The Physiome Project
Rob MacLeod
CVRTI/BE/SCII
Peter Hunter
Auckland University
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
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
Physiome Bioinformatics
Modeling Hierarchies
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Genes
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Proteins
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Biophysical models
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Constitutive laws
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Organ model
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Whole body model
Databases
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Genome
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Protein
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Physiology
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Structural
Bioengineering
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Bioeng. Materials
Clinical medicine
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Clinical
Molecular Biology
Physiology
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
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.
Instrumentation
• Structural measurements
– geometry and tissue microstructure of organs
– present methods too slow and tedious
• Material property measurements
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mechanical, electrical, thermal, etc
variety of species
pathological conditions
nonlinear, coupled parameters
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
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
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 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.
Cardiome Project
Tissue Structure
Heart model
Anatomy
Tissue properties
Model Validation
Drug Discovery
Clinical Applications
Cellular properties
Cardiome Groups
AU
UCSD
Physiome Sciences
Duke
David Bullivant
Peter Hunter
Ian LeGrice
Denis Loiselle
Poul Nielsen
Andrew Pullan
Bruce Smaill
Alistair Young
Jim Covell
Andrew McCulloch
Jeff Omens
Tom Colatsky
Gang Chen
Adam Muzikant
Craig Henriquez et al
Natalia Trayanova et al.
MIT
Oxford
Colin Brennan
Forbes Dewey
Ian Hunter
Chris Bradley
Martyn Nash
Peter Kohl
Denis Noble
Nic Smith
Lausanne
UW (Seattle)
Columbia
JHU
Maastricht
Bill Hunter
Eduardo Marban
Sasha Popel
Rai Winslow
Theo Arts
Frits Prinzen
Rob Reneman
Utah
UCSF
Julius Guccione
Mark Ratcliffe
Tulane
Chris Johnson
Rob MacLeod
Bruno Taccardi
Jim Bassingthwaighte
Eric Feigl
Zheng Li
Technion Israel
Sam Sideman et al
Nathalia Virag et al
CWRU
Yoram Rudy et al
Kevin Costa
Jeff Holmes
Anatomy
• Completed or underway:
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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
Mechanics
• Completed or underway:
– Material properties
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• biaxial tests on dog myocardium (AU)
• shear testing of pig myocardium (AU)
• torsion testing of rabbit pap. muscle (JHU)
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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
Activation
• Completed or underway:
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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:
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Spatial distribution of gap junctions
Drugs -> models -> clinically observable effects
Mutations (eg HERG -> IKr -> LQTS)
Expression profiling in acquired heart disease
Energy Supply & Metabolism
• Completed or underway:
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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
Databases
Cell
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Tissue
Organ(ism)
Structure and spatial parameters
Material properties
Dynamic behavior
Documentation
Communications and interactions
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/
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!)
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
FieldML/AnatML
Conductvities
Organ(ism)
Geometry
AnatML
FieldML
Code
C++
Fortran
Java
Tcl/Tk/Perl
MathML
Graphics
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
MeshML/FieldML/RegionML
• MeshML
– elements of the geometry with
connectivities
• FieldML
– basis functions
– field parameters
• RegionML
– container for meshes and fields
The Future of the Physiome
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Support from other labs
Cooperation between labs
Funding
Technical challenges
Our role?????