Scholarly Literature
This is a database of scholarly literature that concentrates currently on natural and engineered selfish genetic elements (gene drives). The latest are shown here.
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Antiviral effectors and gene drive strategies for mosquito population suppression or replacement to mitigate arbovirus transmission by Aedes aegypti
6634A. E. Williams, A. W. E. Franz, W. R. Reid and K. E. Olson, Insects, 11:1-18. 2020-01-12 20:05:33.
The mosquito vector Aedes aegypti transmits arthropod-borne viruses (arboviruses) of medical importance, including Zika, dengue, and yellow fever viruses. Controlling mosquito populations remains the method of choice to prevent disease transmission. Novel mosquito control strategies based on genetically manipulating mosquitoes are being developed as additional tools to combat arbovirus transmission. Genetic control of mosquitoes includes two basic strategies: population suppression and population replacement. The former aims to eliminate mosquito populations while the latter aims to replace wild populations with engineered, pathogen-resistant mosquitoes. In this review, we outline suppression strategies being applied in the field, as well as current antiviral effector genes that have been characterized and expressed in transgenic Ae. aegypti for population replacement. We discuss cutting-edge gene drive technologies that can be used to enhance the inheritance of effector genes, while highlighting the challenges and opportunities associated with gene drives. Finally, we present currently available models that can estimate mosquito release numbers and time to transgene fixation for several gene drive systems. Based on the recent advances in genetic engineering, we anticipate that antiviral transgenic Ae. aegypti exhibiting gene drive will soon emerge; however, close monitoring in simulated field conditions will be required to demonstrate the efficacy and utility of such transgenic mosquitoes.
Metaphor, Trust and Support for Non-native Species Control
13833P. A. Kohl, S. J. Collins and M. Eichholz, Environmental Communication, 14:672-685. 2020-01-07 15:29:47.
This experimental study used a representative sample of U.S. residents (N = 1,042) to test whether the use of the term "invasive" increases support for non-native species control efforts. The term invasive had a small influence on support for two out of three non-native species control methods. We also found stronger support for control methods using gene editing technologies than control methods using poison.
Wolbachia transinfections in Culex quinquefasciatus generate cytoplasmic incompatibility
6224T. H. Ant, C. Herd, F. Louis, A. B. Failloux and S. P. Sinkins, Insect Molecular Biology, 29:1-8. 2020-01-06 21:43:12.
Culex quinquefasciatus is an important mosquito vector of a number of viral and protozoan pathogens of humans and animals, and naturally carries the endosymbiont Wolbachia pipientis, strain wPip. Wolbachia are used in two distinct vector control strategies: firstly, population suppression caused by mating incompatibilities between mass-released transinfected males and wild females; and secondly, the spread of pathogen transmission-blocking strains through populations. Using embryonic microinjection, two novel Wolbachia transinfections were generated in C. quinquefasciatus using strains native to the mosquito Aedes albopictus: a wAlbB single infection, and a wPip plus wAlbA superinfection. The wAlbB infection showed full bidirectional cytoplasmic incompatibility (CI) with wild-type C. quinquefasciatus in reciprocal crosses. The wPipwAlbA superinfection showed complete unidirectional CI, and therefore population invasion potential. Whereas the wAlbB strain showed comparatively low overall densities, similar to the native wPip, the wPipwAlbA superinfection reached over 400-fold higher densities in the salivary glands compared to the native wPip, suggesting it may be a candidate for pathogen transmission blocking.
Scenario analysis on the use of rodenticides and sex-biasing gene drives for the removal of invasive house mice on islands
6221M. E. Serr, R. X. Valdez, K. S. Barnhill-Dilling, J. Godwin, T. Kuiken and M. Booker, Biological Invasions, 2020-01-06 21:34:59.
