Aedes aegypti Aedes aegypti female, carrier of the dengue virus. Image source: Muhammad Mahdi Karim/Wikimedia Commons.
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Can Oxitec End Mosquito-Borne Diseases with Genetic Tools?

Mosquitoes are much more lethal than their size may suggest. Mosquito-borne diseases — malaria, dengue, chikungunya —  cause nearly 1 million deaths globally every year. These deaths are totally avoidable if we implement tools that control mosquito populations. Chemical control hasn’t been much effective since mosquitoes can lay eggs in standing water and often develop resistance to the chemical agents (similar to agricultural pests, which have similarly disastrous economic consequences). The solution, it seems, is hampering the reproductive biology of these insects rather than eliminating larval or adult insects.

Oxitec, a British company out of Oxford, has been working on a conceptually simple and innovative insect control method for over a decade. The technology it is betting on is Release of Insects with Dominant Lethality, or RIDL (link opens PDF), an advancement over Sterile Insect Technology. It releases genetically engineered male insects that breed with wild females to produce dead progeny; an improvement over the sterile insect technology that produce sterile offspring. That’s what is called nipping a menace in the bud.

Fruitless matings

Insects are genetically modified into RIDL by introduction of a dominant lethal gene. Even a single copy of the gene in the mosquitoes’ genome causes death by accumulation of tTA during the late-larval or late-pupal stages. The condition can be prevented by supplementing tetracycline in their diet, a facility unavailable to the mosquitoes out in the wild. So, when an RIDL male encounters a wild female (only females bite), the progeny die before maturing. If we release a high enough number of males, the chances of such fruitless copulations are pretty high and the native insect population can fall rapidly — and may even be eliminated. The RIDL insects are tagged with a fluorescent marker that helps distinguish them from wild insects for effective population management.

All progeny of matings between RIDL males and wild females die. Image source: Oxitec.
All progeny of matings between RIDL males and wild females die. Image source: Oxitec.

Failures in mechanical sorting sometime lead to few RIDL females being released into the wild. This has been overcome by the development of female-specific RIDL insects. In these, the male progeny can survive without the supplement while the female cannot. Thus, if the supplement is removed from the diet prior to release, only males live to be released. Since this control method is sex-specific, it continues down the generations. Matings between released males and wild females would lead to progeny in which the females don’t survive while the males carry the lethal trait. The fall in population is rapid even though releases must be continued for total control of the insect population.

Oxitec products in the news

Oxitec develops product candidates at its laboratories in the UK which are then tested and evaluated at lab and field settings through partnerships with different agencies. Both bisex and female-specific RIDL insects have been used. Bisex RIDL is included in pink bollworm OX3402 and Aedes aegypti OX513A, while the female-specific control has been used in Mediterranean fruit fly OX3647 and Aedes aegypti OX3604C. Successful trials have been undertaken in collaboration with local partners in the Cayman Islands, Malaysia, and Brazil.

The Cayman trial was preceded by a smaller trial in which approximately 19,000 sterile males were released over 10 hectares in a month. This was done to determine how long check the duration these mosquitoes lived in the wild, how far they travelled, and occurrences of their matings with wild Cayman females. In a larger experiment, over 3 million RIDL males were released over six months in Grand Cayman in 2010. The trial reported an 80% reduction in the Aedes aegypti population over an area of 16 hectares. This reduction is phenomenal given the very low and limited success of other control methods.

Brazil was an obvious choice for a large trial since it has one of the highest dengue rates in the world. In different neighbourhoods in the nation, release of Aedes aegypti  OX513A has led to declines in the local mosquito population in the orders of 92%, 94%, and even 99%. Oxitec do Brasil, a subsidiary of Oxitec, has recently set up a production unit to expand its operations. It has a capacity to produce 2 million Aedes aegypti  OX513A per week. Similar success has been achieved in the US for control of the agricultural pest pink bollworm (Pectinophora gossypiella). The benefits seem to override any fears that the local public might have over the release of GM insects.

Tackling public perception

The foremost public fear with Oxitec products is the release of GM organisms, millions of them actually, into the wild. Oxitec has followed proper biosafety laws as per the local regulations in countries it has conducted trials in. But, the possibility of increasing the population of another organism due to reduced competition (i.e. shifting selective pressures) is a worry that hasn’t been addressed properly. The technology also doesn’t guarantee the complete removal of mosquito-borne diseases or, in some cases, the removal of all serotypes.

Unintended release of RIDL females could prove to be a risk, too. The female’s bite would expose humans to tTA which could induce allergic reaction. Oxitec’s claim that tTA isn’t produced in the mosquitoes’ saliva hasn’t been validated with any scientific study as of yet. In order to gain traction, Oxitec has oversimplified the complex relations between Aedes mosquitoes, dengue virus, other insect species, and humans. If the success of RIDL insects turns out ephemeral, it would be largely due to the oversimplification.

RIDL insects cannot be used along with current control methods since they would lead to a fall in the number of engineered males out in the wild. Convincing people to drop conventional methods and embrace the use of RIDL insects will require significant reduction in costs and increase in public engagement. Whether Oxitec can do this or not could decide how long the bitsy mosquito would remain one of the largest killers on earth.

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Sachin Rawat

PHD Researcher at National Centre for Biological Sciences

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