scitubeproYeah, that’s right, mosquitoes are to be released into the Florida Keys, USA in 2021! ‘Why would anyone take such an insane decision especially amidst the pandemic?’ you might wonder. Well these are not just mosquitoes but genetically modified (GM) mosquitoes being released with the aim of reducing mosquito borne diseases like yellow fever and dengue.
According to WHO, the number of dengue cases has increased by more than 8 folds over the past two decade with about 4.2 million cases being reported in 2019. About half the world’s population is in danger now and what more, there is no specific treatment for dengue!
Since there is no cure for dengue, scientists have resorted to genetic modification. The two of the most common approaches are 1) modifying the male mosquitoes such that they cannot produce viable off springs 2) modifying male and female mosquitoes such that they become resistant to the disease or incapable of transmitting them
Oxitec, a bio-tech company based in UK has developed OX513A strain of Aedes aegypti using the first approach. The patented approach of Oxitec’s GM insects is known as RIDL (Release of insects carrying a Dominant Lethal genetic system) and the mosquitoes are genetically engineered to contain a red fluorescent marker and the RIDL ‘conditional lethality’ trait. Only the male OX513A will be released, thus will not bite and be involved with transmission of disease. These released GMOs can mate with the wild female and produce off springs that die off as larvae. This results in the reduction of total adult mosquito population over time.
Oxitec uses RIDL approach to insert LA513 transposon into the DNA of mosquito resulting in mosquitoes that produce off spring that die in larval stage unless fed with tetracycline. This is because the transgenic mosquitoes express a protein called tTa (tetracycline-controlled transactivator), which is lethal when expressed in high amount. However in the presence of tetracycline the mosquitoes can survive to adulthood. Although the exact mechanism is not understood it is believed that tetracycline binds to tTa, preventing further expression of tTa protein. In laboratory conditions the strain can be supplemented with tetracycline allowing them to grow and reach adulthood.
Figure 1: The structure and function of transposon LA513. LA513 is a non-autonomous piggyBac-based transposon of 8.4 kb. Transgenics are readily identified by red fluorescence due to expression of DsRed2. tTAV is a tetracycline-repressible transcriptional activator. Here, tTAV is under the control of its own binding site, tetO, a minimal promoter from Drosophila hsp70, and a 3' UTR sequence from Drosophila fs(1)K10. In the absence of tetracycline, tTAV binds to tetO and drives expression of more tTAV, in a positive feedback loop. In the presence of tetracycline, tTAV binds tetracycline; this tetracycline-bound form does not bind tetO and so does not lead to expression of more tTAV. Consequently, this construct gives very high levels of expression of tTAV in the absence of tetracycline, but only low, basal expression in the presence of tetracycline. High level expression of tTAV is toxic, possibly due to the interaction of the VP16 domain with key transcription factors, so this construct provides a tetracycline-repressible lethal system.
Source:https://www.researchgate.net/publication/6433535_Late acting_dominant_lethal_genetic_systems_and_mosquito_control/figures?lo=1
Over the last decade, Oxitec has released these mosquitoes in Malaysia, Cayman Island and Brazil. These trials have reduced mosquito population by 80-95%. That sounds great right? Very exciting, living in a world that is free of dengue, zika, yellow fever and even malaria !
Well, if it was only just that easy! There are many ethical, ecological aspects that have to be considered and many scientific questions that needs to be answered. There have been reports that the female progeny of the GM mosquitoes were not dying off as intended and were able to pass on the modifications onto the local mosquito population in Brazil. Another problem is the dependency on tetracycline which is a commonly used antibiotic in human and veterinary medicine and is usually detected in meat, milk, farmed fish and human sewage. Such tetracycline contamination in the environment would increase the survival rate of the off springs. Also the underlying mechanism of this lethal gene is still not well understood. Thus some geneticists have raised concerns saying that precise and predictable results cannot be obtained. The next major concern is the impact it might have on the ecosystem.
What would happen to the animals feeding on mosquitoes if the mosquito numbers reduced drastically? There are also many concerns surrounding individual and community consent.
OX513A is one example of the genetically modified mosquito released into the wild. There are many other studies being conducted. A three year trial in Indonesia using Wolbachia-infected Aedes aegypti mosquitoes has shown promising results. Wolbachia is an intercellular natural symbiotic bacteria in insects that can reduce the capacity of Ae. aegypti to transmit dengue and other related viruses. Researchers are eagerly waiting for the result of this study. Another team of scientists are using CRISPR/cas system to fight malaria using an interesting genetic trick called gene drive. Gene drive is powerful technique that could even wipe off a species and thus has to overcome not only scientific but also ethical and political challenges and will take some time to reach the field.
With the advent of new technologies, new solutions to the problems faced by the world are being devised. However it is important to make sure that by solving one problem we don’t create another. The environmental impacts, ecological impacts, bioethics and geopolitics all have to be strictly considered and the pros and the cons have to be weighed before taking any decision and executing them, because once the damage is done there is no going back!
Author: Ashweni Ramanah
B.Sc. (Special degree in BioChemistry and Molecular Biology) Undergraduate
Faculty of Science University of Colombo
References:
- https://www.who.int/news-room/fact-sheets/detail/dengue-and-severe-dengue
- https://www.the-scientist.com/news-opinion/750-million-gm-mosquitoes-will-be-released-in-the-florida-keys-67855#:~:text=The%20strain%20of%20GM%20mosquitoes,generally%20only%20feed%20on%20nectar.
- http://www.genewatch.org/uploads/f03c6d66a9b354535738483c1c3d49e4/Oxitec_unansweredQs_fin.pdf
- https://www.who.int/news/item/07-09-2020-dengue-control-three-year-indonesia-trial-shows-promising-results
- https://cen.acs.org/biological-chemistry/biotechnology/CRISPR-gene-editing-drives-caged/96/i39
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