sbml: what is it about?

SBML: What Is It About?Michael Hucka, Ph.D.

Department of Computing + Mathematical SciencesCalifornia Institute of Technology

Pasadena, CA, USA

HCLS Systems Biology, June 2012

Email: [email protected] Twitter: @mhucka

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General background and motivations

Brief summary of SBML features

Annotations, connections and semantics

SBML development today

Acknowledgments

Research today: experimentation, modeling, cogitation

One example of a type of model represented in SBML

Tyson et al. (1991) PNAS 88(1):7328–32

Simulationoutput

Must weave solutions from many methods and tools

Different tools ⇒ different interfaces & languages

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Acknowledgments

Format for representing computational models of biological processes

• Data structures + usage principles + serialization to XML

Neutral with respect to modeling framework

• E.g., ODE, stochastic systems, etc.

Development started in 2000, with first specification distributed in 2001

• XML was still relatively new, RDF even more so

SBML = Systems Biology Markup Language

A lingua fra

nca for

software

(not humans)

The process is central

• Called a “reaction” in SBML

• Participants are pools of entities (species)

Models can further include:

• Other constants & variables

• Compartments

• Explicit math

• Discontinuous events

Basic SBML concepts are fairly simple

• Unit definitions

• Annotations

Well-stirred compartments

c

n

Species pools are located in compartments

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

c

n

protein A protein B

gene mRNAn mRNAc

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)

Annotations: machine-readable semantics and links to other resources



...

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 encompasses many types of models

Today: spatially homogeneous models

• Metabolic network models

• Signaling pathway models

• Conductance-based models

• Neural models

• Pharmacokinetic/dynamics models

• Infectious diseases






• Neural models




Find examples inBioModels Databasehttp://biomodels.net/biomodels





• Neural models



Coming: SBML Level 3 packages to support other types

• E.g.: Spatially inhomogeneous models, also qualitative/logical


Find examples inBioModels Databasehttp://biomodels.net/biomodels

SBML Level 1 SBML Level 2 SBML Level 3

predefined math functions user-defined functions user-defined functions

text-string math notation MathML subset MathML subset

reserved namespaces for annotations

no reserved namespaces for annotations

no reserved namespaces for annotations

no controlled annotation scheme

RDF-based controlled annotation scheme

RDF-based controlled 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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Acknowledgments

SBML provides syntax and only limited semantics


No standard identifiers


Low info content


Raw models alone are insufficient

Need standard schemes for machine-readable annotations

• For authorship, publication info

• For links to other data resources

• For semantics of mathematics

Need common guidelines for minimal model quality and content


Low info content









Low info content


Definedby SBML








Low info content


Definedby MIRIAM

Definedby SBML

Linking SBML elements to external resources

}In SBML Level 2–3, MIRIAM annotationsare restricted to this specific form and to appear inside <annotation> elements.

(Other RDF can appear elsewhere in <annotation>)




E.g.: species, compartment, reaction, parameter





Chosen from specific list—http://sbml.org/miriam/qualifiersE.g.: bqbiol:isPartOf





Chosen from specific list—http://sbml.org/miriam/qualifiersE.g.: bqbiol:isPartOf

Taken from public list athttp://sbml.org/miriam

<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>

Example


<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

Example


<bqbiol:is>

</bqbiol:is>

Relationship qualifier

Example

BioModels Database: example of using the annotations

Resolving resource identifiers

For linking to data, need:

• Globally unique, unambiguous identifiers

• ... that are persistent despite resource changes (e.g., changed URLs)

• ... that are maintained by the community

MIRIAM Registry provides data & identifiers.org provides resolvable URIs

• Unlike URNs, can type identifiers.org URI in a web browser

Example:

• EC Code entry #1.1.1.1

- MIRIAM URN: urn:miriam:ec-code:1.1.1

- identifiers.org URI: http://identifiers.org/ec-code/1.1.1.1

Developed by Nicolas Le Novère, Camille Laibe, Nick Juty @ EBI

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Acknowledgments

SBML Level 3 Core

Package X Package Y Package Z

Package W

(dependencies)

