The ERATO Systems Biology Workbench

Hamid Bolouri

ERATO Kitano Systems Biology ProjectCalifornia Institute of Technology &

University of Hertfordshire, UK

Project PIs: Hiroaki Kitano and John Doyle

Software development team: Andrew Finney, Michael Hucka, Herbert Sauro

Collaborators:Adam Arkin (BioSpice), Dennis Bray (StochSim), Igor Goryanin (DBsolve),

Les Loew (VirtualCell), Pedro Mendes (Gepasi), Masaru Tomita (Ecell)

Acknowledgements: Mark Borisuk, Eric Mjolsness, Tau-Mu Yi

Resource Sharing, Motivation

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

Our goal:

provide software infrastructure to enable sharing of simulation software (current and future) and collaboration between developers (and modelers!)

+CH3R

ATP ADPP

~flagellarmotor

Z

Y

PY~

PiB

B~P

Pi

CW-CH3

ATP

WA

MCPs

WA

+ATT

-ATT

MCPs

Signal transduction

MotionLigandbinding

Motor

Example Workbench application: bacterial chemotaxis

Marlovits, Tyson, Novak, & Tyson, Biophysical Chemistry 72(1998) 169-184

k1k2

k3

k6

cyclin

cdc2

phosphorylation site

View from the genome, c=cytoplasmic , n=nuclear , mN=maternal N, nN=nuclear N, MVLAS=maternal vegetally localised catenin activating system

N-dependent-TXF

late signal from ~ 7th cleavage micromeres

Mes-TXF

Endo-Mes-TXF Serrate

?

&

A1Micromere id. factor

ZygoticApical N

X

MVLAS

n

cLiClGSK-3

nN

mN

mes mes

mac / veg2 mic

Late signal from veg2

veg1 veg2

frizzled

endomes endomes

&

OR

Endo-mesGenes

mic mic

&

Endo-only-TXF

OTX

Endo16

A-V model v10, April 4th, 2000

& & & OR &

Endo- specificGenes

& &

Wnt8

&

Maternalactivator

MesGenes

OR

ERATO Systems Biology Workbench: driving principles

• Integrate, don’t reinvent!– integrate existing simulators– use standard application integration methods

• object oriented, XML, Java and related technologies

• Accommodate future tools– minimize need for ad hoc solutions

• object oriented, XML, Java and related technologies

– XML & API standards for future contributors

• Make sure contributors benefit– symmetric plug-in infrastructure– open source code infrastructure software– widen user-base, but protect IPR of contributors

Systems Biology Markup Language [SBML]

• A common XML format for biochemical networks

• Enables exchange of models between simulators

• Developed in collaboration with BioSpice, DBsolve, Gepasi, Jarnac, Ecell, StochSim, VirtualCell

• Available for public review since Sept 2000 at ftp://ftp.cds.caltech.edu/pub/caltech-erato/sbml/sbml.pdf

• Proposed extensions due 2nd Quarter 2001

Example workbench plug-in modules

• Data filtering and preparation

– e.g. image processing, regression, clustering

• Database support

– e.g. web searching, storage management, translators, conflict resolution

• Model description tools

– scripts, languages, schematic tools

• Model preprocessing

– e.g. conserved quantities, redundancy removal

• Maths language / maths description support

• Equation solvers

– e.g. ODE, DAE, PDE, stochastic

• Analysis tools

– e.g. 2/3/4D graphing, bifurcation, MCA

• Optimization and parameter searching

Example potential plug-ins from DBsolve

• Data filtering and preparation – regression to implicit and explicit algebraic equations

• Database support – direct data import from WITT, MPW, KEGG

• Model description tools – stoichiometric matrix

• Model preprocessing – conserved quantities & redundancy removal

• Maths language / maths description support– maths editor

• Equation solvers – mixed ODE + NAE, LSODE

• Analysis tools – 2D graphing, bifurcation, continuation, all steady states

• Optimization and parameter searching– Hooke & Jeeves, Levenburg-Marquardt

Systems Biology Workbench - APIs

• APIs provided by the Workbench for simulators

– Will provide access to a spectrum of current tools

– Integration into 3rd party simulators will require:– SBML output

– One menu item associated with one external library call

– Available Q1 2001

– Lower level APIs for optimization, bifurcation, time-based simulation and data display will follow, Q2 2001

• APIs provided by simulators to plug into Workbench

– Existing collaborators

• no API conformance, we will interface to given APIs

• The minimum requirement:

– Either parse SBML, parse equivalent documented format or provide a model construction API

– Output some documented numeric format or structure

– Future contributors to SBW

• Standard API for independent development available Q2 2001

Systems Biology Workbench - APIs

• APIs provided by the Workbench for simulators

– Will provide access to a spectrum of current tools

– Integration into 3rd party simulators will require:– SBML output

– One menu item associated with one external library call

– Available Q1 2001

– Lower level APIs for optimization, bifurcation, time-based simulation and data display will follow, Q2 2001

• APIs provided by simulators to plug into Workbench

– Existing collaborators

• no API conformance, we will interface to given APIs

• The minimum requirement:

– Either parse SBML, parse equivalent documented format or provide a model construction API

– Output some documented numeric format or structure

– Future contributors to SBW

• Standard API for independent development available Q2 2001

Workbench Development Plan

Task Nov Dec Jan Feb Mar Apr May

Design

GUI and Simulation Engine (Sauro)

Stochastic Simulation (Gibson)

Bifurcation analysis (Goryanin)

Param. optimization (Mendes)

Multi-representation simulation

Linux Port

QA, Install etc