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October 7, 2016

Florida’s Feud Over Zika-Fighting Mosquitoes Heats Up

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Bloomberg Businessweek - On a Tuesday morning in September, under a sweltering tropical sun on the island of Grand Cayman, 140,000 mosquitoes flit around in four large coolers in the back of a gray Toyota minivan. Behind the wheel is Renaud Lacroix, a Ph.D. in biology and medical entomology who works for the British biotechnology company Oxitec. A colleague, Isavella Evangelou, crouches behind him in a tight space next to the coolers. The minivan is idling on the side of a dirt road in West Bay, a quiet neighborhood where iguanas and roosters dart in and out of the yards of small homes painted in Caribbean pastels. The time has come for the mosquitoes to fulfill the purpose for which they were genetically engineered: a kamikaze mission to eliminate their own species.

As the minivan’s air conditioning struggles against the humidity, the two Oxitec scientists prepare for the release—a process that, given the Island of Dr. Moreau–level hysteria that sometimes greets Oxitec’s efforts in test sites around the world, is surprisingly low-tech. First, Evangelou pulls out a piece of light sheet metal that’s been shaped into a foot-wide tube. She sticks one end of the tube through a circular hole cut out of the van’s rear window, then fastens the other end in place with Velcro a few inches from the mouth of a small Dyson fan. Next, she takes her seat in the back, next to the fan, opens one of the coolers, and pulls out one of the 30 plastic containers in which the mosquitoes are waiting. Lacroix puts the van in gear, and off they go.

“Do I need to make a left here, Isavella?” Lacroix asks. Consulting a GPS-equipped tablet, she says yes. As the van slowly winds through the neighborhood, the tablet lets out a beep about every 30 meters. Each time she hears a beep, Evangelou—using little, if any, of the training that earned her a master’s in biology—gently lifts the lid of a plastic container, as close to the fan as she can, and several thousand mosquitoes are blown out through the metal tube and into the neighborhood.

It takes over two and half hours, emptying container after container, to release all the mosquitoes into West Bay. They’ve been doing this three times a week since July; residents used to grimace when they drove by, but now they barely glance over. The procedure seems more disruptive to those of us in the van. Each time Evangelou opens a container, a fair number of mosquitoes escape the wind tunnel and start buzzing around our heads. “There will be a few fliers, yeah,” Lacroix says with a smirk.

“A few” isn’t quite right. Before long, we’re overrun. Being in this van is like being in a Cheech and Chong movie, only with mosquitoes instead of smoke.

“Aren’t we going to get eaten alive?” I ask, trying not to sound too concerned.

“No,” Lacroix says. “They’re males.”

Male mosquitoes, he reminds me, aren’t the ones that bite. Just about the only thing male mosquitoes do, he says, is seek out females, which do the biting. Oxitec is trying to leverage this mating instinct to help wipe out one particular species of mosquito: Aedes aegypti, carrier and spreader of some of the worst insect-borne diseases known to medicine—dengue, malaria, and Zika. The A. aegypti mosquito has evolved to survive even the most effective pesticides. It can lay 500 eggs in just a bottle cap’s worth of water, and it prefers to bite humans over animals, so it lives in places where no one thinks to spray, like under the couch.

The idea behind Oxitec’s experiment is that if enough genetically modified male A. aegypti mosquitoes are released into the wild, they’ll track down large numbers of females in those hard-to-find places and mate with them. The eggs that result from any union with an Oxitec mosquito will carry a fatal genetic trait engineered into the father—a “kill switch,” geneticists call it. The next generation of A. aegypti mosquitoes will never survive past the larval stage, never fly, never bite, and never spread disease. No mosquitoes, no Zika.

Oxitec is far from the first company or research team that’s tried to sterilize an entire insect population. Scientists have been going after A. aegypti in this way since the 1970s, usually by irradiating them. The problem with radiation is that it makes the mosquitoes too weak to get out and breed. The great innovation of the Oxitec method is that it cleverly achieves the same result as sterilization, while leaving mosquitoes able to do what mosquitoes do.

