INFECTIONS
February 6, 2013

Key West's Dengue Fever

There were 27 cases of dengue in 2009. Genetic modification may stop mosquitoes' transmission of this deadly virus. What else will it do?

Which is a more frightening idea, dengue fever gaining a foothold in the U.S. or releasing millions of genetically modified mosquitoes to stop the disease in its tracks?

Residents of Key West, Florida and Florida health officials have been wrestling with this question for months. Right now, it looks like the FDA will act as arbitrator and have the final say on whether a plan to release millions of genetically modified mosquitoes will actually be carried out.

Dengue fever, sometimes simply called dengue, is a viral disease transmitted to people by Aedes mosquitoes, principally, Aedes aegypti. Once found only in the tropics, the disease has increased 30-fold in the last 50 years, an increase that is expected to continue as the world becomes warmer and the range of Aedes increases. The mosquito's range is limited by how cold an area becomes in winter — freezing temperatures kill its overwintering eggs and larvae.

Alarm Bells Begin Ringing

Dengue fever can be fatal. The World Health Organization calls it the most important mosquito-borne viral disease in the world. The CDC estimates that there are at least 100 million cases worldwide per year. But dengue is virtually unknown in the continental U.S. While Aedes is certainly no stranger to Floridians, until recently the last case of dengue acquired in Florida was in 1934.

Then came the year 2009.

In 2009 there were 27 cases of dengue fever identified in Key West. Blood tests of 240 randomly selected residents indicated that over 5% of the total population may have been infected. This was followed by 66 new cases in 2010. For a community of 25,000 that relies heavily on tourism, this was not good news.

Aedes aegypti has been called the stealth bomber of mosquitoes, silent and capable of biting 20 people a day.

Against this backdrop, Michael Doyle, a mosquito expert formerly with the CDC, became executive director of the Florida Keys Mosquito Control District in July 2011. His orders: cut the budget while killing more mosquitoes, and ensure that if Key West made national headlines, it would be for some other reason than dengue.

Aedes aegypti has been called the stealth bomber of mosquitoes, silent and capable of biting 20 people a day. It prefers unsuspecting people's ankles and legs, and it lives in and around homes, not in the open, where chemicals, larvicide and bacteria might be able to combat it effectively. Something more, Doyle realized, was needed.

Doyle settled on a plan where millions of male mosquitoes would be genetically modified in the lab of the British biotech firm Oxitec, (short for Oxford Insect Technologies) giving them a "suicide gene." They would then be released into the wild, where they would mate and pass this lethal gene onto the next generation of mosquitoes, who would die before reaching adulthood.

A similar release of modified mosquitoes in the Cayman Islands reduced the Aedes population by about 80% in three months.

The synthetic gene introduced into the mosquitoes codes for a protein called tTA. While not toxic in itself, this protein is capable of binding to DNA, including a stretch of DNA that causes accelerated production of tTA. This creates a feedback loop where cells vastly overproduce tTA, eventually tying up so much of the cellular machinery that the mosquito dies.

In order to grow mosquitoes in the lab that can be kept alive to be released before they die, they are exposed to tetracycline. The antibiotic tetracycline serves as an antidote to tTA's harmful effects. It binds to tTA and prevents it from binding to DNA and ramping up tTA production.

The results from the Cayman Islands show that once released, male GM mosquitoes are perfectly acceptable mates and can certainly put a dent in the mosquito population.

The lethal tTA gene is a dominant gene, and laboratory-bred GM mosquitoes possess two copies of it (they are homozygous), guaranteeing that they will pass a copy of the gene promoting the overproduction of tTA to all offspring. The gene is call a "late-acting lethal," allowing eggs to hatch and limited development of offspring mosquitoes, but the offspring die well before reaching adulthood.

The results from the Cayman Islands show that once released, male GM mosquitoes are perfectly acceptable mates and can certainly put a dent in the mosquito population.

The Key West release would probably have occurred already except for uncertainties about its legality, including who gets to decide if the release is legal or not. Oxitec's proposal has bounced from the USDA to the EPA to the CDC, all of whom claim they have no jurisdiction over the matter. Now the FDA is reviewing the application.

In Doyle's own words, "I've looked at all other options for Aedes aegypti control, but they're too expensive or environmentally damaging. This sounds like the best option we have going."

Not everyone agrees with him.

Opposition in Key West

The Key West City Commission has passed a non-binding resolution against the plan, calling for more research, demonstrable and measurable outcomes and federal approval first.

A petition against the release, has already garnered over 119,000 signatures, more than four times the population of Key West, making it clear that this is much more than just a local issue.

There are no independent, third-party studies of Oxitec trials underway.

The petition argues that since there have been no cases of dengue fever in Key West for over two years, there's no pressing need for such a radical approach to mosquito control. It also raises environmental questions ranging from the possible spread of antibiotic resistance to the fate of the GM mosquitoes' predators.

A survey of 432 Key West residents conducted in March and April of 2012 found 38% in favor of the release, 26% against the release and 29% who said they were neutral or weren't sure what their opinion was.

There have been some scientific objections raised to a Key West mosquito release. One is that Oxitec has only field-tested the mosquitoes in three places — in the Cayman Islands starting 2008, Malaysia in 2010 and Brazil in 2011 — so results are limited. Another is that it is possible that an 80% reduction in A.aegypti, impressive as it sounds, may not be sufficient to control the spread of dengue.

Only male mosquitoes are supposed to be released into the wild, but an occasional female does slip through the sorting process, possibly one in every 1,500. Only female mosquitoes bite people--males don't even have the body parts that are needed to bite. Theoretically, genetically modified female mosquitoes that bite people could transfer novel proteins to humans, with unknown consequences. Oxitec claims that none of the GM proteins in the mosquitoes enter the salivary glands and so they could not possibly be transferred to humans.

Finally, though the company has published some of its results in scientific journals, it hasn't yet done so for its Cayman Islands trial. The company hopes to publish an article on that trial in Nature Biotechnology later this year. Articles that have been published so far include at least one Oxitec staffer among the authors, and there are no independent, third-party studies of Oxitec trials underway.

But most of the opposition to the trial seems to be based on lack of trust, not on science. People in the U.S. do not trust genetic modification or the companies that perform it. But they have so far been able to do little to slow its use. Polls have consistently shown that at least 90% of people surveyed want GM foods to be labeled. Yet no such laws exist.

Proposition 37, a 2012 California ballot initiative that would have required labeling, was rejected 51.4% to 48.6%, losing by slightly over 350,000 votes. Key West opponents of the mosquito release do not have history on their side.

The FDA decision could come in a few months or drag on for two years. Doyle says that the legalities are such that even if the FDA denies Oxitec's application, he could still conduct the trial and release the mosquitoes legally but that he will not do so.

Interested parties will have to continue keeping an eye on developments. The final chapter on Key West and GM mosquitoes has not yet been written.

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