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Genetically Modified Organisms Being Designed As Living Pesticides With Autocidal Genes

In the urban jungle of Juazeiro in Brazil, an army is being unleashed. It is an army like no other: the soldiers' mission is to copulate rather than fight. But they are harbingers of death, not love. Their children appear healthy at first but die just before they reach adulthood, struck down by the killer genes their fathers passed on to them.

These soldiers are the first of a new kind of creature - "autocidal" maniacs genetically modified to wipe out their own kind. The first animals being targeted with these "living pesticides" are disease-carrying mosquitoes and crop-munching caterpillars, but the approach should work with just about any animal - from fish to frogs and rats to humans. If it is successful, it could transform the way we think about genetically engineered animals and organisms.

Last year, Oxitec and the Mosquito Research and Control Unit of Grand Cayman (MRCU) announced, at the American Society of Tropical Medicine and Hygiene annual meeting in Atlanta, the results of their release of genetically modified sterile mosquitoes into the wild.

It is the first time genetically altered mosquitoes have been set loose in the wild, after years of laboratory experiments and hypothetical calculations. But while scientists believe the trial could lead to a breakthrough in stopping the disease, critics argue the mutant mosquitoes might wreak havoc on the environment.

Oxitec developed the sterile strain to control the dengue-carrying Aedes aegypti mosquito. This sterility can be suppressed with a dietary antidote, allowing the strain to be reared in large numbers. Sterile males are then released to seek out and mate wild females, competing for mates with the wild males. If a female mates with a sterile male she will have no offspring, thus reducing the next generation's population.

In essence, much the same method has already been successfully employed for more than half a century. In the so-called "sterile male technique", large numbers of the target pest are bred, sterilised and the males let loose. When they mate with wild females, the resulting eggs are not viable, so releasing enough sterile males can eventually exterminate wild populations.

Scientists say the sterile male technique is incredibly focused, homing in only on the species you want to control. Pesticides, by contrast, harm a wide range of other species, including us.

So why isn't the method more widely used? The main problem is that it is very difficult to sterilise animals without harming them in other ways. The usual way of sterilising insects is to zap them with radiation, for instance, which leaves the males weakened. Establishing the optimal dose of radiation for a species is thus crucial - too little and fertile insects will be released, too much and the males will be too feeble to compete for females. Working out the optimal dose is best done in the field, but the task is laborious without an easy way to distinguish sterilised insects from wild ones.

When the founder of Oxitec, Luke Alphey, first learned about the sterile insect technique from a colleague in the 1990s, he realised that the molecular tools he was using in his everyday research might provide a better alternative. Within a matter of years, he had created fruit flies with genes that kill their offspring (Science, vol 287, p 2474).

Alphey and his colleagues have created a strain of A. aegypti with two copies of a gene that disrupts the development of offspring. The gene is switched off in the presence of the antibiotic tetracycline, allowing large numbers of perfectly fit mosquitoes to be bred for release. "With our system, the mosquitoes are fundamentally sterile and we're keeping them alive by giving them an artificial antidote," says Alphey. The insects also have the DsRed marker gene, to enable them to be easily monitored.

When these mosquitoes mate with wild females, the eggs hatch and the larvae develop normally until they reach the pupae stage, when the killer genes kick in. Delaying death like this is actually a cunning trick: the doomed larvae compete with wild larvae for resources, further reducing their numbers.

Now a bigger trial is getting under way in Juazeiro, Brazil, which Alphey hopes will be scaled up into a full-scale control programme. In the meantime, Oxitec has been busy developing other, more sophisticated strains, including one particularly devious one.

With both the classical sterile-insect method and the genetic variations on it, it is normally vital to release just males. If you release males and females at the same time, they will mate with each other, reducing the impact upon the wild population. Unfortunately, separating the sexes takes a lot of time and effort in some species. "This is a huge problem if there is a need to release millions of males per week," says Mauro Marelli, an epidemiologist at the University of São Paulo, Brazil, who is working with Oxitec on the trials in Juazeiro.

His team has created a strain in which the females cannot fly. The work was based on the discovery that female mosquitoes have a unique flight muscle protein that males lack, perhaps because females have to fly after a blood meal and so must fly with a much heavier load. Flightless females cannot find people to feed on and cannot mate either, so there is no need to separate the sexes. Envelopes containing millions of eggs could simply be mailed to wherever they are needed. "Just add water and you get instant mosquitoes," says Alphey.

The males that hatch from the eggs will appear normal and can pass the flightless gene to their daughters. Their sons will also inherit a single copy, so they too will produce some flightless daughters. "The construct will persist in the population for several generations but not for long due to its high fitness cost," says Alphey.

Oxitex also has malaria-carrying mosquitoes in its sights, but this is a greater challenge than dengue. For a start, there is often more than one malaria-carrying mosquito species responsible for transmission in a particular area, so effective control would mean targeting each these species separately. In addition, malarial mosquitoes often bite other animals besides humans, so their distribution is less predictable than A. aegypti's.

While Oxitec is leading the way, many other groups around the world are working on similar approaches - and not just for killing insects. "On technical grounds, there's no reason why the logic of sterile insects could not be transferred to vertebrates," says Ronald Thresher, an ecologist working for Australia's national scientific agency, CSIRO.

He thinks the autocidal approach could not only be used to control invasive species such as cane toads, but that it is the only method that could work in many cases. "It's the only hope we have for the long-term control and eradication of these pests," he says. "Other efforts help, but in the end they are Band-Aids in the absence of a real solution."

Thresher has come up with a way to create fish that produce only male offspring. Releasing enough of these "daughterless" fish into the wild, with each passing on the daughterless habit, would turn a thriving invasive population into a bunch of reluctant bachelors destined for extinction.

His method relies on the fact that an enzyme called aromatase is crucial for generating female hormones in fish. Switch off the aromatase gene and you've created a fish that can only produce sons. He has shown the approach works in lab tests on zebrafish, skewing the sex ratio in favour of males for at least three generations.

Models suggest that releasing enough daughterless carp to make up 5 percent of the total population would effectively eradicate carp in the Murray-Darling basin by 2030.

Public acceptance could also be a huge issue, Alphey points out. "A large number of adult male rats - sterile or not - is probably not the way you want to go."


Nevertheless, if autocidal technology lives up to its promise, it could largely or entirely replace pesticides, and it affects only the target species. Last but not least, it is hard to see what could go wrong.

Many engineered plants, for instance, are being given advantageous traits such as disease resistance, so these genes could well spread among wild relatives. Autocidal traits, by contrast, are a great disadvantage and SHOULD disappear from the wild within a few generations after releases stop. "We are putting genes with huge, huge fitness penalties like death into something that's undesirable in the first place," says Alphey.

In theory, wild insects might be able to evolve resistance, for instance, by somehow learning to recognise and avoid insects with lethal genes. But this is much less likely to develop than pesticide resistance, and could be overcome by altering the release strain.

Needless to say, those opposed to genetic engineering are not convinced. "Genetic modification leads to both intended and unintended effects," says Ricarda Steinbrecher of EcoNexus, which describes itself as "a not-for-profit, public interest research organization". "There are potential knock-on effects on many other organisms," she claims.


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