Historically, malaria and dengue control strategies have incorporated insect population control using insecticides, but in recent years, researchers have turned to genetic engineering. By developing mosquitoes that don’t carry such pathogens, researchers hope to stop disease spread.
Culling insects Researchers creating genetically modified (GM) insects generally have one of two goals, which some experts call them as the ‘bite, no-bite’ strategies. “Bite” strategies modify the insects in such a way to prevent disease transmission to humans, whereas “no-bite” strategies aim to reduce or eliminate insect populations altogether, by, for example, rendering them incapable of producing viable offspring. A similar strategy, known as the sterile insect technique (SIT), has been used to successfully shrink populations of tsetse flies, which carry the parasite that causes sleeping sickness. In SIT, male insects are sterilized through irradiation, then released into the wild, where they breed with wild females, but produce no offspring, thereby cutting the size of the next generation.
By regularly releasing enough sterile males, officials can drastically reduce the number of disease-carrying insects. Using genetic engineering could streamline the SIT strategy. In 2002, a method was developed called RIDLBMX HOSPITAL Patient Name: Ali Mohammad Age: 56 years Address: Street No.14 Rx Azithromycin tablets 500 mg once daily x 3 days Send one pack Dr. Ahmad Signature Date: 18/06/15 8 Kuwait Pharmacy Bulletin Summer 2015 release of insects carrying a dominant lethal allele. Aedes aegytpi, the primary carriers of dengue fever, was modified to express a lethal toxin as larvae— but only when not exposed to the antibiotic tetracycline. A diet of tetracycline-rich food allows GM insects to develop normally in the lab, then released into the wild where there is no tetracycline, and progeny inheriting the toxin gene will be killed before adulthood.
The same year, the company Oxitec was formed to implement modified mosquitoes in the field. To date, Oxitec has collaborated with governments in the Cayman Islands, Malaysia, and Brazil to begin releasing mosquitoes in dengue-plagued areas. Just last year, they reported 80 percent mosquito suppression in the Caymans, and the Brazilian trial is ongoing.
The University of Oxford and Imperial College London are also developing a similar tetracyclinebased “no-bite” strategy that renders females flightless. And another collaboration between researchers at the California Institute of Technology and Imperial College London is developing GM males, called “Semele,” which carry a toxin that kills wild females upon mating. These techniques have yet to be tested in the field. Disease-free mosquitoes Some researchers are developing mosquitoes to express anti-malaria peptides and enzymes that inhibit parasite development, for example.
Others, are targeting even earlier stages of infection, engineering mosquitoes to express mouse-derived antibodies that block Plasmodium from ever invading a mosquito’s tissues. Researchers at Johns Hopkins University (JHU) are trying a different tack-tweaking mosquitoes’ own immune systems. The few parasites resilient enough to evade a mosquito’s immune system are the ones that transmit disease, but it was suspected that if the natural immune response of a mosquito is boosted, maybe complete resistance could be achieved. Transgenic Anopheles mosquitoes have already been developed that, better resisted Plasmodium infection, with little cost to longevity and fecundity, and the researchers are currently working to devise similar strategies to combat dengue in A. aegypti mosquitoes as well.
GM versus wild The success of both bite and no-bite strategies depends on the ability of the GM mosquitoes to spread through the wild population. When a GM mosquito mates with a wild mosquito, only some of the offspring will carry the new transgenic resistance genes. To ensure that transgenic genes are pushed into wild populations, scientists are developing “gene drive” strategies that guarantee the offspring of a GM-wild pairing will carry the new resistance genes. While GM males carry a toxin that kills wild females, researchers have also developed GM females that carry an antidote. Thus, male GM mosquitoes only produce offspring with GM females— which are guaranteed to express the GM traits— while killing off wild females to reduce the wild type population.
Another promising gene drive method, not yet tested in mosquitoes, uses a genetic element called Medea, a maternally-derived microRNA that silences expression of a protein important for embryo development, combined with a gene that rescues offspring. If transgenic female fruit flies mate with non-transgenic males, only those progeny that inherited Medea from their mother survive to adulthood. By pairing Medea with transgenic genes of interest, such as those that confer malaria resistance to mosquitoes, scientists hope to quickly propagate the transgenes in insect populations. Yet another method under development relies on a homing endonuclease called I-SceI.
Homing endonuclease genes (HEGs) are selfish genetic elements that can spread themselves to homologous chromosomes, converting heterozygote carriers to homozygotes that must pass on the HEG. Indeed, when researchers engineered Anopheles gambiae mosquitoes to carry I-Scel, they found that it spread quickly through caged populations. The next step is to embed transgenic genes into I-Scel, which the researchers hope will ensure their fast spread as well. With so many different disease-controlling GM mosquitoes in late-stage development, it is predicted that the techniques will be put into field testing and possible practice in the next 5 years or so.