Since the 1960s conservation efforts have focused on recovering island biodiversity by eradicating invasive rodents. These eradication campaigns have led to considerable conservation gains, particularly for nesting seabirds. However, eradications are complex and lengthy endeavors and are even more challenging when humans are co-inhabitants of the targeted island. Furthermore, the method of eradication matters and recent proposals to consider genetic technologies for rodent eradication require specific scrutiny. One such technology is the potential use of a gene drive for biasing offspring sex ratios in invasive house mice, Mus musculus, that would spread and prevent the production of one sex, allowing die-off from lack of reproduction and natural attrition. Practitioners can gain insight into the potential for adoption of this technology from examining stakeholder engagement. This paper uses scenario analysis to address the eradication of rodents on inhabited and uninhabited islands, by specifically comparing the traditional approach of using rodenticides with sex-biasing gene drives. Concurrently the International Union for Conservation of Nature is assessing the risks and value of gene drives in general for conservation. Hence, we make the case that the ethical challenges with the use of gene drive sex-biasing techniques and the effectiveness of this tool will rely as much on its public acceptance and its democratic use as the actual science used to construct the technology.
Beyond Mendelian genetics: Anticipatory biomedical ethics and policy implications for the use of CRISPR together with gene drive in humans.
6227M. W. Nestor and R. L. Wilson, Journal of Bioethical Inquiry, 2020:1-12. 2020-01-03 21:43:18.
Clustered regularly interspaced short palindromic repeats (CRISPR) genome editing has already reinvented the direction of genetic and stem cell research. For more complex diseases it allows scientists to simultaneously create multiple genetic changes to a single cell. Technologies for correcting multiple mutations in an in vivo system are already in development. On the surface, the advent and use of gene editing technologies is a powerful tool to reduce human suffering by eradicating complex disease that has a genetic etiology. Gene drives are CRISPR mediated alterations to genes that allow them to be passed on to subsequent populations at rates that approach one hundred per cent transmission. Therefore, from an anticipatory biomedical ethics perspective, it is possible to conceive gene drive being used with CRISPR to permanently ameliorate aberrant genes from wild-type populations containing mutations. However, there are also a number of possible side effects that could develop as the result of combining gene editing and gene drive technologies in an effort to eradicate complex diseases. In this paper, we critically analyse the hypothesis that the combination of CRISPR and gene drive will have a deleterious effect on human populations from an ethical perspective by developing an anticipatory ethical analysis of the implications for the use of CRISPR together with gene drive in humans.
Gene drives : equity demands civility
6184N. Kofler, Nature, 565:25. 2020-01-03 19:10:06.
At the 14th Conference of the Parties of the United Nations Convention on Biological Diversity late last year, I witnessed the rapid deterioration of a crucial discussion. It was on the potential of synthetic biology in environmental conservation. What started as heckling turned into a yelling match of misinformation. Such disruptive behaviour robbed the global community of a rare opportunity to debate gene drives in a meaningful way. Sidelined young scientists, country delegates and others watched in disbelief.
Technology Factsheet: Gene Drives
7265J. Lunshof, C. Shachar, R. Edison, A. Jayanti, Belfer Center for Science and International Affairs, 2020-01-01 17:03:29.
Gene drives can be defined as genetic elements that pass from parents to unusually high numbers of their offspring due to biased inheritance (sometimes referred to as the possession of “selfish” genetic elements).1,2 There are different ways of achieving this biased inheritance needed for a drive, but the shared outcome is one where the offspring of a parent carrying a certain genetic variant has over a 50% likelihood of inheriting it. With regular inheritance, in the absence of a gene drive, each of the two alleles carried by a parent are equally likely to be inherited by offspring. By implementing modern gene editing technology, such as CRISPR, gene drives can be manufactured by humans to intentionally suppress a target population or spread a trait through a population. For example, gene drives could be used to target weeds, spreading a trait that would reverse their evolved resistance to non-toxic herbicides. Gene drives could also be used for human health purposes, in particular for the control of vector-borne diseases, such as malaria through populations of mosquitos. There are many outstanding governance questions with regards to the specific research, development, testing, and deployment of gene drives—including who should be taking ownership of drafting regulations and policy. At this stage, few countries currently have regulations that are defined specifically for gene drive, and in most countries the closest relevant regulations are those written for a broader swath of gene editing technologies. As there becomes more momentum around the potentially unique opportunities of gene drives though, it is important for U.S. legislators and policymakers to remain engaged in the technology’s technical, ethical, and practical progress and consider technology-specific governance.
