Method for determining natural design principles of biological control circuits

We illustrate a method of controlled mathematical comparison for determining design principles of biological control circuits. The method involves the comparison of alternative circuits that differ in a single process, that are constrained so as to eliminate extraneous differences, and that are compared quantitatively on the basis of a priori criteria for functional effectiveness. We use this method to compare two forms of coupling that are important in the regulation of repressible gene expression. The first form, which is called complete uncoupling, is marked by a constant level of regulator protein. The second form, which is called perfect coupling, is marked by a level of regulator protein that varies coordinately with the level of repressible enzyme under control. Our results indicate that, for a large class of systems, performance is better with perfect coupling than with complete uncoupling if the regulator protein is a repressor, and conversely, that performance is better with complete uncoupling than with perfect coupling if the regulator protein is an activator. These results lead to testable predictions that are consistent with available data.