1. 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

2. Random walk in crowded spaces Orthogonal cylindrical lattice Randomly placed cylinders

3. gfit - software for global analysis of experiments

4. VCell actin polymerization and branching model L. Loew, N. Vacanti, J. Ditlev

5. Virtual Cell – Usage Sept 06 Total Registered VCell Users – 9,644 Users Who Ran Simulations – 1,277 Currently Stored Models – 17,295 Currently Stored Simulations – 30,559 Publicly Available Models – 343 Publicly Available Simulations - 710 Feb 08 → 11,082 → 1,737 → 23,805 → 112,974 → 531 → 1,887

6. The Problem

7. Quantitative 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? Experiment Trends in Cell Biology 13:570-576 (2003)

8. Mathematical Description (view-only, automatically generated) Mathematical Description (view-only, automatically generated) Mathematical Description (view-only, automatically generated) Results Applications Structure mapping (topology to geometry) Initial Conditions Boundary conditions Diffusion constants (if spatial) Electrophysiology protocols Enable/disable reactions Fast reactions Model analysis Stochastic rate conversion Applications Structure mapping (topology to geometry) Initial Conditions Boundary conditions Diffusion constants (if spatial) Electrophysiology protocols Enable/disable reactions Fast reactions Model analysis Stochastic rate conversion Applications Structure mapping (topology to geometry) Initial Conditions Boundary conditions Diffusion constants (if spatial) Electrophysiology protocols Enable/disable reactions Fast reactions Model analysis Stochastic rate conversion Simulations Timecourse Timestep Mesh size Solver type Solver settings Parameter changes Parameter scans Parameter sensitivity Simulations Timecourse Timestep Mesh size Solver type Solver settings Parameter changes Parameter scans Parameter sensitivity Simulations Timecourse Timestep Mesh size Solver type Solver settings Parameter changes Parameter scans Parameter sensitivity Physiology Molecules Structures (topology) Reactions Fluxes

9. Compute Cluster Simulation Worker Service Physiology EditorGeometry 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 Viewer Data 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) Connection Manager Server Manager Database Service Data Export Service Siumulation Data Service Simulation Dispatch Service Simulation Worker Service Compiled Simulation Jobs Batch Scheduler (PBSPro) Storage Cluster Distributed Architecture

10. single model locations/molecules/mechanisms non-spatial apps ODEs, sensitivity analysis multiple simulations spatial apps 1D,2D,3D PDEs reaction/diffusion/advection multiple simulations

11. non-spatial “Math Model” ODEs, sensitivity analysis multiple simulations spatial “Math Model” 1D,2D,3D PDEs reaction/diffusion/advection multiple simulations Math Models

12. Minimal Usage Requirements ► Registration  Free; separate link on website ► Java  Version 1.5 or later (except Mac – 1.4 required)  Runs as installed application or as web applet ► Internet connection (for full functionality)  Required for: ► Database access ► Running simulations ► Viewing results  Fast & without firewalls! – but will use tunneling… ► A large monitor… !

13. Typical usage ► Define physiology  Create compartments  Add species  Add reactions/fluxes ► Create an application  Choose and map geometry (try compartmental first!!)  Specify initial conditions ► Create a simulation  Choose resolution  Choose numerical conditions (timestep!!) ► Run simulation ► View results  Export and analyze data ► Create new simulations… ► Create new applications… ► Create new BioModels…

16. Math and Physics

17. Current Scope and Future Plans ► Intended Users  Biologists  Biophysicists/Mathematicians ► Modeling domain  Compartmental or 1D, 2D, 3D Geometry  Reaction/Diffusion/Membrane Transport  Electric Potential (electrophysiology)  Advection & Directed Transport  Membrane Diffusion  Optimization & parameter scans ► Under development  Stochastic Processes  Complexes  Protocols  Constraints & Virtual Experiments  Stand-alone & grid-based versions  New architecture – plug-ins, modules, etc. (VCell OpenSource)  Cell motility

18. Standards and Resources ► Languages and Ontologies  SBML  CellML ► VCell imports/exports SBML, CellML…  VCML  BioPAX  SBO  SBGN  MIRIAM  MIRIAM2, MIASE, KiSAO… ► Repositories  BioModels database  JWS Online  Database of Quantitative Cellular Signaling  CellML model repository

19. Combinatorial Complexity and Modularity – 2 examples of external tools integration –

20. Solution 1: BioNetGen@VCell http://vcell.org/bionetgen http://vcell.org/bionetgen

22. Solution 2: BioPAX@VCell http://reactome.org http://reactome.org

25. Standalone VCell Applications ► ‘Virtual FRAP’ tool  Data-centric, predefined context  First prototype standalone application ► ‘Virtual Microscopy’ tool  Model-centric, more flexible

26. Leveraging CMU Resources 1. What?  Connect VCell to PSLID and SLIF  Use generative models for “virtual” geometries and “virtual” molecular distributions 2. Why?  Provide a large source of public image-based geometries and quantitative data to VCell users  Provide realistic “artificial” data to complement/supplant real data 3. How?  Search/import interface for CMU databases  XML repository of generative models  Server-side Matlab libraries  Use field data for conversion

27. The Virtual Cell Project Michael Blinov John Carson Yung-Sze Choi Ann Cowan Fei Gao Pavel Kraikiwski Susan Krueger Anu Lakshminarayana Michael Levin Frank Morgan Igor Novak Diana Resasco Li Ye Rashad Badrawi Jeff Dutton Daniel Lucio Dong-Guk Shin John Wagner Elizabeth Weitzke Nick Hernjak Les LoewJim Schaff Ion MoraruBoris Slepchenko