Genetically Modified Mosquitoes: What Could Possibly Go Wrong?

The Zika virus could open the door for a new era of gene-tweaking for pest control and disease prevention.

James Gathany/ CDC / Reuters

History is filthy with stories of pest control gone terribly, terribly wrong.

Consider, for example, the infamous tale of how the mongoose got to the Hawaiian Islands. The sleek carnivore was imported in the 1880s as part of a plan by the sugar industry to subdue the rats that wouldn’t stop gnawing through stalks of sugar cane.

Mongoose do enjoy a tasty rat supper, when the opportunity presents itself, but there was a problem: Rats are active at night, while mongoose are active during the day. So instead of decimating the rat population, the mongoose came to Hawaii and feasted on native birds and their eggs. The rat scourge continued unabated.

Australia implemented a similarly ill-conceived plan when it introduced poisonous toads to its sugar-cane fields in the 1930s as a way to control crop-damaging beetles. The toads thrived and wreaked havoc on native species, while the beetles continued chomping away on the roots and leaves of sugar cane, just as they had before.

Today, the outcome of these and similar pest-control experiments remain parables for the folly of human intervention into complex ecosystems. People have since become better primed to stop and ask, “what if?” before attempting an environmental response that can’t be undone. But, “what if” is never an easy question to answer.

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Today, scientists don’t need mongoose or toads for pest control. In some cases, they can just tweak the genes of the animal or insect they’re trying to vanquish. There’s good evidence to support the idea that genetic modification of the Aedes aegypti mosquito, for example, could help dramatically reduce its population.

Aedes aegypti is the main vector of the Zika virus, a mosquito-borne illness that has public-health officials around the world on edge. In Brazil, hundreds of babies born to Zika-infected mothers have suffered severe birth defects since last year. Public-health officials, who are calling Zika a global emergency, estimate that number will climb well into the thousands in Brazil alone. In the United States and elsewhere, as mosquito season ramps up, people are bracing for additional outbreaks.

At the same time, in a small Florida community near Key West, the Food and Drug Administration is accepting public comments on a proposal from the biotechnology firm Oxitec to introduce genetically modified Aedes aegypti males into the local mosquito population. If Oxitec is successful, its technology could help wipe out Aedes aegypti in the region—and protect people from Zika transmission there.

Oxitec’s plan is to inject mosquito eggs with DNA that contains lethal genes, then release the genetically modified males from that batch of eggs so they can mate with wild females. (Males don’t bite; so releasing only males is a way to make sure the release of these insects doesn’t contribute to the spread of disease.) The offspring of these lab-tweaked males and wild females, having inherited the altered DNA, cannot survive to adulthood. If all goes as planned, the mosquito population should shrink as a result. There’s already good evidence that shows Oxitec’s approach can work. Field tests in Piracicaba, Brazil, resulted in an 82 percent decline to the mosquito population over an eight-month period, Oxitec says.

And there’s a compelling need for trying to control the mosquito population this way. Aedes aegypti don’t just spread Zika, but also dengue fever, yellow fever, and chikungunya virus. “About 40 percent of the global population is at risk [from] this species,” said Andrew McKemey, an entomologist and the head of field operations for Oxitec. “It’s kind of the rat of the mosquito world.”

Besides all that, existing mosquito controls clearly aren’t enough—especially in the United States, where the fight over state and federal Zika funding has devolved into petty politicking, with Republicans blocking emergency funding to fight the disease. “My opinion on how we should proceed is we should aggressively pursue Aedes aegypti control—but we haven’t started that yet, and I’m not sure there’s been the political will to do it,” said Peter Hotez, the dean of the National School of Tropical Medicine at Baylor College of Medicine. “It’s very labor intensive. It requires getting rid of standing bodies of water, putting up window screens, and doing house-to-house insecticidal spray.” The coordinated effort that’s necessary, Hotez says, goes beyond anything the U.S. has ever done to control mosquitoes in the past. As temperatures warm and mosquitoes emerge, it may already be too late for at-risk cities in the states to take the precautions Hotez describes. Which is part of why the promise of genetically modified mosquitoes is so appealing to those who support the idea.

