Nina Alphey

Analyzing the control of mosquito-borne diseases by a dominant lethal genetic system

Motivated by the failure of current methods to control dengue fever, we formulate a mathematical model to assess the impact on the spread of a mosquito-borne viral disease of a strategy that releases adult male insects homozygous for a dominant, repressible, lethal genetic trait. A dynamic model for the female adult mosquito population, which incorporates the competition for female mating between released mosquitoes and wild mosquitoes, density-dependent competition during the larval stage, and realization of the lethal trait either before or after the larval stage, is embedded into a susceptible–exposed–infectious–susceptible human-vector epidemic model for the spread of the disease. For the special case in which the number of released mosquitoes is maintained in a fixed proportion to the number of adult female mosquitoes at each point in time, we derive mathematical formulas for the disease eradication condition and the approximate number of released mosquitoes necessary for eradication. Numerical results using data for dengue fever suggest that the proportional policy outperforms a release policy in which the released mosquito population is held constant, and that eradication in ≈1 year is feasible for affected human populations on the order of 105 to 106, although the logistical considerations are daunting. We also construct a policy that achieves an exponential decay in the female mosquito population; this policy releases approximately the same number of mosquitoes as the proportional policy but achieves eradication nearly twice as fast.

Insect Population Suppression Using Engineered Insects

Suppression or elimination of vector populations is a tried and tested method for reducing vector-borne disease, and a key component of integrated control programs. Genetic methods have the potential to provide new and improved methods for vector control. The required genetic technology is simpler than that required for strategies based on population replacement and is likely to be available earlier. In particular, genetic methods that enhance the Sterile Insect Technique (e.g., RIDL) are already available for some species.

A Model Framework to Estimate Impact and Cost of Genetics-Based Sterile Insect Methods for Dengue Vector Control

Vector-borne diseases impose enormous health and economic burdens and additional methods to control vector populations are clearly needed. The Sterile Insect Technique (SIT) has been successful against agricultural pests, but is not in large-scale use for suppressing or eliminating mosquito populations. Genetic RIDL technology (Release of Insects carrying a Dominant Lethal) is a proposed modification that involves releasing insects that are homozygous for a repressible dominant lethal genetic construct rather than being sterilized by irradiation, and could potentially overcome some technical difficulties with the conventional SIT technology. Using the arboviral disease dengue as an example, we combine vector population dynamics and epidemiological models to explore the effect of a program of RIDL releases on disease transmission. We use these to derive a preliminary estimate of the potential cost-effectiveness of vector control by applying estimates of the costs of SIT. We predict that this genetic control strategy could eliminate dengue rapidly from a human community, and at lower expense (approximately US

Managing Insecticide Resistance by Mass Release of Engineered Insects

2∼30 per case averted) than the direct and indirect costs of disease (mean US

Combining Pest Control and Resistance Management: Synergy of Engineered Insects With Bt Crops

86–190 per case of dengue). The theoretical framework has wider potential use; by appropriately adapting or replacing each component of the framework (entomological, epidemiological, vector control bio-economics and health economics), it could be applied to other vector-borne diseases or vector control strategies and extended to include other health interventions.

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

Abstract 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

ABSTRACT Transgenic crops producing insecticidal toxins are widely used to control insect pests. Their benefits would be lost if resistance to the toxins became widespread in pest populations. The most widely used resistance management method is the high-dose/refuge strategy. This requires toxin-free host plants as refuges near insecticidal crops, and toxin doses intended to be sufficiently high to kill insects heterozygous for a resistant allele, thereby rendering resistance functionally recessive. We have previously shown by mathematical modeling that mass-release of harmless susceptible (toxin-sensitive) insects engineered with repressible female-specific lethality using release of insects carrying a dominant lethal ([RIDL] Oxitec Limited, United Kingdom) technology could substantially delay or reverse the spread of resistance and reduce refuge sizes. Here, we explore this proposal in depth, studying a wide range of scenarios, considering impacts on population dynamics as well as evolution of allele frequencies, comparing with releases of natural fertile susceptible insects, and examining the effect of seasonality. We investigate the outcome for pest control for which the plant-incorporated toxins are not necessarily at a high dose (i.e., they might not kill all homozygous susceptible and all heterozygous insects). We demonstrate that a RIDL-based approach could form an effective component of a resistance management strategy in a wide range of genetic and ecological circumstances. Because there are significant threshold effects for several variables, we expect that a margin of error would be advisable in setting release ratios and refuge sizes, especially as the frequency and properties of resistant alleles may be difficult to measure accurately in the field.

