Featured Articles
Regulatory and policy considerations for the implementation of gene drive-modified mosquitoes to prevent malaria transmission
24859S. L. James, B. Dass and H. Quemada, Transgenic Research, 32:17. 2023-03-15 15:00:05.
Gene drive-modified mosquitoes (GDMMs) are being developed as possible new tools to prevent transmission of malaria and other mosquito-borne diseases. To date no GDMMs have yet undergone field testing. This early stage is an opportune time for developers, supporters, and possible users to begin to consider the potential regulatory requirements for eventual implementation of these technologies in national or regional public health programs, especially as some of the practical implications of these requirements may take considerable planning, time and coordination to address. Several currently unresolved regulatory questions pertinent to the implementation of GDMMs are examined, including: how the product will be defined; what the registration/approval process will be for placing new GDMM products on the market; how the potential for transboundary movement of GDMMs can be addressed; and what role might be played by existing multinational bodies and agreements in authorization decisions. Regulation and policies applied for registration of other genetically modified organisms or other living mosquito products are assessed for relevance to the use case of GDMMs to prevent malaria in Africa. Multiple national authorities are likely to be involved in decision-making, according to existing laws in place within each country for certain product classes. Requirements under the Cartagena Protocol on Biodiversity will be considered relevant in most countries, as may existing regulatory frameworks for conventional pesticide, medical, and biocontrol products. Experience suggests that standard regulatory processes, evidence requirements, and liability laws differ from country to country. Regional mechanisms will be useful to address some of the important challenges.
A male-killing gene encoded by a symbiotic virus of Drosophila
24838D. Kageyama, T. Harumoto, K. Nagamine, A. Fujiwara, T. N. Sugimoto, A. Jouraku, M. Tamura, T. K. Katoh and M. Watada, Nature Communications, 14:1357. 2023-03-13 08:49:35.
In most eukaryotes, biparentally inherited nuclear genomes and maternally inherited cytoplasmic genomes have different evolutionary interests. Strongly female-biased sex ratios that are repeatedly observed in various arthropods often result from the male-specific lethality (male-killing) induced by maternally inherited symbiotic bacteria such as Spiroplasma and Wolbachia. However, despite some plausible case reports wherein viruses are raised as male-killers, it is not well understood how viruses, having much smaller genomes than bacteria, are capable of inducing male-killing. Here we show that a maternally inherited double-stranded RNA (dsRNA) virus belonging to the family Partitiviridae (designated DbMKPV1) induces male-killing in Drosophila. DbMKPV1 localizes in the cytoplasm and possesses only four genes, i.e., one gene in each of the four genomic segments (dsRNA1−dsRNA4), in contrast to ca. 1000 or more genes possessed by Spiroplasma or Wolbachia. We also show that a protein (designated PVMKp1; 330 amino acids in size), encoded by a gene on the dsRNA4 segment, is necessary and sufficient for inducing male-killing. Our results imply that male-killing genes can be easily acquired by symbiotic viruses through reassortment and that symbiotic viruses are hidden players in arthropod evolution. We anticipate that host-manipulating genes possessed by symbiotic viruses can be utilized for controlling arthropods.
Alleviating the burden of malaria with gene drive technologies? A biocentric analysis of the moral permissibility of modifying malaria mosquitoes
24800N. de Graeff, K. R. Jongsma and A. L. Bredenoord, Journal of Medical Ethics, 2023-02-28 08:33:28.
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 relates to whether it is morally permissible to intentionally modify or eradicate mosquitoes in this way and how the inherent worth of humans and non-human organisms should be factored into determining this. Existing analyses of this matter have thus far generally relied on anthropocentric and zoocentric perspectives and rejected an individualist biocentric outlook in which all living organisms are taken to matter morally for their own sake. In this paper, we reconsider the implications of taking a biocentric approach and highlight nuances that may not be evident at first glance. First, we shortly discuss biocentric perspectives in general, and then outline Paul Taylor's biocentric theory of respect for nature. Second, we explore how conflicting claims towards different organisms should be prioritised from this perspective and subsequently apply this to the context of malaria control using GDTs. Our ethical analysis shows that this context invokes the principle of self-defence, which could override the pro tanto concerns that a biocentrist would have against modifying malaria mosquitoes in this way if certain conditions are met. At the same time, the case study of GDTs underlines the relevance of previously posed questions and criticism regarding the internal consistency of Taylor's egalitarian biocentrism.
