Biological signal generators: integrating synthetic biology tools and in silico control

Abstract

Biological networks sense extracellular stimuli and generate appropriate outputs within the cell that determine cellular response. Biological signal generators are becoming an important tool for understanding how information is transmitted in these networks and controlling network behavior. Signal generators produce well-defined, dynamic, intracellular signals of important network components, such as kinase activity or the concentration of a specific transcription factor. Synthetic biology tools coupled with in silico control have enabled the construction of these sophisticated biological signal generators. Here we review recent advances in biological signal generator construction and their use in systems biology studies. Challenges for constructing signal generators for a wider range of biological networks and generalizing their use are discussed.

Keywords: biological networks; biological signal generators; control; microfluidics; optogenetics; signaling dynamics.

Figure 1:

Biological networks, such as the cartoon network shown here, sense extracellular stimuli and convert that stimuli into appropriate intracellular responses. The network transforms a signal and information is encoded in the dynamics and amplitude of component activity (e.g. red signal). A biological signal generator can bypass the upstream network to produce controllable levels of component activity (e.g. blue signal) making it possible to dissect how information is transmitted or to control specific desirable responses.

Figure 2:

Signal generators can be used to gain insight into biological systems. In Bugaj, et al (A) a biological signal generator was used to drive waves of Ras activity and measure how normal and diseased Ras-ERK cascades transmitted that activity. Diseased networks transmitted the signal with less fidelity, leading to hyperactivity of ERK and incorrect interpretation of normally non-proliferative signals. (B) Signal generators can also be used to maintain biological systems in a desirable state. Lugagne, et al used a biological signal generator to control the concentration of two repressors in a bistable toggle switch. By pulsing the concentration of the repressors the authors were able to maintain the toggle switch near its unstable state (orange), a state that could not be obtained without dynamic control.