SBML Level 3: Supporting more categories of models

A package adds constructs & capabilities

Models declare which packages they use

• Applications tell users which packages they support

Package development can be decoupled

Find out more at http://sbml.org/Community/Wiki

Find software in the SBML Software Guide

Find SBML software

Find software in the SBML Software Guide

Representationformat

Model Procedures Results

Minimal inforequirements

Semantics—

Mathematical

Other

SBRML

?

annotations annotations annotations

Growing ecosystem of standards to improve reproducibility

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Acknowledgments

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

Frank Bergmann Nicolas RodriguezLucian Smith Nick Juty

Nicolas Rodriguez Vijayalakshmi ChelliahLinda Taddeo Stuart MoodieAkiya Joukarou Sarah KeatingAkira Funahashi Maciej Swat

Kimberley Begley Lukas EndlerBruce Shapiro Chen Li

Andrew Finney Harish DharuriBen Bornstein Lu Li

Ben Kovitz Enuo HeHamid Bolouri Mélanie CourtotHerbert Sauro Alexander BroicherJo Matthews Arnaud Henry

Maria Schilstra Marco Donizelli

VisionariesHiroaki Kitano

John Doyle

People on SBML Team & BioModels.net Team

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)JST ERATO-SORST Program (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)

We ♥ our

funding agencies

A huge thank you to the communityAttendees at SBML 10th Anniversary Symposium, Edinburgh, 2010

SBML http://sbml.org

BioModels Database http://biomodels.net/biomodels

identifiers.org http://identifiers.org

MIRIAM http://biomodels.net/miriam

MIASE http://biomodels.net/miase

SED-ML http://biomodels.net/sed-ml

SBO http://biomodels.net/sbo

SBRML http://tinyurl.com/sbrml

SBGN http://sbgn.org

URLs

http://sbml.org

http://sbml.org

http://biomodels.net/biomodels

http://biomodels.net/biomodels

http://identifiers.org

http://identifiers.org

http://biomodels.net/miriam

http://biomodels.net/miriam

http://biomodels.net/miase

http://biomodels.net/miase

http://biomodels.net/sed-ml

http://biomodels.net/sed-ml

http://biomodels.net/sbo

http://biomodels.net/sbo

http://tinyurl.com/sbrml

http://tinyurl.com/sbrml

http://sbgn.org

http://sbgn.org

I’d like your feedback!You can use this anonymous form:

http://tinyurl.com/mhuckafeedback



Extra slides

Computational modeling has gained broad appealMetabolic networks: Fung et al. A synthetic gene-metabolic oscillator. Nature 2005; Herrgård et al. A consensus yeast metabolic network reconstruction obtained from a community approach to systems biology. Nat Biotechnol 2008

Signalling pathways: Bray et al. Receptor clustering as a cellular mechanism to control sensitivity. Nature 1998; Bhalla ad Iyengar. Emergent properties of signaling pathways. Science 1998; Schoeberl et al. Computational modeling of the dynamics of the MAP kinase cascade activated by surface and internalized EGF receptors. Nat Biotechnol 2002; Hoffmann et. The IκB-NF-κB signaling module: temporal control and selective gene activation. Science 2002; Smith et al. Systems analysis of Ran transport. Science 2002; Bhalla et al. MAP kinase phosphatase as a locus of flexibility in a mitogen-activated protein kinase signaling network. Science 2002; Nelson et al. Oscillations in NF-κB Signaling Control the Dynamics of Gene Expression. Science 2004; Werner et al. Stimulus specificity of gene expression programs determined by temporal control of IKK activity. Science 2005; Sasagawa et al. Prediction and validation of the distinct dynamics of transient and sustained ERK activation. Nat Cell Biol 2005; Basak et al. A fourth IkappaB protein within the NF-κB signaling module. Cell 2007; McLean et al. Cross-talk and decision making in MAP kinase pathways. Nat Genet 2007; Ashall et al. Pulsatile Stimulation Determines Timing and Specificity of NF-κB-Dependent Transcription. Science 2009; Becker et al. Covering a broad dynamic range: information processing at the erythropoietin receptor. Science 2010

