Dengue, also known as breakbone fever, is endemic in tropical countries and is now being reported in Florida, Europe and Japan. It is spread to people by mosquitoes. There are four subtypes of the virus; they cause a high fever and excruciating joint pain. There is no treatment. Severe cases can develop into a hemorrhagic fever that in 250,000 cases a year, worldwide, is fatal. The World Health Organization says there has been a 30-fold increase in the global incidence of dengue over the past 50 years, and the rate of infection is climbing fast.
The search for a cure
There is no vaccine for dengue. A number of vaccines are in trials; so far none has been found to protect against all the strains of the virus, and most work better in people who have already been exposed once. Governments of countries such as Vietnam and India, with huge dengue burdens, have expressed concern that a privately developed dengue vaccine may be priced too high to allow for mass vaccination campaigns.
What spreads it
Aedes aegypti, the mosquito that carries dengue, also carries chikungunya – a similar virus that causes fever and joint pain, plus a rash, and may leave people who have it debilitated for up to two years. It also spreads zika virus, which resembles dengue and is newly spreading in Latin America, as well as yellow fever.
Why it’s so hard to stop
Aegypti has adapted to live in very close proximity with its preferred meal – humans. It’s now an almost entirely urban mosquito, living inside homes and laying eggs (1,500 for one female in a 30-day lifespan) in a tiny amount of water, trapped in a flowerpot or even a fallen leaf. The eggs, like tiny black pinpricks, can dry out and wait up to a year to hatch. One infected mosquito can pass the disease to many people.
As the morning sky slowly lightened above this central Brazilian city, biologist Guilherme Trivellato settled into the back of a van and got ready. He sat surrounded by hundreds of small plastic containers, each holding 1,158 thrumming mosquitoes, give or take a bug or two. To his left, a jury-rigged tabletop held a Dyson bladeless fan, taped to a plastic tube feeding out the window.
While a colleague drove the van slowly through the quiet streets, Mr. Trivellato opened each pot in front of the fan, sending the mosquitoes tumbling out into the world. A colleague kept a hair dryer, plugged into the dashboard, trained on him to blast out any stragglers. Up and down each street they went, for two hours, until 250,000 new Aedes aegypti mosquitoes were released to seek out the dark corners of closets and garages all through the neighbourhood.
The plastic pots and hair dryer are the ultra-low-tech delivery method for the most sophisticated effort in the world to wipe out this mosquito, and the diseases it carries. The mosquitoes in the pot were bred in a lab by a British biotechnology company called Oxitec. They were all males, genetically altered to fly out, find a female, have sex and die – essentially the normal life plan of a male mosquito – but along the way pass on their altered genes to their offspring. These too will die, as larvae: before they can fly, or, if female, bite – and contract and then pass on a virus such as dengue fever or chikungunya to humans.
The Oxitec method is the most complex new weapon in Brazil’s arsenal in its war on the mosquito. Aegypti, as it is known to its reluctant admirers, spreads dengue and other viruses around the world – an estimated 390 million cases a year of dengue alone, according to a recent study in Nature, of which 96 million made people significantly ill. Brazil, which has both a heavy burden of the disease and a strong public health system, is the locus of innovation in the fight to wipe dengue out.
In addition to the transgenic mosquito, there is also a project to infect mosquitoes with a bacterium that keeps them from being able to pass on dengue; an effort to lure mosquitoes to lay eggs on a tape that prevents them from hatching; an experiment with a mosquito-toxic fungus spread in homes; and a study that is hanging curtains made of insecticide-soaked fabric in schools and hospitals.
But it is the Oxitec method that has garnered the most attention, and provoked the most debate. It is built on the fact that an Aegypti mosquito travels no more than 200 metres in its lifetime – so by flooding the zone with transgenic males, it makes it highly likely a female will mate with one of them, and lay the doomed eggs. The company bills it as the most ecological solution: Currently, to fight dengue, Brazil spends more than $120-million (Can.) a year on millions of tons of insecticides to kill off Aegypti – but the mosquito grows more resistant all the time to the chemicals, which also end up in the water and food chain. Oxitec monitors mosquito population (by checking eggs in the lab for absolute numbers and for how many hatch into their modified larvae) and says that in trials in two sites in Brazil, as well as in Panama and the Cayman Islands, its method has lowered the population by at least 90 per cent.
For some Brazilians, however, the idea of releasing a genetically modified creature into the wild, and sending it off to breed, evokes Pandora’s-box visions of tampering with the ecosystem. Gabriel Fernandes, technical adviser with an environmental organization called AS-PTA, said the government was rash to approve the Oxitec trials, when there is no precedent and only a few years of research into how the transgenic mosquito might interact with the larger ecosystem. “It’s technology that is not proved to be safe or to work, but they are trying to sell it,” he said. “There are still many questions on its safety and potential harm.”
Oxitec CEO Hadyn Parry says those fears are unfounded, and the body that governs biotechnology use in Brazil was assured of it. Aegypti, he notes, is an invasive species in Brazil (it spread to Latin America and Asia from Africa), now entirely adapted to living in urban areas, with discarded car tires as its preferred breeding spot. It has no role as a keystone species (no bat or bird depends on it as food); safety studies show the altered gene does not pass to anything that does eat the transgenic insects, he says. And he argues it has the smallest ecological impact of any dengue control method.
