A closer look at the double-edged sword that gene drives present

In 2003, scientists finished sequencing the complete human genome for the very first time. A global scientific endeavor, the closing of the Human Genome Project was a momentous occasion following 13 years of hard work (1990-2003) and nearly $1 billion of expenditures. [1] Today, anyone can have his or her entire genome sequenced for $2000 in a few days, with more expensive high-throughput machinery capable of doing so in just 24 hours. [2]

Accompanying this exponential increase in sequencing efficiency has been a significant advancement in scientists’ ability to read, understand, and, more recently, manipulate DNA. Of course, one can hardly discuss gene editing without mentioning the CRISPR-Cas9 construct, a powerful tool allowing scientists to make relatively precise edits to specific regions of DNA. CRISPR enables scientists to manipulate genetic material with an unprecedented level of accuracy, and it holds the potential to cure all sorts of previously untreatable genetic diseases.

Nevertheless, CRISPR techniques have only traditionally been used to permanently modify either unicellular organisms or somatic cells, any cell in a multicellular organism aside from reproductive cells. [Footnote: Genetically modified organisms (GMO) are an exception to this norm, but they will not be discussed here as their method of modification is slightly different.] This decision ensures that genetic modifications are not passed on to one’s offspring, an occurrence which could lead to a myriad of unintended future consequences.

A new technology known as gene drives, on the other hand, involves direct manipulation of DNA in reproductive cells and targets specific highly conserved genes — genes for which one allele confers a significant fitness advantage and so is passed on in a higher than average proportion than its counterpart. To build a gene drive, scientists splice a CRISPR-Cas9 “cassette” into a certain allele containing the modified DNA. During meiosis, the modified gene drive allele creates a CRISPR-Cas9 construct which cuts the other allele, leading to its repair by the body using the only other functional copy remaining: the gene drive (Figure 1A). This process ensures that an organism heterozygous for the gene drive always passes it on to its offspring, since the other wild-type allele which would normally prevail half the time in meiosis has been cut and repaired to also carry the modified gene.

In this way, the strength of gene drives lies in their ability to propagate through an entire species after introduction in a small percentage of the population (given sufficient generations have passed, of course). Its only real technical limitations are its confinement to sexually reproducing species and vulnerability to mutations which disrupt the transmission of the modification.

A recent study used this technology in the lab to render a species of mosquitoes infertile and incapable of transmitting malaria. [3] Scientists incorporated a gene drive in the mosquitoes which disrupts the doublesex gene, a gene functioning in sex determination. Males were unaffected, but females carrying two copies of the gene drive began to develop male sexual characteristics and experienced morphological changes in their mouth parts. In other words, female mosquitoes homozygous for the gene drive were unable to bite (and therefore transmit malaria) or reproduce. In this way, heterozygous females spread the gene drive throughout the species while the population gradually drifted towards infertility (since eventually no female mosquitoes will be capable of reproduction). Computer simulations run by the scientists responsible for this work have corroborated the efficacy of the gene drive in the wild, and additional tests have proved that Cas9-resistant mutations were not only rare but also failed to inhibit the spread of the gene drive.

Figure 1: Mechanism and propagation of a gene drive. (a) Gene drive located on one allele cuts the other allele, leading to its repair by the body using the gene drive as a template. Thus, the gene drive is always inherited. (b) Inheritance of a gene drive in a population. The allele for the modification is always inherited due to the mechanism described in (a), but it may take many generations to fully spread throughout a population depending on reproductive speed and other factors.
(Image: Esvelt KM, Gemmell NJ (2017) Conservation demands safe gene drive. PLoS Biol 15(11): e2003850. https://doi.org/10.1371/journal.pbio.2003850)

Studies such as this one provide encouraging evidence that scientists are on the right path for creating gene drives which could be used to eliminate disease vectors — perhaps finally putting an end to diseases like malaria — and inoculate populations of crops from disease (allowing farmers to scale down their use of herbicides and pesticides). But, despite its enormous potential, gene drives are at least decades away from implementation in the field due to a range of ethical and broader scientific concerns.

The ecological impacts of wiping out an entire species are more than enough to give scientists pause to consider the ramifications of introducing a gene drive into the wild. Complex ecosystems only superficially understood by scientists could completely collapse or spiral out of control, leading to a far worse outcome.

Random mutations could occur, potentially resulting in even more harmful genes “piggybacking” on the gene drive and causing a mosquito population to become even more deadly than before. Gene drives might also inadvertently jump to other species in the wild, leading to disastrous effects on a far wider scale than scientists would originally have intended.

With no straightforward answers to these concerns (among many others), it seems unlikely that gene editing technology will fully leave the lab and enter the medical world, barring select few experimental treatments. Nevertheless, gene drives and many other gene editing technologies do not fall under regulatory legislation, and one of the only current restrictions on them is a global scientific consensus to abstain from germline engineering and risky genetic modifications. [4]

However, Chinese scientists have already conducted radical experiments ranging from genetic modification of viable human embryos (which were destroyed) to the more recent controversy of one Chinese scientist using CRISPR to produce the world’s first pair of gene-edited babies. [5] These actions have generated a significant backlash from the scientific community and seem to reveal the startling lack of regulation on gene editing technology. With such easy access to materials for gene editing (CRISPR “kits” are available for purchase all over the internet), one wonders what will stop bioterrorists from wreaking havoc with this technology.

While I don’t have a particular solution in mind (although an international agreement like the Climate Accords seems reasonable), I believe that the development of viable gene drives underscores the fact that gene-editing regulation will eventually concern everyone, whether we like it or not. Technology like gene drives possess enormous potential for shaping the world around us to eliminate deadly diseases and improve lives, but I believe that genetic engineering will pose a much bigger threat than benefit in the future if the issue of its regulation is not soon dealt with.

References

[1] An Overview of the Human Genome Project. (2012, November 8). Retrieved from National Human Genome Research Institute website: https://www.genome.gov/ 12011239/a-brief-history-of-the-human-genome-project/

[2] Wetterstrand, K. (2018, April 25). DNA Sequencing Costs: Data. Retrieved from National Human Genome Research Institute website: https://www.genome.gov/ 27541954/dna-sequencing-costs-data/

[3] Kyrou et al. (2018). A CRISPR–Cas9 gene drive targeting doublesex causes complete population suppression in caged Anopheles gambiae mosquitoes. Nature Biotechnology, 36, 1062-1066. Retrieved from https://www.nature.com/articles/nbt.4245

[4] Oye et al. (2014, August 8). Regulating gene drives. Science, 345(6197), 626-628. Retrieved from http://science.sciencemag.org/content/345/6197/ 626.full

[5] Stein, R. (2018, November 26). Chinese Scientist Says He’s First To Create Genetically Modified Babies Using CRISPR. Retrieved from National Public Radio website: https://www.npr.org/sections/health-shots/2018/11/26/ 670752865/chinese-scientist-says-hes-first-to-genetically-edit-babies

Image Link: https://journals.plos.org/plosbiology/article/figure?id=10.1371/journal.pbio.2003850.g001