From the Lab to the Field: Long-Distance Transport of Sterile Aedes Mosquitoes
24750H. Maïga, M. T. Bakhoum, W. Mamai, G. Diouf, N. S. Bimbilé Somda, T. Wallner, C. Martina, S. S. Kotla, O. B. Masso, H. Yamada, B. B. D. Sow, A. G. Fall and J. Bouyer, Insects, 14. 2023-02-18 19:03:39.
Pilot programs of the sterile insect technique (SIT) against Aedes aegypti may rely on importing significant and consistent numbers of high-quality sterile males from a distant mass rearing factory. As such, long-distance mass transport of sterile males may contribute to meet this requirement if their survival and quality are not compromised. This study therefore aimed to develop and assess a novel method for long-distance shipments of sterile male mosquitoes from the laboratory to the field. Different types of mosquito compaction boxes in addition to a simulation of the transport of marked and unmarked sterile males were assessed in terms of survival rates/recovery rates, flight ability and morphological damage to the mosquitoes. The novel mass transport protocol allowed long-distance shipments of sterile male mosquitoes for up to four days with a nonsignificant impact on survival (>90% for 48 h of transport and between 50 and 70% for 96 h depending on the type of mosquito compaction box), flight ability, and damage. In addition, a one-day recovery period for transported mosquitoes post-transport increased the escaping ability of sterile males by more than 20%. This novel system for the long-distance mass transport of mosquitoes may therefore be used to ship sterile males worldwide for journeys of two to four days. This study demonstrated that the protocol can be used for the standard mass transport of marked or unmarked chilled Aedes mosquitoes required for the SIT or other related genetic control programs.
Review of gene drive modelling and implications for risk assessment of gene drive organisms
24722J. L. Frieß, C. R. Lalyer, B. Giese, S. Simon and M. Otto, Ecological Modelling, 478:110285. 2023-02-13 09:34:10.
Synthetic gene drive (GD) systems constitute a form of novel invasive environmental biotechnology with far-reaching consequences beyond those of other known genetically modified organisms (GMOs). During the last 10 years, the development of GD systems has been closely linked to mathematical modelling which can provide feedback on how to achieve gene drive spread but also may be used to predict the ecological consequences of a gene drive release. GMOs, thus also GD systems, need to pass an environmental risk assessment (ERA) prior to a release into the environment. Models in this respect may play an important role because a release of GD organisms, even at a small scale, may not be reversible. In our review, we analyse the scope and structure of existing models to examine how they may assist the ERA. Our analysis reveals that a majority of models so far are deterministic, non-spatial and not tailored for a specific target organism. Models often use simplified assumptions on the biology of the species and seem to be made to test the effectiveness of the drive. Few models go beyond this and verify whether model predictions may be realistic under field conditions. We identified four advanced models that we judged to be the most ecologically realistic and compared the implemented parameters with ERA requirements by the European Food Safety Authority (EFSA) and World Health Organization (WHO) for genetically modified insects and mosquitoes. Although a number of abiotic and biotic factors are already considered in these models, mating-related factors and traits relevant to the interactions between the GMO and target organisms and with other species are largely excluded. Overall, our results show that biological and ecological realism are still poorly realized in current models and that most models aim to predict efficacy rather than ecological effects. Given the complexity of natural ecosystems, it may not be possible to compile a single model to cover all complexities. Thus, models should be further developed with the purpose to assist specific questions related to the risk assessment of GDs. Moreover, uncertainty will be a key issue for any model used in RA and we see the need to improve this aspect when modelling gene drives.
Assessing potential hybridization between a hypothetical gene drive-modified Drosophila suzukii and nontarget Drosophila species
24610S. Wolf, J. Collatz, J. Enkerli, F. Widmer and J. Romeis, Risk Analysis, 2023-01-24 09:02:35.
Genetically engineered gene drives (geGD) are potentially powerful tools for suppressing or even eradicating populations of pest insects. Before living geGD insects can be released into the environment, they must pass an environmental risk assessment to ensure that their release will not cause unacceptable harm to non-targeted entities of the environment. A key research question concerns the likelihood that nontarget species will acquire the functional GD elements; such acquisition could lead to reduced abundance or loss of those species and to a disruption of the ecosystem services they provide. The main route for gene flow is through hybridization between the geGD insect strain and closely related species that co-occur in the area of release and its expected dispersal. Using the invasive spotted-wing drosophila, Drosophila suzukii, as a case study, we provide a generally applicable strategy on how a combination of interspecific hybridization experiments, behavioral observations, and molecular genetic analyses can be used to assess the potential for hybridization.
