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Gene-edited mosquitoes are ready for the U.S. — but is the U.S. ready for them?

Dengue, mosquitos and the Oxitec approach - part 2

In mid-June, Florida’s department of agriculture and consumer services approved a plan to release millions of genetically modified mosquitoes into the wild. The idea is that, when released, these mosquitoes will venture out and mate with wild mosquitoes in the area, and due to their genetic modifications, produce offspring that never fully mature — thereby reducing the mosquito population over time.

This method has been tested in other parts of the world, but not everyone is convinced it’s ready for primetime in the United States. The Mosquito Control District for the Florida Keys ultimately has final say as to whether Oxitec, the company that makes the genetically modified mosquitoes, can release them in the Florida islands. Although the company withdrew a similar plan in 2018, some experts think the U.S. hasn’t made enough progress when it comes to oversight to start releasing genetically modified animals into the wild.

More than a nuisance

Since the linkage between malaria and mosquitoes was made in the late 19th century, people have been trying to control them, with methods far more comprehensive than simply swatting. “We did a lot of environmental sanitation with the Public Works Administration, but also we got TV and window screens and air conditioning,” Dr. Holly Tuten told Digital Trends. She’s a vector ecologist at the Medical Entomology Lab at the University of Illinois. Now, the vast majority of diseases like malaria, dengue, and yellow fever in the U.S. come from people traveling outside the country. In 2013, however, several people contracted locally acquired dengue fever in Florida. There was another case in the Florida Keys earlier this year.

James Gathany / PHIL

Forty percent of the world’s population lives in an area at risk for dengue. That will worsen with climate change, and its prevalence has gone up 30-fold in the last 50 years, according to the World Health Organization. While the majority of dengue cases are mild, about one in 20 who are infected have a severe reaction, which can lead to internal bleeding and death. There are four serotypes or varieties of dengue, and a second infection from a different type is more likely to have serious complications. A mild reaction might cause flu-like symptoms — a rash, fever, aches, vomiting — but many people report joint aches and fatigues for years afterward, according to The Lancet.

A specific species of mosquito, Aedes aegypti, is the main vector for dengue, Zika, yellow fever, and a variety of other diseases. Draining swamps and spraying crops aren’t universally effective for the mosquito species, which is often found in and around homes. Researchers have found their larvae in flower pots. “Our methods right now are limited to pesticide spraying,” said Dr. Zach Adelman, a professor of entomology at Texas A&M University. Many companies are hoping to bring genetically modified mosquitoes to the U.S. as a species-specific form of pest control. Oxitec, a U.K.-based biotechnology company that develops genetically modified insects to assist in insect control, is arguably the leader in this space. The Environmental Protection Agency (EPA) has granted an experimental use permit (EUP) to the company for a field test of its genetically engineered Aedes aegypti mosquitoes. It could begin its trials as early as this summer in Florida.

Sterile insects

One way to reduce a population is to ensure its offspring don’t survive. With the sterile insect technique (SIT), researchers expose males to gamma rays or chemicals, damaging the chromosomes. They then release the sterilized insects into the wild to mate with females, who — hopefully — don’t produce viable offspring. Only the female mosquitoes bite, so releasing males doesn’t increase disease spread. With continuous releases of new, irradiated males, the population continues to dwindle. It has been used to control pink bollworms and screw-worm flies.

“It’s not a new idea,” said Dr. Jason Rasgon, professor of entomology and disease epidemiology at Pennsylvania State University. “Sterile males strategies have been around for nearly 100 years. They just did it by other methods.” But some of the methods posed potential problems. The irradiated males sometimes had difficulty attracting mates. “It’s not because the females distinguish them,” said Rasgon. “It’s because these things have been bombarded by radiation, and they just kind of suck.” To produce a hardy yet sterile male, researchers turned to genetic modification.

Victor Moriyama / Stringer / Getty

Oxitec has been conducting trials with its mosquitoes since 2009. At the time, some felt the company’s first attempt, on Grand Cayman, lacked sufficient transparency. In the years since, the company has continued to release insects and collect data. It’s also gone through different versions of its GM mosquitoes.

Its current version, OX5034, is fairly new. Its previous version, targeted all offspring — male and female — and was 95% effective, said Dr. Nathan Rose, Oxitec’s head of regulatory affairs. “But it was quite labor-intensive to make those mosquitoes,” he said. The insects would be kept alive with an antidote, then separated by sex as pupae, before the males were released. With the new mosquitoes, only male offspring survive. They can go on to mate and pass on the gene that will also kill any female offspring in the wild.

