Modeling genetic switches with positive feedback loops.

In this paper, we develop a new methodology to design synthetic genetic switch networks with multiple genes and time delays, by using monotone dynamical systems. We show that the networks with only positive feedback loops have no stable oscillation but stable equilibria whose stability is independent of the time delays. In other words, such systems have ideal properties for switch networks and can be designed without consideration of time delays, because the systems can be reduced from functional spaces to Euclidian spaces. Therefore, we can ensure that the designed switches function correctly even with uncertain delays. We first prove the basic properties of the genetic networks composed of only positive feedback loops, and then propose a procedure to design the switches, which drastically simplifies analysis of the switches and makes theoretical analysis and design tractable even for large-scaled systems. Finally, to demonstrate our theoretical results, we show biologically plausible examples by designing a synthetic genetic switch with experimentally well investigated lacI, tetR, and cI genes for numerical simulation. Copyright 2003 Elsevier Science Ltd.