Physiome and Virtual Heart Eun Bo Shim, Ph.D. Department of Mechanical Engineering Kangwon National University

Limitation of Genome Project Genomic theory : 1) Discovery of the gene related with a specific disease 2) Discovery of the protein related with the gene 3) Correction or bypassing of the malfunction protein based on its structure & function or Discovery of gene therapy to replace faulty gene Unsuccessful !!!! Reason : fundamental failure to understand biological complexity

Why ? Problem 1 : the function of a gene is NOT specified in the DNA language Problem 2 : each gene plays roles in MULTIPLE functions Problem 3 : each function arises from co-operation of MANY genes Problem 4 : function also depends on important properties NOT specified by genes - properties of water, lipids, self-assembly etc… Problem 5 : nature has built-in fail-safe ‘redundancy’ - this ONLY emerges at the functional level

Post – Genome Era Genome  Proteome (on-going) Metabolome ……. Physiome : From Genes to Function

What is the Physiome? “The Physiome Project is an integrated program whose mission is to archive and disseminate quantitative data and models of the functional behavior of biological molecules, cells, tissues, organs, and organisms.” Bassingthwaighte (1995): Advances in Experimental Medicine and Biology 1995; 382: 331-9

Proposed Projects 1.Brain and CNS 2.Heart and cardiovascular system 3.Lungs and respiratory system 4.Kidney and urinary system 5.Musculo-skeletal system 6.Alimentary system 7.Reproductive system 8.Endocrine system 9.Haemolymphoid system 10.Integumental system

Physiome Bioinformatics Modeling Hierarchies Databases Genes Proteins Biophysical models Constitutive laws Organ model Whole body model Genome Protein Physiology Structural Bioeng. Materials Clinical Molecular Biology Physiology Bioengineering Clinical medicine

Physiome Molecular & Cell Biology Biochemistry Anatomy Pathophysiology Physiology Bioengineering Computer Science Clinical Research & Trials Drug discovery Physiome

Mathematical Models Level 1 models: Molecular models Level 2 models: Subcellular Markov models Level 3 models: Subcellular ODE models Level 4 models: Tissue and whole organ continuum models Level 5 models: Whole body continuum models Level 6 models: Whole body system models

Physiome Groups BioNoME (UCSD) Cardiome Project (Auckland) Biology Network of Modeling Efforts; limited activity but good pedigree funded by Procter and Gamble for 3 years Cardiome Project (Auckland) the model and most active group Microcirculatory Physiome Project (Johns Hopkins) seems well supported and active Endotheliome Project Pulmonary Physiome

Modeling target in the present Physiome in the Heart (Cardiome)  Virtual heart

가상심장 (Virtual Heart) An example of Physiome 컴퓨터 프로그램으로 가상적으로 구현된 심장 신약개발에 활용 - 1997 Hoffman-LaRoche사 심장병약 개발 시 활용 Fusion technology (Physiology+Mechanics+ Cell biology) - Computational biomedical engineering

Virtual Heart Modeling An example of Physiome 컴퓨터 프로그램으로 가상적으로 구현된 심장 신약개발에 활용 - 1997 Hoffman-LaRoche사 심장병약 개발 시 활용 Fusion technology (Physiology+Mechanics+ Cell biology) - Computational biomedical engineering

Clinical Applications Cardiome Project Heart model Anatomy Tissue Structure Tissue properties Cellular properties Drug Discovery Clinical Applications Model Validation

Anatomy Completed or underway: Vent. geom. & fibre-sheet structure for dog Vent. geom. & fibre-sheets for rabbit Coronary anatomy for pig Atrial geometry & structure for pig Cardiac valve structure

Mechanics Completed or underway: Material properties - ECM structure biaxial tests on dog myocardium shear testing of pig myocardium torsion testing of rabbit pap. muscle ECM structure Functional studies on gene targetted mice Infarct modeling Ventricular aneurysm Acute ischemia

Activation Completed or underway: Needed soon: Ionic current models Spatial distribution of ion channels SA, atrial, AV, HIS, Purkinje Reentrant arrhythmias Defibrillation studies Heart failure Mutations (eg KvLQT1/minK -> IKs -> LQTS) EC coupling Needed soon: Spatial distribution of gap junctions Drugs -> models -> clinically observable effects Mutations (eg HERG -> IKr -> LQTS) Expression profiling in acquired heart disease

Energy Supply & Metabolism Completed or underway: Coronary flow Coronary flow regulation Metabolism & energetics Ischemia Flux balance & kinetic models Needed soon: Integration of different parts of metabolic pathway models with energy supply & demand Coupling to electrophysiology & generation of reentrant arrhythmias

Databases Cell Tissue Organ(ism) Structure and spatial parameters Material properties Dynamic behavior Documentation Communications and interactions

Electrophysiological data Heart modeling Gene/Protein Expression Membrane Transporter Function Cell Electro- physiology Ventricular Anatomy & Mechanics Excitation Generalized Anatomic Database Interface and Analysis Platform Electrophysiological data Models Imaging, Simulation and Electrical Mapping Data Finite Element Modeling Tools Reconstructed Hearts Data Analysis Tools

Membrane Transporter Function & Cell Electrophysiology Models INaCa ICaL ICab IpCa INab Functional Unit { Irel Functional Unit Sarcoplasmic reticulum JSR NSR Iup Ca 2+ Ca 2+ Itr Calsequestrin Troponin/myofilament IK1 IK Ito1 INa INaK ~50,000 Functional Units (FUs) Simulate channel gating in each FU stochastically Couple stochastic simulation with numerical integration of model ODEs

Action potential : diFrancesco – Noble Model

Virtual Heart Modeling Ideal Procedure Cell electro-physiological model and mechanical processes (Tension generated-sliding filament theory)  Insertion into global cardiac geometry on a cell by cell basis  Impossible approach for now !!!  Approximation needed !!!  Bidomain model Computational Procedure  SA node model  Action potential propagation model (bidomain model)  Cross-bridge model (fading memory theory)  Stress – Strain relation (constitutive equation) : Finite element method  Heart muscle deformation (contraction)

Propagation of action potential : Bidomain model

Reconstructed by Nielsen et al, University of Auckland Measurement and Modeling of Whole-Heart Function: Heart Geometry and Fiber Structure Reconstructed by Nielsen et al, University of Auckland Fox and Hutchins (1972). Johns Hopkins Med. J. 130(5): 289-299