The gene drive bubble: New realities

The last couple of years have seen a profound rise in excitement about the many possible uses of gene drive systems (GDSs)—and of the possible drawbacks of this technology. Much of the focus has been on bioethical and biomedical questions about their implementation. On the plus side, a GDS could be used to suppress populations of disease vectors and invasive species. On the negative side, escape of a GDS into a beneficial species could spell its doom. So, how foolproof are they? That’s the question Champer and colleagues set out to answer in this issue of PLOS Genetics. The potential use of GDSs for population control or disease suppression has been appreciated for nearly 60 years [1, 2]. Those possibilities were recognized in response to the discovery of natural forms of gene drive in mice and fruit flies [3–5]. Elementary theory was developed that showed the tremendous selective advantage of a “perfect” GDS, and it was easy to see that a lethal GDS could suppress or even wipe out a species [6–8]. Then, Austin Burt [9] suggested it would be possible to engineer GDSs to achieve these effects—but that was all theoretical. In spite of some exciting results with homing endonucleases [10, 11], an easy-to-engineer GDS remained an exciting but somewhat remote possibility. All that changed thanks to the discovery of a bacterial nuclease system known as CRISPR-Cas9. The discovery of CRISPR-Cas9 meant that Burt’s proposal was closer to reality via the creation of a self-perpetuating gene drive that could be deployed in potentially any genomic location in any eukaryotic species [12]. The advantage of CRISPR-Cas9 over other known nucleases was that the Cas9 nuclease could be directed to cut almost any DNA sequence with exceedingly high specificity—Cas9 uses an easily designed guide RNA to find its target. A GDS is then easily created by inserting CRISPR-Cas9 into the very chromosomal location that it cuts; when the diploid cell is a heterozygote with a CRISPR-Cas9 construct on 1 chromosome but not on the other, CRISPR-Cas9 cuts the “empty” chromosome site, and the cell repairs the cut ends by copying from the CRISPR-Cas9–bearing chromosome (Fig 1). The formerly heterozygous cell now carries CRISPR-Cas9 on both chromosomes. If the cell is a germ cell, the heterozygote breeds as a homozygote, producing only CRISPR-Cas9–bearing gametes. The selective advantage provided by this transmission “doubling” in heterozygotes is powerful (Fig 1). A CRISPR-Cas9 drive can be engineered into a somatically essential gene, provided that heterozygotes maintain normal fitness. Homozygotes will die, of course, and intuition would suggest that such engineering would be an evolutionary nonstarter because the spread of the drive allele should be quickly halted by homozygote death. However, the transmission advantage of drive in heterozygotes overwhelms the disadvantage of homozygote