The ERATO Systems Biology Workbench Michael Hucka, Hamid Bolouri, Andrew Finney, Herbert Sauro ERATO...

The ERATO Systems Biology Workbench

Michael Hucka, Hamid Bolouri,Andrew Finney, Herbert Sauro

ERATO Kitano Systems Biology ProjectCalifornia Institute of Technology, Pasadena, CA, USA

Principal Investigators: John Doyle, Hiroaki Kitano

Collaborators: Adam Arkin (BioSpice), Dennis Bray (StochSim), Igor Goryanin (DBsolve), Les Loew (Virtual Cell), Pedro Mendes

(Gepasi/Copasi), Masaru Tomita (E-Cell)

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Background• Modeling, simulation & analysis are critical

– Huge volumes of data– Many disparate findings

• Rapid rate of software tool development– Roles: data filtering, model creation, model simulation – Many groups are creating many tools

• Different packages have different niche strengths reflecting expertise & preferences of the group

• Strengths are often complementary to those of other packages

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Complementary Strengths of Tools

Tool 7

Tool 3

Tool 4

Tool 2

Tool 6

Tool 5

Tool 1

Multistate reactions/stochastic

Reaction/Diffusion

Visualization of networks

Optimization

Bifurcation analysis

Handle large systems

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Problems• No single package answers all needs of modelers

• No single tool is likely to do so in the near future– Range of capabilities is large– New techniques ( new tools) evolving too rapidly

• Researchers are likely to continue using multiple packages for the foreseeable future

• Problems in using multiple tools:– Simulations & results often cannot be shared or re-used – Duplication of software development effort

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Goal & Approach• Systems Biology Workbench goal: to provide

software infrastructure that – Enables sharing of simulation/analysis software & models

– Enables collaboration between software developers

• Two-pronged approach:– Develop a common model exchange language

• SBML: Systems Biology Markup Language– Develop an environment that enables tools to interact

• SBW: Systems Biology Workbench

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Systems Biology Markup Language

• Problem:– Many software tools, few common exchange formats

• Difficult to take advantage of multiple tools• Difficult to establish repositories of models

• A Solution (In Principle):– Define a common exchange language

• Use a simple, well-supported, textual substrate (XML)• Add components that reflect the natural conceptual

constructs used by modelers in the domain

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• Domain: biochemical network models

• A model is described using a list of components:

– Beginning of model definition» List of unit definitions (optional)» List of compartments» List of species» List of parameters (optional)» List of rules (optional)» List of reactions

– End of model definition

• Each component has a specific structure

Structure of Model Definitions in SBML

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Example

S1

X2

X1

k1*X0

k2*S1

k3*S1

X0

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Example (cont.)<?xml version=“1.0” encoding=“UTF-8”?><sbml level=“1” version=“1”> <model name=“simple”>

<listOfCompartments> <compartment name=“c1” /> </listOfCompartments>

<listOfSpecies> <specie name=“X0” compartment=“c1” boundaryCondition=“true” initialAmount=“1”/> <specie name=“S1” compartment=“c1”

boundaryCondition=“false” initialAmount=“0”/> <specie name=“X1” compartment=“c1”

boundaryCondition=“true” initialAmount=“0”/> <specie name=“X2” compartment=“c1”

boundaryCondition=“true” initialAmount=“0.23”/> </listOfSpecies>

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Example (cont.)<?xml version=“1.0” encoding=“UTF-8”?><sbml level=“1” version=“1”> <model name=“simple”>

<listOfCompartments> <compartment name=“c1” /> </listOfCompartments>

<listOfSpecies> <specie name=“X0” compartment=“c1” boundaryCondition=“true” initialAmount=“1”/> <specie name=“S1” compartment=“c1”

boundaryCondition=“false” initialAmount=“0”/> <specie name=“X1” compartment=“c1”

boundaryCondition=“true” initialAmount=“0”/> <specie name=“X2” compartment=“c1”

boundaryCondition=“true” initialAmount=“0.23”/> </listOfSpecies>

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Example (cont.)<?xml version=“1.0” encoding=“UTF-8”?><sbml level=“1” version=“1”> <model name=“simple”>