But the question of genetic modification remains fraught—in part because of legitimate scientific concerns, but largely because of misinformation and cultural resistance to genetic modification more broadly. A poll conducted by the Annenberg Public Policy Center in February found more than one-third of Americans believed genetically modified mosquitoes were to blame for the spread of Zika. (They’re not.) Others hear “genetic modification” and they think Jurassic Park; or they believe that just because something is natural, it is somehow better.

“The public fears genetic engineering. Nearly all politicians don’t understand it,” said Arthur Caplan, the founding director of the Division of Medical Ethics at NYU School of Medicine. “I don’t think the issue is economic. It is ignorance, distrust, fear of the unknown, fear of prior efforts to use biology to combat pests which went sour.”

“Chemical spray may be familiar, but it is a blunderbuss,” Caplan added.  “Old technology [is] hard to aim, often misfires, and is hard to maintain. Genetic engineering of nasty insect-pests is a rifle—very precise, low risk to the user.”

Genetically modified mosquitoes may be “our best hope” for fighting Zika virus, according to Nina Fedoroff, a molecular geneticist, and John Block, the former U.S. secretary of agriculture, who made their case in The New York Times earlier this month. Beyond Zika, mosquitoes pose such an enormous threat to human health, many scientists have argued, that the most sensible thing to do would be to wipe them out—even if the ecological impact is unknowable.

A technician from Oxitec inspects Aedes aegypti larvae in Campinas, Brazil. (Paulo Whitaker / Reuters)

“Several facts are worth bearing in mind,” the evolutionary biologist Oliva Judson wrote in an op-ed for The New York Times in 2003. “First, our current methods of mosquito control are crude and kill more than just mosquitoes. An extinction gene at least has the benefit of being precise and clean. Second, there's nothing sinister about extinction; species go extinct all the time. The disappearance of a few species, while a pity, does not bring a whole ecosystem crashing down: We’re not left with a wasteland every time a species vanishes. Removing one species sometimes causes shifts in the populations of other species—but different need not mean worse.”

Oxitec, for its part, claims its method of mosquito reduction would be more effective than traditional insecticide anyway, and would cost about the same or possibly less. (McKemey said he couldn’t offer a precise cost estimate because it could vary depending on the location, its human and mosquito populations, and other factors.)

And yet some scientists are still raising questions about the promise of Oxitec’s technology.

“I’m not so concerned about the safety issues. I think the biggest issue now is: Is it going to work?” Hotez said. “It’s only been tested at a small scale. It’s looking promising, to see an 80 to 90 percent reduction of Aedes aegypti mosquitoes, but we don’t really know what 80 to 90 percent means. It could be that we need a 99-percent reduction to get an impact.”

In other words, is an 80-percent reduction in the mosquito population enough to stop the spread of Zika? The short answer is: We don’t know.

The level of mosquito suppression that’s needed to stop disease transmission depends on a wide variety of factors, including the mosquito population, the human population, the amount of disease already circulating, and the proportion of people previously infected, and therefore immune.

“Our technology is about controlling the mosquito population, so we don’t make direct claims that we’re controlling disease,” McKemey, the Oxitec scientist, told me. “Zika is so new that we don’t know exactly the population dynamic of mosquitoes and humans that’s needed to sustain an outbreak. But if you can reduce the mosquito population sufficiently, you can break that transmission cycle.”

The other big question is: How scalable is Oxitec’s approach? Genetically modified mosquitoes may have been successful at reducing the Aedes aegypti population in Piracicaba, where Oxitec has expanded its trials to cover an area that’s home to some 60,000 people; but what about more densely populated areas, or the hundreds of miles of cities and towns along the Gulf Coast?

“In less than a year, from one female Aedes aegypti, you can wind up with a billion progeny,” McKemey told me. “What I’m trying to say is the biology of it is incredibly scalable, and ultimately that’s why these bugs are such a problem—because they’re so prolific. This kind of scalability is not just that you could theoretically scale up to country or continental scale; it has been done and is being done agriculturally.”

There are success stories in agriculture—sterility by genetic modification helped wipe out the New World screwworm in the 1960s, which once devastated livestock in the United States. Similar methods have been used to successfully fight fruit flies in the United States. Sterility as the end-result of genetic modification has other benefits. For one, it basically makes a species breed itself out of existence—rather than introducing a new kind of pest that continues to pass along its altered genes for generations. “There’s an inherent safety aspect to what we’re doing,” McKemey said. “The very thing we’re releasing is designed to disappear from the environment without a trace.”

