Physiome and Virtual HeartPhysiome and Virtual Heart

Eun Bo Shim, Ph.D.

Department of Mechanical EngineeringKangwon National University

Limitation of Genome ProjectLimitation of Genome Project

Genomic theoryGenomic theory ::

1) Discovery of the gene related with a specific disease 1) Discovery of the gene related with a specific disease

2) Discovery of the protein related with the gene2) Discovery of the protein related with the gene

3) Correction or bypassing of the malfunction protein based on its 3) Correction or bypassing of the malfunction protein based on its structure & functionstructure & function

or Discovery of gene therapy to replace faulty geneor Discovery of gene therapy to replace faulty gene

Unsuccessful !!!!Reason : fundamental failure to understand biological complexity

Why ?Why ?

Problem 1Problem 1 : : the function of a gene isthe function of a gene is NOT NOT specified in the DNA language specified in the DNA language

Problem 2Problem 2 : : each gene plays roles ineach gene plays roles in MULTIPLE MULTIPLE functions functions

Problem 3Problem 3 : : each function arises from co-operation of each function arises from co-operation of MANYMANY genes genes

Problem 4Problem 4 : : function also depends on important propertiesfunction also depends on important properties NOT NOT specified by specified by genes - properties of water, lipids, self-assembly etc…genes - properties of water, lipids, self-assembly etc…

Problem 5Problem 5 : nature has built-in fail-safe ‘redundancy’ - this : nature has built-in fail-safe ‘redundancy’ - this ONLYONLY emerges at emerges at the functional levelthe functional level

Post – Genome EraPost – Genome EraGenomeProteome (on-going)Metabolome…….Physiome : From Genes to Function

What is the Physiome?What is the Physiome?

Bassingthwaighte (1995): Advances in Experimental Bassingthwaighte (1995): Advances in Experimental Medicine and Biology 1995; 382: 331-9Medicine and Biology 1995; 382: 331-9

“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.”

Proposed ProjectsProposed Projects

1.Brain and CNS 1.Brain and CNS

2.Heart and cardiovascular system 2.Heart and cardiovascular system

3.Lungs and respiratory system 3.Lungs and respiratory system

4.Kidney and urinary system 4.Kidney and urinary system

5.Musculo-skeletal system 5.Musculo-skeletal system

6.Alimentary system 6.Alimentary system

7.Reproductive system 7.Reproductive system

8.Endocrine system 8.Endocrine system

9.Haemolymphoid system 9.Haemolymphoid system

10.Integumental system 10.Integumental system

Physiome BioinformaticsPhysiome Bioinformatics

GenesGenes

ProteinsProteins

Biophysical modelsBiophysical models

Constitutive lawsConstitutive laws

Organ modelOrgan model

Whole body modelWhole body model

GenomeGenome

ProteinProtein

PhysiologyPhysiology

StructuralStructural

Bioeng. MaterialsBioeng. Materials

ClinicalClinical

Modeling HierarchiesModeling Hierarchies DatabasesDatabases

Molecular Biology

Physiology

Bioengineering

Clinical medicine

Molecular & Cell BiologyMolecular & Cell Biology

BiochemistryBiochemistry AnatomyAnatomy

PathophysiologyPathophysiology PhysiologyPhysiology

BioengineeringBioengineering Computer ScienceComputer Science

Clinical Research & TrialsClinical Research & TrialsDrug discoveryDrug discovery

Physiome

Mathematical ModelsMathematical Models

Level 1 models: Molecular models Level 1 models: Molecular models

Level 2 models: Subcellular Markov modelsLevel 2 models: Subcellular Markov models

Level 3 models: Subcellular ODE modelsLevel 3 models: Subcellular ODE models

Level 4 models: Tissue and whole organ Level 4 models: Tissue and whole organ continuum modelscontinuum models

Level 5 models: Whole body continuum modelsLevel 5 models: Whole body continuum models

Level 6 models: Whole body system modelsLevel 6 models: Whole body system models

Physiome GroupsPhysiome Groups

BioNoME (UCSD)BioNoME (UCSD) Biology Network of Modeling Efforts; limited activity Biology Network of Modeling Efforts; limited activity

but good pedigree but good pedigree funded by Procter and Gamble for 3 yearsfunded by Procter and Gamble for 3 years

Cardiome Project (Auckland)Cardiome Project (Auckland) the model and most active groupthe model and most active group

Microcirculatory Physiome Project (Johns Microcirculatory Physiome Project (Johns Hopkins)Hopkins) seems well supported and activeseems well supported and active

Endotheliome ProjectEndotheliome Project Pulmonary PhysiomePulmonary Physiome

Physiome in the Heart

(Cardiome)

Virtual heart

Modeling target in the present

가상심장 가상심장 (Virtual Heart)(Virtual Heart)

An example of PhysiomeAn example of Physiome 컴퓨터 프로그램으로 컴퓨터 프로그램으로

가상적으로 구현된 심장가상적으로 구현된 심장 신약개발에 활용신약개발에 활용 - - 1997 Hoffman-LaRoche1997 Hoffman-LaRoche 사 사