Bypassing Mendel’s First Law: Transmission Ratio Distortion in Mammals
24587G. Friocourt, A. Perrin, P. A. Saunders, E. Nikalayevich, C. Voisset, C. Coutton, G. Martinez and F. Morel, International Journal Molecular Sciences, 24. 2023-01-13 10:43:58.
Mendel's law of segregation states that the two alleles at a diploid locus should be transmitted equally to the progeny. A genetic segregation distortion, also referred to as transmission ratio distortion (TRD), is a statistically significant deviation from this rule. TRD has been observed in several mammal species and may be due to different biological mechanisms occurring at diverse time points ranging from gamete formation to lethality at post-natal stages. In this review, we describe examples of TRD and their possible mechanisms in mammals based on current knowledge. We first focus on the differences between TRD in male and female gametogenesis in the house mouse, in which some of the most well studied TRD systems have been characterized. We then describe known TRD in other mammals, with a special focus on the farmed species and in the peculiar common shrew species. Finally, we discuss TRD in human diseases. Thus far, to our knowledge, this is the first time that such description is proposed. This review will help better comprehend the processes involved in TRD. A better understanding of these molecular mechanisms will imply a better comprehension of their impact on fertility and on genome evolution. In turn, this should allow for better genetic counseling and lead to better care for human families.
Environmental, Socio-economic, and Health Impact Assessment (ESHIA) for Gene Drive Organisms
24428isaaa Inc. and Outreach Network for Gene Drive Research, ISAAA, 2023-01-11 10:31:02.
Understanding the possible positive and negative impacts that gene drive organisms could have on the environment and people is essential before these technologies are considered for release, whether for research purposes or for use. Different impacts are assessed through different tools and methodologies. While environmental risks are evaluated through specific risk assessments, other dimensions, such as positive and negative impacts on a social, economic, and health level can be assessed through impact assessments. These environmental, socio-economic and health impact assessments can complement the information provided by environmental risk assessments.
Gene editing and agrifood systems
24291FAO, FAO, 2022-12-20 09:22:56.
Gene-editing technologies represent a promising new tool for plant and animal breeding in low- and middle-income countries. They enhance precision and efficiency over current breeding methods and could lead to rapid development of improved plant varieties and animal breeds. However, as for any new technology, they have their merits and demerits. There is, as yet, no international consensus regarding if and how gene-edited organisms should be regulated, and whether their release would fall under the regulatory framework of the Cartagena Protocol on Biosafety to the Convention on Biological Diversity. This science- and evidence-based Issue Paper on gene editing and agrifood systems presents a balanced discussion of the most pertinent aspects of gene editing, including the consequences for human hunger, human health, food safety, effects on the environment, animal welfare, socioeconomic impact and distribution of benefits. Intrinsic ethical concerns and issues of governance and regulation are addressed, and the roles of the public and private sectors, alone and in partnership, are summarized. Various scenarios are also presented for how gene editing might be used in the future to help transform agrifood systems.
Exploring the value of a global gene drive project registry
24279R. I. Taitingfong, C. Triplett, V. N. Vásquez, R. M. Rajagopalan, R. Raban, A. Roberts, G. Terradas, B. Baumgartner, C. Emerson, F. Gould, F. Okumu, C. E. Schairer, H. C. Bossin, L. Buchman, K. J. Campbell, A. Clark, J. Delborne, K. Esvelt, J. Fisher, R., Nature Biotechnology, 2022-12-15 14:15:40.
Recent calls to establish a global project registry before releasing any gene-drive-modified organisms (GDOs) have suggested a registry could be valuable to coordinate research, collect data to monitor and evaluate potential ecological impacts, and facilitate transparent communication with community stakeholders and the general public. Here, we report the results of a multidisciplinary expert workshop on GDO registries convened on 8–9 December 2020 involving 70 participants from 14 countries. Participants had expertise in gene drive design, conservation and population modeling, social science, stakeholder engagement, governance and regulation, international policy, and vector control; they represented 45 organizations, spanning national and local governmental agencies, international organizations, nonprofit organizations, universities, and district offices overseeing local vector control. The workshop aimed to gather perspectives on a central question: “In what ways could a gene-drive project registry both contribute to and detract from the fair development, testing and use of GDOs?” We specifically queried the perceived purpose of a registry, the information that would need to be included, and the perceived value of a registry. Three primary findings emerged from the discussion: first, many participants agreed a registry could serve a coordinating function for multidisciplinary and multisector work activities; second, doing so may require different design elements, depending on the target end-user group and intended purpose for that group; and third, these different information requirements lead to concerns about information sharing via a registry, suggesting potential obstacles to achieving transparency through such a mechanism. We conclude that any development of a gene-drive project registry requires careful and inclusive deliberation, including with potential end-users, to ensure that registry design is optimal.
