The Interplay between Feedback and Buffering in Cellular Homeostasis

Abstract

Buffering, the use of reservoirs of molecules to maintain concentrations of key molecular species, and negative feedback are the primary known mechanisms for robust homeostatic regulation. To our knowledge, however, the fundamental principles behind their combined effect have not been elucidated. Here, we study the interplay between buffering and negative feedback in the context of cellular homeostasis. We show that negative feedback counteracts slow-changing disturbances, whereas buffering counteracts fast-changing disturbances. Furthermore, feedback and buffering have limitations that create trade-offs for regulation: instability in the case of feedback and molecular noise in the case of buffering. However, because buffering stabilizes feedback and feedback attenuates noise from slower-acting buffering, their combined effect on homeostasis can be synergistic. These effects can be explained within a traditional control theory framework and are consistent with experimental observations of both ATP homeostasis and pH regulation in vivo. These principles are critical for studying robustness and homeostasis in biology and biotechnology.

Design and Analysis of a Proportional-Integral-Derivative Controller with Biological Molecules

“…These properties might prove to be essential for applications in metabolic engineering and cellular therapeutics where different considerations and tradeoffs might be at play, and hence different combinatorial variations of the three terms (P, I, or D) might be needed and appropriate. They also might facilitate mixing and matching our designs with those of others, for example using implementation of a naturally occurring derivative motif that was recently analyzed (Hancock et al, 2017) and shown to exhibit excellent noise suppression characteristics at high frequencies.…”

CoRa –A general approach for quantifying biological feedback control

“…Any feedback control system can be analyzed using CoRa, providing a unifying framework under which different feedback mechanisms can be rigorously compared. In fact, we were able to rapidly analyze a large number of distinct feedback control motifs proposed in the literature [2,4,6,7,11,13,15] (Fig. 3; Supplementary Information).…”

Metabolic Buffer Analysis Reveals the Simultaneous, Independent Control of ATP and Adenylate Energy Ratios

“…Determining the design principles behind biological regulation is important for understanding the principles of life, treating complex diseases, and creating de novo synthetic biology [20]. A significant amount of research into this topic has focussed on feedback regulation [2,8,9,18,20,34,35,36,43], a ubiquitous mechanism in biology that acts via biological actuators, such as regulated enzymes [17,38]. But there is a crucial open challenge to determine the underlying principles for biological regulation beyond feedback [20].…”

“…But there is a crucial open challenge to determine the underlying principles for biological regulation beyond feedback [20]. Buffering-the use of reservoirs of molecules to maintain molecular concentrations-is another widespread mechanism for biological regulation [17,38]. Despite its importance, buffering has received considerably less attention than feedback.…”