Strategies and Tactics in Multiscale Modeling of Cell-to-Organ Systems

Abstract

Modeling is essential to integrating knowledge of human physiology. Comprehensive self-consistent descriptions expressed in quantitative mathematical form define working hypotheses in testable and reproducible form, and though such models are always "wrong" in the sense of being incomplete or partly incorrect, they provide a means of understanding a system and improving that understanding. Physiological systems, and models of them, encompass different levels of complexity. The lowest levels concern gene signaling and the regulation of transcription and translation, then biophysical and biochemical events at the protein level, and extend through the levels of cells, tissues and organs all the way to descriptions of integrated systems behavior. The highest levels of organization represent the dynamically varying interactions of billions of cells. Models of such systems are necessarily simplified to minimize computation and to emphasize the key factors defining system behavior; different model forms are thus often used to represent a system in different ways. Each simplification of lower level complicated function reduces the range of accurate operability at the higher level model, reducing robustness, the ability to respond correctly to dynamic changes in conditions. When conditions change so that the complexity reduction has resulted in the solution departing from the range of validity, detecting the deviation is critical, and requires special methods to enforce adapting the model formulation to alternative reduced-form modules or decomposing the reduced-form aggregates to the more detailed lower level modules to maintain appropriate behavior. The processes of error recognition, and of mapping between different levels of model complexity and shifting the levels of complexity of models in response to changing conditions, are essential for adaptive modeling and computer simulation of large-scale systems in reasonable time.

Fig. 1

Diagram of multiscale cell model. Pyramids at each level of complexity represent individual subsystem modules.

Fig. 2

Effect of change of offset on estimation of system steady-state gain. Measured data points are indicated by the small squares.