IntroductionBetween week 3 and 6 of embryonic development, the human heart morphs from a linear tube to a four chambered organ. It is one of the few organs that become functional as it is formed. Remarkably, the conduction system and blood flow both change radically while maintaining cardiac function at every step of development. Heart defects are the most common type of congenital disorder, severely affecting 6/1000 live births. A number of genes have been identified as playing a crucial role in heart morphogenesis. However the mechanisms by which altered gene transcription affects cell signalling, cell behaviour, and tissue-tissue interactions that lead to altered development are not well understood. The tetralogy of Fallot is one type of congenital heart disease (CHD), comprising multiple defects, for which a theory of aetiology exists. However this sits within a spectrum of CHD in which one gene acts through many mechanisms and can cause one of several diseases. Multiscale modelling, mediated through information models, provides a means to study heart development as a system.

MULTISCALE SYSTEMS MODELLING OF THE TETRALOGY OF FALLOT

Ron Summers, Tariq Abdulla, Ryan Imms, Jean-Marc Schleich, Guy Carrault, Alfredo Hernandez and Lucile Houyel1 1 1 2 2 2 3

Electronic and Electrical Engineering, SEIC, Loughborough University, Leics, UK, LE11 3TUE-mail: R.Summers@lboro.ac.uk Web: http://syseng.lboro.ac.ukLTSI, University of Rennes 1, Rennes, F-35000, FranceMarie-Lannelongue Hospital, Paris, F-92350, France

1

2

3

Complexity of CHDTetralogy of Fallot

A

B

C

D

A

B

C

D

B C

D

The tetralogy of Fallot is the most common congenital heart defect causing cyanosis, and is defined as four coinciding anomalies: Pulmonary stenosis An over-riding aorta, displaced to the right Ventricular septal defect (always in the membranous septum) Right ventricle hypertrophy

Normal Heart Tetralogy of Fallot As the four abnormalities co-occur so frequently, it is likely there is a common cause. One theory is that hypoplasia of the subpulmonary conus leads to both pulmonary stenosis and a shorter rotation of the Outflow Tract (OFT), which leads to anomalies , and .

WikipediaUser:Wapcaplet

Several genes control several mechanisms, which lead to one of several CHDs [1]

Several mechanisms are involved in heart development, each of which are controlled by several genes. CHD commonly involves abnormal remodelling of the outflow tract (OFT) which can be caused by a combination of mechanisms, as illustrated below. As the OFT loops behind the atria, it septates into the aorta and pulmonary artery, and wedges aligned with the atrioventricular septum. Thus there is a range of CHDs caused by abnormal degrees of OFT rotation.

Future WorkThere are several important mechanisms in heart development, and each of these can be studied as a multiscale system. The

endocardial cushions are swellings in the early heart tube, which fuse to form the valves and membranous septum, and play a role

in OFT remodelling. Endocardial cushions grow by a process of Epithelial to Mesenchymal Transition (EMT). Cellular behaviour

and tissue interaction during EMT can be simulated as Potts models using Compucell3D. Existing models of signal pathways

involved in EMT are modelled as ODEs and are available in Systems Biology Markup Language (SBML). Future plans are to use

the SBML ODE Solver Library (SOSlib) to incorporate reaction networks within Compucell3D and thus determine intracellular

concentrations 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 this

approach 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 of

cardiovascular 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 of

Physics: Conference Series (in press).

Multiscale ModellingThe modelling framework encompasses spatial scales from 10 m (protein interactions) to 10 m (the primitive heart tube) and

temporal scales from 10 s (molecular events) to 10 s (weeks of development). This is illustrated schematically below, left. The

approach adopted owes much to other methods including those from: systems engineering (e.g. integration technologies and

information modelling); the world-wide Physiome consortium and the EU-funded Network of Excellence on the Virtual

Physiological Human. Modelling approaches suitable for different levels of scale are illustrated, as well as markup language

specifications. These enable model interchange, potentially between tools that are suitable for modelling at different scales.

-9 -3

-6 6

Reference ontologies applicable to the different levels of scale are illustrated along the bottom of the left-hand figure. These are

further split between occurents, independent continuants and dependent continuants. Occurents are processes that unfold

through time, while continuants are entities that exist in full through a period of time. This provides a clear conceptual division

between the spatial and temporal domains. Annotating models, model components and parameters using well defined

ontologies enables reuse and integration. But multiscale modelling presents a challenge in that no single ontology can include

terms of the required specificity. A post-coordinated annotation strategy, which allows the combination of terms from multiple

ontologies, is a partial solution to this issue, and is illustrated above, right. Modelling of morphogenesis provides the further

challenge of increased importance of the temporal domain, which is currently less well defined ontologically.

Ontologies

GO-BP

GO-MF PATO, Mammalian Phenotype

PRO, ChEBI CL, FMA, GO-CC FMA, EHDA Independent Continuant(Proteins, Cells, Structures)

Dependent Continuant(Functions, Roles, Qualities)

Occurent(Processes)

High VEGF

High VEGF

Low VEGF

Notch

Delta4

Snail VE Cadherin

TGF-beta

BMP2

NFAT

VEGF

VEGF

CA2+

Calcineurin

NFATp

TGF-beta

Snail

Wnt /

BetaCat

BMP4

BMP Notch

VE-Cadherin

VEGFHigh

VEGF

Low

VEGF

Heart TubeMorphogenesis

Tissue Transformation

Cell Behaviour

Protein Interaction

NFAT

VEGF

CA2+

Calcineurin

NFATp

Wnt /BetaCat

BMP4

Pathway Models Stochastic Models ODEs

Petri Nets

Boolean Networks

Reaction Diffusion PDEs

Systems of ODEs

Stochastic Petri Nets

Agent Based Models Reactive Animation

Cellular Automata

Cellular Potts

Finite Element Image Analysis

3D Reconstruction

Multiphysics Simulation

10 m-9

10 m-6

10 m-4

10 m-3

10 s-6

10 s-3

10 s3

Molecular Events Cell Signalling Mitosis

10 s6

Heart Development

Spatial Scale

Temporal Scale

SBML CellML FieldMLCBML

Markup

Language

Modelling

Approach

Cell Behaviour

Spatial and temporal scales of the multiscale modelling initiative [2]

Data Source

Gel Electrophoresis

Segemented MRI

Histochemistry

Ontology

PRO, GO-MF

GO-CC

FMA, EHDA

CL

Composite

Annotation

endocardial cushion

decreased

concentration

SNAILPATO

endothelial cell

decreased

concentration

SNAIL

derives_into

membranous part of

cardiac septum

decreased

volumeOPB:area volume

=3 x 10 μm 6 3

OPB:concentration

=53 pg ml -1

Biosimulation

//computation

VAR =

Validation

OMIM / Snomed / AEPC:

Ventricular Septal Defect

Composite annotation of biomedical data from multiscale sources [2]

part_of