Suppressing evolution in genetically engineered systems through repeated supplementation.

The tools provided by genetic engineering can fundamentally alter our technological approaches to medicine, agriculture, and ecology. Through their use, crops have been designed to increase yield while reducing loss from pests and disease (Pellegrino, Bedini, Nuti, & Ercoli, 2018). Critical medications, such as insulin and the mammalian growth hormone‐inhibiting hormone, are now produced using bio‐engineered organisms (Itakura et al., 1977). Genetically engineered organisms have been proposed to help facilitate adaptive responses to climate change, suppress undesirable or invasive populations, and reverse the fixation of deleterious mutations in at‐risk populations of endangered plants and animals (Thomas et al., 2013). In addition, genetic engineering has made vaccines safer, more effective, faster to produce, and could make them easier to disseminate (Basinski et al., 2018; Chahal et al., 2016). Although promising, these new technologies all confront a common challenge: unwanted evolution that may undermine the intent of engineering. Transgenes, stretches of foreign DNA inserted into a host genome, evolve in the same way as any other genetic material. Consequently, if a transgene compromises fitness, selection favors its potentially rapid removal from the population (Sleight, Bartley, Lieviant, & Sauro, 2010; Willemsen & Zwart, 2019). Even when the insert does not reduce fitness, mutations can accumulate, leading to loss of function. This “evolutionary half‐life” poses a significant challenge for the design of successful genetically modified organisms and motivates the identification of designs that slow or arrest evolution of genetic modifications (Bull & Barrick, 2017). One possible solution to suppress evolution in genetically modified organisms comes from population genetics theory demonstrating that gene flow can impede local adaptation (Akerman & Burger, 2014; Bolnick & Nosil, 2007; Crow & Kimura, 1970; Haldane, 1957; Lenormand, 2002; Levene, 1953; Slatkin, 1973; Wright, 1940). In the classic “mainland‐island” models, migration from a mainland to an island can suppress island adaptation. By suppressing local adaptation, immigration can maintain costly phenotypes that would otherwise be displaced by evolution. An interesting question is whether “migration” can be used to maintain essential functions of genetically modified populations in the face of countering selection. In this context, repeated re‐introduction of genetically modified individuals into an evolving population is analogous to a constant level of immigration from a source fixed for locally unfavorable mutations. To address this question, we develop and analyze mathematical models to evaluate the efficacy of repeated introduction (henceforth “supplementation”) as a tool for controlling unwanted evolution in three contexts of genetically engineered populations: bioreactors, gene drives, and transmissible vaccines. In the first, we identify the level of supplementation required to maintain a stable frequency of a desired but deleterious transgene in the microbial population of a bioreactor. In the second, we evaluate the effect of supplementation on the spread and stability of gene drives that experience resistance evolution. In the third, we identify the amount of supplemental direct vaccination required of a transmissible vaccine to prevent its evolutionary decay while maintaining a high enough vaccine coverage to also protect the population against a pathogen.