compatible

• Unit definitions

• Annotations


Some basics of SBML core model encoding

c

n

๏ Well-stirred compartments



c

n

protein A protein B

gene mRNAn mRNAc



c

n

protein A protein B

gene mRNAn mRNAc

๏ Reactions can involve any species anywhere



c

n

protein A protein B

gene mRNAn mRNAc

๏ Reactions can cross compartment boundaries


๏ Reaction/process rates can be (almost) arbitrary formulas


c

n

protein A protein B

gene mRNAn mRNAc

f1(x)

f2(x)

f3(x)f4(x)

f5(x)


๏ “Rules”: equations expressing relationships in addition to reaction sys.


c

n

protein A protein B

gene mRNAn mRNAc

f1(x)

f2(x)

f3(x)

g1(x)g2(x)

.

.

.

f4(x)

f5(x)


๏ “Events”: discontinuous actions triggered by system conditions


c

n

protein A protein B

gene mRNAn mRNAc

f1(x)

f2(x)

f3(x)

g1(x)g2(x)

.

.

.

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


...

f4(x)

f5(x)




...


c

n

protein A protein B

gene mRNAn mRNAc

f1(x)

f2(x)

f3(x)

g1(x)g2(x)

.

.

.

f4(x)

f5(x)

“This event represents ...”

“This is identified by GO id # ...”

“This is an enzymatic reaction with EC # ...”

“This is a transport into the nucleus ...” “This compartment

represents the nucleus ...”


Scope of SBML is not limited to one kind of model

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



Signaling pathway models

Conductance-based models

• “Rate rules” for temporal evolution of quantitative parameters

Hodgkin & Huxley (1952)

A quantitative description of membrane current and its application to conduction and excitation in nerve

J. Physiology 117:500–544







Neural models

• “Events” for discontinuous changesin quantitative parameters

Izhikevich EM. (2003)

Simple model of spiking neurons.

IEEE Trans Neural Net.







Neural models


Pharmacokinetic/dynamics models

• “Species” is not required to be abiochemical entity

Tham et al. (2008)

A pharmacodynamic model for the time course of tumor shrinkage by gemcitabine + carboplatin in non-small cell lung cancer patients

Clin. Cancer Res. 14







Neural models


Pharmacokinetic/dynamics models

• “Species” is not required to be abiochemical entity

Infectious diseases

Munz et al. (2009 )

When zombies attack!: Mathematical modelling of an outbreak of zombie infection

Infectious Disease Modelling Research Progress, eds. Tchuenche et al., p. 133–150

BioModels Database model#MODEL1008060001


0

100

200

300

2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011

(counted in middle of each year)

229 as of July 14 ↓

Number of software systems supporting SBML


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

SBML Level 3 Core

Package X Package Y

Package Z

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















Extends SBML species to represent:• Entities that can exist under

different states affecting their behaviors

• Entities that are complexes of other entities















Models composed of submodels















Grouping model entities together, for conceptual and annotation purposes















Models in which entity variables are not quantities; e.g., boolean models















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


Example: Hierarchical Model Composition

Species ...Compartments ...

Parameters ...Reactions ...

Model “A”

Current SBML


Example: Hierarchical Model Composition



Model “A”

Current SBML



Model “A”

With model composition



Model “B”



Model “C”


More scenarios



Model “A”



Model “B”



Model “B”



Model “B”

...


More scenarios



Model “A”



Model “B”



Model “C”

Model “D”




More scenarios



Model “A”



Model “B”

Separate files/resources



Model “C”

Model “C”

Model “D”



Model “D”

Model “B”

Think: libraries of well-tested

models


Links/references/replacements

Model “outer”

S1 S2

Compartment “c”

Compartment “q”

Model “inner”

X1 X2


Links/references/replacements

Model “outer”

S1 S2

Compartment “c”

Compartment “q”

Model “inner”

X1 X2

Model “outer”

Compartment “c”

S1 S2 inner/X2

Implied model



Overview of SBML


Related efforts

Acknowledgements

Roa

dmap


SBML.org


SBM

L So

ftw

are

Gui

de


SBM

L So

ftw

are

Gui

de

Find SBML software


SBML Software Guide37Friday, July 15, 2011

http://sbml.org/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


Onl

ine

SBM

L Va

lidat

or


Onl

ine

SBM

L Va

lidat

or


Onl

ine

SBM

L Va

lidat

or


Onl

ine

SBM

L Va

lidat

or

Validate SBML files


(Demo)(demo)


http://sbml.org/Facilities/Validator



























How

to

keep

in t

ouch


How

to

keep

in t

ouch

Front-page news


How

to

keep

in t

ouch

Twitter & RSS feeds


How

to

keep

in t

ouch

Mailing lists/forums


SBML mailing lists & online forum interface

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


Software API libraries: libSBML & JSBML


libSBML

๏ Reads, writes, validates SBML

• Hundreds of rules for helping 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)

๏ Can use Expat, libxml2, or Xerces

๏ Open-source under LGPL

๏ Developed by Sarah Keating, Frank Bergman, Ben Bornstein, Akiya Jouraku, & Mike Hucka, with substantial contributions from many other people

Latest stable version: 5.0.0http://sbml.org/Software/libSBML


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)


http://www.ebi.ac.uk/biomodels-main/









Overview of SBML


Related efforts

Acknowledgements

Roa

dmap


Growing community, greater challenges52Friday, July 15, 2011

Representationformat

Model Procedures Results

Minimal inforequirements

Semantics—

Mathematical

Other

SBRML

?

annotations annotations annotations





Semantics—

Mathematical

Other

SBRML

?



