The IUPS Physiome ProjectAuckland Bioengineering Institute

& Maurice Wilkins CentreUniversity of Auckland, NZ

BMSW 2008, Bangalore, India

1. IUPS Physiome Project

Genes Cellstructure-function

Tissue structure-function

Clinicalmedicine

Organ structure-function

ProteinsLipids

Carbohydrat

es

mRNA

…

25,000genes

100,000+proteins

12 organsystems

1body

200+ celltypes

4 tissuetypes

Physiome Project

Genome/Transcriptome/Metabolome/Proteome

Hunter, PJ and Borg, TK. Integration from proteins to organs: The Physiome Project. Nature Reviews Molec & Cell Biol. 4:237-243, 2003

The Challenge: spatial and temporal scales

The diversity of experimental models• bacterial models structural biology• murine models functional genomics• large animal models physiology• human clinical MRI, CT, etcRequires a hierarchy of inter-related models

pathwaymodels

ODEsstochasticmodels

PDEs (continuum models)

gene reg.networks

MD/CG models

• 1 m person• 1 mm electrical length scale of cardiac tissue• 1 m cardiac sarcomere spacing• 1 nm pore diameter in a membrane protein

Space

109

• 109 s (70 yrs) human lifetime• 106 s (10 days) protein turnover• 103 s (1 hour) digest food• 1 s heart beat• 1 ms ion channel HH gating• 1 s Brownian motion

Time

1015

Heart Physiome

Cardiac Structure

Element fields:undeformed coords X,Y,Z (or ) deformed coords x,y,zfibre & sheet orientationselectrical potentialconcentration fields for Ca2+, O2 , etc

Element withHermite basis

Large deformation elasticity theoryFinite element method

1

2

3

u , u , u , etc

material coordinates

Equations: Integral formulation - Galerkin method - Gaussian quadCosta KD, Hunter PJ, Wayne JS, Waldman LK, Guccione JM & McCulloch AD. ASME J. Biomech. Eng. 118:464-472, 1996

Nash MP and Hunter PJ. J. Elasticity. 61(1-3):113-141, 2001

pole

Axialtension

Axial strain

sheet axis

fibre axis

sheet normal Pole-zero constitutive law:

W = k11e112

+ k22e222

+ ….

(a11-e11)2 (a22-e22)

2

Epi

Transmural confocal image of rat myocardium

Endo

fibre

sheet

normal

Constitutive Relations

Denis Noble

Myocardiac Activation

m

mm

CI

dtdV

Action potential duration is critical

Probable clones

T-type calcium current

ITO2 (Ca-activated)

ICl or IKp

IKur or IKq

IK ATP/ACh

If (pacemaker)

Kv4.x

Kv1.5CFTR, TWIK

hCNGKir3.1/3.4, Kir6.x/SUR

Membrane ion channels

CACH1CL-type calcium current

NCXNa-Ca exchange

HERG + MiRP-1IKr

KvLQT1 + minKIKs

Kir2.xIK1 (inward rectifier)

ITO1 (4-AP-sensitive)

CellML

V

time

Ou

tward

cu

rren

t

SCN5A + subunitsSodium current

Inward current pushes the voltage up

Tomlinson KA, Pullan AJ & Hunter PJ. SIAM J Applied Maths. 63(1):324–350, 2002

Activation sequence

Karl Tomlinson

Cell to tissue couplingGiven:• initial geometry • boundary conditions

Update grid point extension ratios

2 Solve cell eqtns for T, z …

3

Update T at Gauss pts4

5 For time dep. cell model, iterate to convergence at each time step

Buist ML, Sands GB, Hunter PJ and Pullan AJ. Annals BME 31:577-588, 2003

Boundary forces

Solve tissue mechanics for deformed mesh

1

X X

XX

Electro-mechanics in ventricular tissue

Nickerson, Smith & Hunter. New developments in a strongly coupled cardiac electromechanical model. Europace, 7, S118-S127, 2005

Smith NP, Pullan AJ & Hunter PJ. SIAM J Appl Maths 62:990-1018, 2002

Coronary flow & energetics

Nic Smith

Cardiovascular system Respiratory system Musculo-skeletal system Digestive system Skin (integument) Urinary system Lymphoid system Female reproductive

system Special sense organs Central nervous system Endocrine system Male reproductive

system

Organ system Physiome Projects

Merryn Tawhai

Lung physiomeAuckland, Iowa & Oxford

airways

blood vessels

diaphragm

alveoli

gas exchange

Eric HoffmanU Iowa

Kumar Mithraratn

e

JustinFernande

z

Musculo-skeletal physiome

Digestive system physiome

Andrew Pullan

Auckland, Singapore, Nevada & Vanderbilt

Martin Buist

Genome

Muscle tissueNerve tissueConnective tissueEpithelial tissue

Circulatory system Respiratory systemMusculo-skeletal systemSkin (integument)Digestive systemCentral nervous system Endocrine systemLymphoid systemMale reproductive system Female reproductive system Special sense organs

Organism (7)

OrganSystem(6)

Organ (5)

Tissue (4)

Cell (3)

Molecule (2)

Atom (1)

GenBankEMBL, DDBJ

TIGR

dbESTdSTS

PIR SwissProt

Prosite

PDBSCOPs

OMIN, Medline PubMed

SNPbase, …

DNA

RNA

Protein

Structure

TissueML

FieldML

C C

H H

H H

AnatML

CellML

Physiome MLs, tools & databases

Strategy:

1. Develop MLs for encoding models2. Develop libraries of open source tools

4. Implement collaborative project environments

5. Implement workflows based on web services

3. Develop model repositories based on MLs

FieldML & Cmgui

CellML models include information about :

• model structure how the parts of a model are related to one another

• mathematics (MathML)equations describing the underlying processes

• metadata (RDF)additional information about the model that allows scientists to search for specific models or model components in a database or other repository

CellML (www.cellml.org)

PoulNielsen

Model repository (www.cellml.org/models)

(a) Model components & metadata

(b) MathML editor

(d) Simulation software

(c) Graphical display

CellML Tools (www.cellml.org/tools)

Cmgui

SummaryThe Physiome project is about:• Models that capture patient-specific geometry (link to clinical imaging)• Multi-physics models based on biophysical mechanisms (can use power of physical constraints) • Constitute laws based on tissue microstructure (only way to deal with spatial variation)• Multi-scale models that link to proteins (can link to disease & drug action)

We need:• Open source software• Markup language standards for encoding models• Web accessible model databases• HPC & grid-enabled tools for collaboration

Acknowledgements:Funding: Heart Foundation of NZ

Health Research Council of NZ Royal Society NZ Marsden FundFdn for Research, Science &

TechnologyMaurice Wilkins Centre CoRE NIH, NSFWellcome Trust, UKEPSRC eScience Integrative Biology

projectEU FP6

Colleagues in the Auckland Bioengineering Institute (ABI) & the Maurice Wilkins Centre (MWC)

Colleagues in Oxford: Denis Noble, David Paterson, Peter Kohl

& many other colleagues around the world

& …

Our graduate students & postdocs

www.physiomeproject.org

www.bioeng.auckland.ac.nz

www.cellml.org