Synthetic biology is a relatively new field that focuses on designing and constructing novel synthetic biological circuits that achieve certain desired functions by using characterized biological building blocks [1]. Synthetic circuits not only help us understand the underlying design principles of natural biological systems, but also show great potential to revolutionize industrial and medical biotechnology, cell therapy, agriculture, biofuels, bioremediation, and biomaterials 2, 3, 4, 5.

The drive to realize new cellular function has led to a multitude of synthetic circuits that implement a relatively small number of motifs. One of these is feedback (both positive and negative), a recurrent motif that was present at the inception of the field of synthetic biology. Indeed, the first three synthetic circuits that initiated the field when they were published in the year 2000, all employed feedback as a central strategy behind their operation. One of these circuits is consists of a simple negative feedback to reduce the variance of an output of interest [6]. The circuit consisted of one transcriptional repressor that inhibits its own production (autoregulation). Adding a second repressor results in a double-negative-feedback circuit. The two mutually inhibiting repressors function as a bistable toggle switch, which is the motif of another of these celebrated early synthetic circuit designs [7]. Adding a third repressor gives a triple-negative-feedback circuit, named the repressilator, which is a cyclic negative-feedback loop composed of three repressors that function as a ring oscillator [8].

In this short review, we focus on circuits that employ negative feedback, one of the most commonly used motifs in synthetic biology due to the many benefits it bestows on a biological design. For example, the pioneering autoregulatory negative-feedback circuit [6] mentioned above, demonstrated its ability to reduce the variance of an output of interest. In Ref. [9], it was shown that by adding a TetR-negative autoregulation to an expression circuit, negative feedback can transform the dose–response curve from sigmoidal to linear. Another benefit of negative feedback lies in its ability to accelerate the step response dynamics by exchanging high gain with speed. Indeed, a metabolic feedback circuit implemented in Ref. [10] was capable of dramatically shortening the rise time of metabolites, decreasing it by as much as 12-fold. Other reported uses of negative feedback include phenotypic robustness by noise suppression [11], concentration tracking [12], performance enhancement of gene expression [13], burden mitigation 14, 15, 16, disturbance attenuation [17], and combined disturbance attenuation and speed through layered negative feedback [18].

When examining the above applications and others, one finds that one the most salient features engendered by negative feedback is robustness — a property that promotes and sustains homeostasis in all living systems. The failure of endogenous mechanisms to effectuate homeostasis can be detrimental to the health of living systems, and indeed many diseases can be directly attributed to the disruption of normal homeostasis [19]. Synthetic negative-feedback circuits, therefore, serve as promising candidates to deliver homeostasis [20] by accompanying or even replacing failed endogenous mechanisms 17, 21.