Behind an unmarked door at the side of an anonymous World War II Nissen hut in the middle of Oxfordshire, England, a group of scientists are attending to the needs of hundreds of thousands of mosquitoes. They provide horse blood for the females to feed on, moist beds for them to lay their eggs and add genes that transform the mosquitoes into what could be the most decisive tool yet invented to combat mosquito-borne disease.
The mosquitoes developed and raised here at the laboratories of Oxford Insect Technologies (Oxitec), a British biotech company based near Didcot, have already infiltrated wild populations in Brazil, Malaysia and the Cayman Islands, and will soon be unleashed in Panama and India. The company hopes that it will reduce populations of disease-carrying mosquitoes by 80 percent, but public opposition to anything “genetically modified” (GM) remains a significant obstacle to the possibility of saving thousands of lives.
Mosquito-borne diseases are one of the major barriers preventing economic progress in the developing world. According to the WHO, 200 million people were victims of malaria in 2010 and 655,000, mostly children, died from it. Dengue fever is believed to affect between 50 million and 100 million people a year and results in about 20,000 deaths.
“From a scientific point of view and an environmental sustainability point of view, we think we have a really good solution to the problem,” Oxitec chief executive officer Hadyn Parry says.
The company, which emerged from Oxford University in 2002, is primarily focused on dengue fever, which can cause excruciating pain and death, and the Aedes aegypti mosquito, which carries it. A. aegypti was mostly found in Africa until about the time of World War II. After that, it was transported by ships all over the world. A. aegypti can now be found in 110 countries and the incidence of dengue fever has risen 30-fold in the past 50 years.
The mosquitoes live near humans and lay eggs in any container holding water in and around homes — from as little as the residue left on a teaspoon to puddles in old tires. Eggs can survive for months after the water evaporates. The mosquitoes prefer small pools of still water that contain rotting organic matter. In their 10-day lives, they have little contact with species other than mammals and their eradication leaves the ecosystem much as it was before they arrived, Oxitec believes.
The main weapons against A. aegypti, pesticides and education, have had little success in preventing its spread. Pesticides are only effective when the mosquitoes can be seen and touched with spray. Educating people to empty any vessel around the home that could contain water is only as effective as the diligence of the individuals involved.
More sophisticated methods of control began after World War II, when scientists in the US began using radiation as a means of controlling insects. Sterilized male insects would then be introduced into the environment to mate with wild females. No offspring would be produced and the productive capacity of a female insect would be lost. The difficulty was in finding the right amount of radiation to sterilize the insect, but not damage him so much that he would be unattractive to females. The scientists achieved this with fruit flies and other insects, but did not succeed with mosquitoes, which were too feeble after sterilization to compete in the wild.
Oxitec’s chief scientific officer, Luke Alphey, found this method inefficient and came up with an alternative using genetic modification that would allow the new mosquitoes to reproduce but only in a limited way. He produced mosquitoes that were engineered to need an antibiotic, tetracycline, to develop beyond the larval stage. The altered males are fed tetracycline in the lab and then introduced into the wild, where they mate with wild females. The offspring need tetracycline to develop, but cannot find it and so die. Only males are introduced into the environment and in a few days, both they and their offspring are dead.
FRANKENFEARS
The company believes its technique is effective, cheap and far less damaging to the environment than the use of pesticides, but its problem is the phrase “genetically modified” and the knee-jerk fears it engenders. Critics see a ruthless corporate giant aiming to monopolize a market for commercial ends, which could have unknown effects on unknown things. For many critics, the mystery is often as potent as the evidence.
Oxitec could not be more different from the multinationals. It employs 40 people, 35 of whom are scientists. It does not have a public relations department, or even person, instead relying on Hadyn Parry and senior scientists to explain its work to the public.
Parry says that the public perception of genetic modification is a barrier the company has to battle against.
“Genetic modification is an approach, a tool,” he says. “It is neither good nor bad. If you take a car and give it to a lunatic, it is quite dangerous, but in the right hands it’s very useful. You have to see what genetic modification produces and see if the risks and benefits are acceptable, but because there is a public perception issue around genetic modification, then we have to overcome the negative perception and that is quite difficult.”
Unlike GM crops, Oxitec’s mosquitoes are not designed to spread their genes down the line or to other species.
“We are not putting an advantage into these mosquitoes; we are putting in a disadvantage, sterility, which is the biggest disadvantage you can have,” Parry says. “You are not spreading your gene down generations because each one is sterile — it dies out. They do not out cross and mate with other species. So you are not spreading your gene laterally or downward.”
Critics of Oxitec say that the company is rushing to commercialize its products to provide a return on investment, massaging research while leaving key questions unanswered.
GeneWatch director Helen Wallace says she has several problems with Oxitec’s findings from its trials. One major issue, she says, is the occurrence of the tetracycline — the antibiotic that the young mosquitoes need to survive — in livestock and meat. Theoretically, if a female mosquito, daughter to a modified one, bit meat or an animal that contained tetracycline, she could survive. Oxitec says that the chance of this happening is very slim and in its most recent trial in the Caymans, it did not find a single mosquito that had survived.
“It’s a very experimental approach which has not yet been successful and may cause more harm than good. They are pushing ahead to commercialize their approach so they can start paying back their investors,” Wallace says.
“I would be happier if there were more experiments in controlled areas, caged areas and labs, before general release in the populated areas. For example, in an area where dengue fever is endemic there’s a possible danger to the public,” she says.
Wallace believes that existing control methods could be just as effective as releasing genetically modified insects and says there are other innovations on the horizon that could be even more successful.
Other critics have accused Oxitec of a lack of transparency. Earlier this year, scientists at the Max Planck Institute for Evolutionary Biology in Germany examined information regarding the release of modified insects into the environment in Malaysia and Grand Cayman that were carried out by Oxitec.
The scientists’ findings suggest that there are “deficits in the scientific quality of regulatory documents and a general absence of accurate experimental descriptions available before releases start.”
Attempts to introduce mosquitoes in the US have also run into difficulties. In 2009, Key West, in Florida, was home to the region’s first outbreak of dengue fever since 1934. Local authorities blanketed the area in pesticides, but the outbreak lasted 15 months and 93 people were infected. Twelve months earlier, Oxitec had begun discussions with local authorities to carry out experiments on the islands, but local activists soon voiced their opposition.
“If you enter the GM space, you get pressure groups and activists who are part of this reaction to the introduction of GM crops. They are very active and they are much bigger than us and they are much better communicators than we are. Some of them put out really outrageous lies and it is very difficult for us to counter that. Mud sticks to a certain extent,” Parry says.
The discussion continued and Oxitec was due to carry out an experiment with between 5,000 and 10,000 mosquitoes in January, but the Florida Keys Mosquito Control District postponed it. Oxitec is not sure when the experiment will now take place.
Friends of the Earth in the US disputes Oxitec’s claim that mosquito numbers can be reduced by releasing more mosquitoes into the environment and says the planned release in Key West creates “health, environmental and ethical challenges” that should be carefully considered.
“Who will regulate their release and who will be legally and financially liable if something goes wrong?” Friends of the Earth’s Eric Hoffman asked in the local newspaper, the Keynoter. “Will Oxitec be required to obtain the free and informed consent of Key West residents?”
On his Friends of the Earth blog, Hoffman also asked what happens when female mosquitoes are released along with the males and what happens when the young mosquitoes do not do what they were modified to do — die at an early stage.
Parry says that about one female is released per 3,000 males, but it would have little effect. It would be able to bite like other mosquitoes, but it would be dengue-free and likely to die before it could bite something with dengue and then infect a human.
On the question of the survival of mosquitoes, Parry says that in laboratory conditions, 5 percent of the mosquitoes survived beyond the larval stage, but in the Cayman Islands tests they did not find a single surviving mosquito. If they did survive, Parry says, they would be shorter-lived than their wild counterparts and more susceptible to pesticides.
There were no cases of dengue fever in the Keys last year, changing the focus of the debate. The arguments of activists who question the technology have gained more weight because there is no immediate public health advantage to counteract.
