Gene-drive Technology Research Articles

Assessing the Efficacy of Gene-Drive Technology in Reducing Malaria Transmission in Sub-Saharan Africa: Current Progress and Future Prospects

Malaria continues to pose a significant public health challenge in Sub-Saharan Africa, necessitating innovative solutions to combat its transmission. This review examined the efficacy of gene-drive technology as a novel approach to reducing malaria transmission through genetic modifications of Anopheles mosquitoes. Utilizing a comprehensive literature review and analysis of experimental studies and pilot projects, we assessed the mechanisms of gene drives, including population suppression and replacement strategies. The findings indicated that gene-drive technology has the potential to significantly alter mosquito populations, thereby diminishing the burden of malaria. However, challenges such as ecological concerns, regulatory complexities, and public acceptance must be addressed for successful implementation. The integration of gene drives with existing malaria control measures, collaborative research efforts, and robust ethical governance is crucial for maximizing effectiveness and ensuring sustainable outcomes. Furthermore, monitoring and evaluation systems are essential for assessing the safety and efficacy of gene-drive initiatives. This review underscored the transformative potential of gene-drive technology in malaria prevention, advocating for continued dialogue among stakeholders to navigate the complexities associated with its application in Sub-Saharan Africa. Keywords: Gene-drive technology, Malaria transmission, Anopheles mosquitoes, Public health, Sub-Saharan Africa.

The boundary problem: Defining and delineating the community in field trials with gene drive organisms.

Despite widespread and worldwide efforts to eradicate vector-borne diseases such as malaria, these diseases continue to have an enormous negative impact on public health. For this reason, scientists are working on novel control strategies, such as gene drive technologies (GDTs). As GDT research advances, researchers are contemplating the potential next step of conducting field trials. An important point of discussion regarding these field trials relates to who should be informed, consulted, and involved in decision-making about their design and launch. It is generally argued that community members have a particularly strong claim to be engaged, and yet, disagreement and lack of clarity exist about how this "community" should be defined and delineated. In this paper, we shed light on this "boundary problem": the problem of determining how boundaries of inclusion and exclusion in (GDT) community engagement should be drawn. As our analysis demonstrates, the process of defining and delineating a community is itself normative. First, we explicate why it is important to define and delineate the community. Second, we demonstrate that different definitions of community are used and intermingled in the debate on GDTs, and argue in favor of distinguishing geographical, affected, cultural, and political communities. Finally, we propose initial guidance for deciding who should (not) be engaged in decision-making about GDT field trials, by arguing that the definition and delineation of the community should depend on the rationale for engagement and that the characteristics of the community itself can guide the effective design of community engagement strategies.

Alleviating the burden of malaria with gene drive technologies? A biocentric analysis of the moral permissibility of modifying malaria mosquitoes

Gene drive technologies (GDTs) have been proposed as a potential new way to alleviate the burden of malaria, yet have also raised ethical questions. A central ethical question regarding GDTs...

Use of Insect Promoters in Genetic Engineering to Control Mosquito-Borne Diseases.

Mosquito transgenesis and gene-drive technologies provide the basis for developing promising new tools for vector-borne disease prevention by either suppressing wild mosquito populations or reducing their capacity from transmitting pathogens. Many studies of the regulatory DNA and promoters of genes with robust sex-, tissue- and stage-specific expression profiles have supported the development of new tools and strategies that could bring mosquito-borne diseases under control. Although the list of regulatory elements available is significant, only a limited set of those can reliably drive spatial-temporal expression. Here, we review the advances in our ability to express beneficial and other genes in mosquitoes, and highlight the information needed for the development of new mosquito-control and anti-disease strategies.

Scalability of genetic biocontrols for eradicating invasive alien mammals

CRISPR-based gene drives offer novel solutions for controlling invasive alien species, which could ultimately extend eradication efforts to continental scales. Gene drives for suppressing invasive alien vertebrates are now under development. Using a landscape-scale individual-based model, we present the first estimates of times to eradication for long-lived alien mammals. We show that demography and life-history traits interact to determine the scalability of gene drives for vertebrate pest eradication. Notably, optimism around eradicating smaller-bodied pests (rodents and rabbits) with gene-drive technologies does not easily translate into eradication of larger-bodied alien species (cats and foxes).

