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Measure Model Manipulate The Center for Cell Analysis and Modeling focuses on creating new technologies for understanding the dynamic distributions of molecules in living cells. Three Technology Development projects integrate multidisciplinary approaches to Measure, Model and Manipulate intracellular events. Developing tools to address a fundamental problem of cell function: how signaling networks regulate, and are regulated by, the spatial organization of molecules in cells Model

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Page 1: Measure Model Manipulate The Center for Cell Analysis and Modeling focuses on creating new technologies for understanding the dynamic distributions of

MeasureModel

Manipulate

The Center for Cell Analysis and Modeling focuses on creating new technologies for understanding the dynamic distributions of molecules in living cells. Three Technology Development projects integrate multidisciplinary approaches to Measure, Model and Manipulate intracellular events.

Developing tools to address a fundamental problem of cell function: how signaling networks regulate, and are regulated by, the spatial organization of molecules in cells

Model

Page 2: Measure Model Manipulate The Center for Cell Analysis and Modeling focuses on creating new technologies for understanding the dynamic distributions of

Random walk in crowded spacesOrthogonal cylindrical lattice Randomly placed cylinders

Page 3: Measure Model Manipulate The Center for Cell Analysis and Modeling focuses on creating new technologies for understanding the dynamic distributions of

gfit - software for global analysis of experiments

Page 4: Measure Model Manipulate The Center for Cell Analysis and Modeling focuses on creating new technologies for understanding the dynamic distributions of

VCell actin polymerization and branching model

L. Loew, N. Vacanti, J. Ditlev

Page 5: Measure Model Manipulate The Center for Cell Analysis and Modeling focuses on creating new technologies for understanding the dynamic distributions of

Virtual Cell – Usage

Sept 06

Total Registered VCell Users – 9,644Users Who Ran Simulations – 1,277Currently Stored Models – 17,295Currently Stored Simulations – 30,559Publicly Available Models – 343Publicly Available Simulations - 710

Feb 08

→ 11,082→ 1,737→ 23,805→ 112,974→ 531→ 1,887

Page 6: Measure Model Manipulate The Center for Cell Analysis and Modeling focuses on creating new technologies for understanding the dynamic distributions of

The ProblemThe Problem

Page 7: Measure Model Manipulate The Center for Cell Analysis and Modeling focuses on creating new technologies for understanding the dynamic distributions of

Quantitative Cell BiologyQuantitative Cell Biology

Predictions

Dynamics of Cellular Structures and

Molecules

Simulation

Hypothesis (Model)

• What are the initial concentrations, diffusion coefficients and locations of all the implicated molecules?

• What are the rate laws and rate constants for all the biochemical transformations?

• What are the membrane fluxes and how are they regulated?

• How are the forces controlling cytoskeletal mechanics regulated?

ExperimentExperiment

Trends in Cell Biology 13:570-576 (2003)

Page 8: Measure Model Manipulate The Center for Cell Analysis and Modeling focuses on creating new technologies for understanding the dynamic distributions of

Mathematical Description(view-only, automaticallygenerated)

Mathematical Description(view-only, automaticallygenerated)

Mathematical Description(view-only, automaticallygenerated)

ResultsResultsResults

Applications

Structure mapping(topology to geometry)Initial ConditionsBoundary conditionsDiffusion constants (if spatial)Electrophysiology protocolsEnable/disable reactionsFast reactionsModel analysisStochastic rate conversion

Applications

Structure mapping(topology to geometry)Initial ConditionsBoundary conditionsDiffusion constants (if spatial)Electrophysiology protocolsEnable/disable reactionsFast reactionsModel analysisStochastic rate conversion

Applications

Structure mapping(topology to geometry)Initial ConditionsBoundary conditionsDiffusion constants (if spatial)Electrophysiology protocolsEnable/disable reactionsFast reactionsModel analysisStochastic rate conversion

Simulations

TimecourseTimestepMesh sizeSolver typeSolver settingsParameter changesParameter scansParameter sensitivity

Simulations

TimecourseTimestepMesh sizeSolver typeSolver settingsParameter changesParameter scansParameter sensitivity

Simulations

TimecourseTimestepMesh sizeSolver typeSolver settingsParameter changesParameter scansParameter sensitivity

Physiology

MoleculesStructures(topology)

ReactionsFluxes

Page 9: Measure Model Manipulate The Center for Cell Analysis and Modeling focuses on creating new technologies for understanding the dynamic distributions of

