The IUPS Physiome Project Auckland Bioengineering Institute & Maurice Wilkins Centre University of Auckland, NZ BMSW 2008, Bangalore, India
Jan 03, 2016
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