Cells adapt to changing environments. Perturb a cell and it returns to a point of homeostasis. Perturb a population and it evolves toward a fitness peak. We review quantitative models of the forces of adaptation and their visualizations on landscapes. While some adaptations result from single mutations or few-gene effects, others are more cooperative, more delocalized in the genome, and more universal and physical. For example, homeostasis and evolution depend on protein folding and aggregation, energy and protein production, protein diffusion, molecular motor speeds and efficiencies, and protein expression levels. Models provide a way to learn about the fitness of cells and cell populations by making and testing hypotheses.

While Escherichia coli has one of the most comprehensive datasets of experimentally verified transcriptional regulatory interactions of any organism, it is still far from complete. This presents a problem when trying to combine gene expression and regulatory interactions to model transcriptional regulatory networks. Using the available regulatory interactions to predict new interactions may lead to better coverage and more accurate models. Here, we develop SEREND (SEmi-supervised REgulatory Network Discoverer), a semi-supervised learning method that uses a curated database of verified transcriptional factor-gene interactions, DNA sequence binding motifs, and a compendium of gene expression data in order to make thousands of new predictions about transcription factor-gene interactions, including whether the transcription factor activates or represses the gene. Using genome-wide binding datasets for several transcription factors, we demonstrate that our semi-supervised classification strategy improves the prediction of targets for a given transcription factor. To further demonstrate the utility of our inferred interactions, we generated a new microarray gene expression dataset for the aerobic to anaerobic shift response in E. coli. We used our inferred interactions with the verified interactions to reconstruct a dynamic regulatory network for this response. The network reconstructed when using our inferred interactions was better able to correctly identify known regulators and suggested additional activators and repressors as having important roles during the aerobic-anaerobic shift interface.