U.K. biotechnology start-up Oxitec Ltd. wants to start U.S. tests of a new weapon in the war on dengue fever: genetically modifying mosquitoes that carry the disease so that their progeny self-destruct.
Dengue, endemic in more than 100 countries, has begun to appear in the continental U.S., with local cases occurring in Key West, Florida, in 2009 and 2010 and in Miami last year. The virus afflicts as many as 100 million people a year globally, about 20 times the number of serious influenza cases, according to the World Health Organization. In its worst form, dengue can cause severe flu-like symptoms and fatal bleeding.
Oxitec has released its GM bugs in Malaysia, the Cayman Islands and Brazil. A proposed trial in Key West has met with resistance from communities who oppose genetic modification and with confusion over regulatory oversight. Still, with no vaccines to prevent dengue and no drugs to treat the disease so painful it’s known as “break-bone fever,” the approach is seen as an increasingly viable option to limit infections.
“It is a promising technology,” says James Logan, a lecturer at the London School of Hygiene and Tropical Medicine who studies the control of disease-carrying insects. “If you stop us being bitten, you stop the disease from being transmitted.”
Oxitec’s efforts are part of a broader push to rein in dengue. Novartis AG of Basel, Switzerland, is researching antiviral medicines and has shelved one that caused side effects in dogs. French drugmaker Sanofi has a dengue vaccine candidate in final testing, and it may be available as early as 2015. The company says the vaccine may generate as much as 1 billion euros ($1.3 billion) in annual sales. Until a vaccine or medicine is approved, mosquito control is the only way to limit infections.
About half of the world’s people are already at risk of infection, and the incidence of dengue is rising as the human population increases and climate change causes mosquitoes to disperse more widely, the Geneva-based WHO says. Mosquitoes that transmit dengue are found in at least 28 U.S. states and may extend their reach as temperatures warm, the New York-based Natural Resources Defense Council said in 2009.
While dengue only kills 2.5 percent of the 500,000 people who develop its most severe form, it costs the Americas about $840 million each year in medical costs, according to a study published last year by researchers at Brandeis University in the American Journal of Tropical Medicine and Hygiene. Dengue also results in about $1.2 billion in indirect costs, mainly from lost productivity, the study found.
Oxitec’s chief scientist, Luke Alphey, found a way to impair the DNA of the dengue-carrying Aedes aegypti mosquito without using radiation, which he says causes widespread genetic damage to the bug. Scientists insert one copy of an altered gene into the mosquito. The modification causes the insects to produce excessive amounts of a protein that disrupts their cell machinery -- unless they’re given the antibiotic tetracycline.
When Abingdon, England-based Oxitec releases male mosquitoes with this gene and they reproduce with wild females, their offspring inherit the trait and, without the antibiotic, die before adulthood, reducing their overall numbers.
“The lethal gene is something that will kill the offspring when it’s inherited,” says Alphey, a visiting professor in zoology at the University of Oxford. The closely held company was spun out from the university in 2002.
Opposition in U.S.
In the U.S., opposition to Oxitec testing is fierce because of uncertainty about possible health risks. Alphey and Oxitec Chief Executive Officer Hadyn Parry in March participated in a meeting in Key West, at which residents voiced concerns about being “guinea pigs” and called for independent validation of Oxitec’s findings.
The Florida Keys spend about $1 million a year on mosquito control, including 12 full-time inspectors who visit about 8,000 properties, according to Michael Doyle, director of the Keys’ Mosquito Control District. An additional 10 full-time employees were hired following the dengue outbreak, Key West’s first since 1936, and it can be hard to reach all the places Aedes aegypti mosquitoes hide, Doyle said at the March meeting.
The cost of using the Oxitec approach would be about $500,000 in the first year, and less in future years, Doyle said in an e-mail.
If successful, deploying GM bugs would allow most of the district’s field staff to work on other projects and greatly reduce the use of pesticides, he said. The project is on hold until final permits are given for “full suppression efforts,” or small releases of Oxitec mosquitoes to gather data for regulators, Doyle said.
“We have no concerns based on current understanding of the technology and the data presented to us,” Doyle said. If serious health issues arise, the releases would be canceled, he said.
The U.S. Department of Agriculture -- which has overseen tests of Oxitec’s genetically altered pink bollworm, an agricultural pest -- said in November it doesn’t have jurisdiction over the mosquito project. Oxitec has opened an investigational new animal drug file with the Food and Drug Administration, Alphey says.
“No genetically engineered mosquitoes will be released in the U.S. without appropriate federal regulatory oversight,” the FDA said in an e-mail.
Elsewhere in the world, the technique has shown results. In Grand Cayman, 80 percent of the Aedes aegypti population was eradicated after two or three generations, sufficient to prevent epidemic transmission, Alphey says.
“It’s worthwhile trying it, but only a combination of things will get rid of this,” said Paul Herrling, chairman of the Novartis Institute of Tropical Diseases in Singapore.
Releasing the modified pests must be done weekly, according to Alphey. That would cost communities in middle-income countries about $5 to $10 per person protected a year, he says. The company aims to drive the cost down to $1 per person a year in poorer countries.
Oxitec’s technology is safe and the company obtains local permission, Parry says.
“In dengue areas, we’re always working with a government entity,” says Parry, who joined the company in 2008.
To GM critics like Helen Wallace, executive director of nonprofit GeneWatch UK, Oxitec’s mosquitoes potentially threaten the balance of nature.
“We’re concerned GM mosquitoes could survive and breed to produce further generations,” Wallace says. “The mosquitoes would become part of a complicated ecosystem that might respond in ways that could be bad for health.”
Wallace cites a case at the Institut Pasteur in Paris, in which 18 percent of offspring of Oxitec-supplied GM mosquitoes survived in the lab. The cat food the Institut Pasteur scientists fed the bugs was made from chickens given the same antibiotic that Oxitec uses as an antidote, according to the company. If other bugs accessed tetracycline in the food chain, the advocacy group says, they might survive and disrupt the ecosystem.
The odds of the 2007 episode recurring in the wild are negligible because tetracycline must be available “at the right range and in the right conditions,” Oxitec’s Parry says.
The challenges facing Oxitec haven’t deterred investors, who have provided 14 million pounds ($23 million) in equity. The company has also won 5 million pounds in grants from sources including the Seattle-based Bill & Melinda Gates Foundation and the U.K. government.
Investors include Providence, Rhode Island-based East Hill Management Co., which has a 31 percent stake and is headed by retired Eaton Vance Corp. Chairman and Chief Executive Officer Landon Clay; Oxford Capital Partners Ltd. of Oxford, England; Hong Kong-based Asia Pacific Capital; and the University of Oxford. Alphey’s stake is about 10 percent.
In theory, Alphey’s gene-modification technique might work against larger vermin.
“Other people have advocated this for mice and rats,” Alphey says. “We’re quite focused on insects.”