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

Annotations add semantics and connections


For semantics of a model’s math

Human- & program-accessible

• Browser interface

• Web services

Math formulas in MathML

Systems Biology Ontology (SBO)





• Web services







• Web services




<sbml ...> ... <listOfCompartments> <compartment id="cell" size="1e-15" /> </listOfCompartments> <listOfSpecies> <species compartment="cell" id="S1" initialAmount="1000" /> <species compartment="cell" id="S2" initialAmount="0" /> <listOfSpecies> <listOfParameters> <parameter id="k" value="0.005" sboTerm="SBO:0000339" /> <listOfParameters> <listOfReactions> <reaction id="r1" reversible="false"> <listOfReactants> <speciesReference species="S1" stoichiometry="2" sboTerm="SBO:0000010" /> </listOfReactants> <listOfProducts> <speciesReference species="S1" stoichiometry="2" sboTerm="SBO:0000011" /> </listOfProducts> <kineticLaw sboTerm="SBO:0000052"> <math> ... <math> ...</sbml>



SBO:0000339



SBO:0000339

“forward bimolecular rate constant, continuous case”


MIRIAM = “Minimum Information Requested In the Annotation of Models”

Addresses 2 general areas

MIRIAM is not specific to SBML

What is MIRIAM?

Requirements for reference correspondence

Scheme for encoding annotations

Annotations for attributing model

creators & sources

Annotations for referring to external

data resources


MIRIAM = “Minimum Information Requested In the Annotation of Models”

Addresses 2 general areas

MIRIAM is not specific to SBML

What is MIRIAM?

Requirements for reference correspondence


Annotations for attributing model

creators & sources

Annotations for referring to external

data resources



MIRIAM cross-references are simple triples

Data type identifier

Data item identifier

Annotation qualifier

Model element

Entity referenced

relationship qualifier(optional)

{ }(Required) (Required) (Optional)

URI chosen from agreed-upon list

Syntax & value space depends on data type

Format:

Controlled 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


Annotations permit inter-database linking


<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>

SBML defines a syntax for annotations




<rdf:Bag> <rdf:li rdf:resource="urn:miriam:obo.chebi:CHEBI%3A15996"/> <rdf:li rdf:resource="urn:miriam:kegg.compound:C00044"/> </rdf:Bag>

Data references




<bqbiol:is>

</bqbiol:is>

Relationship qualifier


“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

by the MIRIAM project

{Chosen by the creator of theentry in MIRIAM Resources


http://www.ebi.ac.uk/miriam

MIRIAM Resources provides URI dictionary & resolver

Community-maintained


http://www.ebi.ac.uk/miriam

MIRIAM Resources provides URI dictionary & resolver

Community-maintained


MIRIAM identifiers now in use by many other projects

Data resources• BioModels Database (kinetic models)• PSI Consortium (protein interaction)• Reactome (pathways)• Pathway Commons (pathways)• SABIO-RK (reaction kinetics)• Yeast consensus model database• E-MeP (structural genomics)

Application software• ARCADIA• BioUML• COPASI• libAnnotationSBML• libSBML• Saint• SBML2BioPAX• SBML2LaTeX• SBMLeditor• semanticSBML• Snazer• SBW• The Virtual Cell


Annotations enable many interesting possibilities

http://www.semanticsbml.org





Semantics—

Mathematical

Other

SBRML

?






Semantics—

Mathematical

Other

SBRML

?



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

<sbml ...> ... <listOfCompartments> <compartment id="cell" size="1e-15" /> </listOfCompartments> <listOfSpecies> <species compartment="cell" id="S1" initialAmount="1000" /> <species compartment="cell" id="S2" initialAmount="0" /> <listOfSpecies> <listOfParameters> <parameter id="k" value="0.005" sboTerm="SBO:0000339" /> <listOfParameters> <listOfReactions> <reaction id="r1" reversible="false"> <listOfReactants> <speciesReference species="S1" stoichiometry="2" sboTerm="SBO:0000010" /> ...

?



Overview of SBML


Related efforts

Acknowledgements

Roa

dmap


People on SBML Team & BioModels Team

SBML Team BioModels.net TeamMichael Hucka Nicolas Le NovèreSarah Keating Camille Laibe

Frank Bergmann Nicolas RodriguezLucian Smith Nick Juty

Nicolas Rodriguez Vijayalakshmi ChelliahLinda Taddeo Michael SchubertAkiya Joukarou Lukas EndlerAkira Funahashi Chen Li

Kimberley Begley Harish DharuriBruce Shapiro Lu LiAndrew Finney Enuo HeBen Bornstein Mélanie Courtot

Ben Kovitz Alexander BroicherHamid Bolouri Arnaud HenryHerbert Sauro Marco DonizelliJo Matthews

Maria Schilstra

VisionariesHiroaki Kitano

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.net70Friday, July 15, 2011

Where to find out more

Thank you for listening!

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/
