Mosquitoes are the primary vectors of diseases such as malaria, dengue, zika, and human immunodeficiency virus infection and acquired immunedeficiency syndrome (HIV/AIDS). The World Health Organization reported that,despite the introduction of new drugs, personal protection, and environmental modification, malaria mortality still accounted for approximately 580,000 deaths globally in 2014 (Gantz et al.,2015). Over many decades, insecticides have been used as an effort to control the population of mosquitoes, but they are hindered by increasing insecticide resistance (Adelman & Tu, 2016). A solution to controlling the spread of these vector-borne diseases is by creating sterile, transgenic mosquitoes to induce sterility and prevent reproduction within a population or limit the lifespan of their offspring (Adelman & Tu, 2016; Caplan et al., 2015). Another solution is to block disease transmission by genetically edit female mosquitoes, which are the only ones that can bite for blood and infect people, to be incapable of carrying certain diseases (Caplan et al.,2015). If the genetically altered genes can be replicated and passed down through many generations of mosquitoes, then the vector-borne diseases would be eradicated sooner. The best choice of genetic technology that can control the population of mosquitoes and decrease the prevalence of vector-borne diseases is the CRISPR/Cas9-based gene drive system.
CRISPR/Cas9-based gene drive technology is a powerful tool that increases the likelihood of an edited trait to be passed on to offspring through sexual reproduction (Caplan et al., 2015). Cas9 and CRISPR, or clustered regularly interspaced short palindromic repeats, is a bacteria-derived endonuclease system that cuts a target DNA sequence complemented by a guide RNA (gRNA). When included as part of a gene drive, a mutation generated by CRISPR-Cas9 will replicate anywhere the genome sequence is complementary to the gRNA, converting individuals heterozygous for the mutation into homozygotes (Webber et al.,2015). Before the use of gene drives, genetically modified organisms would be introduced into the environment to mate with wild-type organisms, but their offspring generally have a 50% chance of inheriting the modified genes. The use of a CRISPR-based gene drive ensures that all offspring and subsequent generations will inherit the edited genome by having the gene drive actively copy the mutation on one chromosome to its partner chromosome (Caplan et al., 2015). The ability of gene drives to increase the frequency of a phenotype denies the frequency predicted byMendelian genetics (Adelman & Tu, 2016).
A CRISPR/Cas9-based gene drive system was used to target female reproduction in the main mosquito vector for malaria, Anophelesgambiae. Andrew Hammond and his colleagues, who disrupted three genes that confer female-sterility phenotype with gene drive constructs, found that the fertility of females was significantly reduced and the transmission rates of 500 G2 progenies for each gene were 94.4-100% (2018). In addition, Valentino M. Gantz and his research team tried using the same method on another malaria-carrying species of mosquitoes of the same genera, Anophelesstephensi. They found that individuals expressing Cas9 in the germ line copy the modified genetic element from one chromosome to its homolog with more than 98% efficiency (2015). These researches show the success of the CRISPR-based gene drive system to replicate genetically modified genes and increase the frequency of desired phenotypes within a population. Gene drives can also be used to reverse insecticide resistance in agricultural pests and herbicide resistance in weeds, or to spread deleterious alleles in invasive species (Unckless et al., 2017).
There are ethical concerns with the use of gene drives to prevent reproduction of invasive species of plants and animals can drive the species to extinction. If the targeted species is an important predator, competitor, symbiont, mutualist, or prey of an ecosystem, its extinction could decrease the populations of nontargeted wild organisms (Unckless et al., 2017). Besides the use of gene drives to reduce reproduction, gene drives can reduce genetic diversity when the modified alleles are driven to fixation in a population,making individuals more vulnerable to purifying selection and natural or anthropogenic pressures (Oye et al., 2014).The US National Academies of Sciences, Engineering, and Medicine (NASEM) committee evaluated the effects of CRISPR/Cas9-based gene drives and recommended that governing authorities and research institutions should consider developing policies and mechanisms to prevent ecological risks. The NASEM committee argued that alternative methods should be considered as they may lack some of the negative effects associated with a gene drive system (Collins, 2016). Human embryos should only be modified somatically to avoid possible consequences in future generations. As gene drive research moves into the future, scientists should act responsibly and balance the benefits and consequences of releasing modified organisms into the natural environment that may raise ethical, legal, or societal issues.
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