The approach was developed by founder Luke Alphey, a British geneticist specializing in vector control, or the elimination of disease-bearing creatures. Oxitec has applied the method in Brazil, Malaysia, and Panama, often with partial support from the Bill & Melinda Gates Foundation, and claims to have reduced the A. aegypti population in tiny test areas by at least 90 percent. That’s a far better percentage than spraying, which usually hits about 50 percent and has a tendency to breed resistance, requiring more and more spraying to get the same low result.

“It takes one or two generations at least to be noticeable,” Lacroix says as he grabs a green fly swatter the size of a tennis racket and starts thwacking away at some of the mosquitoes flying around his head. A. aegypti’s life span ranges from two weeks to a month, so the company will know in a few months if the population is starting to decrease. If it is, Lacroix says, “we can roll out to the rest of the island, drawing down south through the peninsula.” Oxitec charges about $7.50 per person per year in each area it treats. While the price gets cheaper as the A. aegypti population decreases and fewer Oxitec mosquitoes need to be released, the treatments aren’t a short-term prospect: To ensure A. aegypti doesn’t come back, the company continues releasing its mosquitoes on an open-ended basis.

Chief Executive Officer Haydn Parry has called Oxitec’s method “a dead end” for the A. aegypti species. And, of course, in the age of Zika, such a dead end couldn’t be more desirable. Since the news emerged last spring that a spike in cases of microcephaly in Brazil appeared to have been caused by Zika, politicians and public-health officials from around the world have been beating a path to Oxitec’s door. U.S. officials were among them, even as Congress dithered all summer before finally, in late September, approving the funding of countermeasures to prevent large outbreaks. “I don’t think time is on our side,” Parry told a congressional committee in May. “I think the utmost urgency is required. I’ve just come from Puerto Rico, and we could have a catastrophe on our hands if we are not careful.” The big winner if Oxitec ends up enlisted to fight Zika in the U.S. would be Intrexon, a biotech company run by billionaire Randal Kirk, which acquired Oxitec for $160 million in the summer of 2015.

This August, the U.S. Food and Drug Administration approved Oxitec’s first stateside experiment, in Key Haven, Fla., an unincorporated area separated by a narrow stretch of water from Key West. In many respects, you couldn’t ask for a better test site in America. It’s secluded, tropical, and surrounded by water, which prevents new mosquitoes from entering the area. If the Oxitec method works in Key Haven, then Florida, and the country, could have a powerful tool to help stop an incipient public-health crisis.

There is, however, an obstacle. Oxitec has been trying to conduct a trial in the Keys for seven years, ever since a dengue outbreak there. Local opponents have thwarted those attempts for years, and now they’ve forced a pair of referendums, set for November, on the Key Haven test. Officials from the local Mosquito Control District have pledged to be guided by that vote—even if it means saying no to the FDA’s approved experiment, with a major Zika crisis looming over Florida. In public meetings, on local radio, and, of course, online, opponents have all but commandeered the conversation about mosquitoes and Zika in the Keys. They call Oxitec’s tactics unethical and underhanded. They call the company’s science untested, unproven, and unsafe. Above all, they’re worried about unintended consequences. Their not-so-affectionate name for the Oxitec mosquitoes: Frankenflies.

The Florida Keys Mosquito Control District (MCD) is run by a board of five commissioners—elected officials, not bureaucrats—and commands a $10 million annual operating budget and 69 full-time employees. When there’s trouble, the board can decide more or less unilaterally how to deal with it. In 2009, when A. aegypti brought dengue to the Keys for the first time in nearly eight decades, the board responded with an aggressive approach that saw workers go door to door to persuade residents to eliminate standing water and take other preventive measures. The disease subsided, but only after 88 people were infected. That was when the Mosquito Control District went searching for something that might be capable of wiping out A. aegypti completely. Enter Oxitec.

In 2011 the MCD announced that all of the city of Key West—its 25,000 citizens, its millions of visitors—would be subject to a trial of Oxitec’s technology, overseen by the FDA. The MCD said the price tag would be less than $10 per resident, and it expected to break even on the investment by requiring less aerial spraying against the mosquito. The Keys, however, have no shortage of activists who know how to push back against government. Ed Russo is chairman of the Florida Keys Environmental Coalition, a group formed after the 2010 Deepwater Horizon oil spill. He’s also worked as a business consultant to Donald Trump, and recently wrote a short e-book titled Donald J. Trump: An Environmental Hero. (Trump was the first donor to the coalition.) Russo’s group was among those incensed that the MCD appeared to be fast-tracking the Oxitec experiment by having it overseen by the FDA, which would treat the GMO technology as an animal drug, rather than as a biopesticide, which might have required a complete environmental impact statement from the U.S. Environmental Protection Agency. “If you even want to take down one tree in a wetland, you need an EIS,” Russo says. “And these clowns don’t want to do an EIS? And we’re considered anti-science?”

