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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Determining the Sterilization Doses under Hypoxia for the Novel Black Pupae Genetic Sexing Strain of Anastrepha fraterculus (Diptera, Tephritidae)

16672
P. D. Giustina, T. Mastrangelo, S. Ahmad, G. Mascarin and C. Caceres,  Insects,  12. 2021-03-30 13:38:24.
Our study reports for the first time the dose-sterility response under hypoxia for two different A. fraterculus strains. The pupae were derived from a bisexual strain (a Brazilian-1 population) and a recently developed genetic sexing strain (GSS-89). Two hours prior to irradiation, pupae were transferred to sealed glass bottles and irradiated when oxygen concentration was below 3%. Four types of crosses with nonirradiated flies of the bisexual strain were set to assess sterility for each radiation dose. For males from both strains, Weibull dose–response curves between radiation doses and the proportion of egg hatch, egg-to-pupa recovery, and recovery of adults were determined. The GSS males revealed high sterility/mortality levels compared to males from the bisexual strain at doses < 40 Gy, but a dose of 74 Gy reduced egg hatch by 99% regardless of the male strain and was considered the sterilizing dose. The fertility of irradiated females was severely affected even at low doses under hypoxia.

Systematic identification of plausible pathways to potential harm via problem formulation for investigational releases of a population suppression gene drive to control the human malaria vector Anopheles gambiae in West Africa

16668
J. B. Connolly, J. D. Mumford, S. Fuchs, G. Turner, C. Beech, A. R. North and A. Burt,  Malaria Journal,  20:170. 2021-03-29 18:49:26.
Population suppression gene drive has been proposed as a strategy for malaria vector control. A CRISPR-Cas9-based transgene homing at the doublesex locus (dsxFCRISPRh) has recently been shown to increase rapidly in frequency in, and suppress, caged laboratory populations of the malaria mosquito vector Anopheles gambiae. Here, problem formulation, an initial step in environmental risk assessment (ERA), was performed for simulated field releases of the dsxFCRISPRh transgene in West Africa.

Sterile Insect Technique in an Integrated Vector Management Program against Tiger Mosquito Aedes albopictus in the Valencia Region (Spain): Operating Procedures and Quality Control Parameters

16663
C. Tur, D. Almenar, S. Benlloch-Navarro, R. Argilés-Herrero, M. Zacarés, V. Dalmau and I. Pla,  Insects,  12. 2021-03-23 14:20:04.
The Agriculture Department of the Valencian Region is promoting an ongoing pilot project to evaluate the efficacy of an integrated vector management program (IVM) based on the use of the SIT as the main method of control. The laboratory studies for evaluating the entomological efficacy of SIT through the phased conditional testing process recommended by World Health Organization and the International Atomic Energy Agency (WHO-IAEA) are addressed. This study describes the routine operating procedures and quality control parameters for the medium-scale rearing of sterile male A. albopictus. More than 15 million sterile males have been produced and released in an area of 80 ha between 2018 and 2020. Of the initial L1 larvae, we recovered 17.2% of male pupae after sex sorting to be sterilized and released on the field, while the rest of the pupae remained available to maintain the rearing colony. The residual percentage of females after sex sorting was on average 0.17%. The obtained values in terms of production and quality control as well as the proposed rearing methodology can be useful for designing a medium-scale mosquito-rearing pipeline.

Experimenting with co-development: a qualitative study of gene drive research for malaria control in Mali

16639
S. Hartley, K. Ledingham, R. Owen, S. Leonelli, S. Diarra and S. Diop,  Social Science and Medicine,  2021-03-21 14:37:21.
Our findings suggest co-development is opening up previously expert-dominated spaces as researchers attempt to take responsibility for the societal implications of their work. However, its main function is as a project management tool to enable and instrumentally support technological development, field trials and eventual deployment. This function extends into areas which are traditionally the responsibility of the state, such as regulatory development, facilitated by Mali’s fragile political and economic situation. Paradoxically, co-development simultaneously depoliticises gene drive, masking power relations and closing down substantive debate and agency. Characterised by extreme poverty, conflict and weak institutions, Mali may become a site for technological experimentation where there is little interrogation of gene drive or its governance.

