Finding conventional methods of malaria control insufficient to eliminate the disease, some researchers have turned to genetics to control the mosquito population.
Malaria control schemes based on the concept of replacing vector populations with mosquitoes of the same species unable to transmit are currently being evaluated in several laboratories.
Gene drive mosquitoes, many researchers consider, have tremendous potential to help eliminate malaria.
In sexually reproducing organisms, most genes follow Mendelian rules of transmission in a 50:50 ratio. This means that of the two copies of every chromosome; any single copy of a gene normally has a 50% percent chance of being passed on to an individual’s offspring. This process of gene transmission is described as ‘fair’ and does not in itself change the frequencies of alternative genes in a population. The two copies are transmitted by an individual at the same rate that they were inherited by the individual.
But there may be occasions wherein some genes are transmitted to more than 50% of the progeny. Gene drive refers to this process of preferential or biased inheritance from one generation to the next. Mendelian transmission of genes does not in itself lead to changes in allele frequency over time, whereas gene drive can. The most efficient gene drives might ensure an inheritance bias of nearly 100 percent. Here, the genetic sequence doubles in frequency.
Gene drive is a natural process that has independently evolved many times in many species. There have been several documented cases of gene drives existing in nature, with selfish genes invading several different insect species.
Now researchers have developed a technique that introduces a genetic element that cheats the normal rules of Mendelian inheritance.
So, if we know the genes that are responsible for key mosquito traits, we can theoretically introduce a genetic modification into the insects, which reduces malaria transmission. Going by this principle, a wide diversity of synthetic gene drive systems has been proposed for vector control.
Several multiple gene drive approaches have recently shown promise in laboratory settings. They include mosquito population replacement with introduced genes that limit malaria transmission, driving-Y chromosomes to collapse a mosquito population, and disrupting a fertility gene to achieve population suppression or collapse.
A mechanistic, spatially explicit, stochastic, individual-based mathematical model is used to simulate each gene drive approach in a variety of sub-Saharan African settings. Each gene drive approach provides a tool for malaria elimination.
In fertility gene drive approach, a selfish gene that spreads through a population through non-Mendelian inheritance is used. If the introduced driving gene disrupts a fertility gene, then its spread through a local vector population could suppress the population or even collapse it. Such an approach has been proposed using homing endonuclease genes (HEGs) and this approach has been demonstrated in the laboratory with HEGs and using CRISPR/Cas9 nucleases as well.
In driving-Y approach, the Y chromosome in the modified male mosquito damages the X chromosomes in the germline, resulting in gametes that predominantly carry a Y chromosome. This approach has been successfully demonstrated through a series of lab experiments. It ensures that modified males have predominantly male offspring, as do their male offspring in turn. This could, eventually, lead to local population collapse.
Population replacement is another gene drive approach. In this case, gene drive focuses on fixation instead of collapsing the local vector population. This introduced construct could knock out a gene required for mosquito infection by the parasite. Or it could knock out in a gene that provided a defence against parasite infection or facilitated onward transmission to humans.
Once achieved, the impact of gene drive technology would stay for years after elimination. A successful gene drive construct would prevent any loss of impact due to pyrethroid resistance and would ramp down transmission potential regardless of vector feeding behaviours and bionomics, proponents of the technology aver.
Driving genetic immunity
In a Johns Hopkins University study on mosquitoes genetically modified to be more resistant to malarial parasite found that GM mosquitoes could possibly drive their genetic immunity into mosquito populations to which they are introduced.
Genetic modification of a bacteria found in the gut of the mosquito could effectively kill off the malaria-causing parasite before it can develop properly, shows another study from JHU researchers.
The researchers demonstrated that modulation of the microbiota of P. falciparum–resistant immune-enhanced GM mosquitoes renders them more competitive than wild type mosquitoes through mating preference in mixed-cage populations.
The use of proper promoter-transgene combinations to modulate the mosquito microbiota can facilitate the spread of GM mosquitoes in a population, according to researchers.
Even though work in the laboratory has provided a number of proof-of-principle demonstrations of key aspects of gene drive interventions for malaria control, they are yet to be put on field trials.
Gene drive technology is currently being evaluated by regulators and other stakeholders. Gene drive constructs also pose several issues for regulators due to their novelty.