Transcript COM 4120 ART Computational modelling and simulation in biology

Systems Biology of the Heart
Richard Clayton
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Ventricular fibrillation
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Experimental maps of electrical activity during VF
Davidenko et al, Nature 1992, 355 349-51
First image of
a spiral wave
in a thin
section of
sheep heart
More recent movie of spiral
wave in a rabbit heart (Movie
from the Living State Physics
group, Vanderbilt University,
Tenessee)
Experimental work looks at
the surface of the heart, but
not within the tissue, this is
a major justification for
modelling
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The heart as a system
 Heart is an electromechanical
pump; electrical activation of heart
cells (the action potential) initiates
contraction.
 Electrical properties of cells are well
characterised experimentally.
 Mechanical properties of cardiac
tissue, and coupling of electrical
and mechanical properties are less
well understood.
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The heart as a system
The beating heart: an
electromechanical
A fully integrative cardiac model needs
pump
 Cardiac action potential.
 Intracellular Ca2+ storage and
release.
 Coupling of electrical and
mechanical activity.
 Electrical coupling of cells.
 Mechanical coupling of cells.
 Anatomy.
 Boundaries.
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The heart as a system
The beating heart: an
electromechanical
A fully integrative cardiac model needs
pump
 Cardiac action potential.
 Intracellular Ca2+ storage and
release.
 Coupling of electrical and
mechanical activity.
 Electrical coupling between cells.
 Mechanical coupling between cells,
and mechanical properties of
tissue.
 Anatomy.
 Boundaries.
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Cardiac model hierarchy
Anatomy
Coupling between cells
Action potential
Voltage + time
dependence of
ion channel
conductances
Intracellular
calcium
handling
(storage and
release)
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Model hierarchy

Integrative model,
simulates processes at
molecular, cell, tissue and
organ level.

Can be validated at cell
and tissue levels.

Some gene polymorphisms
affect ion channel
properties. Models can be
used to study how mutant
ion channels affect
function at cell, tissue and
organ levels (but we
haven’t done organ level
simulation yet).
Anatomy
Coupling between cells
Action potential
Voltage + time
dependence of
ion channel
conductances
Intracellular
calcium
handling
(storage and
release)
Systems Biology talk July 2004
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Virtual torso with
ECG electrodes
Ventricular fibrillation
in virtual heart
Simulated ECG
signal
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Analysis
 Successes.
•
•
Spiral waves in the heart predicted in 1960s, and observed in 1990s.
Many experimentalists now see value in modelling.
 Failures.
•
Many different cell models available, little consistency between
research groups.
 Technologies.
•
•
Continuous (PDE) models of cell to cell coupling.
High performance computing (shared and distributed memory).
 Expectations.
•
•
Insights into mechanisms that initiate and sustain fibrillation.
Rational drug design.
 Education.
•
An appealing subject to teach, and is a good case study for modelling
and simulation in physiology.
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