The Physiome Project

1. The Physiome Project Rob MacLeod CVRTI/BE/SCII Peter Hunter Auckland University

2. 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) • coined the term for the first time

3. 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

4. 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 Bioinformatics Modeling Hierarchies Databases

5. 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

6. Visualization Tools • Interrogation of model parameters • Animated visualization of computational output • From molecular level through to the whole body • Web based • Coupled to the computational models in a user-friendly fashion.

7. Instrumentation • Structural measurements • geometry and tissue microstructure of organs • present methods too slow and tedious • Material property measurements • mechanical, electrical, thermal, etc • variety of species • pathological conditions • nonlinear, coupled parameters

8. Physiome Groups • BioNoME (UCSD) • 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

9. Physiome Links • www.ornl.gov/TechResources/Human_Genome/faq/faqs1.html • the mother of all bioscience megaprojects • bionome.sdsc.edu/ • source of some data and info • www.physiome.org/ • the home site; poorly maintained • www.esc.auckland.ac.nz/People/Staff/Hunter/physiome.html • the best place to start the search • http://www.esc.auckland.ac.nz/sites/physiome/index.html • home of the *ML’s • www.bme.jhu.edu/news/microphys/ • microcirculatory physiome project • http://www.physiome.com/ • the company • www.IBB.gatech.edu/HiltonHead/hiltonheadworkshop.html • the next relevant meeting on the physiome

10. BioNoME Project (UCSD) • Biology Network of Modeling Efforts • Funded by Procter and Gamble for 3 years • Contains interface to models that run on remote supercomputer (at UCSD) • Only biophysical models are Beeler-Reuter and Luo-Rudy I • Anatomical models of the heart and microcirculation • Limited activity but good pedigree

11. Microcirculation Physiome “Thus, we propose to develop a database of the microcirculation that encompasses anatomical and functional data with mathematical and computational models, computational engines, and tools for integration.” • Many particpants (based at JHU): • U Western Ontario, Auckland, U Tennessee, U Virginia, JHU, U Arizona • Projects • anatomy, e.g., using GIS • functional descriptions of microcirculation, transport, etc.

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

13. Cardiome Groups AU David Bullivant Peter Hunter Ian LeGrice Denis Loiselle Poul Nielsen Andrew Pullan Bruce Smaill Alistair Young JHU Bill Hunter Eduardo Marban Sasha Popel Rai Winslow UCSF Julius Guccione Mark Ratcliffe UCSD Jim Covell Andrew McCulloch Jeff Omens MIT Colin Brennan Forbes Dewey Ian Hunter Maastricht Theo Arts Frits Prinzen Rob Reneman Utah Chris Johnson Rob MacLeod Bruno Taccardi Physiome Sciences Tom Colatsky Gang Chen Adam Muzikant Oxford Chris Bradley Martyn Nash Peter Kohl Denis Noble Nic Smith UW (Seattle) Jim Bassingthwaighte Eric Feigl Zheng Li Technion Israel Sam Sideman et al Duke Craig Henriquez et al Tulane Natalia Trayanova et al. Lausanne Nathalia Virag et al CWRU Yoram Rudy et al Columbia Kevin Costa Jeff Holmes

14. Anatomy • Completed or underway: • Vent. geom. & fibre-sheet structure for dog (AU) • Vent. geom. & fibre-sheets for rabbit (UCSD, JHU) • Coronary anatomy for pig (UCSD) • Atrial geometry & structure for pig (UCSD, AU, ...) • Cardiac valve structure (AU) • Automated measurement rig (AU & MIT) • Needed soon: • Geom. & fibre-sheet structure for pig, human • Geom. & fibre-sheet structure for hypertrophy etc

15. Mechanics • Completed or underway: • Material properties - • biaxial tests on dog myocardium (AU) • shear testing of pig myocardium (AU) • torsion testing of rabbit pap. muscle (JHU) • ECM structure (UCSD, Columbia, AU, JHU) • Functional studies on gene targetted mice (UCSD) • Infarct modelling (UCSD, Columbia, AU) • Ventricular aneurysm (UCSF) • Acute ischaemia (UCSD, UWash) • Needed soon: • Microstructure & mechanical properties of cytoskeleton & ECM

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

17. Energy Supply & Metabolism • Completed or underway: • Coronary flow (AU) • Coronary flow regulation (UW) • Metabolism & energetics (UW, Oxford, AU) • Ischaemia (Oxford, AU) • Flux balance & kinetic models (UCSD, CWRU) • Needed soon: • Integration of different parts of metabolic pathway models • with energy supply & demand • Coupling to electrophysiology & generation of reentrant arrhythmias

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

19. CellML Cell CellML Code MathML Graphics C++ Fortran Java Tcl/Tk/Perl http://www.esc.auckland.ac.nz/sites/physiome/cellml/pages/index.html http://www.physiome.com/

20. XML www.w3.org/XML/ • XML is a method for putting structured data in a text file • XML looks a bit like HTML but isn't HTML • XML is text, but isn't meant to be read • XML is a family of technologies • XML is verbose, but that is not a problem • XML is new, but not that new • XML is license-free, platform-independent and well-supported • (Note: supports MathML!)

21. CellML Basics • Experiment (simulation) • model description • preparation (species, boundary conditions, other conditions) • variables (to overwrite those extracted from and existing database) • independent variables (time, space) • experimental results (from simulation) • Model description most advanced component

22. FieldML/AnatML Geometry Conductvities Organ(ism) AnatML FieldML Code MathML Graphics C++ Fortran Java Tcl/Tk/Perl

23. AnatML • <body part> • description of geometry • uses CMISS data structures • <body group> • links to other body parts • <placement> • location of the body part in space

24. MeshML/FieldML/RegionML • MeshML • elements of the geometry with connectivities • FieldML • basis functions • field parameters • RegionML • container for meshes and fields

25. The Future of the Physiome • Support from other labs • Cooperation between labs • Funding • Technical challenges • Our role?????