A comparison of the Trojan Y Chromosome strategy to harvesting models for eradication of nonnative species
J. J. Lyu, P. J. Schofield, K. M. Reaver, M. Beauregard and R. D. Parshad, Natural Resource Modeling, 2019-12-31 20:21:43.The Trojan Y Chromosome strategy (TYC) is a promising eradication method for biological control of nonnative species. The strategy works by manipulating the sex ratio of a population through the introduction of supermales that guarantee male offspring. In the current study, we compare the TYC method with a pure harvesting strategy. We also analyze a hybrid harvesting model that mirrors the TYC strategy. The dynamic analysis leads to results on stability of solutions and bifurcations of the model. Several conclusions about the different strategies are established via optimal control methods. In particular, the results affirm that either a pure harvesting or hybrid strategy may work better than the TYC method at controlling a nonnative species population. Recommendations for resource managers Where harvesting is feasible, it is as effective if not more effective than the classical TYC method. Therein managers may attempt harvesting female fish while stocking males or harvesting both male and female fishes. Managers may attempt linear harvesting, saturating density-dependent harvesting, and unbounded density-dependent harvesting. Linear harvesting is seen to be the most effective. We caution against the outright use of harvesting due to various density-dependent effects that may arise. To this end hybrid models that involve a combination of harvesting and TYC-type methods might be a better strategy. One may also use harvesting as a tool in mesocosm settings to predict the efficacy of the TYC strategy in the wild.
A typology of community and stakeholder engagement based on documented examples in the field of novel vector control
6032C. E. Schairer, R. Taitingfong, O. S. Akbari and C. S. Bloss, PLoS Neglected Tropical Diseases, 13:e0007863. 2019-12-30 20:46:44.
Background Despite broad consensus on the importance of community and stakeholder engagement (CSE) for guiding the development, regulation, field testing, and deployment of emerging vector control technologies (such as genetically engineered insects), the types of activities pursued have varied widely, as have the outcomes. We looked to previous CSE efforts for clarity about appropriate methods and goals. Our analysis yielded a typology of CSE, and related vocabulary, that describes distinctions that funders, organizers, and scholars should make when proposing or evaluating CSE. Methods We compiled available formal documentation of CSE projects, starting with projects mentioned in interviews with 17 key informants. Major features of these examples, including the initiators, target groups, timing, goals, and methods were identified using qualitative coding. Based on these examples, subcategories were developed for a subset of features and applied to the identified cases of CSE in the documents. Co-occurrence of subcategorized features was examined for patterns. Results We identified 14 documented examples CSE projects, which were comprised of 28 distinct CSE activities. We found no clear patterns with respect to timing. However, we found that grouping examples according to whether initiators or targets could enact the immediate desired outcome could help to clarify relationships between goals, methods, and targets.
Biomphalaria glabrata Granulin Increases Resistance to Schistosoma mansoni Infection in Several Biomphalaria Species and Induces the Production of Reactive Oxygen Species by Haemocytes
13835J. R. Hambrook, A. A. Gharamah, E. A. Pila, S. Hussein and P. C. Hanington, Genes, 11:12. 2019-12-28 15:36:48.
In this study, we demonstrate that in vivo addition of Biomphalaria glabrata pro-granulin (BgGRN) can reduce Schistosoma mansoni infection success in numerous Biomphalaria sp. when challenged with different S. mansoni strains. We also demonstrate that cleavage of BgGRN into individual granulin subunits by elastase results in the stimulation of haemocytes to produce reactive oxygen species.
Mathematical modeling of self-contained CRISPR gene drive reversal systems
6023M. G. Heffel and G. C. Finnigan, Scientific Reports, 9:20050. 2019-12-27 20:31:43.
