Duke Medical Ethics Journal
Ethical Concerns in Using Gene Drives on Mosquitoes to Combat Malaria and Ways Forward
By: Stanley Park
Malaria is a life-threatening disease caused by parasites usually transmitted by an infective female Anopheles mosquito. According to WHO, 405,000 people died from approximately 228 million cases of malaria in 2018. Numerous prevention methods have been proposed from insecticide-treated mosquito nets to vaccine development, but none have been completely successful (WHO 2019). Hence, the rise in gene drives to prevent mosquito transmission has come into the spotlight, and the development of CRISPR/Cas9 gene editing technology has only advanced gene drive research. The fast-moving nature of the field, however, raises numerous ethical concerns that should be addressed before implementing the technology. This paper will discuss ethical concerns in the environment in using gene drives on
Anopheles mosquitoes to eliminate malaria, considering benefits and risks and justice. This paper will also outline frameworks to address the aforementioned ethical concerns.
Gene drives for mosquitoes
Gene drives are “systems of biased inheritance in which the ability of a genetic element to pass from a parent to its offspring through sexual reproduction is enhanced” (NAS 2016). Using CRISPR/Cas9 technology, a gene drive can be inserted into a
mosquito’s genome and replicated in future copies. The mosquito’s offspring will inherit the gene drive and a normal gene from its other parent. The CRISPR portion of the gene drive will then cut the normal gene, and the gene drive will be used as a guide to repair the cut gene. Thus, both genes in the offspring will have been modified (Scudellari 2019). There are two ways gene drives can be applied to eliminate malaria in mosquitoes: population suppression and replacement. The former transmits gene drives to reduce the number of individuals in a population, while the latter transmits gene drives to change the population’s genotype. Proof-of-concept studies have demonstrated the feasibility of using CRISPR/Cas9 to develop gene drives in mosquitos for both methods (Hammond et al. 2016; Gantz et al. 2015). Either method can theoretically reduce the morbidity and mortality caused by malaria.
Ethical concerns in the environment
“Balancing present and future benefits and risks” has been identified as the central ethical and social question to decide whether to pursue any genetic technology (President’s Commission 1982). Though the possibility of eliminating
malaria offers substantial environmental benefits, many stakeholders have raised concerns about environmental harms that may arise from using gene drives.
One potential benefit is the conservation of endangered species like the Hawaiian avifauna by preventing mosquitoes from transmitting avian malaria. Evolutionary history suggests that avian malaria could be a significant threat to the Hawaiian avifauna (van Riper and Scott 2001). Introducing a gene drive to the infective mosquitos could prevent them from
transmitting the disease, successfully conserving the likes of the Hawaiian avifauna. It is important to note that the conservation of such species is crucial in maintaining a balanced and healthy ecosystem (Cho 2019) This conservation strategy can be extended to any species threatened by malaria.
Despite these benefits, a potential risk is the possibility of spreading the gene vector to non-target populations by gene flow. Gene flow is the spread of genes caused by migration between populations (Slatkin 1987). If there is sufficient gene flow, the two populations could have equivalent allele frequencies (Slatkin 1985). In fact, gene flow among various Anopheles populations was evident for insecticide resistant genes (Weeraratne et al. 2018). This has serious implications for the use of gene drives on mosquitoes. Adding a gene drive for a target mosquito population can be lethal or maladaptive (NAS 2016). The spread of such genes to a non-target population could lead to a significant reduction or suppression of the non-target population, creating unintended ecological consequences. For instance, some valuable predatory species may have depended on the non-target population, and its reduction would likely cause a decrease in the predatory species (Teem et al. 2019). This could instigate further changes at various levels of the food chain (Estes et al. 2011), causing widespread environmental disruption.
There are many more benefits and risks gene drives on mosquitoes can have on the environment (Deplazes-Zemp et al. 2020). In order for gene drives on mosquitoes to be ethically permissible, all conceivable risks should first be identified, then there must be an assurance that the potential benefits outweigh the risks. This raises a few questions: 1) How do we identify all
conceivable risks of gene drives? 2) Who decides that the benefits outweigh the risks?
