Tweaking biological switches through a better understanding of bistability behavior

Abstract

Many biological events are binary. The switch between mutually exclusive OFF to ON state in response to a stimulus is frequently mediated by a control circuit with a positive and/or a negative feedback. Such a system typically exhibits hysteresis with its switching ON and OFF stimulus levels dependent on the current state of the system. The system can be shown to be bistable both experimentally and mathematically. Work to synthesize such switches by combining natural or engineered components has begun to illustrate the potential of such control circuits in many areas of applications.

Figure 1

(a) A two-gene network with positive (arrows) and negative (blunt arrows) feedback loops. (b) Graded response at individual gene level. (c) System demonstrating hysteresis, the threshold concentration for switching the system from OFF to ON state (point D) is higher than that required to switch the system from reverse direction (point B). (d) Bistable response at the system level. Region enclosed within ABCD has three steady states for each concentration of stimulus. Two are stable and experimentally observable. The one unstable one (dashed line) can be theoretically demonstrated.

Figure 2

(a) Schematic diagram of the ScbA/ScbR system regulating antibiotic production in Streptomyces coelicolor. Arrows represent positive regulation and blunt arrows represent repression. Red and blue colors denote positive an negative feedback respectively. The brown color indicates negation of repression control and the dash line indicates negative feedback directed toward a negative feedback. ScbR acts both as an autorepressor as well as a repressor of ScbA. The signaling molecule Scb1 (stimulus) derepresses ScbR repression of itself and ScbA by binding to ScbR. Depression of ScbA causes Scb1 synthesis, causing further synthesis of ScbA and Scb1. The response of ScbR to stimulus Scb1 has been shown to have a bistable behavior. (b) Cell cycle hysteresis observed in Xenopus oocyte cell maturation. The genetic network involves a number of positive feedback loops which impart the system hysteresis. The positive feedback loops include activation by dephospohorylation of Cdc2/cyclin by Cdc25. Cdc2 is involved in the activation of Cdc25, which in turn activates Cdc2 and inactivates Myt1. Myt1 is an inhibitor of Cdc2. (Adapted from Pomerening et al, 2003 [7])(c) Differentiation of hematopoietic stem cells from a multi-lineage gene expression state to two different lineages, macrophage and neutrophil. The primary cell fate determinants are PU.1 and CEBP/α which are expressed constitutively. They are involved in induction of both macrophage specific and neutrophil specific genes. Secondary cell fate determinants Egr/Nab and Gfi-1 are responsible for inducing macrophage and neutrophil specific genes respectively. (Adapted from Laslo et al, 2006 [4])