Ethical Considerations for Gene Drive: Challenges of Balancing Inclusion, Power and Perspectives.

Progress in gene-drive research has stimulated discussion and debate on ethical issues including community engagement and consent, policy and governance, and decision-making involved in development and deployment. Many organizations, academic institutions, foundations, and individual professionals have contributed to ensuring that these issues are considered prior to the application of gene-drive technology. Central topics include co-development of the technology with local stakeholders and communities and reducing asymmetry between developers and end-users. Important questions include with whom to conduct engagement and how to define community acceptance, develop capacity-building activities, and regulate this technology. Experts, academics, and funders have suggested that global frameworks, standards, and guidelines be developed to direct research in answering these important questions. Additionally, it has been suggested that ethical principles or commitments be established to further guide research practices. The challenging and interesting contradiction that we explore here is that the vast majority of these conversations transpire with little or no input from potential end-users or stakeholders who, we contend, should ultimately determine the fate of the technology in their communities. The question arises, whose concerns regarding marginalization, disempowerment, and inequity should be included in discussions and decisions concerning how inequities are perceived and how they may be addressed? At what stage will true co-development occur and how will opinions, perspectives and knowledge held by low-income country stakeholders be applied in determining answers to the questions regarding the ethics being debated on the academic stage? Our opinion is that the time is now.

Gene-drive mosquitoes: a prospect for future malaria control.

Despite major developments in malaria control over the past two decades, the disease continues to scourge the human population across the globe. Rising concerns such as insecticide resistance amongst vector mosquitoes are a cause of huge fear amongst healthcare providers and policymakers. Amidst such dire circumstances, a recent development may form the blueprint for future malaria control as for the first time ever researchers were able to decimate an entire mosquito population using gene-drive technology within a span of one year in a multi-generation, ecologically challenging study. Despite some concerns, the technology displayed a high potential of becoming a powerful tool in malaria control.

Ending Malaria with Gene Drive Technologies? A Normative Analysis of the Role of Humans in Nature

"Gene drive technologies (GDT) promote the rapid, progressive spread of gene alterations within a population or a species of wild organisms. If GDT are successfully developed and implemented, they could help to resolve intractable problems in the realm of vector-borne disease, invasive species and pest control, but these technologies have also raised concerns regarding the moral permissibility of interfering in nature in this way. In particular, it has been argued that perspectives on humans’ relationship to nature and their impact on and manipulation of ecosystems play a crucial role in determining the moral permissibility of GDT. Nonetheless, these perspectives have thus far remained underexplored in the emerging ethical debate on GDT. In this presentation, I identify these perspectives and concerns and analyse them normatively. Four issues are demonstrated to be of central importance in deciding whether (a particular) use of GDT is in accordance with the relationship humans should have to nature: (1) the moral status of and direct duties towards different organisms; (2) the prioritisation of duties towards different organisms in case of conflicting claims; (3) the moral (ir)relevance of ‘wildness’; and (4) the moral status of holistic entities such as species and ecosystems. The normative positions that can be taken on these issues are presented and critically assessed to determine the moral permissibility of particular applications of GDT. Doing so elucidates the central trade-offs and points of contention in the ethical debate on interfering in nature in this way. "

Gene-drive suppression of mosquito populations in large cages as a bridge between lab and field

CRISPR-based gene-drives targeting the gene doublesex in the malaria vector Anopheles gambiae effectively suppressed the reproductive capability of mosquito populations reared in small laboratory cages. To bridge the gap between laboratory and the field, this gene-drive technology must be challenged with vector ecology.Here we report the suppressive activity of the gene-drive in age-structured An. gambiae populations in large indoor cages that permit complex feeding and reproductive behaviours.The gene-drive element spreads rapidly through the populations, fully supresses the population within one year and without selecting for resistance to the gene drive. Approximate Bayesian computation allowed retrospective inference of life-history parameters from the large cages and a more accurate prediction of gene-drive behaviour under more ecologically-relevant settings.Generating data to bridge laboratory and field studies for invasive technologies is challenging. Our study represents a paradigm for the stepwise and sound development of vector control tools based on gene-drive.