심장병약 개발 시 활용심장병약 개발 시 활용 Fusion technology Fusion technology (Physiology+Mechanics+ Cel(Physiology+Mechanics+ Cel

l biology)l biology) - Computational biomedic- Computational biomedic

al engineeringal engineering

Virtual Heart ModelingVirtual Heart Modeling An example of PhysiomeAn example of Physiome 컴퓨터 프로그램으로 가상적으로 구현된 심장컴퓨터 프로그램으로 가상적으로 구현된 심장 신약개발에 활용신약개발에 활용 - - 1997 Hoffman-LaRoche1997 Hoffman-LaRoche 사 심장병약 개발 시 활용사 심장병약 개발 시 활용 Fusion technology Fusion technology (Physiology+Mechanics+ Cell biology)(Physiology+Mechanics+ Cell biology) - Computational biomedical engineering- Computational biomedical engineering

Cardiome ProjectCardiome ProjectTissue Structure

Tissue properties

Model ValidationDrug Discovery

Clinical Applications

Cellular properties

AnatomyHeart modelHeart model

AnatomyAnatomy

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

MechanicsMechanics

Completed or underway:Completed or underway: Material properties Material properties - -

biaxial tests on dog myocardiumbiaxial tests on dog myocardium shear testing of pig myocardiumshear testing of pig myocardium torsion testing of rabbit pap. muscletorsion testing of rabbit pap. muscle

ECM structureECM structure Functional studies on gene targetted mice Functional studies on gene targetted mice Infarct modelingInfarct modeling Ventricular aneurysmVentricular aneurysm Acute ischemiaAcute ischemia

ActivationActivation Completed or underway:Completed or underway:

Ionic current models Ionic current models Spatial distribution of ion channels Spatial distribution of ion channels SA, atrial, AV, HIS, PurkinjeSA, atrial, AV, HIS, Purkinje Reentrant arrhythmiasReentrant arrhythmias Defibrillation studiesDefibrillation studies Heart failure Heart failure Mutations (eg KvLQT1/minK -> IKs -> LQTS)Mutations (eg KvLQT1/minK -> IKs -> LQTS) EC couplingEC coupling

Needed soon: Needed soon: Spatial distribution of gap junctionsSpatial distribution of gap junctions Drugs -> models -> clinically observable effectsDrugs -> models -> clinically observable effects Mutations (eg HERG -> IKr -> LQTS)Mutations (eg HERG -> IKr -> LQTS) Expression profiling in acquired heart diseaseExpression profiling in acquired heart disease

Energy Supply & MetabolismEnergy Supply & Metabolism

Completed or underway:Completed or underway: Coronary flowCoronary flow Coronary flow regulationCoronary flow regulation Metabolism & energeticsMetabolism & energetics IschemiaIschemia Flux balance & kinetic models Flux balance & kinetic models

Needed soon: Needed soon: Integration of different parts of Integration of different parts of

metabolic pathway models metabolic pathway models with energy supply & demandwith energy supply & demand Coupling to electrophysiology & Coupling to electrophysiology &

generation of reentrant arrhythmiasgeneration of reentrant arrhythmias

DatabasesDatabases

CellCell TissueTissue Organ(ism)Organ(ism)

Structure and spatial parametersStructure and spatial parameters Material propertiesMaterial properties Dynamic behaviorDynamic behavior DocumentationDocumentation Communications and interactionsCommunications and interactions

Heart modelingHeart modeling

Gene/ProteinExpression

MembraneTransporter

Function

CellElectro-

physiology

VentricularAnatomy &Mechanics

VentricularExcitation

Electrophysiological data

Models

Generalized Anatomic DatabaseInterface and Analysis Platform

Imaging, Simulation and ElectricalMapping Data

Finite Element Modeling Tools

Reconstructed Hearts

Data Analysis Tools

Membrane Transporter FunctionMembrane Transporter Function& Cell Electrophysiology M& Cell Electrophysiology Modelsodels

ICabICaL IpCa

IK1 IK INaK

INab

INa

Troponin/myofilamentTroponin/myofilament

Calsequestrin

Irel

JSR NSR

Itr

Ca 2+Ca 2+

Sarcoplasmic reticulumIup

INaCa

FunctionalUnit

{

~50,000 Functional Units (FUs)

Simulate channel gating in each FU stochastically

Couple stochastic simulation with numerical integration of model ODEs

Ito1

Functional Unit

Action potential : diFrancesco – Noble ModelAction potential : diFrancesco – Noble Model

Virtual Heart ModelingVirtual Heart Modeling

Ideal ProcedureIdeal Procedure Cell electro-physiological modelCell electro-physiological model and mechanical processes and mechanical processes (Tension generated-sliding filament theory)(Tension generated-sliding filament theory) Insertion into global cardiac geometry on a cell by cell basisInsertion into global cardiac geometry on a cell by cell basis Impossible approach for now !!! Impossible approach for now !!! Approximation needed !!! Approximation needed !!! Bidomain model Bidomain model

Computational Procedure Computational Procedure SA node modelSA node model Action potential propagation model (bidomain model)Action potential propagation model (bidomain model) Cross-bridge model (fading memory theory)Cross-bridge model (fading memory theory) Stress – Strain relation (constitutive equation) : Finite element metStress – Strain relation (constitutive equation) : Finite element met

hodhod Heart muscle deformation (contraction)Heart muscle deformation (contraction)

Propagation of action potential : Bidomain modelPropagation of action potential : Bidomain model

Fox and Hutchins (1972). Johns Hopkins Med. J. 130(5): 289-299

Measurement and Modeling of Whole-Heart Measurement and Modeling of Whole-Heart Function:Function:

Heart Geometry and Fiber StructureHeart Geometry and Fiber Structure

Reconstructed by Nielsen et al, University of Auckland