No Environmental Release of Gene Drive Organisms
24114Anonymous, STOP GENE DRIVES, 2022-11-30 09:32:55.
We urge governments to prevent the environmental release of gene drive organisms and to establish a global moratorium on the release of gene drive organisms at the UN Convention on Biological Diversity (CBD). Gene drives work against natural rules of inheritance forcing nearly 100% instead of the usual 50% of offspring to inherit their genetically engineered traits. Whereas existing biosafety systems are designed to limit the spread and persistence of living modified organisms to mitigate against adverse impacts, gene drives are intended to spread genetic modifications to alter species and ecosystems. This would undermine the integrity of the UN Cartagena Protocol and international and national biosafety systems, including the procedures for Advanced Informed Agreement (AIA) of countries and Free, Prior and Informed consent (FPIC) of Indigenous Peoples and local communities.
A CRISPR endonuclease gene drive reveals distinct mechanisms of inheritance bias
24021S. A. N. Verkuijl, E. Gonzalez, M. Li, J. X. D. Ang, N. P. Kandul, M. A. E. Anderson, O. S. Akbari, M. B. Bonsall and L. Alphey, Nature Communications, 13:7145. 2022-11-21 09:45:13.
CRISPR/Cas gene drives can bias transgene inheritance through different mechanisms. Homing drives are designed to replace a wild-type allele with a copy of a drive element on the homologous chromosome. In Aedes aegypti, the sex-determining locus is closely linked to the white gene, which was previously used as a target for a homing drive element (wGDe). Here, through an analysis using this linkage we show that in males inheritance bias of wGDe did not occur by homing, rather through increased propagation of the donor drive element. We test the same wGDe drive element with transgenes expressing Cas9 with germline regulatory elements sds3, bgcn, and nup50. We only find inheritance bias through homing, even with the identical nup50-Cas9 transgene. We propose that DNA repair outcomes may be more context dependent than anticipated and that other previously reported homing drives may, in fact, bias their inheritance through other mechanisms.
SHOULD WE CREATE GENE DRIVE GREY SQUIRRELS
23962S. Hartley and T. Law, GeneDriveGovernance.org, 2022-11-09 11:48:04.
UK scientists have proposed gene drive as a management tool to control grey squirrels. Now is a good time to talk about this emerging technology because the hopes and concerns of experts, stakeholders and the public can help to determine if or how it might be developed. To help foster this debate, we made a short research film on gene drive grey squirrels. The film draws on our social science research to show the complexity of the problem of grey squirrel control and invites you to think about whether scientists should develop gene drive squirrels or not.
Leveraging a natural murine meiotic drive to suppress invasive populations
23835L. Gierus, A. Birand, M. D. Bunting, G. I. Godahewa, S. G. Piltz, K. P. Oh, A. J. Piaggio, D. W. Threadgill, J. Godwin, O. Edwards, P. Cassey, J. V. Ross, T. A. A. Prowse and P. Q. Thomas, Proceedings of the National Academy of Sciences, 119:e2213308119. 2022-11-08 09:36:13.
Invasive rodents are a major cause of environmental damage and biodiversity loss, particularly on islands. Unlike insects, genetic biocontrol strategies including population-suppressing gene drives with biased inheritance have not been developed in mice. Here, we demonstrate a gene drive strategy (t(CRISPR)) that leverages super-Mendelian transmission of the t haplotype to spread inactivating mutations in a haplosufficient female fertility gene (Prl). Using spatially explicit individual-based in silico modeling, we show that t(CRISPR) can eradicate island populations under a range of realistic field-based parameter values. We also engineer transgenic t(CRISPR) mice that, crucially, exhibit biased transmission of the modified t haplotype and Prl mutations at levels our modeling predicts would be sufficient for eradication. This is an example of a feasible gene drive system for invasive alien rodent population control.
