Part Two: Could “friendly” mosquitoes defend the vulnerable?

While Part One focussed on one method of advanced biological control to influence mosquito populations, what technology is emerging to use the mosquitoes themselves to eliminate the threat?

This is second in a series, Alternative methods to fight Mosquito-borne diseases
Part One: Could a spider-toxin weaponised fungus fight Malaria?
Part Two: Could “friendly” mosquitoes defend the vulnerable?

Although Malaria is constrained to being spread by Anopheles mosquitoes, the Aedes aegypti mosquito is a primary vector for a multitude of diseases including Zika, Dengue, yellow fever and Chikugunya. Many of these diseases have no cure or specific treatment options, and while vaccines are available for Dengue and Yellow fever the majority of people are left unprotected from the diseases spread by Aedes.

OxitecLogoIn June this year, a UK-based firm Oxitec announced a successful first field deployment of their genetically modified Friendly non-biting mosquitoes. The trial began in May 2018, and has achieved up to a 96% suppression of mosquito populations in four urban communities under the approval of CTNBio, Brazil’s national biosafety authority.

So how are these Friendly™ mosquitoes so human friendly?

Oxitec’s technology is formed around the insertion of two genes into the insects genetic code – one is the “self-limiting” gene, and the other is a fluorescent marker DsRed2.

The self-limiting gene is described by Oxitec as the heart of their method of insect control. This gene causes the insects’ embryonic cells to over-produce a protein which heavily interferes with the development of the embryo, causing self-termination and preventing it surviving to adulthood. The interfering protein is called tTAV, and the self-limiting gene producing it can be turned off by using it’s antidote tetracycline.

Oxitec’s 2nd generation technology targets females only, so only female larvae produce the tTAV protein, so adding the antidote to the insects food allows them to be reared in the factory without females dying off pre- sexual reproductive age. As female mosquitoes only start biting humans when they are adults, the danger is eradicated before its begun.

The male mosquitoes, however, carry the gene yet do not produce the tTAV protein, allowing them to survive into adulthood and seek out wild females to pass on the gene to their offspring. Each subsequent generation pass on the gene to half their offspring, ensuring the gene persists long enough to lower the population while declining over time so there is no permanent change in the gene pool.

SCIENTIFIC DEEP DIVE

tTAV, the product of the self-limiting gene, is the abbreviation of tetracycline-controlled transactivator.

tTAV is under the control of the binding site of it’s own gene, called tetO. Binding sites are associated with specialised proteins called transcription factors that allow transcription to occur. When transcription factors are bound to the site, the genes product can be made, and in this case the genes product acts in a similar way.

In the absence of tetracycline, tTAV binds to tetO increasing the expression of tTAV and creating a positive feedback loop. The more tTAV is produced the more it binds to tetO and so on. At very high tTAV levels, it interferes with the expression of essential genes thus interfering with normal development causing termination of the insect at pupal/larval stage.

In the presence of tetracycline, tTAV binds to tetracycline and is unable to bind to tetO. This means no positive feedback loop is created, thus only low levels of tTAV are found in the cells and the insect survived.  There is no access to tetracycline in the wild so females cannot survive in this application.

DsRED2 - Oxitec
Source: Oxitec

The second gene that is inserted is a fluorescent marker, DsRED2. This allows the insects to produce a protein throughout their body which glows under a specific lighting format, as shown on the left. DsRed2 is a non-allergenic non-toxic protein that enables the researchers to easily identify and monitor the insects that have the gene, thereby assessing how effective the deployment in a field setting is. 

How did they fare against their wild not-so-friendly counterparts? 

The field tests took place in 4 densely-populated urban areas in Campina Brazil, 2 of which received a lower release rate while the other 2 received a high release rate. While the lower release rate areas showed an impressive average of 89% population reduction, the higher release areas showed an average reduction of 93% with the highest a staggering 96%. 

This technology not only directly causes population decline, but also has the ability to reverse the insecticide resistance seen in wild-type insect populations. Using the same technology, Oxitec can introduce genes that make the insects susceptible to the traditional pesticides via the released male cohort. As discussed in Part One, insecticide resistance is becoming a huge issue with the mosquito populations transmitting Malaria. According to Unicef, over 1 million people die from malaria each year, with most casualties being under 5 years old, and 90% of cases occurring in Africa.  In June 2018 Oxitec announced their partnership with the Bill & Melinda Gates Foundation to research applying their technology to the Malaria crisis, with funding dating back many years.

This technology is an elegant way to have a real impact in fighting disease without introducing further chemicals or insecticides, and I am looking forward to seeing how this technology will be used in the future.

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