1. Digital Human Meeting FAS, July 23, 2001 NLM, Bethesda, MD

2. “Biology must graduate from the cartoon diagram.”
-Bruce Alberts, NAS President
Princeton Institute for Integrative Genomics
Symposium on Biological Networks
May 2001

3. The Physiome Sciences Vision…
Providing technology to enable the creation of computer-based biological models from subcellular to organism levels
Promoting the acceptance of standards to permit the integration, exchange, and extension of models across organizational and geographic boundaries

4. Hierarchical modeling of biology
Physiome Sciences’ Approach
Hierarchical modeling of biology
Organ Systems
Individual Pathways
Cell
Organs
Signaling
systems

5. Pitfalls in building biological models
“Point” solutions
Models should be reusable and extensible
“Black boxes”
Data and assumptions should be accessible
Static data content
Models should be able to integrate new data as they become available
Defined ADME
Spelled out Toxicology

6. Overcoming pitfalls: In Silico CellTM architecture
3rd party applications
Modeling
tools
Mathematics
Database
CellMLTM
MathML
Simulations

7. What is CellMLTM? An extensible mark-up language (XML) that
Describes structure and mathematics of (sub)cellular models
Embeds metadata and documentation
Defines an extension mechanism
Facilitates re-use of models and model components (encapsulation)
Biological scope examples version 1.0:
Excitable cells
Reaction networks
Signaling pathways

8. Why CellMLTM?
Models are traditionally hard-coded in C, C++, Matlab, Mathematica
Publications often contain an incomplete set of equations and data
Very difficult to duplicate results and to exchange and extend models
CellML permits users to exchange all the information needed to represent (and run) a model

9. Development of CellMLTM as an open standard
“Physiome” Mark-Up Languages (CellML, FieldML, AnatML) developed as open standards in collaboration with University of Auckland
Website:
Mailing List:
Edit/Run/Validate Tools for CellML (Q3 2001)
CellML model repository (Q4 2001)

10. Modeling tool: Pathway Editor
Source: Jim Broach, Princeton University
Modeling tool: Pathway Editor

11. Modeling tool: Cell Editor
Permits integration of biochemistry (pathways) and electrophysiology within a cell-based tool
Outputs models to other software platforms for assembling more complex (organ, system) models

12. Modeling cardiac heterogeneity: single cell response to drug
Experimental data
Simulated Data
from Burashnikov and Antzelevitch, 1998
BCL = 300, 500, 1000, 2000, 4000, 6000 msec

13. Modeling cardiac heterogeneity: integrate from single cell to tissue
Anatomy
Ion channel density
Physiology AP
IKs
Ito
Epi
INa (late)
Endo
ECG 1x 6x
Expression level
Anatomy
Genome
Physiome

14. Predicting cardiac safety Antihistamines
Simulated ECG
analysis
Simulated cellular APs
at 3 concentrations
Input data
DQT
Amount of drug block
Worse 
DAPD
DQT
Better 
DAPD
Concentration (µM)
IKs
IKr
Ito

15. Summary
Physiome is working to provide a flexible framework for modeling biology across scales from the subcellular upwards.
Spatial heterogeneity in cardiac muscle as a case study towards integrated modeling of the heart.
XML-based standards (CellML, SBML, FieldML, AnatML) will facilitate exchange and reuse of models and components. We’ll have tools out soon.
Open source? We’re interested, but have yet to adopt an official stance.

16. for more info: