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While great advances have been made in the lab, malaria-resistant mosquitoes are still a long way from being airborne, reports Katherine Nightingale.

When researchers first genetically modified an Anopheline mosquito — the type that spreads malaria — it was hailed as a major step towards creating armies of malaria-resistant mosquitoes that could take over populations, leaving them unable to transmit the disease.

But ten years since it was created, there are still no GM mosquitoes buzzing around the plains of Africa. Malaria-resistant mosquitoes have yet to even leave the laboratory.

Their production is taking much longer than first envisaged — and other ways of manipulating mosquitoes to stem disease transmission are overtaking them.

Survival of the fittest

After the 1998 genetic modification of Aedes aegypti, which transmits dengue virus, yellow fever and chikungunya virus, came the creation of the first GM anopheline mosquito in 2000. Two years later, scientists created the first malaria-resistant GM mosquito.

Marcelo Jacobs-Lorena leads the laboratory that produced this mosquito, which worked by producing an antimalarial substance when it fed on blood.

But GM mosquitoes are not necessarily fitter than their wild counterparts. Mechanisms are needed to ensure that the antimalarial genes are 'driven' through populations instead of dying out. This has proved to be a major challenge.

"Up to now — almost ten years later — no one has really found out how to do that," saysJacobs-Lorena, a professor at the Johns Hopkins Malaria Institute, United States.

One approach has been the 'selfish genes' — or 'Medea' — approach. These genes have been shown, in fruit flies, to ensure their carriers' survival.

But scientists have not yet managed to combine Medea genes with malaria resistance genes in fruit flies, which they use as models. Nor have they successfully transferred the Medea effect into mosquitoes. This should be possible within 2–3 years, says Anthony James, a professor of microbiology and molecular genetics at the University of California at Irvine, United States.

GM bacteria: a new way forward?

Instead of waiting for genetic drive systems to be perfected, Jacobs-Lorena has switched to genetically modifying a different organism: bacteria that live in mosquitoes.

His team has shown that when the bug Escherichia coli is modified so that it produces the same malaria-inhibiting molecule that first made mosquitoes resistant, the mosquito itself displays a lower level of malaria infection.

"The question is similar to the one we had with the transgenic mosquitoes — how do you introduce a GM bacteria into mosquitoes in the field? That is a challenge which we think we have a handle on."

Jacobs-Lorena's team is collaborating with an Italian laboratory to work with types of bacteria called Asaia that occur naturally in mosquitoes. Asaia is passed from female mosquitoes to their offspring.

Jacobs-Lorena hopes to one day produce a 'cocktail' of bacteria, each secreting a different antimalarial molecule, to ward off resistance in a way similar to combining antimalarial drugs. Creating the bacteria and testing their spread through populations should take about 8–10 years, he says.

Dengue hope

That he sees 8–10 years as a shortcut gives an indication of just how far from the field disease-resistant GM mosquitoes are. Another GM strategy, however, is much closer to fruition.

Instead of using genetic engineering to create resistance, researchers at biotech company Oxitec a spin-off from Oxford University, United Kingdom are using GM to reduce A. aegypti mosquito populations.

The method targets dengue fever, a disease which infects up to 100 million people each year and for which there is no treatment or vaccine.

The Oxitec team uses a system known as RIDL (release of insects carrying a dominant lethal) to genetically sterilise mosquitoes. Their strategy is based on releasing male GM mosquitoes that can't produce viable offspring.

One benefit of using Wolbachia is the bacteria's ability to spread through mosquito populations

Flickr/AJC1

In one example, offspring all die at the larval or pupal stage and, in the other, female offspring cannot fly or feed and therefore cannot mate.

"It's a self-limiting system, you release sterile males, they mate with wild females and the progeny die before they can bite and transmit disease. If you release them for long enough the wild population will decline and collapse," says Luke Alphey, research director of Oxitec.

The first strategy was tested in successful contained trials in a purpose-built house in Malaysia during 2007–2008. The second strategy, developed by a large consortium funded by the Gates Foundation's Grand Challenges in Global Health programme, is being tested in outdoor cages in Mexico. Open field trials of both strategies are being planned.

Oxitec is concentrating on this kind of 'population suppression' strategy rather than disease resistance because it should have an impact sooner, says Alphey.

But whether the technique is sustainable in the long term is doubtful, says James, who is principal investigator of the Gates-funded consortium. The very property that could make these mosquitoes more acceptable to regulators and the public — that the transgene dies out with the mosquito — means that the mosquitoes have to be released continually.

"You have to have the political will ... It's a public health paradox: if you spend a whole lot of money releasing mosquitoes you don't have a problem, but if you stop doing it, then you do," says James.

Amongst the objections to using GM mosquitoes is the issue of the 'empty niche', in which other — perhaps more dangerous — insects might move into the ecological niche vacated by the mosquitoes.

But Alphey says the issue is not unique to GM mosquitoes and he is confident that there are few insects that would replace A. aegypti, particularly given that it isn't a native species in most of the areas where it spreads dengue fever.

"We've done extensive environmental analysis and it's very hard to see any significant, tangible risk from releasing these insects."

Non-GM solutions

Closer still to field trials is a non-GM approach. A team of researchers led by Scott O'Neill from the University of Queensland, Australia, will start field trials of its dengue-resistant mosquitoes — which contain a bacterium called Wolbachia — in about six months, he says.

The researchers originally found that a strain of Wolbachia cuts the lifespan of mosquitoes so much that they cannot pass on the dengue virus.

But more recently they have discovered that many Wolbachia strains also make the mosquitoes resistant to the virus — though they do not yet know how.

The researchers have tested the mosquitoes in a large 'greenhouse' in Australia complete with mock-ups of houses — and volunteers for the mosquitoes to feed on.

"When we introduce Wolbachia mosquitoes into a wild population, they quickly invade," says O'Neill.

Initial field trials in Australia — for which the team is awaiting government approval after an extensive risk analysis — will check safety, followed by larger trials assessing whether the method cuts dengue transmission in Vietnam next year. The whole process should take around three years, says O'Neill.

One benefit of using Wolbachia is the bacterium's ability to spread through populations. It is transmitted only by the female mosquito, via its eggs, to its offspring. Unusually, if a male infected with Wolbachia mates with a female that is not, her eggs die.

"That makes it interesting from a bio-control perspective because [the bacterium] can spread very effectively yet is quite specific so we don't have to worry so much about secondary environmental effects," says O'Neill.

Wolbachia already lives in around two-thirds of insects, including some mosquitoes that bite humans, so the risk to human health is tiny, says O'Neill. And because the bacteria are spread only from female to offspring there is little chance of them infecting other insects.

But it's unlikely to be a permanent solution. Resistance could emerge eventually, says O'Neill, so he is working on different Wolbachia strains that could be deployed one after another to prolong effectiveness — like changing from one insecticide to another.

Political hurdles

Despite progress in O'Neill's non-GM approach, he acknowledges that it is likely to be the elusive, disease-resistant mosquito that has the most potential in the long term.

James, who works on both resistant and sterile GM mosquitoes, agrees. "[Disease-resistant mosquitoes] are envisioned to be able to achieve not only control and elimination but also target the more ambitious goal of eradication," says James.

There is strong support for O'Neill's non-GM approach from Australia and Vietnam

O'Neill/McGraw Lab, University of Queensland

But public attitudes and regulatory processes may prove to be the biggest barrier.

O'Neill's field trials are going ahead because of strong community support for the idea in both Australia and Vietnam. But GM technology is controversial in many countries and campaigning groups such as Greenpeace are against GM science, whatever its aims.

"The political/social side of GM is a major hurdle," says Andrew Read, professor of biology and entomology at Penn State University in the United States.

"The first GM vector product will be critical it needs to work really well and alleviate suffering right away."

Jacobs-Lorena says that the public might be more accepting of GM insects and bacteria than of crops because the insects have the potential to save lives, rather than produce cheaper food.

But a 2001 Zogby International poll found that just 39 per cent of Americans surveyed agreed with genetically modifying insects to fight disease.

The insects may prove more popular in developing countries where people see first-hand the devastation of malaria and dengue fever.

The WHO is developing guidelines for countries to use as the basis for developing their own regulations for the field testing and release of GM insects. Draft guidelines should be ready by October this year, Yeya Touré, leader of the Innovative Vector Control Interventions programme at the WHO, told SciDev.Net.

He is confident that GM mosquitoes will have a role to play in future malaria and dengue control and says that the Cayman Islands, Malaysia and Mexico are interested in using GM sterile mosquitoes to tackle dengue.

As for the armies of disease-resistant GM mosquitoes, they may not be a pie in the sky anymore, but they're not airborne either — and seem unlikely to be anytime soon.

Katherine Nightingale is SciDev.Net's South East Asia regional news editor.

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