There is a critical need for further research into methods to control biological populations. Numerous challenges to agriculture, ecological systems, and human health could be mitigated by the targeted reduction and management of key species (e.g. pests, parasites, and vectors for pathogens). The discovery and adaptation of the CRISPR/Cas editing platform co-opted from bacteria has provided a mechanism for a means to alter an entire population. A CRISPR-based gene drive system can allow for the forced propagation of a genetic element that bypasses Mendelian inheritance which can be used to bias sex determination, install exogenous information, or remove endogenous DNA within an entire species. Laboratory studies have demonstrated the potency by which gene drives can operate within insects and other organisms. However, continued research and eventual application face serious opposition regarding issues of policy, biosafety, effectiveness, and reversal. Previous mathematical work has suggested the use of modified gene drive designs that are limited in spread such as daisy chain or underdominance drives. However, no system has yet been proposed that allows for an inducible reversal mechanism without requiring the introduction of additional individuals. Here, we study gene drive effectiveness, fitness, and inducible drive systems that could respond to external stimuli expanding from a previous frequency-based population model. We find that programmed modification during gene drive propagation could serve as a potent safeguard to either slow or completely reverse drive systems and allow for a return to the original wild-type population.
Experimental population modification of the malaria vector mosquito, Anopheles stephensi
6182T. B. Pham, C. H. Phong, J. B. Bennett, K. Hwang, N. Jasinskiene, K. Parker, D. Stillinger, J. M. Marshall, R. Carballar-Lejarazú and A. A. James, PLOS Genetics, 15:e1008440. 2019-12-19 19:05:32.
The experimental introduction of manipulated genes into insect species has a long history in basic genetics. Recent advances in genome editing technologies have spurred considerable effort to exploit these methodologies to provide genetic solutions to some of the worst medical and agricultural problems caused by insects. Insect population suppression and population modification approaches have been proposed to control transmission of vector-borne diseases, including malaria. We used small cage trials to explore the efficacy of non-drive and gene-drive releases to deliver anti-malarial effector genes to a vector mosquito, Anopheles stephensi. We show that both approaches can work to introduce genes to high percentages, but as expected, the gene-drive approaches were more efficient in that they needed only a single release with a much lower number of released insects. The gene-drive females in our studies exhibited a significant load that resulted in some cage populations going to extinction. Furthermore, the accumulation of drive-resistant target genes prevented full introduction of the transgenes in those cages that did not go extinct. While none of the strains evaluated here are proposed for open release, these laboratory cage trials reveal features that can be used to improve next-generation gene-drive strains for population modification.
Gene drives for schistosomiasis transmission control
6341T. Maier, N. J. Wheeler, E. K. O. Namigai, J. Tycko, R. E. Grewelle, Y. Woldeamanuel, K. Klohe, J. Perez-Saez, S. H. Sokolow, G. A. De Leo, T. P. Yoshino, M. Zamanian and J. Reinhard-Rupp, PLoS Neglected Tropical Diseases, 13:e0007833. 2019-12-19 18:18:55.
Schistosomiasis is one of the most important and widespread neglected tropical diseases (NTD), with over 200 million people infected in more than 70 countries; the disease has nearly 800 million people at risk in endemic areas. Although mass drug administration is a cost-effective approach to reduce occurrence, extent, and severity of the disease, it does not provide protection to subsequent reinfection. Interventions that target the parasites' intermediate snail hosts are a crucial part of the integrated strategy required to move toward disease elimination. The recent revolution in gene drive technology naturally leads to questions about whether gene drives could be used to efficiently spread schistosome resistance traits in a population of snails and whether gene drives have the potential to contribute to reduced disease transmission in the long run. Responsible implementation of gene drives will require solutions to complex challenges spanning multiple disciplines, from biology to policy. This Review Article presents collected perspectives from practitioners of global health, genome engineering, epidemiology, and snail/schistosome biology and outlines strategies for responsible gene drive technology development, impact measurements of gene drives for schistosomiasis control, and gene drive governance. Success in this arena is a function of many factors, including gene-editing specificity and efficiency, the level of resistance conferred by the gene drive, how fast gene drives may spread in a metapopulation over a complex landscape, ecological sustainability, social equity, and, ultimately, the reduction of infection prevalence in humans. With combined efforts from across the broad global health community, gene drives for schistosomiasis control could fortify our defenses against this devastating disease in the future.
