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

2. 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

3. 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

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

5. 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

6. 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

7. 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

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

9. 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

10. 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

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

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

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

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

15. 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

16. 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

17. 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

18. 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

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

20. 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

21. 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

22. Action potential : diFrancesco – Noble Model

23. 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)

24. Propagation of action potential : Bidomain model

25. 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):