Modeling metabolism has been generally based on the numerous cellular reactions to be in steady state with respect to the external fluxes on the cell boundary. The essence of this “steady state” approach is the identification of all the reaction rates (fluxes), both external and internal to the cell, that together constitute metabolism. The steady state is expressed by homogeneous algebraic equations that must be solved to obtain the reaction rates. There are many more reactions than species in metabolic systems resulting in a gross imbalance between the number of unknowns and the number of equations.
Flux balance approaches have dealt with this circumstance by seeking to identify fluxes that are experimentally accessible, a strategy that continues to grow in scope (such as by the systematic use of isotopic tracers), as a means to enable estimation of other fluxes that are not accessible. Resolution of the indeterminacy, however, has depended on fortification with additional conceptual tools such as maximizing the biomass yield. Regulatory processes, which are a vital component of metabolism in that they determine what reactions are in fact active in metabolism, are not an explicit aspect of flux balance approaches.
A rational framework for modeling metabolism must accommodate the prediction of all fluxes and in particular the external fluxes which must reflect the consequences of metabolic regulation. Such a framework is therefore forced to address regulatory processes in a comprehensive way. In this regard, the cybernetic modeling concept1 developed by our research group, that has been evolving since the early eighties, has progressively accommodated features of regulation that have not been within the scope of other modeling approaches. This seminar will focus on an exposition of this framework and its successes together with an assessment of its promise in large scale metabolic modeling and metabolic engineering.