Cellular Open Resource (COR): an environment for the modelling of cardiac cellular and multi-cellular electrophysiology

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Cardiovascular disease is the number one killer in the UK, with just under 238,000 fatalities p.a., and accounts for 39% of all deaths (Office for National Statistics, 2002). An important area of cardiovascular research is cardiac electrophysiology, the study of electrical function, and malfunction, of the heart. Some 45 years ago, Denis Noble published the first mathematical model of the electrical activity of a cardiac muscle cell. His subsequent modelling work has developed tools that are useful for data interpretation, hypothesis formation, experimental planning, teaching, and it was even accepted by the US Food and Drug Administration in recent hearings. The further development of such models would be facilitated by dedicated modelling environments, which have thus far been targeted at either modellers or teachers, leaving aside most experimentalists. As a result, they either offer powerful numerical techniques (mainly useful to modellers) or a user-friendly interface (mainly useful to teachers) / but not both at the same time, reducing applicability and take-up. The life cycle of a model involves several stages (work on the 'blackboard', implementation, submission for publication, actual publication and use by others), all of which being subject to human error when it comes to the coding/writing of the mathematics behind the model. This is obviously a major concern, since weeks, if not months, can literally be spent trying to track down the problem(s). A dedicated language, CellML (see http://www.cellml.org/), was therefore specified, and there are now hundreds of models that are available in that format. Sadly, there are just a handful of environments that can execute CellML models, and even fewer that allow for their editing. The first CellML capable environment, Cellular Open Resource (COR; see http://cor.physiol.ox.ac.uk/), has been developed by our group. It is also the first environment to allow for both the editing and execution of CellML files. It has, from its inception, been targeted at both researchers (be they modellers or experimentalists) and teachers. A beta version was offered earlier this year and is already being used in 33 countries worldwide. As a proof of concept, its focus has been on supporting CellML (i.e. cellular modelling) and assessing whether such an environment would be of relevance to the aforementioned groups of professionals. The high acceptance rate of COR has gone beyond all expectations. The purpose of any CellML model is to be executed to address a particular problem. This may involve pausing and resuming a simulation after having interactively changed some of the cell model's properties. This can already be done in COR, but should be improved by implementing a concept of COR Project, which could be seen as a formal way of describing a virtual experiment through time. Such a feature would be of obvious use to modellers, but also to experimentalists who could use it to interactively test a series of hypothesis before carrying out the corresponding 'wet' experiments, while teachers could use it to create tutorials. We will, in the latter context, provide a set of tutorials that are based on a practical class on cardiac cellular electrophysiology at Oxford. This will not only be useful to teachers in the field, but also to illustrate the utility of COR's concepts. Simulations that involve several virtual cells (i.e. multi-cellular modelling) are also highly desirable (arrhythmias are multi-cellular phenomena). We therefore intend to offer such a feature, focused on cardiac electrophysiology, for which the science is well established, and this will be implemented using the best numerical techniques available. The concept of COR Project will be both enhanced to account for the multi-cellular nature of such simulations and illustrated through examples based on our own modelling work and on basic principles of multi-cellular cardiac electrophysiological modelling.