Expanded web feature: Bright spark brings virtual heart a step closer
Scientists reveal results from European research initiative
Duration: 0:01:52. Video and audio help
Peter Kohl describes how modelling can improve healthcare
Video footage of individual heart cells has revealed a link between cell structure and the generation of ‘calcium sparks’ that control the heartbeat at the cellular level. The finding is part of an international research drive to develop biomedical models to help improve heart research, diagnosis and, in the long run, treatment.
The coordinated action of billions of cells cause the chambers of the heart to contract and relax, pumping blood around the body. But in many heart diseases, synchronisation between different parts of the heart is disrupted.
A good heart: hard to find
It’s not clear where this disruption occurs, or even if the problem can be pinpointed to a single faulty part. Because the heart is made up of different types of cell that combine their actions as tissues, it could be a malfunction in the timing between or within tissues. Moreover, any local problem could be at the tissue, cellular or sub-cellular level, creating the headache of studying multiple, complex and interacting components at vastly different scales.
It’s like trying to locate an off-note in an orchestra when any one player, instrument, or part thereof, could be out of tune. One man brave enough to try is Peter Kohl, a physiologist at the University of Oxford. Kohl is one of the principal investigators of the Virtual Physiological Human (VPH) project, a Europe-led initiative to marry clinical data and biomedical imaging to construct sophisticated mathematical models that can better predict the onset and development of disease.
Kohl says the VPH is a huge collaborative effort, involving many teams in the UK, Europe, and from overseas. "VPH is all about trying to build the tools, the environment, and the ontologies to form a community to allow us to move toward computational and mathematical modelling of biological function."
On the ground, that means combining huge clinical data sets to better simulate cardiac functioning. This could mean scanning thousands of histological slices of an organ, hearts with arrhythmias (an irregular heartbeat) for instance, with the intention of combining that information with other data sets, such as electron micrographs or electrocardiograms of hearts with the same condition. "It’s trying to integrate bits of information from decades of a reductionist approach to molecular biology," Kohl says. "Basically, trying to put Humpty Dumpty back together."
Reconstructing a fully-functioning organ from disparate data is an immense task, but unlike all the King’s men, modern scientists are armed with the latest computer-aided imaging techniques. Transmission electron microscopy offers incredible resolution, but at a cost of a true three-dimensional view of the specimen. Kohl says that new techniques use thick specimen slices and more than one hundred images are taken as the specimen is incrementally rotated. "If you take enough pictures of a semi-transparent object and if you have enough angles you can reconstruct it in a 3D image," Kohl explains.
It’s an approach that is starting to show dividends. Investigating the interactions between the heart’s electrical control and mechanical pump activity at the cellular level, Kohl's recent studies, funded by BBSRC and the British Heart Foundation, have revealed a new link between the cell skeleton and how calcium signals control cardiac movement.
3D reconstruction of heart tissue and vascular architecture. Image: Dr Martin Bishop, University of Oxford
Click to view full-size image (102KB)
Calcium is the essential link between electrical activation and muscle contraction throughout the body. The mechanical movement of cells in turn feeds back to affect calcium ion activity. One manifestation of this is the classic Frank-Starling law of the heart, which states that heart muscle responds to an increasing blood volume by generating more forceful contractions to expel that blood. It’s an essential feedback mechanism to prevent too much blood entering the heart, but more than a century after its discovery, the underlying mechanisms of this phenomenon are not completely understood.
By attaching microscopic carbon fibres to individual heart cells, the Oxford team, in collaboration with researchers in Japan (see BBSRC in Japan below) and the US, was able to expose single cardiac cells to a controlled ‘mechanical stretch’, similar to what cells would experience in the intact organ. This ‘pull’ was transferred from the cell surface to internal calcium stores, causing an acute increase in all-or-nothing (quantal) calcium release events made visible as ‘calcium sparks’ using fluorescent dyes (ref 1).
Further investigation revealed that the increase in calcium spark rate was dependent on intact cell skeleton structures called microtubules, protein filaments that span the cell and presumably transfer the mechanical ‘pull’ to the calcium release channels.
Space-time plot of calcium fluorescence, illustrating the increase in spark rate in a heart cell before (top) and during (bottom) mechanical stretch. SL is sarcomere length.
Image: University of Oxford
Click to view full-size image (473KB)
"Our major finding was that the axial stretch of cardiac myocytes [muscle cells] increases calcium spark rate, and intact cytoskeletal structure is required for this phenomenon," says study co-author Gentaro Iribe from Okayama University, Japan. He adds that such a basic finding about the load-dependency of calcium handling in heart muscle cells could be an important in revealing mechanisms of cardiac failure in an overloaded heart.
"It's a finding quite out of the blue," says Mark Cannell from the University of Auckland, New Zealand, who detailed his thoughts on the finding in an editorial for the journal Circulation Research (ref 2). "As far as I know there was no precedent for such a structural linkage in heart muscle." He adds that the paper points to new directions for studying the control of calcium metabolism and he believes this will lead to more experiments to gauge the strength of the effect.
And these experiments could lead to new drugs in the future, perhaps to control the way the heart reshapes itself. At the very least, it demonstrates that an approach to link structure and function from the level of the organ down to the sub-cellular nanometre scale can reveal the patterns that determine real, visible and life-threatening dynamics of an organ.
Sufferers of coronary heart disease, which kills more than 100,000 people each year in the UK, could be among the first to benefit from treatment tailored to the individual, for example by guiding the precise placement of an artery-supporting stent or pacemaker wire. "Personalised treatments are some years ahead," Kohl says. "But we are putting in place parts of the puzzle."
Kohl says this approach could be referred to as the ‘physiome’, akin to ‘big science’ studies like The Human Genome Project. But he adds that modelling every chemical interaction in every biological system is not practicable at present. "It’s impossible with a brute force approach to model it all. You would have to link together all the computers in the world and you would still probably not be able to do it. Tools to link relevant information across all levels are only just emerging and that’s why it is such an exciting project."
BBSRC’s Japan Partnering Award (JPA) scheme provides resources to BBSRC-supported research groups to allow them to forge long-term partnerships with Japanese scientists within the field of systems biology. In a reciprocal scheme, the Japanese Science and Technology Agency provides similar funds to Japanese researchers.
Gentaro Iribe from Okayama University, Japan, says the JPA programme aids international collaboration. "I visited the Oxford group to have discussions, and run some of the experiments of this project". He adds that further collaboration is ongoing and that the Oxford team have visited Japan for discussion and technical support.
Funding through the JPA scheme, and similar funded schemes with India and China, is intended to enhance the capacity BBSRC-funded scientists to collaborate at an international level. Up to £50,000 is available over a 4-year period for travel, subsistence and other activities, such as workshops or exchanges, with one or more research groups in the participating country.
See related links for more information.
- Axial Stretch of Rat Single Ventricular Cardiomyocytes Causes an Acute and Transient Increase in Ca2+ Spark Rate (external link), Circulation Research, 2009
- Pulling on the Heart Strings: a New Mechanism Within Starling’s Law of the Heart? (external link) Circulation Research, 2009
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