The idea of using a “gene drive” to decrease the transmission of malaria by suppressing the mosquito population has been around for about 15 years. For the first time, complete suppression of an Anopheles gambiae mosquito population has been achieved, bringing this technology one step closer to becoming a reality.

Researchers led by Andrea Crisanti, Ph.D., professor of molecular parasitology at Imperial College London, constructed a CRISPR-Cas9 based gene drive that not only caused the crash of a population. It also showed no signs of resistance of the targeted gene in the modified mosquito.

Austin Burt, Ph.D., professor of evolutionary genetics at Imperial College London and an author on the paper, calls this work “a great step forward” and Omar Akbari, Ph.D., assistant professor at the University of California, San Diego told GEN that the paper is “a major advance for the gene drive field.” Indeed, every gene drive researcher that GEN spoke with echoed the same excitement for the findings in this paper and the impact that they will have on the field. Kevin Esvelt, Ph.D., an assistant professor of the MIT Media Lab told GEN, “the social and diplomatic challenges of securing international agreement are now arguably more formidable than the remaining technical hurdles.”

Gene drives, well documented in nature, increase the odds that a gene will be passed on to offspring. They can be used to spread genetic alterations in wild animal populations and the introduction of the genome editing tool CRISPR-Cas9 has quickly advanced the engineering of gene drives in the last 5 years.

The paper entitled, “A CRISPR-Cas9 gene drive targeting doublesex causes complete population suppression in caged Anopheles gambiae mosquitoes,” published today in Nature Biotechnology, targeted the “doublesex” gene—the gene responsible for determining whether a mosquito develops as male or female. The team did the work in A. gambiae mosquitoes, one of the most efficient malaria vectors that is particularly significant in sub-Saharan Africa. The gene drive disrupted a region of the doublesex gene that is responsible for female development. Therefore, both male progeny who carry this modified gene and females with only one copy are not affected. However, females with both copies of the modified gene are completely sterile and fail to bite. Not only that, but the gene drive was copied nearly 100% of the time, showing rapid spread and population suppression in a small cage setting.

Dr. Crisanti tells GEN, “What was most exciting [about these results] was to observe that although mutants were generated they were not functional and to see the mosquito population progressively losing its reproductive capability to the point that no more eggs were produced.” He adds that “when Kyros [Kyrou, a research postgrad at Imperial College London and first author on the paper] came into my office with the data, I could not believe that that had happened.”

One of the most impressive aspects of this work was the small number of modified animals needed to eliminate the population. Dr. Esvelt tells GEN, “Anyone building a potentially invasive gene drive system should now be extra careful to use safeguards beyond simple walls and cages, because current models suggest that only a few organisms are needed to begin altering a wild population.”

Dr. Akbari explains, “There are two ways of going about creating gene drives: suppression and replacement.” He elaborates that researchers had given up on suppression because the pressure for the animal to evolve to resist was too great. Valentino Gantz, Ph.D., associate research scientist at the University of California, San Diego agrees, telling GEN that he is “not a big fan of population suppression schemes.” He adds, “However, here the authors designed a construct that reduces female fertility leaving the males untouched. This is a great strategy for population suppression schemes in the field as the gene drive can still propagate through the males.”

By doing this, they have reinvigorated the idea that suppression can work, in large part due to the lack of resistance in their system. Dr. Burt adds, “This is the first paper to deal with resistance in a head on way in a cage population.” Resistance occurs when the targeted gene develops mutations that both render it non-susceptible to the gene drive. This mutation and resistance to the drive are then passed on to the offspring through mating, rendering the gene drive nonfunctional.

“In principle, the gene drive design is similar in function to previous gene drive constructs we have made,” Tony Nolan, Ph.D., senior research fellow at Imperial College London and an author on the paper, tells GEN. “The reason it was possible to achieve total suppression with this design is due to the conservation of the site recognized by the drive—the site is in a key region of the gene that simply does not tolerate mutations very well that might otherwise prevent the gene drive from recognizing it.”

However, Dr. Esvelt points out that the data presented in the paper do not mean that this gene drive is resistance proof. He tells GEN, “Evolution is a numbers game, so the populations tested in this study don’t say much about whether resistance would arise in wild populations a million times larger, only that it would probably crash local populations enough to make at least a temporary dent and thereby save quite a few lives.”

Dr. Nolan knows that there is “still plenty of work to do.” Dr. Akbari looks forward to seeing the gene drive tested in a wild population from Africa, to ascertain the efficiency of the drive in diverse genetic backgrounds.

Moving carefully over the next couple of steps will be important. Dr. Esvelt also points out that “if the scientists are wrong and the target species do interbreed with other Anopheles mosquitoes, the fact that the doublesex target sequence is highly conserved means it might spread into non-target mosquito species.” He cautions that “any accident would likely lead to a social backlash—an unnecessary 10-year delay would mean 3-million children dying of malaria who might otherwise have been saved.”

When asked if he found anything surprising while working on this project, Dr. Burt quickly answered, “no” adding that “the gene drive worked exactly as it was supposed to.” After pausing, he added while chuckling, “well, I guess that when things work so well in science, it is quite surprising.”

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