Modeling with the Systems Biology Workbench

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Modeling with the Systems Biology Workbench

• Herbert M Sauro
• Frank Bergmann
• University of Washington
• Department of Bioengineering
• Seattle, WA

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Why Develop Software?

• Basic simulation software can now be purchased
  off the self, a much cheaper option that
  developing equivalent solutions in house.
• Reasons for Academia to development software
• New algorithms
• New visualization techniques
• New biological applications.
• Pushing the envelope on software
• provision in Systems Biology.

SimBiology Matlab (30 man hours)
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Topics

1. Modeling
2. Architecture
3. Using the software

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Differential Equation Models
Basic System Equations
v reaction rate
Let S be a molecular species in a cellular map
Molecule S
then the rate at which S changes in time is given
by the equation


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Differential Equation Models
Simple example


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Model Definition
Stoichiometry Matrix
Species Vector
Rate Vector
Parameter Vector
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What we Actually Use
Reduced Stoichiometry Matrix
Independent Species
Dependent Species
Part of the Link Matrix
Conservation Vector Totals
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An Example
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An Example
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An Example
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Why is Reduction Important?
Because it permits us to compute a non-singular
Jacobian
Reduced Stoichiometry Matrix
Elasticity Matrix
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Transfer Function
Transfer Function


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Why is the Jacobian Important?
Steady-State
Time Course
Stochastic
Jacobian
Elasticities
Kinetic Laws
(N N L K C)
r
Model
Stoichiometry
SBML
SBW
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Choosing Appropriate Rate Laws

• Different kinds of rate laws for continuous
  modeling
• Mass-action
• Aggregate Rate laws, e.g. Michaelis-Menten
• Power Laws S Systems
• LinLog

Joseph Heijnen and Diana Visser Delft University
of Technology, The Netherlands
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Choosing Appropriate Rate Laws
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SBW Architecture
SBW is a lightweight framework that allows
different applications written in different
languages and on different platforms to
communicate.
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SBW Architecture
Remote Communication
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SBW Architecture
Remote Communication
Web Service
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SBW Architecture
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Perspectives Developer
Windows, Linux and Mac OSX
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Programmers Perspective

• Small application programming interface (API)
• Minimize the amount of work necessary to
  implement
• - Libraries implement inter-program
  communications
• - A registry of services for applications to
  query
• - XML-based model representation (SBML)

- Modular, distributed, broker-based architecture
Uses a simple lightweight binary TCP/IP
communication protocol
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Message Structure

• - Messages are passed as binary streams via
  TCP/IP
• - Blocking and non-blocking calls
• - Exception handling built-in

Supported types in the payload Byte, Boolean,
int, double, string, complex, arrays,
lists Details on SBWs internal architecture can
be found at Sauro HM, Hucka M, Finney A,
Wellock C, Bolouri H, Doyle J and Kitano H.
(2003) Next generation simulation tools the
Systems Biology Workbench and BioSPICE
integration. OMICS. 2003 Winter7(4)355-72.
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Resource Structure
mathModule
Module Level

log
trig

Service Level
log10

sin
ln

cos
Method Level
exp

tan
Demo Inspector
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Exposing methods
public class sbwInterface Help("Returns
the Sine of a value") public double Sin(double
value) return Math.Sin (value)

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Using Other Modules VS Addon
C,C,C
Module Lib File
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Example - Matlab
Building Matlab Services
function y myAdd (a, b) SBW module
SBWMath SBW service myService SBW
method myAdd service myService sigdouble
myAdd(double,double) y a b
Calling SBW from Matlab CLI
sbwconnect getSBML sbwGetMethod (JDesigner,
model, string getSBML()) sbwStr sbwCall
(getSBML)
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Web Services from SBW/BioSPICE
A Web Application is provided that allows every
SBW Module to be wrapped up in a Web Service
Web Service Generator web page available
at http//134.173.97.95/sbwwebservicecreatorinterf
ace/webform1.aspx
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Web Interface Example
http//134.173.97.95/simulation/webform1.aspx
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Categories
Dynamically locate services in a given category