Ethics of Genome Editing

16622
European Group on Ethics,  European Group on Ethics in Science and New Technologies,  2021-03-19 18:16:09.
This Opinion addresses the profound ethical questions raised and revived by them. It analyses various domains of application, from human health to animal experimentation, from livestock breeding to crop variety and to gene drives. With its wide view across areas, it identifies underlying and overarching issues that deserve our concerted attention, among them, the different meanings that ought to be attributed to humanness, naturalness or diversity. This enables conclusions that provide panoramic perspectives complementing narrower, area-specific analyses. In the same vein, the Opinion is concerned with the global dimension of genome editing and its regulation and formulates recommendations with a particular focus on the international level.

Evaluating unintended consequences of intentional species introductions and eradications for improved conservation management

16631
D. E. Pearson, T. J. Clark and P. G. Hahn,  Conserv Biol,  2021-03-19 14:52:01.
We conducted a global literature review of these conservation actions to quantify how often unintended outcomes occur and to elucidate their underlying causes. We found that studies reported intended outcomes in 51% of cases, a combination of intended outcomes and unintended outcomes in 26% of cases, and strictly unintended outcomes in 10% of cases. Hence, unintended outcomes were reported in 36% of all cases evaluated. In evaluating overall conservations outcomes (weighing intended vs unintended effects), some unintended effects are fairly innocuous relative to successful conservation objectives whereas others result in serious unintended consequences in recipient communities. Importantly, we also found that studies that assessed a greater number of community interactions with the target species were more likely to report unintended outcomes, suggesting that unintended consequences may be under-reported due to insufficient vetting.

The ethical scientist in a time of uncertainty

16620
L. Zoloth,  Cell,  184:1430-1439. 2021-03-18 17:59:56.
Using the example of gene drives for malaria control to explore the problem of deep uncertainty in biomedical research, I argue that profound uncertainty is an essential feature. Applying the language and presumptions of the discipline of philosophical ethics, I describe three types of uncertainty that raise ethical challenges in scientific research. Rather than mitigate these challenges with excessive precautions and limits on progress, I suggest that researchers can cultivate classic values of veracity, courage, humility, and fidelity in their research allowing science to proceed ethically under conditions of deep uncertainty.

Driving to Safety: CRISPR-Based Genetic Approaches to Reducing Antibiotic Resistance

16614
E. Bier and V. Nizet,  Trends in Genetics,  2021-03-18 17:34:35.
The complex and challenging problem of reducing antibiotic resistance (AR) requires a network of both societal and science-based solutions to preserve the most lifesaving pharmaceutical intervention known to medicine. In addition to developing new classes of antibiotics, it is essential to safeguard the clinical efficacy of existing drugs. In this review, we examine the potential application of novel CRISPR-based genetic approaches to reducing AR in both environmental and clinical settings and prolonging the utility of vital antibiotics.

Ultra-conserved sequences in the genomes of highly diverse Anopheles mosquitoes, with implications for malaria vector control

16629
S. M. O'Loughlin, A. J. Forster, S. Fuchs, T. Dottorini, T. Nolan, A. Crisanti and A. Burt,  G3-Genes Genomes Genetics,  2021-03-18 14:15:51.
Here we search for conserved sequences of 18bp and over in an alignment of 21 Anopheles genomes, spanning an evolutionary timescale of 100 million years, and characterise the resulting sequences according to their location and function. Over 8000 ultra-conserved elements were found across the alignment, with a maximum length of 164 bp. Length-corrected gene ontology analysis revealed that genes containing Anopheles ultra-conserved elements were over-represented in categories with structural or nucleotide binding functions. Known insect transcription factor binding sites were found in 48% of intergenic Anopheles ultra-conserved elements. When we looked at the genome sequences of 1142 wild-caught mosquitoes we found that 15% of the Anopheles ultra-conserved elements contained no polymorphisms. Our list of Anopheles ultra-conserved elements should provide a valuable starting point for the selection and testing of new targets for gene-drive modification in the mosquitoes that transmit malaria.