Compute Cluster

Simulation Worker Service

Physiology Editor Geometry EditorApplication Editor

Physiology

Reactions

Species

Structures

Fluxes

Diagrams

Application

Reaction Specificatio

n

Species Specificatio

n

Electrical Protocols

Structure Mapping

Model Analysis

Simulation Editor Simulation

Monitor

MathDescription

Geometry

Domains

Parameters

Equations

Simulation

Math Description

Parameter Overrides

Solver Specifications Data ViewerData Exporter

Math Generation Service

Slow Reaction Stoichiometry Analyzer

Fast Reaction Stoichiometry Analyzer

Electrical Circuit Analyzer

Math Description Generator

Geometry

Subvolumes

Regions

Surfaces

Connection Service

Authentication Service

Job Control Service

Data Service

Persistence Service

Remote Message Handler

Document Manager

Simulation Data

JMS Broker

(SonicMQ)

Siumulation Data Service

Data Export Service

Database Service

Simulation Dispatch Service

Database(Oracle)

ConnectionManager

ServerManager

Database ServiceDatabase Service

Data Export ServiceData Export

Service

Siumulation Data ServiceSiumulation Data

Service

Simulation Dispatch ServiceSimulation

Dispatch Service

Simulation Worker ServiceSimulation

Worker Service

Compiled Simulation JobsCompiled

Simulation JobsCompiled Simulation JobsCompiled

Simulation JobsCompiled Simulation JobsCompiled

Simulation JobsCompiled Simulation Jobs

Batch Scheduler(PBSPro)

StorageCluster

Distributed ArchitectureDistributed Architecture

Page 10: Measure Model Manipulate The Center for Cell Analysis and Modeling focuses on creating new technologies for understanding the dynamic distributions of

single modellocations/molecules/mechanisms

non-spatial appsODEs, sensitivity analysismultiple simulations

spatial apps1D,2D,3D PDEsreaction/diffusion/advectionmultiple simulations

Page 11: Measure Model Manipulate The Center for Cell Analysis and Modeling focuses on creating new technologies for understanding the dynamic distributions of

non-spatial “Math Model”ODEs, sensitivity analysismultiple simulations

spatial “Math Model”1D,2D,3D PDEsreaction/diffusion/advectionmultiple simulations

Math ModelsMath Models

Page 12: Measure Model Manipulate The Center for Cell Analysis and Modeling focuses on creating new technologies for understanding the dynamic distributions of

Minimal Usage Minimal Usage RequirementsRequirements

► RegistrationRegistration Free; separate link on websiteFree; separate link on website

► JavaJava Version 1.5 or later (except Mac – 1.4 required)Version 1.5 or later (except Mac – 1.4 required) Runs as installed application or as web appletRuns as installed application or as web applet

► Internet connection (for full functionality)Internet connection (for full functionality) Required for:Required for:

► Database accessDatabase access► Running simulationsRunning simulations► Viewing resultsViewing results

Fast & without firewalls! – but will use tunneling…Fast & without firewalls! – but will use tunneling…► A large monitor… !A large monitor… !

Page 13: Measure Model Manipulate The Center for Cell Analysis and Modeling focuses on creating new technologies for understanding the dynamic distributions of

Typical usageTypical usage► Define physiologyDefine physiology

Create compartmentsCreate compartments Add speciesAdd species Add reactions/fluxesAdd reactions/fluxes

► Create an applicationCreate an application Choose and map geometry (try compartmental first!!)Choose and map geometry (try compartmental first!!) Specify initial conditionsSpecify initial conditions

► Create a simulationCreate a simulation Choose resolutionChoose resolution Choose numerical conditions (timestep!!)Choose numerical conditions (timestep!!)

► Run simulationRun simulation► View resultsView results

Export and analyze dataExport and analyze data► Create new simulations…Create new simulations…► Create new applications…Create new applications…► Create new BioModels…Create new BioModels…

Page 14: Measure Model Manipulate The Center for Cell Analysis and Modeling focuses on creating new technologies for understanding the dynamic distributions of
Page 15: Measure Model Manipulate The Center for Cell Analysis and Modeling focuses on creating new technologies for understanding the dynamic distributions of
Page 16: Measure Model Manipulate The Center for Cell Analysis and Modeling focuses on creating new technologies for understanding the dynamic distributions of

Math and PhysicsMath and Physics

iii R

t

C Fdiv

RT

FD=CzCCD i

iiiiiiiii VF ,

CkBAkiR 11

k1 A + B C , k1

Page 17: Measure Model Manipulate The Center for Cell Analysis and Modeling focuses on creating new technologies for understanding the dynamic distributions of

Current Scope and Future Current Scope and Future PlansPlans

► Intended UsersIntended Users BiologistsBiologists Biophysicists/MathematiciansBiophysicists/Mathematicians

► Modeling domainModeling domain Compartmental or 1D, 2D, 3D GeometryCompartmental or 1D, 2D, 3D Geometry Reaction/Diffusion/Membrane TransportReaction/Diffusion/Membrane Transport Electric Potential (electrophysiology)Electric Potential (electrophysiology) Advection & Directed TransportAdvection & Directed Transport Membrane DiffusionMembrane Diffusion Optimization & parameter scansOptimization & parameter scans