• Categories permit SBW applications to recognize
  standard interfaces
• in other SBW applications. We currently have
  three defined categories
• Translation
• Analysis
• Simulation

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Categories
Translation
SBW applications that define the translation
category are capable of translating SBML into
some other format (eg Matlab, XPP) and
returning the translation to the caller.
Analysis
SBW applications that define the analysis
category are capable of accepting an SBML model
and by implication are capable of doing
something with the model.
Simulation
SBW applications that define the simulation
category mean they support the simulation API.
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User Experience
Categories permit users to move seamlessly from
one application to another taking with them the
model under study
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SBW Menu
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Perspectives User
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Available SBW Simulators
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Available SBW Modules
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Examples Model Editors
JDesigner
cellDesigner
http//www.sys-bio.org/
http//celldesigner.org/
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Discovering Qualitative Behavior
Discovery Tool Used to search for possible
oscillators and bistable switches in
stoichiometric networks. The tool uses a
search technique based on a genetic algorithm.

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Discovery Tool
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Specialist ModulesEmery Conrads Oscill8
Interface
Implements the Analysis category so that models
can be accessed from SBW.
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Specialist Modules Structural Analysis Tool
Implements the analysis category.
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Specialist Modules Frequency Analysis Tool
Implements the Analysis category and permits
the frequency response of a model to be
determined.
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Specialist Modules Stochastic Simulators
Implements the analysis category and permits
models to be simulated using a stochastic
solver. Supports additional analysis such as PDF
generation, Power Spectra, autocorrelation, popula
tion metrics. The GUI implements a callback to
the Gillespie simulators to support the progress
bar.
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Auto layout of SBML models
We use this tool to take raw SBML and generate
SBML containing the layout standard that is being
developed by the SBML community. Uses a spring
and mass model to determine layout. Has specific
rules for determining Bezier orientation and
Includes a gravity field to main cohesion of
disconnected sub-graphs. Anastasia Deckard
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3D Visualization of Simulation Runs
Based on OpenGL, currently an installer is
available for Windows but the source is portable
to the Mac and Linux. Requires a decent graphics
card for maximum gratification! (
http//public.kgi.edu/fbergman )
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3D Visualization of Simulation Runs
Based on OpenGL, currently an installer is
available for Windows but the source is portable
to the Mac and Linux. Requires a decent graphics
card for maximum gratification!
(http//public.kgi.edu/fbergman )
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3D Visualization of Simulation Runs
QT Based version
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SBW Workflow for 3D Tool
Structural Analysis Module
SBML Module
Simulator
Model Editor
3D Interface
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Availability

RoadRunner (Simulator) X X X
Network Layout ( Service / GUI ) X / X X / X / X
SimDriver (Simulator GUI) X X
StructAnalysis Tool X X
Bifurcation Discovery Tool X X
Jarnac / JarnacLite X - / - / X
SBML Translators X X X
3D Tool X X X
JDesigner X - -
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Example Usage
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Acknowledgments
Frank Bergmann (SBW) Ravi Rao (Structural
Analysis) Vijay Chickarmane (Bif Discovery
Tool) Anastasia Deckard (Docs, layout tool) Sri
Paladugu (libSBML intregration) Mike Hucka and
Ben Bornstein (libSBML) Alan Hindmarsh
(CVODE) Nowak and Weimann (NLEQ) LAPACK
(NSF/DOE) Availability
GTL
www.sys-bio.org http//public.kgi.edu/fbergman
BioSPICE
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Exposing methods
// create a new service sbwInterface oService
new sbwInterface() // create SBW
module ModuleImplementation oModule new
ModuleImplementation( "edu.kgi.trig", Tri
g Module", LowLevel.ModuleManagementType.Uniqu
eModule, "Provides Trig Functions") // add
the service to it oModule.addService( trig",
Trig Module", "plugin/math/trig", Provides
Trig Functions", ref oService)
oModule.run(args)
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Generic Simulation Interface
Any simulator that implements the Sim API (even
level 1) will automatically be able to use the
interface via this generic simulation interface.
Those API methods that are not supported are
disabled in the interface.