Gene regulatory networks: McAdams and Shapiro. Circuit simulation of genetic networks. Science 1995; Yue et al. Genomic cis-regulatory logic: Experimental and computational analysis of a sea urchin gene. Science 1998; Von Dassow et al. The segment polarity network is a robust developmental module. Nature 2000; Elowitz and Leibler. A synthetic oscillatory network of transcriptional regulators. Nature 2000; Shen-Orr et al, Network motifs in the transcriptional regulation network of Escherichia coli. Nat Genet 2002; Yao et al. A bistable Rb-E2F switch underlies the restriction point. Nat Cell Biol 2008; Friedland. Synthetic gene networks that count. Science 2009

Pharmacometrics models: Labrijn et al. Therapeutic IgG4 antibodies engage in Fab-arm exchange with endogenous human IgG4 in vivo. Nat Biotechnol 2009

Physiological models: Noble. Modeling the heart from genes to cells to the whole organ. Science 2002; Izhikevich and Edelman. Large-scale model of mammalian thalamocortical systems. PNAS 2008

Infectious diseases: Perelson et al. HIV-1 dynamics in vivo: Virion clearance rate, infected cell life-span, and viral generation time. Science 1996; Nowak. Population dynamics of immune responses to persistent viruses. Science 1996;

Software tools survey 2011

General features of the survey

Online, implemented using commercial survey website

28 questions

• Mix of multiple choice and fill-in-the-blank

85 responses by July 2011

• Removed incomplete responses

• 81 software tools left

Avoided “corrections” to data

Question: Which of the following categories best describe your software? (Check all that apply.)

Purposes of the software systems

Total number of software tools

Simulation software

Analysis s/w (in addition, or instead of, simulation)

Creation/model development software

Visualization/display/formatting software

Utility software (e.g., format conversion)

Data integration and management software

Repository or database

Framework or library (for use in developing s/w)

S/w for interactive env. (e.g., MATLAB, R, ...)

Annotation software0 20 40 60 80

11

13

13

14

16

23

31

31

40

42




Simulation software










11

13

13

14

16

23

31

31

40

42

1/4 1/2 3/4




Simulation software










11

13

13

14

16

23

31

31

40

42

Question: Regardless of whether your software provides simulation capabilities, what modeling frameworks does the package support when working with SBML files?

Mathematical frameworks

Ordinary differential equations (ODE)

Discrete stochastic simulation

Discontinuous event handling

Differential-algebraic equations (DAE)

Logical/Boolean networks

Delay-differential equations (DDE)

Partial differential equations (PDE)

None of the above, or other framework0 20 40 60 80

20

8

9

11

17

25

28

54


Question: Regardless of whether your software provides simulation capabilities, what modeling frameworks does the package support when working with SBML files?

Mathematical frameworks

Ordinary differential equations (ODE)

Discrete stochastic simulation

Discontinuous event handling

Differential-algebraic equations (DAE)

Logical/Boolean networks

Delay-differential equations (DDE)

Partial differential equations (PDE)

None of the above, or other framework0 20 40 60 80

20

8

9

11

17

25

28

54


E.g.: FBA

Other supported standards

MIRIAMSBO

SBGNBioPAXCellML

SED-MLMFAML

PNMLSBOL

0 5 10 15 20

111

33

613

1416

Total # software tools supporting other standards

(Warning: different scale)

Question: Which other standards does your software support?

Availability of software

Fee-based2%

Free98%

Fees for academics

Fee-based10%

Free90%

Fees for non-academics

Notavail.21%

Codeavailable

79%

Is source code available?

sbml: what is it about?

Technology

types of models

sbml level

inhomogeneous models

sbml participants

limited semanticsraw

netbio neural models

pathway models http

sbml simulation outputtyson