Articulating ‘free, prior and informed consent’ (FPIC) for engineered gene drives
5800George, D. R., T. Kuiken and J. A. Delborne, Proceedings of the Royal Society B: Biological Sciences, 286:20191484.. 2019-12-19 14:30:32.
Recent statements by United Nations bodies point to free, prior and informed consent (FPIC) as a potential requirement in the development of engineered gene drive applications. As a concept developed in the context of protecting Indigenous rights to self-determination in land development scenarios, FPIC would need to be extended to apply to the context of ecological editing. Without an explicit framework of application, FPIC could be interpreted as a narrowly framed process of community consultation focused on the social implications of technology, and award little formal or advisory power in decision-making to Indigenous peoples and local communities. In this paper, we argue for an articulation of FPIC that attends to issues of transparency, iterative community-scale consent, and shared power through co-development among Indigenous peoples, local communities, researchers and technology developers. In realizing a comprehensive FPIC process, researchers and developers have an opportunity to incorporate enhanced participation and social guidance mechanisms into the design, development and implementation of engineered gene drive applications.
Fitness consequences of a non-recombining sex-ratio drive chromosome can explain its prevalence in the wild
5797Dyer, K. A. and D. W. Hall, Proceedings of the Royal Society B: Biological Sciences, 286:20192529. 2019-12-19 14:27:34.
Understanding the pleiotropic consequences of gene drive systems on host fitness is essential to predict their spread through a host population. Here, we study sex-ratio (SR) X-chromosome drive in the fly Drosophila recens, where SR causes the death of Y-bearing sperm in male carriers. SR males only sire daughters, which all carry SR, thus giving the chromosome a transmission advantage. The prevalence of the SR chromosome appears stable, suggesting pleiotropic costs. It was previously shown that females homozygous for SR are sterile, and here, we test for additional fitness costs of SR. We found that females heterozygous for SR have reduced fecundity and that male SR carriers have reduced fertility in conditions of sperm competition. We then use our fitness estimates to parametrize theoretical models of SR drive and show that the decrease in fecundity and sperm competition performance can account for the observed prevalence of SR in natural populations. In addition, we found that the expected equilibrium frequency of the SR chromosome is particularly sensitive to the degree of multiple mating and performance in sperm competition. Together, our data suggest that the mating system of the organism should be carefully considered during the development of gene drive systems.
Gene drive: progress and prospects
5795Wedell, N., T. A. R. Price and A. K. Lindholm, Proceedings of the Royal Society B: Biological Sciences, 286:20192709. 2019-12-19 14:25:02.
Gene drive is a naturally occurring phenomenon in which selfish genetic elements manipulate gametogenesis and reproduction to increase their own transmission to the next generation. Currently, there is great excitement about the potential of harnessing such systems to control major pest and vector populations. If synthetic gene drive systems can be constructed and applied to key species, they may be able to rapidly spread either modifying or eliminating the targeted populations. This approach has been lauded as a revolutionary and efficient mechanism to control insect-borne diseases and crop pests. Driving endosymbionts have already been deployed to combat the transmission of dengue and Zika virus in mosquitoes. However, there are a variety of barriers to successfully implementing gene drive techniques in wild populations. There is a risk that targeted organisms will rapidly evolve an ability to suppress the synthetic drive system, rendering it ineffective. There are also potential risks of synthetic gene drivers invading nontarget species or populations. This Special Feature covers the current state of affairs regarding both natural and synthetic gene drive systems with the aim to identify knowledge gaps. By understanding how natural drive systems spread through populations, we may be able to better predict the outcomes of synthetic drive release.