Governing Gene Drive Technologies: A Qualitative Interview Study

Background Gene drive technologies (GDTs) bias the inheritance of a genetic element within a population of non-human organisms, promoting its progressive spread across this population. If successful, GDTs may be used to counter intractable problems such as vector-borne diseases. A key issue in the debate on GDTs relates to what governance is appropriate for these technologies. While governance mechanisms for GDTs are to a significant extent proposed and shaped by professional experts, the perspectives of these experts have not been explored in depth. Methods A total of 33 GDT experts from different professional disciplines were interviewed to identify, better understand, and juxtapose their perspectives on GDT governance. The pseudonymized transcripts were analyzed thematically. Results Three main themes were identified: (1) engagement of communities, stakeholders, and publics; (2) power dynamics, and (3) decision-making. There was broad consensus amongst respondents that it is important to engage communities, stakeholders, and publics. Nonetheless, respondents had diverging views on the reasons for doing so and the timing and design of engagement. Respondents also outlined complexities and challenges related to engagement. Moreover, they brought up the power dynamics that are present in GDT research. Respondents stressed the importance of preventing the recurrence of historical injustices and reflected on dilemmas regarding whether and to what extent (foreign) researchers can legitimately make demands regarding local governance. Finally, respondents had diverging views on whether decisions about GDTs should be made in the same way as decisions about other environmental interventions, and on the decision-making model that should be used to decide about GDT deployment. Conclusions The insights obtained in this interview study give rise to recommendations for the design and evaluation of GDT governance. Moreover, these insights point to unresolved normative questions that need to be addressed to move from general commitments to concrete obligations.

Optimized CRISPR tools and site-directed transgenesis towards gene drive development in Culex quinquefasciatus mosquitoes

Culex mosquitoes are a global vector for multiple human and animal diseases, including West Nile virus, lymphatic filariasis, and avian malaria, posing a constant threat to public health, livestock, companion animals, and endangered birds. While rising insecticide resistance has threatened the control of Culex mosquitoes, advances in CRISPR genome-editing tools have fostered the development of alternative genetic strategies such as gene drive systems to fight disease vectors. However, though gene-drive technology has quickly progressed in other mosquitoes, advances have been lacking in Culex. Here, we develop a Culex-specific Cas9/gRNA expression toolkit and use site-directed homology-based transgenesis to generate and validate a Culex quinquefasciatus Cas9-expressing line. We show that gRNA scaffold variants improve transgenesis efficiency in both Culex quinquefasciatus and Drosophila melanogaster and boost gene-drive performance in the fruit fly. These findings support future technology development to control Culex mosquitoes and provide valuable insight for improving these tools in other species.

Designing gene drives to limit spillover to non-target populations.

The prospect of utilizing CRISPR-based gene-drive technology for controlling populations has generated much excitement. However, the potential for spillovers of gene-drive alleles from the target population to non-target populations has raised concerns. Here, using mathematical models, we investigate the possibility of limiting spillovers to non-target populations by designing differential-targeting gene drives, in which the expected equilibrium gene-drive allele frequencies are high in the target population but low in the non-target population. We find that achieving differential targeting is possible with certain configurations of gene-drive parameters, but, in most cases, only under relatively low migration rates between populations. Under high migration, differential targeting is possible only in a narrow region of the parameter space. Because fixation of the gene drive in the non-target population could severely disrupt ecosystems, we outline possible ways to avoid this outcome. We apply our model to two potential applications of gene drives—field trials for malaria-vector gene drives and control of invasive species on islands. We discuss theoretical predictions of key requirements for differential targeting and their practical implications.