New self-sexing Aedes aegypti strain eliminates barriers to scalable and sustainable vector control for governments and communities in dengue-prone environments
23796S. A. M. Spinner, Z. H. Barnes, A. M. Puinean, P. Gray, T. Dafa’alla, C. E. Phillips, C. Nascimento de Souza, T. F. Frazon, K. Ercit, A. Collado, N. Naish, E. Sulston, G. C. Ll. Phillips, K. K. Greene, M. Poletto, B. D. Sperry, S. A. Warner, N. R. Rose, G, Frontiers in Bioengineering and Biotechnology, 10. 2022-10-25 07:35:02.
For more than 60 years, efforts to develop mating-based mosquito control technologies have largely failed to produce solutions that are both effective and scalable, keeping them out of reach of most governments and communities in disease-impacted regions globally. High pest suppression levels in trials have yet to fully translate into broad and effective Aedes aegypti control solutions. Two primary challenges to date–the need for complex sex-sorting to prevent female releases, and cumbersome processes for rearing and releasing male adult mosquitoes–present significant barriers for existing methods. As the host range of Aedes aegypti continues to advance into new geographies due to increasing globalisation and climate change, traditional chemical-based approaches are under mounting pressure from both more stringent regulatory processes and the ongoing development of insecticide resistance. It is no exaggeration to state that new tools, which are equal parts effective and scalable, are needed now more than ever. This paper describes the development and field evaluation of a new self-sexing strain of Aedes aegypti that has been designed to combine targeted vector suppression, operational simplicity, and cost-effectiveness for use in disease-prone regions. This conditional, self-limiting trait uses the sex-determination gene doublesex linked to the tetracycline-off genetic switch to cause complete female lethality in early larval development. With no female progeny survival, sex sorting is no longer required, eliminating the need for large-scale mosquito production facilities or physical sex-separation. In deployment operations, this translates to the ability to generate multiple generations of suppression for each mosquito released, while being entirely self-limiting. To evaluate these potential benefits, a field trial was carried out in densely-populated urban, dengue-prone neighbourhoods in Brazil, wherein the strain was able to suppress wild mosquito populations by up to 96%, demonstrating the utility of this self-sexing approach for biological vector control. In doing so, it has shown that such strains offer the critical components necessary to make these tools highly accessible, and thus they harbour the potential to transition mating-based approaches to effective and sustainable vector control tools that are within reach of governments and at-risk communities who may have only limited resources.
Anopheles homing suppression drive candidates exhibit unexpected performance differences in simulations with spatial structure
23734S. E. Champer, I. K. Kim, A. G. Clark, P. W. Messer and J. Champer, eLife, 11:e79121. 2022-10-14 06:37:55.
Recent experiments have produced several Anopheles gambiae homing gene drives that disrupt female fertility genes, thereby eventually inducing population collapse. Such drives may be highly effective tools to combat malaria. One such homing drive, based on the zpg promoter driving CRISPR/Cas9, was able to eliminate a cage population of mosquitoes. A second version, purportedly improved upon the first by incorporating an X-shredder element (which biases inheritance towards male offspring), was similarly successful. Here, we analyze experimental data from each of these gene drives to extract their characteristics and performance parameters and compare these to previous interpretations of their experimental performance. We assess each suppression drive within an individual-based simulation framework that models mosquito population dynamics in continuous space. We find that the combined homing/X-shredder drive is actually less effective at population suppression within the context of our mosquito population model. In particular, the combined drive often fails to completely suppress the population, instead resulting in an unstable equilibrium between drive and wild-type alleles. By contrast, otherwise similar drives based on the nos promoter may prove to be more promising candidates for future development than originally thought.
Points to consider in seeking biosafety approval for research, testing, and environmental release of experimental genetically modified biocontrol products during research and development
23648W. K. Tonui, V. Ahuja, C. J. Beech, J. B. Connolly, B. Dass, D. C. M. Glandorf, et al., Transgenic Research, 31:607. 2022-10-04 08:24:50.
Novel genetically modified biological control products (referred to as “GM biocontrol products”) are being considered to address a range of complex problems in public health, conservation, and agriculture, including preventing the transmission of vector-borne parasitic and viral diseases as well as the spread of invasive plant and animal species. These interventions involve release of genetically modified organisms (GMOs) into the environment, sometimes with intentional dissemination of the modification within the local population of the targeted species, which presents new challenges and opportunities for regulatory review and decision-making. Practices developed for GMOs, primarily applied to date for GM crops may need to be adapted to accommodate different types of organisms, such as insects, and different technologies, such as gene drive. Developers of new GM biocontrol products would benefit from an early understanding of safety data and information that are likely to be required within the regulatory dossier for regulatory evaluation and decision making. Here a generalizable tool drawing from existing GM crop dossier requirements, forms, and relevant experience is proposed to assist researchers and developers organize and plan their research and trialing. This tool requires considering specifics of each investigational product, their intended use, and country specific requirements at various phases of potential product development, from laboratory research through contained field testing and experimental release into the environment. This may also be helpful to risk assessors and regulators in supporting their systematic and rigorous evaluation of new biocontrol products.