At a particularly heated community meeting with the MCD board in 2012, Russo asked a series of questions about Oxitec’s protocols and whether the MCD was prepared for problems. Russo says the board had no answers for him that day, and no answers over the next two months. Then the MCD announced that, after consulting with the FDA, it had decided to move the venue for the experiment. Instead of Key West, the proposed trial would be conducted in Key Haven, a small community of 144 homes on a neighboring island. “That’s when all the flags went up and the sirens wailed,” Russo says. “Would you let your family take part in a scientific experiment without your informed consent in writing? If you’re a prisoner in an institution in the United States, you are given that right.”

Mila de Mier, a real estate agent in the Keys, started a Change.org petition to “say no to genetically modified mosquitoes in the Florida Keys,” which eventually got 170,000 signatures from around the country. Activists worldwide offered support and expertise. It took de Mier years, and the threat of a lawsuit, to get the MCD to say how many A. aegypti mosquitoes it estimated were in Key Haven. When she secured the data, earlier this year, it indicated that there were practically none—or at least not enough to call for traditional spraying methods. De Mier, who’s emerged as a grass-roots leader of the resistance, says she realized that as successful as Oxitec’s method was said to be, it had never faced serious public scrutiny before coming to the U.S. “I saw what they did in Brazil,” she says. “They brought a truck around with a loudspeaker, and they made a song. ‘God sent you the mosquito to heal you.’ That was the public engagement.” (Oxitec does use vehicles with loudspeakers in Brazil, but it also distributes more scientifically based information.)

As Oxitec prepared its full proposal to the FDA, the company released more details, and others started asking questions. Meagan Hull, a longtime resident, wondered why, if Oxitec’s method was all about male GMO mosquitoes, did the company’s data say it also let loose some females in its test—about 1 per 1,000 males? Did those females mate, and breed, and bite? Had anyone studied the long-term effects of that? Wouldn’t some Keys residents almost certainly be bitten by a GMO mosquito? Even the males, some said, might create antibiotic resistance in the community, because all the mosquitoes Oxitec grows in its lab are doused during the larval stage with tetracycline, to bypass their kill switches and allow them to grow to adulthood. “The tetracycline’s going to cause resistance,” says John Norris, a local physician. “They care nothing about the fact that they are breeding resistant germs of no purpose.” He’s gotten more than a dozen local doctors to sign a letter objecting to the plan.

David Bethune, a computer programmer and artist, wondered why Oxitec seemed so sanguine about long-term effects. “We don’t understand how the science works, but we do understand that when you put a genetically modified organism into the wild, there are going to be other consequences than just reducing the population,” he says. Chief among them: What might take A. aegypti’s place in the ecosystem? Something stronger? “Just to say, ‘We’ve got it all worked out’ is really unnecessarily arrogant,” Bethune says. “We’re the little guinea pigs on an island that they thought of as Margaritaville. They thought that we would all be out having a cocktail and just not care?”

Then the Zika crisis emerged late last year, and the debate went off the rails. In January a Reddit thread, posted in a forum known for floating conspiracies, raised the possibility that it was Oxitec’s testing in Brazil that had caused the birth defects public health officials were attributing to Zika. The anonymous author posited that some of Oxitec’s GMO offspring do, in fact, survive and pass on their genes, blending with Zika to create a megavirus that brought about microcephaly. The entire notion has been disproved—chiefly because the concentration of birth defects in Brazil is located 400 miles from Oxitec’s test site, and the A. aegypti mosquito travels only a few hundred yards in its lifetime. But that hasn’t kept some opponents in the Keys from revisiting the question, even now.