Meiotic Cas9 expression mediates genotype conversion in the male and female mouse germline.

16618
A. J. Weitzel, H. A. Grunwald, R. Levina, V. M. Gantz, S. M. Hedrick, E. Bier and K. L. Cooper,  2021.03.16.435716,  2021-03-17 17:52:21.
We previously showed that such a system of genotype conversion from heterozygous to homozygous after a sequence targeted CRISPR/Cas9 double strand DNA break is feasible in the female mouse germline. In the male germline, however, all double strand breaks were instead repaired by end joining mechanisms to form an 'insertion/deletion' (indel) mutation. These observations suggested that timing Cas9 expression to coincide with meiosis I is critical to favor conditions when homologous chromosomes are aligned and interchromosomal homology directed repair (HDR) mechanisms predominate. Here, using a Cas9 knock-in allele at the Spo11 locus, we show that meiotic expression of Cas9 does indeed mediate genotype conversion in the male as well as in the female germline. However, the low frequency of both HDR and indel mutation in both male and female germlines suggests that Cas9 may be expressed from the Spo11 locus at levels too low for efficient double strand DNA break formation. We suggest that more robust Cas9 expression initiated during early meiosis I may improve the efficiency of genotype conversion and further increase the rate of 'super-Mendelian' inheritance from both male and female mice.Competing Interest StatementVMG, SMH, EB, and KLC hold advisory board positions with Synbal, Inc. All other authors declare that they have no competing interests.

Differentiated impacts of human interventions on nature: Scaling the conversation on regulation of gene technologies

18750
J. A. Heinemann, D. J. Paull, S. Walker and B. Kurenbach,  Elementa: Science of the Anthropocene,  9. 2021-03-17 13:35:29.
Biotechnology describes a range of human activities in medicine, agriculture, and environmental management. One biotechnology in particular, gene technology, continues to evolve both in capacity and potential to benefit and harm society. The purpose of this article is to offer a policy bridge from unproductive descriptions of gene technology to useful methods for identifying sources of significant biological and socioeconomic risk in complex food systems. Farmers and the public could be voluntarily and involuntarily interacting with new techniques of genome editing and gene silencing in entirely new ways, limiting the usefulness of previous gene technology histories to predict safety. What we believe is a more consistent, verifiable, and practical approach is to identify the critical control points that emerge where the scale effects of a human activity diverge between risk and safety. These critical control points are where technical experts can collaborate with publics with different expertise to identify and manage the technology. The use of technical terminology describing biochemical-level phenomena discourages publics that are not technical experts from contesting the embedded cultural perspectives and uncertainty in “scientific” concepts and prejudice the risk discourse by ignoring other issues of significance to society. From our perspective as gene technologists, we confront the use of pseudo-scale language in risk discourse and propose an escape path from clashes over whether risks that arise spontaneously (from nature) can be perfectly mimicked by gene technology to a discussion on how to best control the risks created by human activity. Scale is conceptually implicit and explicit in gene technology regulation, but there is no agreement about what scales are most useful to managing risk and social expectations. Both differentiated governance (risk-tiered) and responsible research and innovation models could accommodate the critical control points mechanism that we describe.

