H-059. Building Biological Memory by Coherent Linkage of Distinct Positive Feedback Loops

D-E. Chang, A. Reifler, S. Leung, D. B. Forger, A. J. Ninfa;
Univ. of Michigan, Ann Arbor, MI.

We investigated whether strong biological memory could be built up piece-meal, by linking positive feedback loops (employing different biochemical mechanisms) in a coherent fashion. We used two bistable systems based on positive feedback described previously: one was a genetic toggle switch in which an activator protein drives transcription of it’s own structural gene from a promoter that is repressed by constitutively-produced LacI repressor. As expected, the positive feedback of activator on its own synthesis resulted in bistability over a range of gratuitous inducer concentrations. A second positive feedback loop was provided by placing the lacY structural gene under the control of the genetic toggle switch, such that galactoside permease brings about transport of the inducer that increases its own expression. As expected, this positive feedback also resulted in bistability over a range of gratuitous inducer concentrations. When both positive feedback loops linked in a coherent fashion, a dramatic synergism in terms of bistability over a very broad range of gratuitous inducer concentrations was observed. With modest increase of the concentration of repressor, the range of inducer concentrations at which bistability was observed shifted to higher concentrations of gratuitous inducer, and the amplitude of the output decreased. Under some cellular growth conditions, the switch behaved approximately as an irreversible “developmental” switch that once induced, remained in the ON state indefinitely. In another situation, the switch behaved as a noise-dependent switch. Together, these results show that strong biological memory can be built up piece-meal using positive feedback, and its properties can be tuned by varying key parameters.