Ancient gene drives: an evolutionary paradox
5792Price, T. A. R., R. Verspoor and N. Wedell, Proceedings of the Royal Society B: Biological Sciences, 286:20192267. 2019-12-19 14:21:02.
Selfish genetic elements such as selfish chromosomes increase their transmission rate relative to the rest of the genome and can generate substantial cost to the organisms that carry them. Such segregation distorters are predicted to either reach fixation (potentially causing population extinction) or, more commonly, promote the evolution of genetic suppression to restore transmission to equality. Many populations show rapid spread of segregation distorters, followed by the rapid evolution of suppression. However, not all drivers display such flux, some instead persisting at stable frequencies in natural populations for decades, perhaps hundreds of thousands of years, with no sign of suppression evolving or the driver spreading to fixation. This represents a major evolutionary paradox. How can drivers be maintained in the long term at stable frequencies? And why has suppression not evolved as in many other gene drive systems? Here, we explore potential factors that may explain the persistence of drive systems, focusing on the ancient sex-ratio driver in the fly Drosophila pseudoobscura. We discuss potential solutions to the evolutionary mystery of why suppression does not appear to have evolved in this system, and address how long-term stable frequencies of gene drive can be maintained. Finally, we speculate whether ancient drivers may be functionally and evolutionarily distinct to young drive systems.
Transcontinental dispersal of Anopheles gambiae occurred from West African origin via serial founder events
14311H. Schmidt, Y. Lee, T. C. Collier, M. J. Hanemaaijer, O. D. Kirstein, A. Ouledi, M. Muleba, D. E. Norris, M. Slatkin, A. J. Cornel and G. C. Lanzaro, Communications Biology, 2. 2019-12-19 12:47:18.
Here we present population genomic analyses of 111 specimens sampled from west to east Africa, including the first whole genome sequences from oceanic islands, the Comoros.
Exterminator genes: The right to say no to ethics dumping
5654Bassey-Orovwuje, M., J. Thomas and T. Wakeford, Development, 62:121-127. 2019-12-17 18:09:38.
The scientific-industrial complex is promoting a new wave of genetically modified organisms, in particular gene drive organisms, using the same hype with which they tried to persuade society that GMOs would be a magic bullet to solve world hunger. The Gates Foundation claims that GDOs could help wipe out diseases such as malaria. Powerful conservation lobby groups claim GDOs will protect engendered species. Not only are the benefits from GDOs based, like their predecessors, on flawed ecological thinking, but they are backed by the same agri-business interests that have devastated agroecological farming systems. The rights of communities to say ‘no’ to new genetic technologies is being eroded, despite United Nations agreements, such as the Convention on Biological Diversity, which call for the free, prior and informed consent of affected communities to be respected. By exporting their field trials to countries with weak regulatory regimes and lowering of the standards of consent the Gates Foundation’s Target Malaria project has already been guilty of ethics dumping. These developments demonstrate the urgent need to democratize the development of new technologies.
A selfish genetic element linked to increased lifespan impacts metabolism in female house mice
5652Lopes, P. C. and A. K. Lindholm, The Journal of Experimental Biology, 2019:212704. 2019-12-17 18:01:15.
Gene drive systems can lead to the evolution of traits that further enhance the transmission of the driving element. In gene drive, one allele is transmitted to offspring at a higher frequency than the homologous allele. This has a range of consequences, which generally include a reduction in fitness of the carrier of the driving allele, making such systems “selfish”. The t haplotype is one such driver, found in house mice. It is linked to a reduction in litter size in matings among heterozygous animals, but also to increased lifespan in wild females that carry it. Here, we tested whether carrying the t haplotype was associated with altered resting metabolic rate (RMR). We show that females carrying the t haplotype decrease RMR as they increase in size, compared to wildtype females or males of either genotype. Our study elucidates a plausible mechanism by which a selfish genetic element increases lifespan.
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