Genetically Encoded CRISPR components Yield Efficient Gene Editing in the Invasive Pest, Drosophila suzukii

16602
N. P. Kandul, E. J. Belikoff, J. Liu, A. Buchman, F. Li, A. Yamamoto, T. Yang, I. Shriner, M. J. Scott and O. Akbari,  bioRxiv,  2021.03.15.435483. 2021-03-16 18:28:51.
Here we have developed transgenic strains that encode three different terminators and four different promoters to express Cas9 in both the soma and/or germline of SWD. The Cas9 lines were evaluated through genetic crossing to transgenic lines that encode single guide RNAs targeting the conserved X-linked yellow body and white eye genes. We find that several Cas9/gRNA lines display very high editing capacity. Going forward, these tools will be instrumental for evaluating gene function in SWD and may provide tools useful for the development of new genetic strategies for control of this invasive species.

Ugandan stakeholder hopes and concerns about gene drive mosquitoes for malaria control: new directions for gene drive risk governance

16600
S. Hartley, R. D. J. Smith, A. Kokotovich, C. Opesen, T. Habtewold, K. Ledingham, B. Raymond and C. B. Rwabukwali,  Malaria Journal,  20:149. 2021-03-16 18:12:21.
The African Union’s High-Level Panel on Emerging Technologies identified gene drive mosquitoes as a priority technology for malaria elimination. The first field trials are expected in 5–10 years in Uganda, Mali or Burkina Faso. In preparation, regional and international actors are developing risk governance guidelines which will delineate the framework for identifying and evaluating risks. Scientists and bioethicists have called for African stakeholder involvement in these developments, arguing the knowledge and perspectives of those people living in malaria-afflicted countries is currently missing. However, few African stakeholders have been involved to date, leaving a knowledge gap about the local social-cultural as well as ecological context in which gene drive mosquitoes will be tested and deployed. This study investigates and analyses Ugandan stakeholders’ hopes and concerns about gene drive mosquitoes for malaria control and explores the new directions needed for risk governance.

Lessons from Drosophila: Engineering Genetic Sexing Strains with Temperature-Sensitive Lethality for Sterile Insect Technique Applications

T. N. M. Nguyen, A. Choo and S. W. Baxter,  Insects,  12. 2021-03-13 16:03:00.
Some of the most successful Genetic Sexing Strains (GSS) reared and released for SIT control were developed for Mediterranean fruit fly (Medfly), Ceratitis capitata, and carry a temperature sensitive lethal (tsl) mutation that eliminates female but not male embryos when heat treated. The Medfly tsl mutation was generated by random mutagenesis and the genetic mechanism causing this valuable heat sensitive phenotype remains unknown. Conditional temperature sensitive lethal mutations have also been developed using random mutagenesis in the insect model, Drosophila melanogaster, and were used for some of the founding genetic research published in the fields of neuro- and developmental biology. Here we review mutations in select D. melanogaster genes shibire, Notch, RNA polymerase II 215kDa, pale, transformer-2, Dsor1 and CK2α that cause temperature sensitive phenotypes. Precise introduction of orthologous point mutations in pest insect species with CRISPR/Cas9 genome editing technology holds potential to establish GSSs with embryonic lethality to improve and advance SIT pest control.

Current Effector and Gene-Drive Developments to Engineer Arbovirus-Resistant Aedes aegypti (Diptera: Culicidae) for a Sustainable Population Replacement Strategy in the Field

16596
W. R. Reid, K. E. Olson and A. W. E. Franz,  J Med Entomol,  2021-03-12 20:35:28.
Conventional mosquito control efforts based on insecticide treatments and/or the use of bednets and window curtains are currently insufficient to reduce arbovirus prevalence in affected regions. Novel, genetic strategies that are being developed involve the genetic manipulation of mosquitoes for population reduction and population replacement purposes. Population replacement aims at replacing arbovirus-susceptible wild-type mosquitoes in a target region with those that carry a laboratory-engineered antiviral effector to interrupt arboviral transmission in the field.

