Robust modelling, measurement and analysis of human and animal metabolic systems

Modelling human and animal metabolism is impeded by the lack of accurate quantitative parameters and the large number of biochemical reactions. This problem may be tackled by: (i) study of modules of the network independently; (ii) ensemble simulations to explore many plausible parameter combinations; (iii) analysis of 'sloppy' parameter behaviour, revealing interdependent parameter combinations with little influence; (iv) multiscale analysis that combines molecular and whole network data; and (v) measuring metabolic flux (rate of flow) in vivo via stable isotope labelling. For the latter method, carbon transition networks were modelled with systems of ordinary differential equations, but we show that coloured Petri nets provide a more intuitive graphical approach. Analysis of parameter sensitivities shows that only a few parameter combinations have a large effect on predictions. Model analysis of high-energy phosphate transport indicates that membrane permeability, inaccurately known at the organellar level, can be well determined from whole-organ responses. Ensemble simulations that take into account the imprecision of measured molecular parameters contradict the popular hypothesis that high-energy phosphate transport in heart muscle is mostly by phosphocreatine. Combining modular, multiscale, ensemble and sloppy modelling approaches with in vivo flux measurements may prove indispensable for the modelling of the large human metabolic system.