Building with a scaffold: emerging strategies for high- to low-level cellular modeling

Computational cellular models are becoming crucial for the analysis of complex biological systems. An important new paradigm for cellular modeling involves building a comprehensive scaffold of molecular interactions and then mining this scaffold to reveal a hierarchy of signaling, regulatory and metabolic pathways. We review the important trends that make this approach feasible and describe how they are spurring the development of models at multiple levels of abstraction. Pathway maps can be extracted from the scaffold using 'high-level' computational models, which identify the key components, interactions and influences required for more detailed 'low-level' models. Large-scale experimental measurements validate high-level models, whereas targeted experimental manipulations and measurements test low-level models.