On Modeling Metabolic Systems

Modeling metabolism has been generally based on the numerouscellular reactions to be in steady state with respect to theexternal fluxes on the cell boundary. The essence of this"steady state" approach is the identification of all thereaction rates (fluxes), both external and internal to the cell,that together constitute metabolism. The steady state isexpressed by homogeneous algebraic equations that must be solvedto obtain the reaction rates. There are many more reactions thanspecies in metabolic systems resulting in a gross imbalancebetween the number of unknowns and the number of equations.Flux balance approaches have dealt with thiscircumstance by seeking to identify fluxes that areexperimentally accessible, a strategy that continues to grow inscope (such as by the systematic use of isotopic tracers), as ameans to enable estimation of other fluxes that are notaccessible. Resolution of the indeterminacy, however, hasdepended on fortification with additional conceptual tools suchas maximizing the biomass yield. Regulatory processes, which area vital component of metabolism in that they determine whatreactions are in fact active in metabolism, are not an explicitaspect of flux balance approaches.A rational framework for modeling metabolism mustaccommodate the prediction of all fluxes and in particular theexternal fluxes which must reflect the consequences of metabolicregulation. Such a framework is therefore forced to addressregulatory processes in a comprehensive way. In this regard, thecybernetic modeling concept[1] developed by our research group,that has been evolving since the early eighties, hasprogressively accommodated features of regulation that have notbeen within the scope of other modeling approaches. This seminarwill focus on an exposition of this framework and its successestogether with an assessment of its promise in large scalemetabolic modeling and metabolic engineering.