Scientists are developing a variety of innovative ideas for engineering the end of disease threats from mosquitoes. What will work -- and what are the downsides? Pictured: a pupal Aedes aegypti mosquito.

For the Mosquito Problem, a Bumper Crop of Ideas

In the ongoing battle against the Zika virus and the mosquitoes that carry it, a number of scientists have extolled the potential virtues of “gene drives,” a technology that could be used to aggressively and quickly spread a modified gene – one that might, say, render females of a disease-carrying mosquito species sterile – into wild mosquito populations. The result would be a rapid and decisive elimination of that species, and it’s an idea that has generated a good deal of discussion and concern, particularly among researchers who worry about the unintended consequences.

But what if gene-drive technology could be deployed not as a means of vanquishing disease-laden mosquito species, but of bequeathing them with genetic resistance to disease-causing viruses in the first place? That’s what George Dimopoulos, a professor at Johns Hopkins University, suggested at a recent meeting of the American Society for Microbiology in Boston. Dimopoulos said he was hoping to piggyback on gene drive technology, which exploits the precision gene editing tool known as Crispr, to boost mosquito immune systems and make them resistant to viruses like Zika, dengue and chikungunya.

It’s a bit of a blue-sky idea at the moment, but it joins a dizzying array of technologies and techniques that are at various points in the development pipeline — all of them aimed at neutering, one way or another, the ability of certain mosquito species to deliver disease payloads to the human population.

Gene drive technology is clearly attracting the most attention these days, but to weigh just how realistic Dimopoulos’s twist might be, it helps to understand how gene drives work. Michael Specter, writing earlier this month in The New Yorker magazine, provides an elegant description:

[It] works by overriding the traditional rules of genetic inheritance. Normally, the progeny of any sexually reproductive organism receives half its genome from each parent. For decades, however, biologists have been aware that some genetic elements are “selfish”: evolution has bestowed on them a better-than-fifty-per-cent chance of being inherited. But, until scientists began to work with CRISPR, which permits DNA to be edited with uncanny ease and accuracy, they lacked the tools to make those changes.

[Researchers subsequently] realized that, by attaching a gene drive to a desired DNA sequence with Crispr, you could permanently alter the genetic destiny of a species. That’s because, with Crispr, a change made on one chromosome would copy itself in every successive generation, so that nearly all descendants would inherit the change.

Dimopoulos, who has spent years characterizing mosquito immune systems to understand which chemical pathways control the insects’ immunity to different viruses, reckoned that if one or several pathways could be strengthened and genetically engineered into mosquitoes, they might render them resistant to viruses. It’s not that far-fetched a dream, Dimopoulos told the audience: Protect humans from Zika by immunizing Aedes aegypti, the very mosquitoes that carry the virus.

Some experts say the concept is far off.

Kevin Esvelt, the leader of the Sculpting Evolution group at the MIT Media Lab who is credited with developing Crispr gene drive technology, said in an email that Dimopoulos’s ideas, while interesting, are too theoretical to be considered a solution to Zika. “The scenario remains distant, and especially so given that we’re talking about a hypothetical immunity boost, its hypothetical resistance properties, and a hypothetical global agreement to use a Crispr-based global drive system,” Esvelt said, adding: “That does not mean it is a bad idea.”

“It’s not seen any field testing yet,” said Zach Adelman, an associate professor in entomology at Virginia Tech. Without field trials where resources like food are constrained, it’s unclear how these mosquitoes will perform, he said. Could mosquitoes now live longer with a better immune system? And what effects will longer-lived mosquitoes have? “Those are certainly questions that need to be answered,” Adelman said.

Of course, any novel approach to genetic engineering raises a host of ancillary questions and uncertain downsides. And yet, in a world beset by Zika, few ideas for solutions are likely to be dismissed out of hand — and as such, innovation and experimentation is expanding rapidly. Adelman, for example, is working with colleagues on a genetic modification that, coupled with a gene drive, could force maleness through a mosquito population — and thereby crash it. Esvelt is currently working with colleagues to develop a technique called “daisy drives” — a Crispr-based variation on gene drive technology. “Daisy drives systems are Crispr-based, but don’t spread indefinitely,” Esvelt said, “and so could be used to alter or suppress only local populations.”

Meanwhile, several other experimental approaches to suppressing mosquito populations have progressed beyond the laboratory. Australia, Brazil, Indonesia, Vietnam and the United States are currently piloting experiments that would use the Wolbachia bacteria to infect and suppress disease-carrying mosquitoes. And the British biotechnology company Oxitec is raising mosquitoes bred to require an antibiotic to survive. Once males are released and reproducing in the wild, their offspring die off without the antibiotic antidote. So far, Oxitec has released mosquitoes in Brazil, Panama and the Cayman Islands.

In the end, experts suggest that all of these proposals — and gene drive technology in particular, given its potential potency and irreversibility — will require much more scrutiny to determine overall safety. A report issued earlier this month by the National Academies of Sciences, Engineering, and Medicine declared as much.

“Many proposed applications of gene drive research aim to solve environmental and public health challenges, including the reduction of poverty and the burden of vector-borne diseases, such as malaria and dengue, which disproportionately impact low and middle income countries,” the authors of that report noted. “However, due to their intrinsic qualities of rapid spread and irreversibility, gene drive systems raise many questions with respect to their safety relative to public and environmental health. Because gene drive systems are designed to alter the environments we share in ways that will be hard to anticipate and impossible to completely roll back, questions about the ethics surrounding use of this research are complex and will require very careful exploration.”

That’s likely to be sound advice no matter which mosquito control technologies are deployed.