Identifying environmental risks of gene drives on mosquitoes
There are two important components to identifying environmental risks of gene drives: 1) Computer modelling 2) Field tests and staged open-field releases.
The diverse and complex life cycles of mosquitoes with unique environments means there are innumerable possible situations researchers need to evaluate, which field tests cannot completely take into account (Smith et al. 2017). Computational modelling, therefore, is essential to study the possible risks of gene drives in mosquitoes in numerous situations, especially with advancements in AI. Researchers were able to demonstrate through case studies that data-driven modelling based on AI is capable of simulating environmental services (Willcock et al. 2018). It is also worth mentioning that because computer modelling does not directly affect reality, it is a safe and ethical way of assessing risk. Hence, computer modelling should be widely used to identify risks in the usage of gene drives in mosquitoes.
However, no computational model will be able to replicate all the variables in the natural environment, meaning such models may not be able to identify all the risks. Thus, field tests and staged open-field releases are necessary. The latter, especially, will offer insight regarding potential risks grounded in reality, as it involves releasing mosquitoes with gene drives into an open environment. In the context of gene drives, factors like effects on the population level, wild-type target species or non-target species can be measured (NAS 2016). Because these tests may have long-lasting effects on the natural environment, it is important that computational models and laboratory studies show confidence that the anticipated risks are tolerable.
"In order for gene drives on mosquitoes to be ethically permissible, all conceivable risks should first be identified, then there must be an assurance that the potential benefits outweigh the risks."
Ethical concerns in site selection
In selecting sites for field tests or staged open-field releases of mosquitoes with gene drives, justice becomes an ethical concern. Injustice can occur when a burden is unduly imposed on a community. Researchers from developed countries will
likely select sites in malaria-endemic locations, which are mostly developing or underdeveloped countries (Lavery et al. 2008). The drastic difference in status between the two parties could lead to instances of injustice. For instance, while a local community may refute genetically modified organisms (GMO), and hence the use of gene drives in mosquitoes (Adalja et al. 2016), the researchers could use undue influences like unreasonably high compensations to conduct staged open-field releases. This constrains the local community to make a decision they otherwise would not have. In order to prevent such instances of injustice, there must be profound engagements with various stakeholders like developers, scientific oversight committees, regulators, and especially, the local community.
Engaging the community effectively and ethically poses challenges in research. Informed consent practices have been the focus of engaging communities in research (Lavery et al. 2008). However, informed consent is not sufficient to fully engage the local community. In fact, studies have shown informed consent to be an ineffective way of ensuring that people comprehend the research being conducted (Sugarman et al. 1999).
Though the context is different, the Model Ethical Protocol can be a useful guide to developing ways to engage meaningfully with local communities (Weiss et al. 1997), which I have adapted and modified. First, prior to visiting the testing site, researchers should learn about the population’s culture, the population’s structure, and its past experiences with GMO. The
preparation allows researchers to identify potentially unjust practices like inappropriately imposing western beliefs, which they can discuss with the local community. Second, when researchers arrive at the testing site, they should comprehensively discuss the purpose, procedure, and risks and benefits of the research with the local community. Various community perspectives should be represented, such as that of local social scientists or public health officials who have interest in community development and can identify community representatives (Lavery et al. 2008). Researchers should also expect engagement with the community to be long-term to further build trust. Finally, researchers should acquire informed consent from the
participants. I reiterate that informed consent should not be relied upon as a means to engage with the community.
Another worthwhile point to mention is that if there are unintended consequences and harm for the local community during research, the researchers have a responsibility not to abandon the community (Lavery et al., 2008). For instance, the genetically modified mosquito may become susceptible to a new parasite that harms human health in consequence of the gene drive. Abandoning the local community then creates an unfair burden on the local community, and the researchers should prepare and take measures to alleviate the unintended consequences and harm.
Though this paper only discusses engagement with local communities, appropriate administrative authorities at the national level must approve of the field test as well (Lavery et al. 2008). This is because mosquitoes with gene drives could potentially migrate and affect areas beyond the local community being tested.
Who decides that the benefits outweigh the risks?