In contrast, other gene-modification methods of mosquito control might attempt to alter a mosquito’s DNA so that it’s not as good at transmitting a virus; but it would still be able to produce viable offspring. Those approaches are, McKemey told me, “more of a genie-out-of-a-bottle situation.”

“The potential benefit of that other approach is you might need to release [the gene-altered mosquitoes] less often, but the downside is something unforeseen happens, and it’s out there,” he said.

Something unforeseen isn’t out of the question for Oxitec’s approach, either, though.

“You need to be concerned about what you don’t know,” said Ravi Durvasula, a professor of Medicine and Infectious Diseases at University of New Mexico School of Medicine. “Oxitec’s [approach] itself is fine, scientifically, but there are always the what-if scenarios. What if, for some reason, it doesn’t work—and reverts back to a wild-type state?”

What Durvasula means is, what if the desired gene mutation doesn’t take, and people end up releasing mass quantities of new mosquitoes that end up making the Zika problem worse? Durvasula calls this the “most obvious concern,” but he also says it’s improbable.

“It’s also unlikely that this mutant is going to somehow mutate again and give you something undesirable,” he added. “Certainly there have been small-scale field releases where it’s been stable, it’s done what it’s supposed to do, and they didn’t wind up with bird-sized mosquitoes or something else weird. Oxitec has gone through a lot of rigorous testing, but these what-if scenarios—one can’t be 100 percent certain that this is foolproof.”

What if, for example, the gene modification ends up altering a mosquito’s behavior—making it more aggressive, or changing its host preference. (In the case of Aedes aegypti, which already prefers humans, a change in host preference might not be so bad.) Or what if the mosquitoes end up transferring their altered genes horizontally—to other non-target species, rather than just to their own offspring? This is more of a problem with genetically modified bacteria, which has also been proposed to fight Zika, but Durvasula says unplanned horizontal gene transfer is unlikely to create any issues among Aedes aegypti that are genetically modified to be sterile.

“You can start to fantasize about every possible fate of that gene, but it’s impossible to test all of that in a lab,” he said. “And once you’ve released a trait into a population, there cannot be a recall. This is what scares people. People get creeped out by these things.”

Genetically modified male Aedes aegypti mosquitoes at an Oxitec plant (Paulo Whitaker / Reuters)

That fear is standing in the way of engineering Aedes aegypti into “well-deserved oblivion,” says Caplan, the bioethicist from NYU. But fear may also be a boon to the effort to genetically modify mosquitoes.

Despite widespread misinformation, about 43 percent of those polled in the February Annenberg survey said they believed genetically modified mosquitoes could help minimize the spread of the disease. A follow-up poll by Annenberg, in March, found 53 percent of those surveyed either strongly or somewhat favored releasing genetically modified mosquitoes to combat Zika.  Several other polls have demonstrated similar public support for the kind of approach Oxitec is proposing in Florida. Another poll, conducted by Purdue University and the Associated Press, found “overwhelming” support—among 78 percent of those surveyed—for using genetically modified mosquitoes in the fight against Zika.

“You take something like Zika virus,” Durvasula said. “These diseases that can emerge in weeks. Babies are being born with deformities. There’s the thought of sexual transmission of a virus that people barely understand. Talk about fear factor. Then you say, let’s look at the two sides of it; we have some fear about these genetically modified mosquitoes, but we’re terrified of this disease which can spread quickly—and for which there’s no cure and the vaccine is still being developed. If you weigh these, that’s where people might say genetic modification may be the lesser of two evils.”

“Think about how people control mosquitoes now,” he added. “Dumping pesticides over hundreds of square miles ... driving through the city with canisters on motorbikes, spraying willy-nilly. That’s an incredibly toxic approach. As people better understand the side effects of pesticides, they may say, ‘Well, this other way, there’s nothing toxic about it, and no one’s dying from mosquitoes that are sterile.’ The more these of these kinds of diseases show up—the more big, big outbreaks around the world—I think there will be a time when people say, ‘We need to try something new.’”