Parry welcomes questions about the value of the company’s work, but says that anything it does must be sanctioned by each country’s regulatory body.
“So whereas we compile the dossier and carry out tests to validate our arguments, the regulators form an independent and expert body that look at all safety and environmental impact issues in great depth,” he says.
Oxitec has had fewer problems with public opinion in countries where dengue fever is more common. Regulations in dengue-afflicted countries can be quite severe. In Singapore, a householder can be fined for leaving a glass of water in the garden, a potential breeding site for mosquitoes. In Malaysia, if someone contracts dengue, their home and every home within a 200m radius must be fogged with pesticide, inside and out.
The more serious the problem, the keener are the authorities to try new approaches.
“So if you take Brazil in the 70s, they declared themselves free of A. aegypti and now they have millions of cases and spend a billion dollars a year trying to get rid of it,” Parry says.
SUCCESSFUL TRIAL
Oxitec is now producing mosquitoes in Brazil in conjunction with a local company following a successful initial trial. It recently reported that it reduced the number of Aedes mosquitoes by 85 percent, compared with an area where the company’s mosquitoes were not released. If a further trial goes well, Oxitec will apply for its first commercial license, which offers the prospect of earning money for the first time in the company’s history.
Aside from startup costs, such as production facilities, training and equipment, Oxitec estimates that its technique would cost less than US$9.40 per person per year, and half that in India, where labor costs are much lower.
“This is not a rich man’s tool; there’s no point in protecting a rich man’s mansion,” Parry says. “You want to protect a community, so it’s got to be cheap.”
Oxitec’s technique has applications for agriculture, as well as public health. One target is the tomato leaf miner Tuta absoluta, a pest which arrived in Europe from Brazil in 2006.
“You get an insect coming in, but without its natural predators it goes out of control, and then everyone sprays the hell out of it and then it gets resistant and you don’t have enough types of chemical to manage the resistance. With our solution, you just take out the species itself,” Parry says.
Oxitec has already tested its method with Anopheles mosquitoes, which spread malaria.
“We could have outdoor trials in five years’ time,” Parry says. “We have transformed it, modified it. It can be done — it’s only a question of time and money. Our plan is to prove it works in dengue and then people will be willing to invest the money for the next stages.”
It is unlikely that any single method could completely eradicate any species of mosquito, but the introduction of Oxitec’s modified mosquitoes could combine with existing techniques, such as bed nets and education, to manage mosquito-borne diseases far more effectively than is being done presently.
However, just as the human response becomes more sophisticated, so does the mosquito. Scientists are now reporting that mosquitoes have started feeding earlier in the day in response to the widespread use of bed nets at nighttime.
The scientists at Oxitec have tried to test every possible problem that could arise from the release of their mosquitoes.
“No innovation or adventure is risk-free, but the trouble with unforeseen consequences is that they cannot be foreseen,” Parry says. “We go through a regulatory process, we ask what could possibly go wrong and we publish our findings for peer review. Our biggest challenge is communication — to get a responsible and sensible debate within a system where you get a small number of diehard activists who are dead against anything we do. We have a product that works, that is safe and is cost-effective, and we need to get that message across.”
More GM advances
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■ The first Enviropig was created at the University of Guelph, Canada, in 1999 as a more eco-efficient alternative to Yorkshire pigs. Enviropigs were genetically enhanced to digest the phosphorus that pigs create when they eat cereal grains, and excrete less of the environmentally damaging chemical than ordinary pigs — reducing the risk of water and soil pollution. However, Health Canada was unable to assess the safety of the GM animals for human consumption, so the university lost its funding for Enviropigs and the 10 remaining animals were euthanized earlier this year.
■ AquAdvantage salmon grow into a full-sized salmon twice as fast as regular salmon, and were declared safe to eat in 2010 by the US Food and Drug Administration. The decision has been controversial, but Ron Stotish of AquaBounty (the US company behind GM salmon) claims that it will help to meet increasing demand for the fish “by producing more fish in less time compared to current salmon farming techniques.”
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