► Under developmentUnder development Stochastic ProcessesStochastic Processes ComplexesComplexes ProtocolsProtocols Constraints & Virtual ExperimentsConstraints & Virtual Experiments Stand-alone & grid-based versionsStand-alone & grid-based versions New architecture – plug-ins, modules, etc. (VCell New architecture – plug-ins, modules, etc. (VCell

OpenSource)OpenSource) Cell motilityCell motility

Page 18: Measure Model Manipulate The Center for Cell Analysis and Modeling focuses on creating new technologies for understanding the dynamic distributions of

Standards and ResourcesStandards and Resources► Languages and OntologiesLanguages and Ontologies

SBMLSBML CellMLCellML

► VCell imports/exports SBML, CellML… VCell imports/exports SBML, CellML… VCML VCML BioPAXBioPAX SBOSBO SBGNSBGN MIRIAMMIRIAM MIRIAM2, MIASE, KiSAO…MIRIAM2, MIASE, KiSAO…

► RepositoriesRepositories BioModels databaseBioModels database JWS OnlineJWS Online Database of Quantitative Cellular SignalingDatabase of Quantitative Cellular Signaling CellML model repositoryCellML model repository

Page 19: Measure Model Manipulate The Center for Cell Analysis and Modeling focuses on creating new technologies for understanding the dynamic distributions of

Combinatorial Combinatorial ComplexityComplexity

and Modularityand Modularity

– 2 examples of external – 2 examples of external tools integration – tools integration –

Page 20: Measure Model Manipulate The Center for Cell Analysis and Modeling focuses on creating new technologies for understanding the dynamic distributions of

Solution 1: BioNetGen@VCellSolution 1: BioNetGen@VCell

http://vcell.org/bionetgenhttp://vcell.org/bionetgen

Page 21: Measure Model Manipulate The Center for Cell Analysis and Modeling focuses on creating new technologies for understanding the dynamic distributions of
Page 22: Measure Model Manipulate The Center for Cell Analysis and Modeling focuses on creating new technologies for understanding the dynamic distributions of

Solution 2: BioPAX@VCellSolution 2: BioPAX@VCell

http://reactome.orghttp://reactome.org

Page 23: Measure Model Manipulate The Center for Cell Analysis and Modeling focuses on creating new technologies for understanding the dynamic distributions of

a)

b)

c)

Page 24: Measure Model Manipulate The Center for Cell Analysis and Modeling focuses on creating new technologies for understanding the dynamic distributions of

DB1(Reactome.or)

DB2(NetPath.org)

DB3(BioModels.net)

MetaModel(BioPax)

MetaModel(BioPax)

VCellPhysiological

Model

MergedMetaModel(BioPax)

BioPax modelingframewoek

SBMLModel

SBMLModel

BioPax modelingframewoek

BioPax modelingframewoek

SBMLModel

DB1(Reactome.or)

DB2(NetPath.org)

DB3(BioModels.net)

BioPAX Model BioPAX Model

VCellPhysiological

Model

MergedBioPAX Model

VCell repositoryof reusableSBML Models

BioPax modelingframework

Reusable S BMLModel

Reusable S BMLModel

BioPax modelingframework

BioPax modelingframework

Reusable S BMLModel

VCellPhysiological

Model

VCellPhysiological

Model

VCellPhysiological

Model

VCellPhysiological

Model

Page 25: Measure Model Manipulate The Center for Cell Analysis and Modeling focuses on creating new technologies for understanding the dynamic distributions of

Standalone VCell ApplicationsStandalone VCell Applications

► ‘‘Virtual FRAP’ toolVirtual FRAP’ tool Data-centric, predefined contextData-centric, predefined context First prototype standalone applicationFirst prototype standalone application

► ‘‘Virtual Microscopy’ toolVirtual Microscopy’ tool Model-centric, more flexibleModel-centric, more flexible

Page 26: Measure Model Manipulate The Center for Cell Analysis and Modeling focuses on creating new technologies for understanding the dynamic distributions of

Leveraging CMU ResourcesLeveraging CMU Resources1.1. What?What?

Connect VCell to PSLID and SLIFConnect VCell to PSLID and SLIF Use generative models for Use generative models for

“virtual” geometries and “virtual” geometries and “virtual” molecular distributions“virtual” molecular distributions

2.2. Why?Why? Provide a large source of public Provide a large source of public

image-based geometries and image-based geometries and quantitative data to VCell usersquantitative data to VCell users

Provide realistic “artificial” data Provide realistic “artificial” data to complement/supplant real to complement/supplant real datadata

3.3. How?How? Search/import interface for CMU Search/import interface for CMU

databasesdatabases XML repository of generative XML repository of generative

modelsmodels Server-side Matlab librariesServer-side Matlab libraries Use field data for conversionUse field data for conversion


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