Guidance framework for testing of genetically modified mosquitoes

Reproduced in accordance with the publishers guidelines "The use of content from this health information product for all non-commercial education, training and information purposes is encouraged".Commissioned by TDR and the Foundation for the National Institutes of Health (FNIH), this framework was drafted by four different working groups (efficacy; safety; ethical, legal and social; and regulation), each of which received comments about their draft from experts in the field and the public. Genetically modified mosquitoes (GMM) engineered to be incapable of transmitting certain pathogens or able to reduce populations of similar native mosquito vectors have emerged as a promising new tool to combat vector-borne diseases like malaria and dengue in the more than 100 countries where they’re endemic. The guidance framework aims to foster quality and consistency among processes for testing and regulating new genetic technologies by proposing standards of efficacy and safety testing comparable to those used for trials of other new public health tools. The framework does not represent the views of the World Health Organization (WHO) or FNIH or provide recommendations on what to do. Rather, it is a document that brings together what is known, based on current research evidence, about how best to evaluate GMM

Pest control and resistance management through release of insects carrying a male-selecting transgene

Development and evaluation of new insect pest management tools is critical for overcoming over-reliance upon, and growing resistance to, synthetic, biological and plant-expressed insecticides. For transgenic crops expressing insecticidal proteins from the bacterium Bacillus thuringiensis (‘Bt crops’) emergence of resistance is slowed by maintaining a proportion of the crop as non-Bt varieties, which produce pest insects unselected for resistance. While this strategy has been largely successful, multiple cases of Bt resistance have now been reported. One new approach to pest management is the use of genetically engineered insects to suppress populations of their own species. Models suggest that released insects carrying male-selecting (MS) transgenes would be effective agents of direct, species-specific pest management by preventing survival of female progeny, and simultaneously provide an alternative insecticide resistance management strategy by introgression of susceptibility alleles into target populations. We developed a MS strain of the diamondback moth, Plutella xylostella, a serious global pest of crucifers. MS-strain larvae are reared as normal with dietary tetracycline, but, when reared without tetracycline or on host plants, only males will survive to adulthood. We used this strain in glasshouse-cages to study the effect of MS male P. xylostella releases on target pest population size and spread of Bt resistance in these populations

Managing insecticide resistance by mass release of engineered insects.

Transgenic crops producing insecticidal toxins are now widely used to control insect pests. The benefits of this method would be lost if resistance to the toxins spread to a significant proportion of the pest population. The primary resistance management method, mandatory in the United States, is the high-dose/ refuge strategy, requiring toxin-free crops as refuges near the insecticidal crops, and the use of toxin doses sufficiently high to kill insects heterozygous for a resistance allele, thereby rendering resistance functionally recessive. We propose that mass-release of harmless susceptible (toxin-sensitive) insects could substantially delay or even reverse the spread of resistance. Mass-release of such insects is an integral part of release of insects carrying a dominant lethal (RIDL), a method of pest control related to the sterile insect technique. We show by mathematical modeling that specific RIDL strategies could form an effective component of a resistance management strategy for plant-incorporated protectants and other toxins

Five things to know about genetically modified (gm) insects for vector control

Copyright: © 2014 Alphey, Alphey. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited

Modelling optimal strategies for novel genetics-based pest management

Genetic transformation techniques for pest insects have enabled the development of novel methods to mitigate the enormous harm done by insects to human health (through transmission of diseases) and to agriculture (through damage to crops or livestock). I use mathematical modelling to analyse strategies using autocidal genetic constructs (dominant lethal genes that are repressible during mass-rearing); in parallel several research groups are developing the strains and the laboratory and field experimental work. Engineered insects would be released in large numbers and compete for mates, and their progeny would inherit one copy of a dominant lethal gene and die. The lethal mechanism can be made stage- or sex-specific. The aim is to reduce the number of pest insects in a population, suppressing numbers to a less harmful level or local elimination. I examine the evolutionary, ecological, and economic cost and benefit aspects of these novel interventions. I consider application of this genetic technology against agricultural pest insects, combined with genetically modified crop plants engineered to produce insecticidal toxins, to which field-evolved resistance is emerging. Using a theoretical framework, I analyse the gene frequency evolution of resistant alleles and show that strategies using genetic constructs that are selectively lethal only to females could help to manage both pests and resistance. I investigate potential resistance to the lethal mechanism of the genetic construct itself. I use population genetics and population dynamics models to explore the impact of heritable biochemically-based resistance on the effectiveness of genetic strategies for reducing populations of important pests in agriculture or public health. Released insects are homozygous for susceptibility to the lethal construct; this has an inherent element of resistance dilution. Finally, I analyse genetic vector control methods to reduce the transmission of human disease. I combine vector population dynamics and epidemiological models with techniques for assessing cost-effectiveness of a genetic strategy for controlling a vector mosquito, and show that disease elimination is feasible on a practical timescale and economically beneficial

