Host Defense and Parasite Evasion
Eric S. Loker, Bruce V. Hofkin in Parasitology, 2023
If allelic versions of genes such as TEP1 associated with refractoriness could be identified, then the possibility of introducing them into vector populations exists, a topic that will be addressed further in Chapter 9. For a variety of reasons, getting these engineered genes to spread in a natural population may be difficult and require the application of a gene drive. A gene drive “enhances the ability of alleles to pass on to the next generation: Thus, the result of a gene drive is the preferential increase of a specific genotype, the genetic makeup of an organism that determines a specific phenotype (trait), from one generation to the next, and potentially throughout the population” (National Academy of Sciences, 2016). Development and use of gene drives for vector or parasite control is discussed further in Chapter 9.
Balancing social justice and risk management in the governance of gene drive technology
Christine Hauskeller, Arne Manzeschke, Anja Pichl in The Matrix of Stem Cell Research, 2019
The term ‘gene drive’ refers to a form of genetic engineering that allows for the distribution of genetic modifications through biological populations at a pace that is significantly faster than natural reproduction and older forms of genetic engineering. Once a genetic change has been introduced into an organism, this modification then ‘drives’ through a biological population until each organism has inherited the change. This means that the release – accidental or intentional – of a single or a few modified organisms could quite possibly genetically change all populations of a species through the world (Esvelt, 2016). Gene drive technology is associated with important benefits such as agricultural applications (for example the control of invasive species), environmental applications (the conservation of species that would otherwise become extinct), as well as healthcare applications (especially the control of disease infections such as malaria, dengue fever, and Zika) (Saey, 2015).
Two unresolved issues in community engagement for field trials of genetically modified mosquitoes
Published in Pathogens and Global Health, 2019
The method that alters the mosquito populations has several potential risks and limitations. First, the targeted species might evolve resistance to the gene drive. This problem would need to be overcome before the method could induce permanent changes in the population [3,23]. Second, the method might not work as intended. It might, for example, immunize the mosquito population against malaria but equip it to carry another disease [2,3]. Third, pathogens might evolve in response to changes in the targeted mosquito population [3]. For example, the malaria parasite might develop resistance to lethal proteins introduced into the Anopheles populations. Fourth, the gene drive could become linked to other, not-targeted genes in the mosquito population, with unpredictable effects [3]. Fifth, the gene drive could have adverse impacts on non-target species if it infects these species by means of horizontal gene transfer and attaches to genes that are expressed in harmful ways. However, as noted above, the probability that this type of event would happen is very low, due to the rarity of horizontal gene transfer [20]. In sum, the ecological and evolutionary consequences of using gene drives to alter mosquito populations to enable them to resist diseases are not well-understood at present and require further study [3,12].
Considerations for the governance of gene drive organisms
Published in Pathogens and Global Health, 2018
Larisa Rudenko, Megan J. Palmer, Kenneth Oye
The other major mechanism contributing to the lack of effectiveness of a gene drive is the same as would be found in any target/eradication interaction, namely, random mutations in the pathogen population that allow for the selective survival of those individuals resistant to the eradicator (e.g. pesticide, herbicide, antimicrobial), and loss of the effectiveness of the intended effect of the proposed gene drive organism.
Public health concerns over gene-drive mosquitoes: will future use of gene-drive snails for schistosomiasis control gain increased level of community acceptance?
Published in Pathogens and Global Health, 2020
The most daunting concern about the use of gene-drive vectors is the possibility of gene drive failure. In this context, CRISPR/Cas9-based knockout of susceptible genes and/or knockin of resistant genes may fail under certain conditions. Failure may occur inherently in the CRISPR/Cas9 system itself, when the Cas9-mediated double-strand incision in the DNA sequence is sewn back together via nonhomologous end joining (NHEJ) repair mechanism which is error-prone [24,46]. Failure may also ensue as a result of (i) natural genetic variation of the target gene sequence within a population [47,48] or (ii) genetic mutation in the target gene sequence [46]. In the first circumstance, it is possible that the modified vectors work effectively somewhere (such as where they are developed) and not elsewhere (such as in areas with different geographic variants of the vector or target pathogen). For example, a recent genome analysis of wild Anopheles mosquitoes from across Africa found extreme genetic diversity among populations of the same species [49]. Such heterogeneity, as observed by Ogola et al., [50] underlies variation in vector competence and Plasmsodium infectivity, and could have practical implications on the development of gene-drive mosquitoes. In the same vein, compatibility polymorphism is not an uncommon phenomenon in snail/schistosome interactions [51]. A transcriptomic analysis by Galinier et al., [52] showed that some known molecular determinants of Schistosoma mansoni infectivity in Biomphalaria glabrata are variable genetically and in their level of expression among different combinations of the vector/parasite strains [52]. In the second circumstance, pathogens generally demonstrate tenacious ability to evolve resistance and circumvent every control stratagem devised against them, not excluding the transgene-driven vector immunity. The evolutionary counteractive response in the target pathogen could result in disease resurgence after a period of effective control [53]. There is also a concern over possible evolution of new pathogen strains or variants due to natural selection against the anti-pathogen payload effects. It has been speculated that this occurrence may be accompanied by an unforeseen event. For instance, a new pathogen variant might be more difficult to control than the previous version [54]. Considering possible increased virulence of the evolved pathogen variant, James et al., [39] suggested an assessment of the genotypic or phenotypic changes in pathogens after passage through gene-drive vectors. Some potential pathways to mitigate the risk of gene drive resistance [as postulated by 24, and 46] have been considered experimentally by Buchman et al., [55] and Champer et al [56]. This however remains a part of the research yet to be concluded in the development of an efficient gene drive technology. Taken together, since developing these ideas for vector/pathogen targets will require a lot of research effort, experimental advancement and convincing proofs of the concept; and since there is currently no effective way to prevent or suppress the repair of CRISPR/Cas9 gene drive-induced cleavage through the NHEJ pathway, the issue of gene drive failure remains a formidable barrier.
Related Knowledge Centers
- Dengue Fever
- Genetic Engineering
- Malaria
- Mendelian Inheritance
- Zika Fever
- Herbicide
- Pesticide Resistance
- Unintended Consequences
- Selfish Genetic Element
- Intragenomic Conflict