Proportions of different habitat types are critical to the fate of a resistance allele

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 insects life-history parameters influence those outcomes.

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

Vector-borne diseases cause immense suffering and economicdamage. Vector control remains a key element of mitigation andcontrol strategies, particularly for pathogens such as dengueviruses for which there are no specific drugs or vaccines. Yetexisting vector control tools are limited; toxic chemicals are themainstay but difficult to deliver due to vector behaviour, emergingresistance, and/or environmental concerns. Genetically modifiedvectors—presently only mosquitoes—offer complementary newapproaches to integrate with the best existing methods. Modifiedmosquitoes will actively seek out wild mosquitoes as mates, withhigh species specificity and minimal off-target effects.Within this overall scheme, many different genetic modifica-tions have been proposed, all delivered via this mating-basedmechanism (‘‘vertical transmission’’). These may be classifiedaccording to the persistence of the modification: ‘‘self-sustain-ing’’ genetic systems are intendedto persist or spread invasivelyin the wild population after an initial release period, while ‘‘self-limiting’’ systems will disappear relatively rapidly unlessmaintained by more releases. Another classification is byintended effect: ‘‘population suppression’’ strategies aim, likemost current vector control programmes, to reduce the numberof vector mosquitoes in the target area, while ‘‘populationreplacement’’ strategies aim to reduce the ability of affectedmosquitoes to transmit specified pathogens, with any reductionin total number of mosquitoes being incidental. In either case,the intended result is fewer competent vectors, thereby reducingthe force of infection. In computer simulations, several suchstrategies are capable of eliminating transmission in theprogramme area.These approaches are not entirely new. Some proposals [1] aresimply applications of modern genetics to improve on the classicalSterile Insect Technique (SIT) [2], in which radiation-sterilisedinsects are released to mate with wild counterparts and therebyreduce the reproductive potential of the target pest population,leading to suppression or even local elimination. SIT has beenused successfully on large and small scales against some majoragricultural pests. This close relationship to an existing methodmeans that the rollout, use, strengths, and weaknesses of such self-limiting population suppression strategies are fairly predictableand well understood. For self-sustaining strategies, looser analogiesmay be drawn with classical biological control, in which an exoticpredator or parasite is introduced with the intention that it shouldestablish permanently and thereby help control the pest. Thisanalogy highlights both key strengths of self-sustaining systems—potential long-term benefit without further human action—andweaknesses—relative lack of control post-release—relative to self-limiting ones. Simulation modelling is a vital tool to inform straindevelopment and risk assessment and mitigation, especially of themore invasive self-sustaining systems in which release is essentiallyirreversible.

Transgenic conTrol of vecTors: The effecTs of inTerspecific inTeracTions

We describe a simple deterministic theoretical framework for analysing the gene frequency evolution of two alternative alleles at a single genetic locus in a habitat comprising two environments in which the genotypes have different relative fitnesses. We illustrate this for adaptation of pest insects, where one allele (resistance to toxins expressed in transgenic crops) is favoured in one environment (transgenic plants) and the other allele (susceptibility to toxins) is favoured in the other environment (‘refuges’ of non-transgenic plants). The evolution of allele frequencies depends on selection pressure because of relative sizes of the environments and relative fitnesses of the genotypes in each environment. We demonstrate that there are critical threshold proportions for habitat division that determine equilibrium allele frequencies. The stability of the system depends on relationships between the relative genotype fitnesses. In some cases, the division of the habitat in exactly the threshold proportions removes selection pressure and maintains polymorphism at all allele frequencies.