Genetically Modified Mosquitoes and Gene Drives: Engineering our Future

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Mosquito-borne diseases affect almost 700 million people each year. These diseases can be deadly, especially in places where access to medicine or healthcare is limited. There are many methods used to try and control these diseases – vector control, insecticide, medicines, and even forms of mosquito birth control– but one method that has been the subject of attention and controversy in recent years is the genetic modification of mosquitoes so that they cannot carry certain diseases.

The goal of these genetically modified mosquitoes is to eliminate the vectors of several dangerous disease. The vector is the vehicle that harbors and transmits a disease. For malaria, Zika virus, dengue and more, the vector is mosquitoes. With genetically modified mosquitoes, scientists hope to develop mosquitoes that are unable to be vectors for infectious diseases. Without a vector, the parasite that causes a disease cannot be transmitted to humans.

 

Photo: Ae. aegypti mosquitoes

Genetically modified mosquitoes are created by altering the DNA of a mosquito. The DNA is the genetic code that holds all information for the development, growth, and reproduction of that organism.

As the genetic modification of mosquitoes to either resist or not transmit certain diseases is a very recent field of study, a variety of methods are being used to see how this can best be carried out. Earlier this year, a team led by researchers from the University of California completed a trial in which broadly neutralizing antibodies were added to Ae.aegypti mosquito DNA. This trial focused on dengue fever, the viral disease caused by four different dengue viral (DENV) serotypes, or strains. The genes for these antibodies are taken from humans and must be engineered to be compatible with mosquitoes.  Antibodies must be specific – for example, when scientists are genetically engineering mosquitoes that spread dengue, only dengue antibodies will be effective. These antibodies work by neutralizing the virus strain, typically by blocking the virus from entering the cells.

When this genetically modified mosquito mates, it will pass on the antibodies to its progeny. If the progeny mosquitoes become infected with dengue virus, the antibodies will neutralize the virus strains. By doing this, the mosquito will no longer have dengue, and thus cannot spread the virus to a human. Lab tests showed positive results – modified mosquitoes had a significantly reduced infection rate when compared to wild-type (unmodified) mosquitoes.

 For this technique to be effective in the wild, it would need to be coupled to a gene drive. A gene drive is technology that can defy the natural rules of heredity. Genes are the parts of DNA that cause traits, and organisms have two copies of each gene. One copy of each gene comes from each parent via the sperm and egg. Each gene copy has a 50% chance of being chosen for the sperm or egg to be passed on to the offspring. However, gene drives can alter the probability of a certain gene copy being chosen to be passed on and inherited. Instead of a 50% chance to be chosen, that probability can be increased to almost 100% or decreased to almost 0% via gene drives.

Photo: Natural inheritance and gene drive inheritance

If a gene drive is coupled to another gene, both will be passed on together to the progeny. Target Malaria, a group of scientists aiming to use genetic engineering to eliminate malaria, has had success with this coupling. Instead of using an antibiotic gene, Target Malaria focused on using the sex-distorter gene drive that will create a population of mostly male Anopheles mosquitoes. Since only female mosquitoes can bite and infect humans, a population of male mosquitoes will stop the spread of malaria and will eventually die out as fewer and fewer mates will be available.

Lab tests using the sex-distorter gene drive have shown success. In a 2020 study, Target Malaria researchers found that the insertion of this gene drive created a heavily male population, and eventually led to population reduction. The gene used as the gene drive was the doublesex gene, a highly conserved gene, or a gene that does not readily mutate. This is another breakthrough – for gene drives to be successful, the mutation rate needs to be low. Finding a gene drive that doesn’t easily mutate means it is less likely to become resistant to the sex distorter component.

Gene drive technology, however, is far from perfect. One major problem is mutations. Random mutations can and do occur, interfering with the efficacy of the gene drives. Although this issue can be somewhat avoided by using a gene that is highly conserved (such as the doublesex gene), the possibility will always be there. Additionally, ethical concerns abound – if mosquitoes and fruit flies can have their DNA edited, what else can this technology be used for? Scientists try to account for this issue by creating a reversal drive to undo their gene drive if needed, but there are bound to be ramifications from the use of this technology.  

With the existence of insect birth control (Sterile Insect Technique and Incompatible Insect Technique), what advantages do these new genetically modified mosquitoes offer?

  • Most forms of insect birth control require large numbers of insects to be continuously released into the environment. Based on current research, genetically modified mosquitoes that are coupled to a gene drive can spread their genes from a low starting frequency. A modest number of these genetically modified mosquitoes can transmit their new genes throughout a large population.
  • This new method is potentially even more effective than Wolbachia IIT. When the University of California researchers added antibodies to the Ae. aegypti mosquito DNA, they included a control test of mosquitoes treated with Wolbachia IIT. Mosquitoes that were homozygous (had two copies) for the antibody gene were more effective at stopping the spread of dengue that Wolbachia IIT mosquitoes. Heterozygous mosquitoes that only had one copy of the antibody had the same efficacy as the Wolbachia IIT mosquitoes.

 

These methods of genetic modification and gene drives have not been tested in the wild. There are still many more stages of testing before these mosquitoes will be viable options, but for now they remain an area of further study and a potential future fix for vector-borne diseases.

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