IBM and NeSC workshop on Protein Science
National e-Science Centre, Edinburgh, March
15-16 2002
| From genes to whole
organs: supercomputing the activity of the heart. D. Noble Biological modelling of cells, organs and systems has reached a very significant stage of development. Particularly at the cellular level, there has been a long period of iteration between simulation and experiment (Noble& Rudy, 2001). We have therefore achieved the levels of detail and accuracythat are required for the effective use of models in drug development. To beuseful in this way, biological models must reach down to the level of proteins (receptors, transporters, enzymes etc), yet they must also reconstruct functionality right up to the levels of organs and systems. Thisis now possible and three important developments have made it so: 1.. Relevant molecular and biophysical data on many proteins and the genesthat code for them is now available. This is particularly true for iontransporters (Ashcroft, 2000) 2.. The complexity of the biological processes that can now be modelled is such that valuable counter-intuitive predictions are emerging (Noble & Colatsky, 2000). Multiple target identification is also possible. 3.. Computer power has increased to meet the demands. Even very complex cell models involving up to 50 different protein functions can be run on single processor machines, while parallel computers are now powerful enough to enable whole organ modelling to be achieved. (Kohl et al 2000). Run times though are huge. This kind of work can use all the computing power that can be thrown at it. I will illustrate these points with reference to models of the heart. I will also indicate how the same approach can be applied to many other organs and systems. The criterion that models must reach down to the level of proteins automatically guarantees that they will also reach down to the level of gene mutations when these are reflected in identifiable changes in protein function (Noble 2001). Changes in expression levels characteristic of disease states can also be represented. These developments ensure that it will be possible to use simulation as an essential aid to patient stratification. I will illustrate these points with reference to sodium channel mutations. Ashcroft, FM (2000) Ion Channels and Disease. London: Academic Press. Kohl P, Noble D, Winslow RL & Hunter P (2000) Computational modelling of biological systems: tools and visions. Phil Trans Roy Soc Lond A358 579-610 Noble D. (2001) From genes to whole organs: connecting biochemistry to physiology. J Goode (Ed) Novartis Foundation Symposium volume 239 on Complexity in Biological Signalling. (in press) Noble D & Colatsky T J (2000) A return to rational drug discovery: computer-based models of cells, organs and systems in drug target identification. Emerging Therapeutic Targets, 4, 39-49. Noble D & Rudy Y (2001) Models of cardiac ventricular action potentials: iterative interaction between experiment and simulation. Phil Trans Roy Soc A 359, 1127-1142 |
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