The determination that the benefits outweigh the risks for using gene drives on mosquitoes is heavily dependent on the stakeholders. Local communities suffering from higher rates of malaria may be more accepting of risks of gene drives (NAS 2016). Anti-GMO groups like Friends of the Earth are strongly against gene drives as they fear it will be “misused by agribusiness and military interest” (Perls 2016). Entomologists like Metcalf wrote that “Species should be regarded as sacred and man indeed has no right to destroy them.” Stakeholders from different venues have different values, and therefore analyze benefits and risks differently. This is a complex and multi-layered matter that is beyond the scope of this paper. It raises the question of who should be involved in the decision, what platforms should be used to instigate productive discussions, and what measures should be taken for a consensus to be reached. The National Academies of Sciences offers recommendations on how decisions can be made in their framework “Gene Drives on the Horizon” (NAS 2016). Researchers and stakeholders should take these recommendations into account while moving forward with gene drives.
The ethical and social consequences of using gene drives in mosquitoes to combat malaria is complex. This paper discusses ethical issues in the environment, weighing the risks and benefits as well as evaluating justice. However, the determination of whether gene drives on mosquitoes will be permissible should be based on the intersection among the environment, public health, and human values. How gene drives should be governed both nationally and internationally should also be considered. Despite its complexity, interdisciplinary work considering perspectives from various fields must be strongly encouraged to address the ethical and social issues. As Kahn says, “It can be frightening to act, but sometimes, not acting is worse” (Kahn 2016).
Adalja, Amesh, Tara Kirk Sell, Meghan Mcginty, and Crystal Boddie. 2016. “Genetically Modified (GM) Mosquito Use to Reduce Mosquito-Transmitted Disease in the US: A Community Opinion Survey.” PLoS Currents. https://doi.org/10.1371/currents.outbreaks.1c39ec05a743d41ee39391ed0f2ed8d3.
Cho, Renee. 2019. “Why Endangered Species Matter.” State of the Planet. Columbia University. Last modified March 26, 2019. https://blogs.ei.columbia.edu/2019/03/26/endangered-species-matter/.
Deplazes-Zemp, Anna, Ueli Grossniklaus, François Lefort, Pie Müller, Jörg Romeis, Adrian Rüegsegger, Nicola Schoenenberger, Eva M. Spehn. 2020. “Gene drives: benefits, risks, and possible applications.” Swiss Academies Factsheets 15 (4)
Estes, James A., John Terborgh, Justin S. Brashares, Mary E. Power, Joel Berger, William J. Bond, Stephen R. Carpenter, et al. 2011. “Trophic Downgrading of Planet Earth.” Science 333, no. 6040: 301–6. https://doi.org/10.1126/science.1205106.
Gantz, Valentino M., Nijole Jasinskiene, Olga Tatarenkova, Aniko Fazekas, Vanessa M. Macias, Ethan Bier, and Anthony A. James. 2015. “Highly Efficient Cas9-Mediated Gene Drive for Population Modification of the Malaria Vector Mosquito Anopheles Stephensi.” Proceedings of the National Academy of Sciences 112, no. 49. https://doi.org/10.1073/pnas.1521077112.
Hammond, Andrew, Roberto Galizi, Kyros Kyrou, Alekos Simoni, Carla Siniscalchi, Dimitris Katsanos, Matthew Gribble, et al. 2016. “A CRISPR-Cas9 Gene Drive System Targeting Female Reproduction in the Malaria Mosquito Vector Anopheles Gambiae.” Nature Biotechnology 34, no. 1: 78–83. https://doi.org/10.1038/nbt.3439.
Kahn, Jennifer. 2016. “Gene Editing Can Now Change an Entire Species -- Forever.” Filmed February 2016, TED video, 12:18.
Lavery, James V., Thomas W. Scott, and Laura C. Harrington. 2008. “Ethical, Social, and Cultural Considerations for Site Selection for Research with Genetically Modified Mosquitoes.” The American Journal of Tropical Medicine and Hygiene 79, no. 3: 312–18. https://doi.org/10.4269/ajtmh.2008.79.312.
National Academies of Sciences, Engineering, and Medicine. 2016. “Gene Drives on the Horizon: Advancing Science, Navigating Uncertainty, and Aligning Research with Public Values.” Washington, DC: The National Academies Press. https://doi.org/10.17226/23405.
