Metabolic networks: a signal-oriented approach to cellular models

Complete genomes, far advanced proteomes, and even 'metabolomes' are available for at least a few organisms, e.g., Escherichia coli. Systematic functional analyses of such complete data sets will produce a wealth of information and promise an understanding of the dynamics of complex biological networks and perhaps even of entire living organisms. Such complete and holistic descriptions of biological systems, however, will increasingly require a quantitative analysis and the help of mathematical models for simulating whole systems. In particular, new procedures are required that allow a meaningful reduction of the information derived from complex systems that will consequently be used in the modeling process. In this review the biological elements of such a modeling procedure will be described. In a first step, complex living systems must be structured into well-defined and clearly delimited functional units, the elements of which have a common physiological goal, belong to a single genetic unit, and respond to the signals of a signal transduction system that senses changes in physiological states of the organism. These functional units occur at each level of complexity and more complex units originate by grouping several lower level elements into a single, more complex unit. To each complexity level corresponds a global regulator that is epistatic over lower level regulators. After its structuring into modules (functional units), a biological system is converted in a second step into mathematical submodels that by progressive combination can also be assembled into more aggregated model structures. Such a simplification of a cell (an organism) reduces its complexity to a level amenable to present modeling capacities. The universal biochemistry, however, promises a set of rules valid for modeling biological systems, from unicellular microorganisms and cells, to multicellular organisms and to populations.