“If you are using insecticides, then you are blasting all the mosquito species at the same time with all the chemicals, affecting all the food chain at the same time,” he said in a telephone interview from Oxford. “There are 6,000 mosquito species around the world; we’re just trying to wipe out one that gives you dengue.”
In the Piracicaba neighbourhood that gets drenched with male Aegypti three mornings a week, the residents are stoically putting up with the invasion. In every home here, someone has had dengue this year – cases in Sao Paulo state are up 300 per cent from last year. “I’m in favour of anything they can do to get rid of it,” said Fatima Nicolau, 61, describing how she lay in bed unable to bear the excruciating pain of even lifting her head. Her husband got dengue a week later. While Ms. Nicolau talked, mosquitoes flitted in to settle briefly on her dark trousers; she said she drank a Coke with her hand over the glass because otherwise the surface mottled with mosquitoes. “It’s always like this on Mondays,” she said, waving one hand around her head.
The second mosquito-modifying method being tested in Brazil has generated less discussion because there is no GMO factor. In this experiment, run by a not-for-profit initiative called Eliminate Dengue, mosquitoes are infected with a bacterium called wolbachia. It is found in 60 per cent of insect species, but not, naturally, Aegypti. Australian biologist Scott O’Neill led a team that discovered six years ago that wolbachia from fruit flies could be transferred into a breeding population of Aegypti – and mosquitoes with the bacterium can’t pass on dengue (or, it seems, chikungunya or yellow fever or other serious mosquito-born illnesses now resurgent in Brazil.) Tens of thousands of lab-reared infected mosquitoes are now being released in neighbourhoods in Rio de Janeiro; when they mate with wild mosquitoes, they spread the bacteria into the general population and, in theory, block the disease.
Dr. Parry, with Oxitec, points out that the transgenic mosquito, should it one day be found to be causing a problem, can be stopped in its tracks simply by not releasing more, since the males die in days – while once the wolbachia-infected mosquito is established in the wild, there is no bringing it back. “Why would we want to bring them back?” countered Prof. O’Neill. “Wolbachia is already in 60 per cent of the insects around you – it’s naturally occurring in the environment. In all the trials we’ve done there are no adverse consequences.”
A key difference between the methods is cost. “What’s really nice about wolbachia, as opposed to other interventions, is that it’s front-loaded and sustainable,” Prof. O’Neill, in a telephone interview from Victoria, Australia, said about his method. While studies are ongoing to see whether the infected mosquitoes continue to maintain the dengue-blocking ability, all evidence so far is that they do, he said – meaning that a town would only have to do the release once. The project is targeting a price of $2-$3 per person.
Oxitec, a for-profit company spun off from Oxford University research, declines to put a price per person or to say what it would cost a town like Piracicaba (where the current project is a trial) to buy the service. Mr. Parry noted that a city might choose to do the whole area, if dengue is severe, or only the worst-hit neighbourhoods, which would affect cost.
But the company has to release millions of mosquitoes to wipe them out in even a small area (4.3 million mosquitoes in a neighbourhood in Panama for a trial, or nearly 5,000 mosquitoes for each of 900 residents, for example). There is a huge release initially, and then an ongoing program to “maintain suppression.” Oxitec says that while that initial release will be costly, in a place such as Piracicaba the maintenance program would cost roughly the same amount as the current $6 per person the municipality spends on dengue control.
Giovanini Coelho, who heads Brazil’s national dengue control program, said he is delighted to see innovation in fighting a disease that has plagued humans for so long, but he is restraining himself from optimism yet. “Up until now we don’t have any evidence that transgenic mosquitoes [or other methods] affect the amount of dengue,” he said. (It’s an extremely difficult thing to demonstrate, however, because people move around: You can wipe out the mosquitoes in a neighbourhood or even a town, but there is no way to prove that a person who gets dengue was bitten there, or while visiting grandma down the road.)
Prof. O’Neill says his organization is gearing up for large randomized-controlled trials. Mr. Parry said he understands the desire for this data, but it is unnecessary. “This is the mosquito that spreads dengue, and no mosquito equals no dengue,” he said; and Brazil doesn’t have any epidemiological data on how well its pesticide program controls dengue.
Mr. Coelho does not accept this argument. “This technology is being developed by a private company, one that obviously wants to sell this product. We need to see research in independent publications, reviewed by specialists.” The government body that controls the use of genetically modified organisms in Brazil has approved the use of the Oxitec mosquito, but the ministry of health has not yet licensed it as a product for sale.
Sofia Pinto, a geneticist who supervises the mosquito production facility that Oxitec has built in the city of Campinas, says the company is at work on cheaper, larger-scale ways to breed the bugs – using aquaculture – and mechanized ways of distributing them. Already they could suppress all the mosquitoes in a city of 100,000 people in a year.
Ms. Pinto, who spends her days in a hot and fetid lab surrounded by trays of wriggling larvae and cages of laying females feeding on trays of blood, is untroubled by the skeptics. And when she talks to people who live in places such as Piracicaba, in the midst of a raging dengue outbreak, they aren’t interested in all the debates either. “They say kill it,” she said. “Just kill the mosquito.”
With a report from Manuela Andreoni
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