Trends in Biotechnology
Building with a scaffold: emerging strategies for high- to low-level cellular modeling
Section snippets
Descending from the scaffold to high- and low-level pathway models
A good way to visualize this pathway mapping procedure is as a descent through a series of models at increasing levels of detail and decreasing levels of abstraction (Box 1). At the highest level of abstraction, the goal is to analyse the complete interaction scaffold to extract the basic components and connectivity of the pathway of interest. We term these connectivity-driven models ‘High Level’ or ‘Level One’ (L1) pathway models. At a more detailed level, we might wish to supplement the
Systematic experiments for characterizing networks and states
Signaling and regulatory pathways consist of some number of components, such as genes, proteins and small molecules, wired together in a complex network of intermolecular interactions. Recent technological developments are enabling us to define and interrogate these pathways more directly and systematically than ever before, using two complementary approaches. First, it is now possible systematically to measure the molecular interactions themselves, by screening for protein–protein, protein–DNA
Extracting L1 models from the interaction scaffold
To arrive at an L1 model of a pathway or cellular process of interest, data on molecular interactions and states are integrated in a multi-tiered pathway mapping strategy (Fig. 1). First, the global molecular interaction scaffold is constructed from systematic measurements of protein–protein interactions, protein–DNA interactions and/or metabolic reactions. In the case of budding yeast, a maximal set might include 14 941 protein–protein interactions (catalogued in the DIP™ database), 5631
From L1 to L2 models
At the other end of the level spectrum (L2 models), one wishes to build models with predictive capability for cell behavior that are physicochemical in nature and based on low level molecular detail. For instance, consider an altered DNA sequence leading to a modified protein structure, which in turn yields an altered rate constant in a cell signaling process governing cell proliferation, differentiation or migration. Can we predict how that sequence change would propagate to a change in cell
Coverage versus leverage: the two phases of experimental design
The systematic pathway mapping approach has important implications for experimental design. Just as pathway modeling has multiple levels (L1 and L2), so experiments to specify and validate these models are performed in distinct modes or phases (A and B; see Fig. 3). The goal of the initial phase (phase A) is to perform experiments that are comprehensive in nature, to stimulate the pathway of interest broadly and to perturb all of its components. We might consider all perturbations of a certain
Perspectives
Where are pathway modeling efforts headed in the future? It is revealing that, outside biotechnology and the pharmaceutical industry, nearly every sector of manufacturing depends on computer simulation and modeling for product development. Circuit manufacturers rely on computer aided design (CAD) tools to model the wiring of transistors and other circuit components as well as their two- and three-dimensional layouts on the silicon wafer. Likewise, automotive engineers can estimate how many
Acknowledgements
We are indebted to J. Lauffenburger, J. Doyle and O. Ozier for inspiring discussions and for very helpful comments on the manuscript. T.I. was generously supported by a research fellowship from Pfizer; D.L. was supported by grants from DARPA and NIGMS.
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