“It’s these chemicals you’re spraying that are causing microcephaly,” one local environmental activist, Doug Hattendorf, said in September at a meeting in Key West, where town commissioners were deliberating over a proposed resolution supporting the Key Haven project. “There’s no proof of Zika causing microcephaly, except what Oxitec says,” he added.

“I have nothing against spraying whatsoever,” said Judy Martinez, another neighbor, at the same meeting. “But I am against monkeying around with Mother Nature. They’re going to kill us off, that’s what’s going to happen.” The resolution was ultimately voted down.

The Florida Keys Environmental Coalition takes no official position on the Oxitec-Zika conspiracy theory. But Barry Wray, the group’s executive director, is willing to keep the conversation going. “We’re witnessing the results of the microcephaly question gradually evolve,” he says. Wray is also happy to give oxygen to another roundly denied conspiracy theory—that the local government was won over by Oxitec in a less-than-aboveboard way. “There’s some more nefarious things that have occurred and are occurring right now, and I’m not at liberty to talk about those right at the moment,” he says.

Then he smiles. “I would say that if you don’t consider all the spectrum of things you’ve experienced over your life, then you’re not thinking broadly enough.”

Derric Nimmo, Oxitec’s head of public-health research, remains slightly baffled by the dissidents’ claims. “I’ve done town hall meetings, done board meetings, gone door to door,” he says; the exchanges are mostly cordial, but strained. “I’ve kind of turned into, rather by accident, a communication person for Oxitec in the Keys.” It’s not a natural fit for him. “I’m a scientist at heart. It’s my background, you know, a Ph.D. My postdoc was all about molecular biology in insects. And so I’ve had to learn to try and—not dumb that down, that’s the wrong word—to try to communicate that in a simple way that people can understand.”

He moves through the criticisms as quickly as he can. Even if some females are released, he says, they will have the same kill switch gene the males have, and their offspring will die in the larval stage. If the females do end up biting anyone, it would have the same impact as any ordinary mosquito bite; all the lab-bred mosquitoes are screened for disease before being released. The amount of tetracycline used on the mosquitoes is “extremely low,” he says, trivial next to what you’d find in, say, a typical pig farm. As for long-term impacts, the GMO mosquitoes never effectively reproduce, which means the entire system is closed. “Within six to eight weeks there’s no evidence of [Oxitec mosquitoes] in the wild at all,” he says.

During the 60-day public-comment period for the FDA’s review of Oxitec’s proposal, he says, “there were 2,700 comments, and the FDA, the CDC, and the EPA have looked at all of those, and they’ve said there’s nothing here scientifically valid that changes our minds.” Yet for years now he’s been forced into a rear-guard action.

The whole Reddit conspiracy theory drives Nimmo to distraction. “We’ve also had several articles from independent people, saying this is not true, but it does keep coming up, all the time. So we just have to keep answering it.”

“The age of engineered biology is actually well under way,” declares Randal Kirk. The Intrexon CEO speaks a mile a minute, with a proselytizer’s zeal. “We’re not pure altruists,” he says. “We are running a business here. But believe it or not, we do a lot of thinking at Intrexon about how we might improve the world.”

Kirk, who has homes in San Francisco and Virginia but spends most of his time in West Palm Beach, Fla., sold his drug distribution company, General Injectables & Vaccines, in 1998 for $65 million. He then started New River Pharmaceuticals, which was acquired by Shire for $2.6 billion in 2007, and followed with Clinical Data, a genetic-testing company acquired by Forest Laboratories for $1.2 billion in 2011. Around 2004, he invested $300 million in Intrexon, which a molecular geneticist named Thomas Reed founded in 1998 as the human genome was being sequenced, to assemble a library of standardized DNA components—“hot rod parts,” as Kirk calls them—that could be used to make designer genes. Kirk took the company public in 2013. Before acquiring Oxitec last summer, Intrexon bought AquaBounty Technologies, which genetically modifies salmon to make them grow faster, and Okanagan Specialty Fruits, which makes apples that don’t turn brown.

