The classic genetic toggle switch used two mutually repressing transcription factors, which gives rise to bistablity and hysteresis (Gardner et al.
2000; Litcofsky et al.
2012). Subsequently, genetic switches were also constructed using positive autoregulatory feedback loops (Isaacs et al.
2003; Atkinson et al.
2003). More recently, circuits combining mutual repression with positive autoregulatory feedback have been built, including the addition of a single positive feedback loop (Lou et al.
2010) and double positive autoregulatory loops, resulting in a quadrastable switch (Wu et al.
2017). The genetic toggle switch has also been coupled with quorum sensing systems to create a population-based switch, which switched states dependent on the local cell density (Kobayashi et al.
2004). In bacterial cells, the cellular context is of increasing interest and this can affect genetic switch performance in a number of ways including changes in stability at low molecule numbers (Ma et al.
2012), plus dependence on host growth rate (Tan et al.
2009), sequence orientation (Yeung et al.
2017) and copy number (Lee et al.
2016). This suggests that natural systems have likely evolved mechanisms that are robust to some of these factors. However, gene regulatory networks are only one way to create switch-like behaviours. Alternatives include the use of recombinases, which allow the DNA itself to flip orientation (Friedland et al.
2009; Bonnet et al.
2012; Courbet et al.
2015; Fernandez-Rodriguez et al.
2015), and the use of transcriptional (RNA) systems (Kim et al.
2006). Accompanying theoretical and computational work has been equally diverse, with insights into possible network topologies (Angeli et al.
2004; Otero-Muras et al.
2012), stochasticity (Tian and Burrage
2006; Munsky and Khammash
2010; Jaruszewicz and Lipniacki
2013; Leon et al.
2016), robustness (Kim and Wang
2007; Barnes et al.
2011), time dependent transient behaviour (Verd et al.
2014), and emergent properties of populations of switches linked by quorum sensing (Kuznetsov et al.
2004; Wang et al.
2007; Nikolaev and Sontag
2016). Following the pioneering work in bacteria, there has now been an explosion of engineered switches for mammalian systems (see Kis et al.
2015 for a comprehensive review), which use components from diverse backgrounds (prokaryotic, eukaryotic and synthetic), and target a variety of applications.