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

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

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

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

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

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

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

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

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: www.CellML.org Mailing List: info@CellML.org Edit/Run/Validate Tools for CellML (Q3 2001) CellML model repository (Q4 2001)

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

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

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

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

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

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.

for more info: www.physiome.com info@physiome.com