Gene drives, or systems that accelerate the spread of desirable genetic traits into a population, may be built to achieve specific levels of spread when released into the wild. By exerting control over the degree of spread, those who unleash gene drives may realize the benefits promised by gene drives—the suppression of disease-carrying or crop-destroying insects—while minimizing the risks that unintended genetic changes could occur that would lead to undesirable ecological outcomes.

A gene drive engineered to allow for a high degree of control was recently introduced by scientists based at the University of California, San Diego (UCSD). The new gene drive is a “split drive” system.

Details appeared in an article titled, “Inherently confinable split-drive systems in Drosophila.” The article demonstrates that split-drive systems may allow various genetic parameters and strategies to be used to either limit or extend drive potential.

A basic gene drive incorporates two basic elements: a DNA-cutting enzyme (called Cas9) and a guide RNA (or gRNA) that targets cuts at specific sites in the genome. A slightly more elaborate gene drive may incorporate additional genetic cargo—for example, a gene that carries a beneficial trait such as susceptibility to pesticides. Following the Cas9/gRNA cut, the gene drive, along with any additional genetic cargo, is copied into the break site through a DNA repair process.

While classic gene drives are designed to spread autonomously, the newly developed system, a split-drive system, is designed with controls that separate the genetic implementation processes. The split-drive system consists of a non-spreadable Cas9 component inserted into one location in the genome and a second genetic element that can copy itself—along with a beneficial trait—at a separate site.

When both elements are present together in an individual, an “active gene drive” is created that spreads the element carrying the beneficial trait to most of its progeny. Yet, when uncoupled, the element carrying the beneficial trait is inherited under typical generational genetics rules, or Mendelian frequencies, rather than spreading unrestrained.

“We hypothesized that drives targeting genes essential for viability or reproduction also carrying recoded sequences that restore endogenous gene functionality should benefit from dominantly-acting maternal clearance of NHEJ alleles combined with recessive Mendelian culling processes,” the article’s authors wrote. “Here, we test split gene drive (sGD) systems in Drosophila melanogaster that are inserted into essential genes required for viability (rab5, rab11, prosalpha2) or fertility (spo11).”

By creating slight fitness costs that eventually eliminate the Cas9 enzyme from the population, the split-drive system vastly increases control and safety of the genetic deployments.

“In single generation crosses, sGDs copy with variable efficiencies and display sex-biased transmission,” the article noted. “In multigenerational cage trials, sGDs follow distinct drive trajectories reflecting their differential tendencies to induce target chromosome damage and/or lethal/sterile mosaic Cas9-dependent phenotypes, leading to inherently confinable drive outcomes.”

“Studying drives in essential genes is not a novel idea, per se, but we observed that certain split situations were able to spread a cargo effectively upon a first introduction while leaving no trace of Cas9 after a few generations, as well as few mistakes in the DNA repair process that got rapidly diluted out,” said Gerard Terradas, PhD, first author in the Nature Communications paper and a researcher in the UCSD division of biological sciences.

The Nature Communications paper also spells out advantages on how gene drives are perceived by the public, as efforts to alter wild populations could be flexibly designed in a variety of ways per the desired outcome.

“We hope that the flexible design features we have developed will be broadly applicable by enabling tailored approaches to controlling insect vectors and pests in diverse contexts,” said UCSD distinguished professor Ethan Bier, PhD, senior author of the Nature Communications study.