1. MULTISCALE SYSTEMS MODELLING OFTHE TETRALOGY OF FALLOT 1 1
12 2 23Ron Summers, Tariq Abdulla, Ryan Imms, Jean-Marc Schleich,
Guy Carrault, Alfredo Hernandez and Lucile Houyel1Electronic and
Electrical Engineering, SEIC, Loughborough University, Leics, UK,
LE11 3TUE-mail: [email protected] Web:
http://syseng.lboro.ac.uk2LTSI, University of Rennes 1, Rennes,
F-35000, France3Marie-Lannelongue Hospital, Paris, F-92350,
FranceIntroductionBetween week 3 and 6 of embryonic development,
the human heart morphs from a linear tube to a four chamberedorgan.
It is one of the few organs that become functional as it is formed.
Remarkably, the conduction system andblood flow both change
radically while maintaining cardiac function at every step of
development. Heart defects arethe most common type of congenital
disorder, severely affecting 6/1000 live births. A number of genes
have beenidentified as playing a crucial role in heart
morphogenesis. However the mechanisms by which altered
genetranscription affects cell signalling, cell behaviour, and
tissue-tissue interactions that lead to altered developmentare not
well understood. The tetralogy of Fallot is one type of congenital
heart disease (CHD), comprising multipledefects, for which a theory
of aetiology exists. However this sits within a spectrum of CHD in
which one gene actsthrough many mechanisms and can cause one of
several diseases. Multiscale modelling, mediated throughinformation
models, provides a means to study heart development as a
system.Tetralogy of Fallot Complexity of CHDThe tetralogy of Fallot
is the most common Several mechanisms are involved in heart
development, each of whichcongenital heart defect causing cyanosis,
and is are controlled by several genes. CHD commonly involves
abnormaldefined as four coinciding anomalies:remodelling of the
outflow tract (OFT) which can be caused by a A Pulmonary
stenosiscombination of mechanisms, as illustrated below. As the OFT
loops B An over-riding aorta, displaced to the rightbehind the
atria it septates into the aorta and pulmonary artery and C
Ventricular septal defect wedges aligned with the atrioventricular
septum. Thus there is a range (always in the membranous septum) of
CHDs caused by abnormal degrees of OFT rotation. D Right ventricle
hypertrophyWikipediaUser:Wapcaplet ABCD Normal HeartTetralogy of
FallotAs the four abnormalities co-occur so frequently, it islikely
there is a common cause. One theory is thathypoplasia of the
subpulmonary conus leads to bothpulmonary stenosis and a shorter
rotation of theOutflow Tract (OFT), which leads to anomalies B ,
Cand D . Several genes control several mechanisms, which lead to
one of several CHDs [1]Multiscale Modelling -9-3The modelling
framework encompasses spatial scales from 10 m (protein
interactions) to 10 m (the primitive heart tube) and-66temporal
scales from 10 s (molecular events) to 10 s (weeks of development).
This is illustrated schematically below, left. Theapproach adopted
owes much to other methods including those from: systems
engineering (e.g. integration technologies andinformation
modelling); the world-wide Physiome consortium and the EU-funded
Network of Excellence on the VirtualPhysiological Human. Modelling
approaches suitable for different levels of scale are illustrated,
as well as markup languagespecifications. These enable model
interchange, potentially between tools that are suitable for
modelling at different scales.-9-6 -4-3 Composite Spatial Scale10 m
10 m10 m 10 mBiosimulation OntologyData SourceAnnotationProtein
Cell Tissue Heart Tube Gel ElectrophoresisInteraction
BehaviourTransformationMorphogenesisSNAILdecreasedHigh VEGFHigh
VEGF//computationconcentrationPRO, GO-MF2+VEGF CABMP2Snail VE
CadherinVAR = CalcineurinpVEGFNotchendothelial cellNFATNFATDelta4
Low VEGFVEGF VE-Cadherin2+ CA TGF-beta CalcineurinTGF-beta Wnt
/BetaCat Low VEGFp NFAT NFATVEGFSnailpart_of High VEGF Wnt /
BMPBetaCat NotchBMP4BMP4 Markup Language SBML CellML CBML
FieldMLSNAIL Histochemistry Modelling Pathway Models Stochastic
ModelsAgent Based Models Finite Elementdecreased PATO
OPB:concentration Approach ODEsReaction Diffusion PDEsReactive
AnimationImage Analysis =53 pg ml -1concentration Petri Nets
Systems of ODEsCellular Automata 3D ReconstructionGO-CC Boolean
Networks Stochastic Petri NetsCellular PottsMultiphysics
Simulationendocardial cushionIndependent ContinuantCL PRO, ChEBICL,
FMA, GO-CC FMA, EHDA Validation(Proteins, Cells, Structures)
derives_into OntologiesGO-MF Cell BehaviourPATO, Mammalian
Phenotype Dependent Continuant Segemented MRI(Functions, Roles,
Qualities) decreased GO-BPOccurent OPB:area
volume(Processes)63volume =3 x 10 mTemporal Scalemembranous part
ofFMA, EHDA-6-33 6cardiac septumOMIM / Snomed / AEPC:10 s 10 s10
s10 sMolecular EventsCell SignallingMitosis Heart
DevelopmentVentricular Septal Defect Spatial and temporal scales of
the multiscale modelling initiative [2] Composite annotation of
biomedical data from multiscale sources [2]Reference ontologies
applicable to the different levels of scale are illustrated along
the bottom of the left-hand figure. These arefurther split between
occurents, independent continuants and dependent continuants.
Occurents are processes that unfoldthrough time, while continuants
are entities that exist in full through a period of time. This
provides a clear conceptual divisionbetween the spatial and
temporal domains. Annotating models, model components and
parameters using well definedontologies enables reuse and
integration. But multiscale modelling presents a challenge in that
no single ontology can includeterms of the required specificity. A
post-coordinated annotation strategy, which allows the combination
of terms from multipleontologies, is a partial solution to this
issue, and is illustrated above, right. Modelling of morphogenesis
provides the furtherchallenge of increased importance of the
temporal domain, which is currently less well defined
ontologically.Future WorkThere are several important mechanisms in
heart development, and each of these can be studied as a multiscale
system. Theendocardial cushions are swellings in the early heart
tube, which fuse to form the valves and membranous septum, and play
a rolein OFT remodelling. Endocardial cushions grow by a process of
Epithelial to Mesenchymal Transition (EMT). Cellular behaviourand
tissue interaction during EMT can be simulated as Potts models
using Compucell3D. Existing models of signal pathwaysinvolved in
EMT are modelled as ODEs and are available in Systems Biology
Markup Language (SBML). Future plans are to usethe SBML ODE Solver
Library (SOSlib) to incorporate reaction networks within
Compucell3D and thus determine intracellularconcentrations in a
multiscale model. From a chronological perspective, we are using
state charts to represent processes and sub-processes in heart
development hierarchically. The UML formalism allows the recursive
stacking of state machines, and thisapproach neatly matches the
problem of modelling in multiple time scales.References[1] F.
Bajolle, S. Zaffran, and D. Bonnet, "Genetics and embryological
mechanisms of congenital heart diseases.," Archives
ofcardiovascular diseases, vol. 102, 2009, pp. 59-63.[2] T.
Abdulla, R. Imms, J.M. Schleich, and R. Summers, "Multiscale
information modelling for heart morphogenesis," Journal ofPhysics:
Conference Series (in press).