A transcomplementing gene drive provides a flexible platform for laboratory investigation and potential field deployment

CRISPR-based gene drives can spread through wild populations by biasing their own transmission above the 50% value predicted by Mendelian inheritance. These technologies offer population-engineering solutions for combating vector-borne diseases, managing crop pests, and supporting ecosystem conservation efforts. Current technologies raise safety concerns for unintended gene propagation. Herein, we address such concerns by splitting the drive components, Cas9 and gRNAs, into separate alleles to form a trans-complementing split–gene-drive (tGD) and demonstrate its ability to promote super-Mendelian inheritance of the separate transgenes. This dual-component configuration allows for combinatorial transgene optimization and increases safety by restricting escape concerns to experimentation windows. We employ the tGD and a small–molecule-controlled version to investigate the biology of component inheritance and resistant allele formation, and to study the effects of maternal inheritance and impaired homology on efficiency. Lastly, mathematical modeling of tGD spread within populations reveals potential advantages for improving current gene-drive technologies for field population modification.

Modelling the potential of genetic control of malaria mosquitoes at national scale

BackgroundThe persistence of malaria in large parts of sub-Saharan Africa has motivated the development of novel tools to complement existing control programmes, including gene-drive technologies to modify mosquito vector populations. Here, we use a stochastic simulation model to explore the potential of using a driving-Y chromosome to suppress vector populations in a 106 km2 area of West Africa including all of Burkina Faso.ResultsThe consequence of driving-Y introductions is predicted to vary across the landscape, causing elimination of the target species in some regions and suppression in others. We explore how this variation is determined by environmental conditions, mosquito behaviour, and the properties of the gene-drive. Seasonality is particularly important, and we find population elimination is more likely in regions with mild dry seasons whereas suppression is more likely in regions with strong seasonality.ConclusionsDespite the spatial heterogeneity, we suggest that repeated introductions of modified mosquitoes over a few years into a small fraction of human settlements may be sufficient to substantially reduce the overall number of mosquitoes across the entire geographic area.

Population genetics of Anopheles funestus, the African malaria vector, Kenya

BackgroundAnopheles funestus is among the major malaria vectors in Kenya and sub-Saharan Africa and has been recently implicated in persistent malaria transmission. However, its ecology and genetic diversity remain poorly understood in Kenya.MethodsUsing 16 microsatellite loci, we examined the genetic structure of An. funestus sampled from 11 locations (n = 426 individuals) across a wide geographical range in Kenya spanning coastal, western and Rift Valley areas.ResultsKenyan An. funestus resolved as three genetically distinct clusters. The largest cluster (FUN1) broadly included samples from western and Rift Valley areas of Kenya with two clusters identified from coastal Kenya (FUN2 and FUN3), not previously reported. Geographical distance had no effect on population differentiation of An. funestus. We found a significant variation in the mean Plasmodium infectivity between the clusters (χ2 = 12.1, df = 2, P = 0.002) and proportional to the malaria prevalence in the different risk zones of Kenya. Notably, there was variation in estimated effective population sizes between the clusters, suggesting possible differential impact of anti-vector interventions in represented areas.ConclusionsHeterogeneity among Kenyan populations of An. funestus will impact malaria vector control with practical implications for the development of gene-drive technologies. The difference in Plasmodium infectivity and effective population size between the clusters could suggest potential variation in phenotypic characteristics relating to competence or insecticide resistance. This is worth examining in future studies.

Gene-drive-mediated extinction is thwarted by population structure and evolution of sib mating.

Background and objectivesGenetic engineering combined with CRISPR technology has developed to the point that gene drives can, in theory, be engineered to cause extinction in countless species. Success of extinction programs now rests on the possibility of resistance evolution, which is largely unknown. Depending on the gene-drive technology, resistance may take many forms, from mutations in the nuclease target sequence (e.g. for CRISPR) to specific types of non-random population structures that limit the drive (that may block potentially any gene-drive technology).MethodologyWe develop mathematical models of various deviations from random mating to consider escapes from extinction-causing gene drives. A main emphasis here is sib mating in the face of recessive-lethal and Y-chromosome drives.ResultsSib mating easily evolves in response to both kinds of gene drives and maintains mean fitness above 0, with equilibrium fitness depending on the level of inbreeding depression. Environmental determination of sib mating (as might stem from population density crashes) can also maintain mean fitness above 0. A version of Maynard Smith’s haystack model shows that pre-existing population structure can enable drive-free subpopulations to be maintained against gene drives.Conclusions and implicationsTranslation of mean fitness into population size depends on ecological details, so understanding mean fitness evolution and dynamics is merely the first step in predicting extinction. Nonetheless, these results point to possible escapes from gene-drive-mediated extinctions that lie beyond the control of genome engineering.Lay summaryRecent gene drive technologies promise to suppress and even eradicate pests and disease vectors. Simple models of gene-drive evolution in structured populations show that extinction-causing gene drives can be thwarted both through the evolution of sib mating as well as from purely demographic processes that cluster drive-free individuals.

