This document discusses multiscale modeling and its application to understanding congenital heart defects. It outlines modeling at the anatomic, cellular, protein, and genome levels. At the anatomic level, it describes the normal heart anatomy and the specific defects seen in Tetralogy of Fallot. At the cellular level, it discusses epithelial to mesenchymal transition during heart development. At the protein level, it mentions modeling Notch signaling pathways. And at the genome level, it refers to gene regulation processes involved in forming Tetralogy of Fallot. Future work is needed in areas like scale linking, biological networks, multiscale modeling methodology, and software for integrating models across scales.

1. Progress on Measurement in
Biology & Medicine:
Multiscale Systems Engineering
Ron Summers
Dept Electronic & Electrical Engineering, Loughborough University, UK
R.Summers@lboro.ac.uk
http://www-staff.lboro.ac.uk/~lsrs1

2. Outline
• Introduction to the Team
• Multiscale Modelling
Anatomic Level of Analysis
Cellular Level of Analysis
Protein Level of Analysis
Genome Level of Analysis
• Future Work

3. International Team

4. Multiscale Modelling
Context

5. Engineering Dimension
“…multiscale modelling is the field of solving
physical problems which have important
features at multiple scales, particularly
multiple spatial and (or) temporal scales”.
Wikipedia, accessed 2010

6. Scales of Measurement
Hunter P, Robbins P, Noble D (2002)
The IUPS human physiome project.
Eur J Physiol 445 1-9

7. Medical Dimension
• Why is it important to better understand
congenital heart defects ?
• What is the Tetralogy of Fallot from an
anatomical standpoint ?
• Which embryological processes are
involved in the formation of the Tetralogy
of Fallot ?

8. Why is it important to know more about the congenital
heart defect and particularly about the Tetralogy of Fallot ?
The prevalence of congenital heart defects,
the most common congenital anomaly
observed in newborns, has been reported to
be 5-10 per 1000 births
 10% of the childhood mortality
Tetralogy of Fallot is the most common form
of cyanotic congenital heart disease.
It affects 9%-15% of all infants and children
with congenital heart disease (CHD) which
represents 55%-70% of all cyanotic
congenital malformations
We need to improve our knowledge about
this abnormality

9. Multiscale Modelling
Anatomic Level

10. Aorta
Pulmonary artery
Right
Ventricle
Anterior view Posterior view

11. Anatomy of the Normal Human Heart

12. Tetralogy of Fallot
desaturation
Pulmonary Stenosis
Ventricular Septal Defect by
malalignment
Dextroposition of the Aorta
(aortic overriding)
Right ventricular hypertrophy

13. Normal Anatomic Development
Membranous
Septum
Muscular
Septum
Nature

14. Multiscale Modelling
Cellular Level

15. Scales of Measurement
Hunter P, Robbins P, Noble D (2002)
The IUPS human physiome project.
Eur J Physiol 445 1-9

18. Epithelial to Mesenchymal Transition
Notch Delta

19. EMT Simulations

20. In vitro EMT
Wildtype Notch1 BMP2
L. Luna-zurita et al. “Integration of a Notch-dependent mesenchymal gene
program and Bmp2-driven cell invasiveness regulates murine cardiac
valve formation,” The Journal of Clinical Investigation, vol. 120, 2010.

24. Multiscale Modelling
Protein Level

26. Multiscale Modelling
Genome Level

27. Which embryological processes are involved
in the formation of the Tetralogy of Fallot ?
Scale of tissue and cells

28. Which embryological processes are involved in the
formation of the Tetralogy of Fallot ?
Scale of gene regulation

29. Future Work

30. A lot of work remains…
• Information Issues
• Scale-linking
• Biological Networks
• Methodological Issues
• Multiscale Model Process
• Multiscale Model Validation
• Multiscale Visualization
• Software Issues
• Multiscale Software Programming
• Patho-physiological Issues
• Anatomic Definition of Tetralogy of Fallot

31. Thank you for your
attention

32. Biophotonics Imaging System
Optical Physiological Tomography: Concepts
Electronic sub system
ency W
High USB
Frequ Hz (4
00 avel
6–9 – 9 en
00 gth
nm
)
Oxygen level
Oxygen level
Micro-
Micro-
O2%
electronics
Fast
digital
Low
Camera
Multi-
Multi-
wavelength
illuminator
Photonics sub system
Comprises biomedical photonics, microelectronics engineering,
systems engineering, applied signal and image processing, and
multiscale modelling/simulation