Perls, Dana. 2016. “Permanently Changing a Species: What Could Go Wrong?” Friends of the Earth. Last modified June 8, 2016. https://foe.org/blog/permanently-changing-species-go-wrong/.
Perkins, John H. 2012. “The Philosophical Foundations.” In Insects, Experts, and the Insecticide Crisis: The Quest for New Pest Management Strategies , edited by Perkins, John H., 183-207. Springer Science & Business Media
Pugh, Jonathan. 2016. “Driven to Extinction? The Ethics of Eradicating Mosquitoes with Gene-Drive Technologies.” Journal of Medical Ethics 42, no. 9: 578–81.
Scudellari, Megan. 2019. “Self-Destructing Mosquitoes and Sterilized Rodents: the Promise of Gene Drives.” Nature 571, no. 7764: 160–62. https://doi.org/10.1038/d41586-019-02087-5.
Slatkin, M. 1987. “Gene Flow and the Geographic Structure of Natural Populations.” Science 236, no. 4803: 787–92. https://doi.org/10.1126/science.3576198.
Slatkin, Montgomery. 1985. “Rare Alleles As Indicators Of Gene Flow.” Evolution 39, no. 1: 53–65. https://doi.org/10.1111/j.1558-5646.1985.tb04079.x.
Smith, Thomas A., Nakul Chitnis, Melissa Penny, and Marcel Tanner. 2017. “Malaria Modeling in the Era of Eradication.” Cold Spring Harbor Perspectives in Medicine 7, no. 4.
Sugarman, Jeremy, Douglas C. Mccrory, Donald Powell, Alex Krasny, Betsy Adams, Eric Ball, and Cynthia Cassell. 1999. “Special Supplement: Empirical Research on Informed Consent: An Annotated Bibliography.” The Hastings Center Report 29, no. 1. https://doi.org/10.2307/3528546.
Teem, John L., Aggrey Ambali, Barbara Glover, Jeremy Ouedraogo, Diran Makinde, and Andrew Roberts. 2019. “Problem Formulation for Gene Drive Mosquitoes Designed to Reduce Malaria Transmission in Africa: Results from Four Regional Consultations 2016–2018.” Malaria Journal
18, no. 1. https://doi.org/10.1186/s12936-019-2978-5.
United States. 1982. “President's Commission for the Study of Ethical Problems in Medicine and Biomedical and Behavioral Research.” United States code annotated. United States vol. Title 42 Sect. 300v as added 1978.
van Riper III, Charles, and J. Michael Scott,. 2001.” Limiting factors affecting native birds of Hawaii.” Studies in Avian Biology , no. 22:221-233.
Weeraratne, Thilini C., Sinnathambi N. Surendran, Catherine Walton, and S. H. P. Parakrama Karunaratne. 2018. “Genetic Diversity and Population Structure of Malaria Vector Mosquitoes Anopheles Subpictus, Anopheles Peditaeniatus, and Anopheles Vagus in Five Districts of Sri Lanka.” Malaria Journal 17, no. 1. https://doi.org/10.1186/s12936-018-2419-x.
Weiss, Kenneth M., L. Luca Cavalli-Sforz, Georgia M. Dunston, Marcus Feldman, Henry T. Greely, Kenneth K. Kidd, Mary-Claire King, John A. Moore, Emoke Szathmary, Catherine M. Twinn, Russell Thornton, Ryk, Ward. 1997. “Proposed model ethical protocol for collecting DNA samples.” Houston law review vol. 33(5): 1431-74.
Willcock, Simon, Javier Martínez-López, Danny A.p. Hooftman, Kenneth J. Bagstad, Stefano Balbi, Alessia Marzo, Carlo Prato, et al. 2018. “Machine Learning for Ecosystem Services.” Ecosystem Services 33: 165–74. https://doi.org/10.1016/j.ecoser.2018.04.004.
World Health Organization. 2019 . ”World malaria report 2019.” World Health Organization. https://apps.who.int/iris/handle/10665/330011. License: CC BY-NC-SA 3.0 IGO