Stakeholder attitudes towards the use of recombinant technology to manage the impact of an invasive species: Sea Lamprey in the North American Great Lakes

Several factors, including: (1) on-going difficulties of cost-effectively managing invasive species; (2) recent successes in using recombinant genetics to suppress mosquito populations; and, (3) developments in gene-drive technology, have re-invigorated interest in using genetic biotechnology to manage the impacts of invasive species. However, the extent to which there is ‘social license’ to develop and use these technologies has not been widely canvassed. We surveyed stakeholders involved directly and indirectly in managing Sea Lamprey (Petromyzon marinus) in the upper North American Great Lakes and a key community group of resource users—recreational fishers—to assess their support and concerns about researching, developing, and potentially implementing recombinant methods that an expert group assessed as likely to be effective in managing Sea Lamprey in the Great Lakes. Both groups overwhelmingly supported initiating R&D and, if risks were deemed very low, undertaking steps towards implementation. The key concern expressed by both groups was the risk of impacts to non-target taxa, including valued native populations of Sea Lamprey outside of the Great Lakes. Few respondents expressed opposition based on ethical or moral grounds, which contrasts with previous surveys on the use of recombinant technology in general. The broad support for R&D into recombinant approaches is likely to reflect trust in the nominated implementing agency (the Great Lakes Fishery Commission), its history of extensive consultation prior to undertaking management actions, and the hope that genetic biocontrol could “solve” the Sea Lamprey problem rather than simply managing it.

Advances in Vector Control Science: Rear-and-Release Strategies Show Promise… but Don't Forget the Basics.

Both chikungunya and Zika viruses have recently swept from Africa across the Pacific to the Americas, causing major outbreaks of disease in humans. In the meantime, dengue epidemics continue throughout the tropics. Traditional vector control programs based on strategies from 1950s and 1960s have been relatively ineffective in combating recent epidemics. In response, new methods involving the rearing and releasing of large numbers of mosquitoes to eliminate or modify local Aedes populations are being developed, with several currently conducting field releases in high-risk countries. These advances, include the release of Wolbachia-infected Aedes aegypti and Aedes albopictus, for either its virus-blocking capabilities, sterilization by cytoplasmic incompatibility, or both; the release of Aedes carrying dominant lethal genes, such as the OX513A strain of A. aegypti; and other emerging techniques, such as advancing gene-drive technologies, are summarized, as well as current stages of development and primary operational and regulatory hurdles. Although these technologies show great promise, none are ready for widespread rollout for cities of millions of people. Thus, efforts should be made to avoid methods such as space sprays that have failed and improve existing technologies to increase their efficacy.

Target Malaria Has a Killer in Its Sights: Eliminating the world?s deadliest disease has been a priority for decades, and, thanks to innovative gene-drive technology, Target Malaria is getting closer to achieving that goal.

The mosquito is the deadliest animal in the world (Figure 1). It is the main carrier of parasites that cause malaria, which is a bigger killer than any other disease in history; in fact, some blame malaria for the deaths of half the humans who have ever lived. Today, malaria continues to have a devastating effect on the health of millions of people.

Driven to extinction? The ethics of eradicating mosquitoes with gene-drive technologies

Mosquito-borne diseases represent a significant global disease burden, and recent outbreaks of such diseases have led to calls to reduce mosquito populations. Furthermore, advances in ‘gene-drive’ technology have raised the...