No Intrexon company has successfully brought a product to market yet. And Intrexon’s gene-designing system, a technology known as UltraVector, has never been submitted to any peer-reviewed journal. One vocal critic of Intrexon, TheStreet’s Adam Feuerstein, has compared the company to Theranos in its lack of transparency and has called Kirk a “wheeler-dealer.” An industry analysis published in May by Spotlight Research characterized Kirk’s holdings as “an intricate web of micro cap, zero revenue, free cash flow negative companies that seem to exist for the sole purpose of inflating [Intrexon’s] revenue and profitability.” Kirk waves off all that. “Competitors and people who for whatever reason may not like us, they’re free to say whatever they wish,” he says. “I’ve always focused throughout my entire career on the creation of intrinsic value, and in order to do that, it’s not always possible for us to talk publicly about everything we’re doing.”

Instead, Kirk speaks more broadly and loftily about genetic modification—how it existed in the ecosystem long before Oxitec came along, most likely starting with the breeding of cereal grain in Mesopotamia, which led to the creation of seed and the portability of food. “Almost none of the things that we think of as natural are actually natural,” he says. “Cows, pigs, chickens, horses, strawberries, corn. We have been genetically engineering things both deliberately and accidentally for thousands of years, and we’ve been creating millions upon millions of mutations without any ability to document what they were.”

As for A. aegypti, Kirk argues, that particular species has prospered around the world only because “we have genetically modified it for decades through the use of pesticides. This is the most anthropophilic mosquito. In other words, it loves us. We’ve genetically evolved it to love us.” The Oxitec method, Kirk says, is an elegant way of undoing that work.

Kirk is on the opposite end of the political spectrum from some wealthy Keys activists like Russo. He’s raised $785,000 over the years for Hillary Clinton’s running mate, Tim Kaine. (“He’s just a tremendous intellect,” Kirk says, recalling one dinner during which Kaine recited lines from Nabokov’s Pale Fire.) What he shares with Russo, however, is a certain doubt about the government’s ability to deal with Zika. “It’s a deplorable state of affairs I think today in Washington,” Kirk says. “I’m not talking about corruption. I’m talking about laziness.” He mentions the glacial efforts by politicians to form a common framework among agencies like the USDA, EPA, and FDA for addressing Zika.

That said, Kirk thinks Congress’s delay in addressing the $1.9 billion Zika bill put forth by the White House may accidentally have served the public well. “When the president first proposed his spending, they didn’t talk about disease vector control at all,” he says. “Now even the president knows that disease vector control is very, very important.”

To which Russo answers: Anything that helps Oxitec test humans without their consent is part of the problem. “I didn’t know there was any connection between Oxitec and the Democratic Party,” he says. “But this never should have gotten this far. Government is failing at all levels.”

The swelling controversy in the Keys was enough to force two separate referendums on Nov. 8—one for Key Haven residents and one for all of Monroe County, which contains the Keys and a portion of the Everglades. The results won’t be binding, but three of the five Mosquito Control District commissioners have promised to honor the will of the people.

If the Keys scuttle the project, it may go against broader public opinion. A national survey released in February by Purdue University found that 78 percent of those surveyed supported using GMO mosquitoes to fight Zika. Last month a bipartisan group of 61 Florida state legislators issued a statement asking the FDA to use emergency powers to give them Oxitec right now. “What’s happened now is you have various mosquito districts saying, ‘Why can’t we use this technology?’ ” says Parry, Oxitec’s CEO. If the vote goes against Oxitec, “we would move the trial somewhere else,” he muses. “But obviously it would be more preferable and more convenient to do it where we planned to do it.”

Even if Oxitec is chased away, the idea of undermining A. aegypti at a genetic level will persist. More-sophisticated gene-editing techniques, such as Crispr/Cas9, have been developed, and new businesses will emerge to take advantage of them. The scientific community is largely unperturbed by the idea of removing the A. aegypti mosquito from the face of the earth. “The disappearance of a few species, while a pity, does not bring a whole ecosystem crashing down,” evolutionary biologist Olivia Judson has written. “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.”

In Grand Cayman, the government is moving forward. In a few years, A. aegypti might be eliminated from an entire island, the first time such a thing has happened. Maybe that will lead to something unexpected, or maybe it won’t. In the Keys, some would rather take their chances with Zika than risk the unknown. “We are setting a standard for the rest of the world,” de Mier says. “Today it’s a mosquito, tomorrow God only knows what is going to happen.”