Transgenic control of vectors: The effects of interspecific interactions

The control of insect vectors through conventional sterile insect or transgenic technologies (e.g., RIDL®) is an intense focus of research in the combat against vector-borne disease. While the population dynamic implications of these control strategies are reasonably well-established, the effects of interspecific competition between different vectors and control strategies have not previously been explored. Different control intervention methods can affect the interaction and potential coexistence of vector species. By altering the shape of the zero net growth isoclines, conventional and transgenic control can affect patterns of vector coexistence and/or exclusion through Allee effects and transient dynamics. Further, transgenic control methods can mediate coexistence between target and non-target species and this can have important consequences for the persistence of disease and community ecological interactions

Data from: Resistance to genetic insect control: modelling the effects of space

Genetic insect control, such as self-limiting RIDL2 (Release of Insects Carrying a Dominant Lethal) technology, is a development of the sterile insect technique which is proposed to suppress wild populations of a number of major agricultural and public health insect pests. This is achieved by mass rearing and releasing male insects that are homozygous for a repressible dominant lethal genetic construct, which causes death in progeny when inherited. The released genetically engineered ('GE') insects compete for mates with wild individuals, resulting in population suppression. A previous study modelled the evolution of a hypothetical resistance to the lethal construct using a frequency-dependent population genetic and population dynamic approach. This found that proliferation of resistance is possible but can be diluted by the introgression of susceptible alleles from the released homozygous-susceptible GE males. We develop this approach within a spatial context by modelling the spread of a lethal construct and resistance trait, and the effect on population control, in a two deme metapopulation, with GE release in one deme. Results show that spatial effects can drive an increased or decreased evolution of resistance in both the target and non-target demes, depending on the effectiveness and associated costs of the resistant trait, and on the rate of dispersal. A recurrent theme is the potential for the non-target deme to act as a source of resistant or susceptible alleles for the target deme through dispersal. This can in turn have a major impact on the effectiveness of insect population control

Zip file of README text and R scripts

This zip file contains R scripts containing code and functions for running simulations of the model. The README file describes what each file does

Interplay of population genetics and dynamics in the genetic control of mosquitoes

Some proposed genetics-based vector control methods aim to suppress or eliminate a mosquito population in a similar manner to the sterile insect technique. One approach under development in Anopheles mosquitoes uses homing endonuclease genes (HEGs)—selfish genetic elements (inherited at greater than Mendelian rate) that can spread rapidly through a population even if they reduce fitness. HEGs have potential to drive introduced traits through a population without large-scale sustained releases. The population genetics of HEG-based systems has been established using discrete-time mathematical models. However, several ecologically important aspects remain unexplored. We formulate a new continuous-time (overlapping generations) combined population dynamic and genetic model and apply it to a HEG that targets and knocks out a gene that is important for survival. We explore the effects of density dependence ranging from undercompensating to overcompensating larval competition, occurring before or after HEG fitness effects, and consider differences in competitive effect between genotypes (wild-type, heterozygotes and HEG homozygotes). We show that population outcomes—elimination, suppression or loss of the HEG—depend crucially on the interaction between these ecological aspects and genetics, and explain how the HEG fitness properties, the homing rate (drive) and the insect's life-history parameters influence those outcomes.Copyright 2014 Nina Alphey and Michael B. Bonsall. Published by the Royal Society under the terms of the Creative Commons Attribution License http://creativecommons.org/licenses/by/3.0/, which permits unrestricted use, provided the original author and source are credited