“It was just surprising to me and my coauthors that, in the face of such an important decision to release the first genetically modified mosquito into the wild, that there wasn’t an external scientific board or panel that could help EPA make that decision.”

Not all the male mosquitoes will receive that gene, though. “Only half of the sons will inherit the transgene. The other half won’t,” said Adelman. “And so that means that each generation, the number containing transgene will be divided by half.” If Oxitec kept pumping its GM mosquitoes into the population, it could theoretically get to zero. But if it stopped, the wild mosquitoes would eventually rebound to pre-release levels. “Mosquitoes have pretty high reproductive rate,” said Rasgon, so the revival could happen fairly quickly. “It becomes more efficient the longer you do it, but it’s still temporary.”

The impermanence of the collapse is reassuring to Rasgon. It’s not what’s called a gene-drive technique, which is designed to spread throughout the entire population, even with limited release. “Those are the ones that scare me a little bit, because if something goes wrong, there’s no good way, necessarily, to recall it,” he said.

Don’t call it Jurassic Park

Despite the reversibility of the Oxitec technology, some experts want the EPA to take more safety precautions before any trial releases occur in the U.S. Dr. Jennifer Kuzma, Ph.D., co-founder and co-director of the Genetic Engineering and Society (GES) Center at North Carolina State University, co-authored two articles raising concerns, one in The Conversation and one in The Boston Globe. “It was just surprising to me and my coauthors that, in the face of such an important decision to release the first genetically modified mosquito into the wild, that there wasn’t an external scientific board or panel that could help EPA make that decision,” said Kuzma.

While the EPA did a risk assessment, Kuzma said the risk assessment was published after the public comment period. That meant outside experts couldn’t raise questions or concerns based on that information. “It’s not necessarily even what’s missing in the risk assessment, but it’s the assumptions that are made and the way that certain data is privileged more than other types of data or certain interpretations of the data are privileged more than other interpretations,” she said. During the comment period, members of the public submitted over 30,000 questions and concerns.

Victor Moriyama / Stringer / Getty

“We’re not even trying to, like, ring this huge bell and say, ‘Oh, my God. Oh, my God. Jurassic Park. Oh, my God. Crazy, mutant mosquitoes,’” said Tuten, who was co-author on The Conversation article. She thinks Oxitec’s technology has a lot of potential. “My concerns aren’t specifically with genetically modified mosquitoes, per se, but with regulatory processes that we use to evaluate and validate the technologies for wild releases,” she said.  

“How can we make regulation and risk assessment as robust as possible in the face of completely novel technology? That’s kind of the crux of the issue,” she added. For example, Tuten would like U.S. regulatory agencies like the EPA to adopt a standard risk assessment that could be adapted to specific areas where genetically modified animals are being released. “It makes sense, when you’re initially evaluating the technology, to be looking at the organism itself within the larger ecosystem,” she said. She’d like to see monitoring of other mosquito species in the area, to see the effect of Aedes aegypti collapse on those insects and their disease agents.

One option would be doing cage field trials, mixing the GM mosquitoes with members of the wild population in outdoor cages and monitoring the outcome. “I know that’s difficult to do, but it seems like it’s something that would have been a good next step,” said Kuzma. Such a trial would provide data about introgression — the genetic mixing that will take place as the males and their offspring continue to mate with the wild mosquitoes.

While sterile male strategies are used in the U.S., one of the main methods of pest control is done by spraying insecticide. This can lead to resistance, and it’s also indiscriminate. “Normally, mosquito control is broad,” said Tuten. It usually affects all species of mosquitoes, so there’s less concern about whether the loss of one type will boost the prevalence of another.

Texas A&M’s Adelman doesn’t think the loss of Aedes aegypti would be much mourned. “They’re an artifact of colonization,” he said. “It’s living in backyards, which are not terribly complex ecosystems, and there are no real predators that specialize in them at all,” he added.

“I do think that safe release of GM mosquitoes is possible,” said Tuten. She just wants the process to be transparent, with as much input from impartial third parties as possible. “The challenge here isn’t who’s right, who’s wrong,” she said. “That’s not the challenge at all. The challenge here is, we have amazing technologies that are at our disposal. How can we best use it?”

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