When More is Less: Mosquito Population Suppression Using Sterile, Incompatible and Genetically Modified Male Mosquitoes

18708
S. L. Dobson,  Journal of Medical Entomology,  58:1980-1986. 2021-03-11 13:50:08.
The current review of the Sterile Insect Technique (SIT) is motivated by new technologies and the recent renaissance of male release field trials, which is driving an evolution in mosquito control and regulation. Practitioners that are releasing male mosquitoes would do well to learn from past successes and failures, including political and public engagement complications. With examples that include nuanced integrations of the different technologies, e.g., combinations of Wolbachia and irradiation, it is critical that scientists understand and communicate accurately about the technologies, including their evolving management by different regulatory agencies in the USA. Some male release approaches are considered ‘pesticides’ and regulated by federal and state agencies, while other male release approaches are unregulated. It is important to consider how the new technologies fit with the more ‘traditional’ chemical applications of adulticides and larvicides. The economics of male release programs are substantially different from traditional control costs, which can be a challenge to their adoption by abatement districts. However, there is substantial need to overcome these complications and challenges, because the problem with invasive mosquitoes grows ever worse with factors that include insecticide resistance, globalization and climate change.

femaleless Controls Sex Determination and Dosage Compensation Pathways in Females of Anopheles Mosquitoes

16910
E. Krzywinska, L. Ferretti, J. Li, J.-C. Li, C.-H. Chen and J. Krzywinski,  Current Biology,  31:1084-1091.e4. 2021-03-08 18:07:47.
Here we show that in the African malaria mosquito Anopheles gambiae, a gene, which likely arose in the Anopheles lineage and which we call femaleless (fle), controls sex determination in females by regulating splicing of dsx and fruitless (fru; another terminal gene within a branch of the sex determination pathway). Moreover, fle represents a novel molecular link between the sex determination and dosage compensation pathways. It is necessary to suppress activation of dosage compensation in females, as demonstrated by the significant upregulation of the female X chromosome genes and a correlated female-specific lethality, but no negative effect on males, in response to fle knockdown. This unexpected property, combined with a high level of conservation in sequence and function in anopheline mosquitoes, makes fle an excellent target for genetic control of all major vectors of human malaria.

Sex Determination and Dosage Compensation: femaleless Is the Link in Anopheles Mosquitoes

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M. Scott,  Current Biology,  31:R260-R263. 2021-03-08 18:03:44.
A new study finds that the femaleless gene is essential for sexual development and repression of X-chromosome dosage compensation in the malaria vector Anopheles gambiae. This could provide the basis for a new genetic approach to control this pest.

Experts’ moral views on gene drive technologies: a qualitative interview study

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N. de Graeff, K. R. Jongsma and A. L. Bredenoord,  BMC Medical Ethics,  22:25. 2021-03-08 13:56:59.
Gene drive technologies (GDTs) promote the rapid spread of a particular genetic element within a population of non-human organisms. Potential applications of GDTs include the control of insect vectors, invasive species and agricultural pests. Whether, and if so, under what conditions, GDTs should be deployed is hotly debated. Although broad stances in this debate have been described, the convictions that inform the moral views of the experts shaping these technologies and related policies have not been examined in depth in the academic literature.

Eliminating Mosquitoes with Precision Guided Sterile Males

16563
M. Li, T. Yang, M. Bui, S. Gamez, T. Wise, N. P. Kandul, J. Liu, L. Alcantara, H. Lee, J. R. Edula, R. Raban, Y. Zhan, Y. Wang, N. DeBeaubien, J. Chen, H. M. Sanchez C, J. B. Bennett, I. Antoshechkin, C. Montell, J. M. Marshall and O. S. Akbari,  bioRxiv,  2021.03.05.434167. 2021-03-06 20:07:26.
Here we develop a molecular genetic control system termed precision guided sterile insect technique (pgSIT) in Aedes aegypti. PgSIT uses a simple CRISPR-based approach to generate sterile males that are deployable at any life stage. Supported by mathematical models, we empirically demonstrate that released pgSIT males can compete, suppress, and eliminate mosquitoes in multigenerational population cages. This platform technology could be used in the field, and adapted to many vectors, for controlling wild populations to curtail disease in a safe, confinable, and reversible manner.

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