The Physiome ProjectThe Physiome Project

Rob MacLeodCVRTI/BE/SCII

Peter HunterAuckland University

What is the Physiome?What is the Physiome?

• Bassingthwaighte (1995): Advances in Experimental Medicine and Biology 1995;382:331-9)– coined the term for the first time

“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

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 BioinformaticsPhysiome Bioinformatics

• Genes

• Proteins

• Biophysical models

• Constitutive laws

• Organ model

• Whole body model

• Genome

• Protein

• Physiology

• Structural

• Bioeng. Materials

• Clinical

Modeling HierarchiesModeling Hierarchies DatabasesDatabases

Molecular Biology

Physiology

Bioengineering

Clinical medicine

Mathematical ModelsMathematical 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

Visualization ToolsVisualization 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.

InstrumentationInstrumentation

• 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

Physiome GroupsPhysiome 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

Physiome LinksPhysiome 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

BioNoME Project (UCSD)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

Microcirculation PhysiomeMicrocirculation Physiome

• 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.

“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.”

Cardiome ProjectCardiome ProjectTissue Structure

Tissue properties

Model ValidationDrug Discovery

Clinical Applications

Cellular properties

AnatomyHeart model

Cardiome GroupsCardiome GroupsAUDavid BullivantPeter HunterIan LeGriceDenis LoisellePoul NielsenAndrew PullanBruce SmaillAlistair Young

JHUBill HunterEduardo MarbanSasha PopelRai Winslow

UCSFJulius GuccioneMark Ratcliffe

UCSDJim CovellAndrew McCullochJeff Omens

MITColin BrennanForbes DeweyIan Hunter

MaastrichtTheo ArtsFrits PrinzenRob Reneman

UtahChris JohnsonRob MacLeodBruno Taccardi

Physiome SciencesTom ColatskyGang ChenAdam Muzikant

OxfordChris BradleyMartyn NashPeter KohlDenis NobleNic Smith

UW (Seattle)Jim BassingthwaighteEric FeiglZheng Li

Technion IsraelSam Sideman et al

DukeCraig Henriquez et al

TulaneNatalia Trayanova et al.

LausanneNathalia Virag et al

CWRUYoram Rudy et al

ColumbiaKevin CostaJeff Holmes

AnatomyAnatomy

• 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

MechanicsMechanics• 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

ActivationActivation• 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

Energy Supply & MetabolismEnergy 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

DatabasesDatabases

CellCell TissueTissue Organ(ism)Organ(ism)

• Structure and spatial parameters• Material properties• Dynamic behavior• Documentation• Communications and interactions

CellMLCellML

CellML

Code MathML Graphics

CellCell

C++FortranJavaTcl/Tk/Perl

http://www.esc.auckland.ac.nz/sites/physiome/cellml/pages/index.html http://www.physiome.com/

XMLXML• 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!)

www.w3.org/XML/

CellML BasicsCellML 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

FieldML/AnatMLFieldML/AnatML

AnatMLFieldML

Code MathML Graphics

Organ(ism)Organ(ism)

C++FortranJavaTcl/Tk/Perl

GeometryConductvities

AnatMLAnatML

• <body part>– description of geometry– uses CMISS data structures

• <body group>– links to other body parts

• <placement>– location of the body part in space

MeshML/FieldML/RegionMLMeshML/FieldML/RegionML

• MeshML– elements of the geometry with

connectivities

• FieldML– basis functions – field parameters

• RegionML– container for meshes and fields

The Future of the PhysiomeThe Future of the Physiome

• Support from other labs

• Cooperation between labs

• Funding

• Technical challenges

• Our role?????