<listOfCompartments> <compartment name=“c1” /> </listOfCompartments>

<listOfSpecies> <specie name=“X0” compartment=“c1” boundaryCondition=“true” initialAmount=“1”/> <specie name=“S1” compartment=“c1”

boundaryCondition=“false” initialAmount=“0”/> <specie name=“X1” compartment=“c1”

boundaryCondition=“true” initialAmount=“0”/> <specie name=“X2” compartment=“c1”

boundaryCondition=“true” initialAmount=“0.23”/> </listOfSpecies>

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Example (cont.)<listOfReactions>

<reaction name=“reaction_1” reversible=“false”> <listOfReactants> <specieReference specie=“X0” stoichiometry=“1”/> </listOfReactants> <listOfProducts> <specieReference specie=“X0” stoichiometry=“1”/> </listOfProducs> <kineticLaw formula=“k1 * X0”> <listOfParameters> <parameter name=“k1” value=“0”/> </listOfParameters> </kineticLaw> </reaction>

<reaction name=“reaction_2” reversible=“false”> <listOfReactants> <specieReference specie=“S1” stoichiometry=“1”/> </listOfReactants> . . .

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Some Points About SBML• Users do not write in XML — software tools do!• SBML is being defined incrementally

– SBML Level 1 covers non-spatial biochemical models• Intentionally kept simple for maximal compatibility

– SBML Level 2 will extend Level 1 with more facilities

• Defined in abstract form (UML) + textual descriptions– Used to define XML encoding + XML Schema

Level 2

Level 3?

Level 1

E.g.: • Composition• Geometry• Arrays… others

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Systems Biology Workbench• Open-source, integrated software environment

that enables sharing of computational resources– Allows software developers to build interprocess

communications facilities into their applications

• From the user’s perspective:– One SBW-enabled application can interact with another– Each application or module offers services to others

• E.g.: ODE solution, time-based simulation, visualization, etc.

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From the User’s Perspective

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From the User’s Perspective

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From the User’s Perspective

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Behind the Scenes

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From the Programmer’s Perspective

• Desirable features– Small application programming interface (API)– Libraries that implement inter-program communications– A registry of services for applications to query– XML-based model representation (SBML)

• Uses well-known, proven technologies– Communications via message-passing over plain sockets– Modular, distributed, broker-based architecture

• API provides two styles:– “Low-level”: call/send operations + directory services– “High-level”: object-oriented interface layered on top

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Driving Principles• Keep it language-neutral

– We’ll provide C++, Java, Delphi libraries for Win, Linux• But can be implemented in any language

• Keep it simple– Simple message-passing scheme

• Avoid complexity & size of CORBA• Easy to make cross-platform compatible• Easy to make distributed

– Simple low-level API, convenient higher-level API

• Make sure contributors benefit– Open source development– Symmetric infrastructure: no application dominates

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Modules Planned• Data filtering & preparation

• Database support– E.g.: web searching, storage management

• Model definition & manipulation– E.g.: scripting languages, visual editors

• Equation solvers– E.g.: ODEs, DAEs, stochastic

• Analysis & visualization tools– E.g.: bifurcation, 2-D/3-D/4-D plotting

• Optimization & parameter searching

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Summary & Availability• SBML

– Level 1 specification is publicly available• http://www.cds.caltech.edu/erato

– Support being added by other groups to their apps

• SBW– Preliminary test implementation completed– Production version is now in development

• Draft API definition & other info available– http://www.cds.caltech.edu/erato/sbw/docs

– Expect first public release in November atICSB 2001 (http://www.icsb2001.org)

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Outline1) Background and motivations

I.e., why are we doing this?

2) Systems Biology Markup Language (SBML)

Model description language & exchange format

3) Systems Biology Workbench

Infrastructure for connecting software tools

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Scope of SBML• Domain: biochemical network models

S1 S2 S3X0 X1

K1*X0 - S1*K2

S3/Ki

Vmax*S1

Km+S1

k3*S2

k4*S2 - k5*S3 k6*S3

k7*S3*S12

X2