Daisy-chain gene drives: The role of low cut-rate, resistance mutations, and maternal deposition
23623S. A. N. Verkuijl, M. A. E. Anderson, L. Alphey and M. B. Bonsall, PLOS Genetics, 18:e1010370. 2022-09-19 14:37:34.
Author summary Reducing the harm of pest species by the introgression of traits into a wild population is often limited by the difficulties of mass rearing and release of modified individuals. Gene drives present an opportunity to substantially reduce the release frequencies required to spread a particular modification. However, uniform modification of a target species is, with a few specific exceptions, not necessary or desirable. Self-limiting gene drives, such as daisy-chain gene drives, have been widely discussed as a potential solution, allowing the invasiveness of a drive release to be tuned to the target population. Here, we investigate through computational modelling how daisy-chain gene drives perform when subjected to commonly observed inefficiencies associated with CRISPR-Cas9-based inheritance biasing. Compared to a self-perpetuating drive, daisy-chain gene drives are sensitive to factors that cause their separate elements to segregate prematurely. In particular, a reduction in the DNA cut-rate and an increase in the formation of resistance alleles. We find that the effect of inefficiencies in the drive mechanism is generally more pronounced when the drive is at low frequencies. With low rates of migration, this substantially reduces daisy-chain gene drives spread into a neighbouring non-target population.
Selfish evolution of placental hormones
23534G. Keegan and M. M. Patten, Evolution, Medicine, and Public Health, 10:391-397. 2022-09-10 05:50:19.
We hypothesize that some placental hormones—specifically those that arise by tandem duplication of genes for maternal hormones—may behave as gestational drivers, selfish genetic elements that encourage the spontaneous abortion of offspring that fail to inherit them. Such drivers are quite simple to evolve, requiring just three things: a decrease in expression or activity of some essential maternal hormone during pregnancy; a compensatory increase in expression or activity of the homologous hormone by the placenta; and genetic linkage between the two effects. Gestational drive may therefore be a common selection pressure experienced by any of the various hormones of mammalian pregnancy that have arisen by tandem gene duplication. We examine the evolution of chorionic gonadotropin in the human lineage in light of this hypothesis. Finally, we postulate that some of the difficulties of human pregnancy may be a consequence of the action of selfish genes.We show how placental hormones that have arisen via tandem gene duplication from maternally produced hormones may subsequently experience selection as selfish genetic elements and spread through populations despite causing reproductive inefficiency. We examine the implications of this hypothesis and point to some empirical tests.
Rational engineering of a synthetic insect-bacterial mutualism
23473Y. Su, H.-C. Lin, L. S. Teh, F. Chevance, I. James, C. Mayfield, K. G. Golic, J. A. Gagnon, O. Rog and C. Dale, Current Biology, 2022-08-29 07:21:11.
Summary Many insects maintain mutualistic associations with bacterial endosymbionts, but little is known about how they originate in nature. In this study, we describe the establishment and manipulation of a synthetic insect-bacterial symbiosis in a weevil host. Following egg injection, the nascent symbiont colonized many tissues, including prototypical somatic and germinal bacteriomes, yielding maternal transmission over many generations. We then engineered the nascent symbiont to overproduce the aromatic amino acids tyrosine and phenylalanine, which facilitate weevil cuticle strengthening and accelerated larval development, replicating the function of mutualistic symbionts that are widely distributed among weevils and other beetles in nature. Our work provides empirical support for the notion that mutualistic symbioses can be initiated in insects by the acquisition of environmental bacteria. It also shows that certain bacterial genera, including the Sodalis spp. used in our study, are predisposed to develop these associations due to their ability to maintain benign infections and undergo vertical transmission in diverse insect hosts, facilitating the partner-fidelity feedback that is critical for the evolution of obligate mutualism. These experimental advances provide a new platform for laboratory studies focusing on the molecular mechanisms and evolutionary processes underlying insect-bacterial symbiosis.
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