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A refractory gene will only have an epidemiologically useful effect if it is present in a significant fraction of the target population. It will probably also have to keep both prevalence and effectiveness high for many vector generations. How can this be achieved? Getting to a high prevalence by simple introgression is difficult in a numerically large population, though not necessarily impossible Rasgon, However, since the refractory gene is likely to impose a fitness cost on the mosquitoes, it is likely that both be selected against in terms of prevalence, and also perhaps in terms of loss of function Marrelli et al.

A system is therefore required which will increase the prevalence within the population over time, despite a selective disadvantage.

Several systems have been proposed Sinkins and Gould, , but none developed even to proof-of-principle stage in a mosquito. However, a Medea -like system has been demonstrated in Drosophila melanogaster Chen et al. By using a lethal transgene and an unlinked repressor, this provides an initial increase in allele frequency of the repressor, but over time both the lethal transgene and the repressor decline in frequency.

Though having some gene drive properties, this is therefore still a self-limiting system, which helps to illustrate that there is a spectrum of invasiveness or persistence in genetic systems. At one extreme we have high-penetrance dominant lethal systems killing both males and females, where the transgene is not expected to persist beyond the immediate progeny of the released individuals. Then there are female-lethal systems, where the sons survive but the transgene will still disappear rapidly due to its high fitness cost. Refractory genes that are designed to be neutral will also decline in frequency, but much more slowly due to their much lower fitness cost some fitness penalty seems inevitable.

A transient gene drive system like killer—rescue can provide some boost beyond the initial allele frequency, but still eventually declines. This has a high invasion threshold making it relatively unlikely to invade non-target populations well isolated from any target populations. Medea -like systems have a much lower invasion threshold and so are much more likely to spread aggressively into distant populations Chen et al. Transposons, long proposed as the basis for gene drive systems though not yet demonstrated, are also potentially highly invasive James, While the relationship of IIT and RIDL with the well-known SIT is clear, there are not such obvious analogies with current methods to guide the testing, deployment, and use of gene drive systems.

Some affinity may be found with classical biological control, where the intention is to introduce a parasitoid or predator to control a pest population, expecting that the biocontrol agent will establish and provide long-lasting control, albeit usually incomplete, for the indefinite future. As with classical biological control, there are concerns regarding the lack of control over the gene drive system once released, its unknown evolutionary trajectory post-release, and the essentially irreversible nature of a release, at least in the case of large-scale releases.

On the other hand, while sterile-male control looks economically attractive Atkinson et al. A further issue is the possibility that success may lead to decreased vigilance or the loss of capacity to implement previously effective measures if such existed. While this applies to all control methods, whether genetic or not, it may be a significant concern in respect of the use of long-term self-sustaining systems.

This is likely to require significant ongoing resource expenditure. One striking exception to the slow progress with refractoriness and gene drive systems has come from work on Wolbachia in Ae. Though originally developed for IIT and life-shortening strategies, it was observed that infection with certain strains of Wolbachia dramatically reduced susceptibility to a range of pathogens Hedges et al. Wolbachia are capable of spreading through insect populations as a heritable modification by manipulating the host's reproductive biology Burt and Trivers, ; Hancock et al.

This raised the possibility that certain strains of Wolbachia might provide a complete gene-drive-plus-refractory-gene package. Attention has focused on wMel, a strain of Wolbachia from Drosophila melanogaster and a laboratory-isolated pathogenic derivative wMelPop. Interestingly—and highlighting the diversity of Wolbachia —wMel infection has a similar dengue-blocking effect in Ae. As with cytoplasmic incompatibility, the molecular basis of this pathogen-blocking phenotype is not known, though various studies have implicated upregulation of immune genes or production of reactive oxygen species, or competition for a limited resource such as cholesterol Kambris et al.

In principle, therefore, a suitable strain of Wolbachia could provide an invasive refractoriness phenotype. Though such invasive genetic systems are seen as relatively risky for reasons outlined above, Wolbachia is not especially invasive, particularly for a strain that has a significant fitness cost, as appears to be the case for wMelPop Hancock et al. Introduction of a single infected female can still lead to Wolbachia invading that population, especially if the effective population size is low Jansen et al.

Since Wolbachia are naturally occurring, albeit not in Ae. This may seem rather odd if one considers that addition of any single gene, or less, of DNA from Wolbachia would trigger such an oversight, but the addition of the whole genome does not. However, it is clear that here, as for conventional genetic engineering of mosquitoes, the relevant research groups have worked hard to clarify and then to comply with all applicable regulations O'Connor et al.

For any self-sustaining genetic system, key questions relate to the initial ability to spread and confer the desired phenotype, and the possibility that evolutionary responses will compromise this, or have some other undesirable effect. Though in principle the large-scale use of such systems may be reversible by further genetic intervention, restoring the status quo ante is at best uncertain; this irreversibility has been a major discussion point in respect of gene drive systems.

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In the case of Wolbachia , one may predict that the introduced strain will co-adapt with Ae. However, while the direction seems clear, the rate of decay is very hard to predict, and many generations of protection may be provided. Lack of permanent effect is hardly a reason not to act, but might this tapering protection have some negative aspect? Consequences might include selection for resistant strains of virus.

Though initial experiments suggested that wMel infection gave strong refractoriness Walker et al. This suggests that a Wolbachia strain with refractoriness that is incomplete—either as its initial phenotype or arising through co-adaptation with the mosquito—could select for virus strains with higher titre in humans, an undesirable trait.

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It is also striking that, unlike normal uninfected mosquitoes, Ae. This would appear to provide strong selection for increased human biting preference, a trait which is central to the transmission of human-specific pathogens, as well as to biting nuisance. Unlike the more catholic Ae.

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These issues illustrate the difficulty of predicting the consequences of releasing a self-sustaining genetic system relating to future evolutionary responses. On the one hand Wolbachia is arguably natural—though this may also be true of the elements of an engineered system; in both cases the association with Aedes aegypti is artificially induced, a product of modern biotechnology. To further blur the lines, gene transfer from Wolbachia to insect nuclear genomes is well known, and this can lead to stable transfer of expressed genes Klasson et al.

On the other hand, a complex uncharacterised system is by definition less well understood and correspondingly more likely to throw up surprises.

Global Health Impacts of Vector-Borne Diseases: Workshop Summary.

The refractoriness phenotype was a major, beneficial surprise; the human blood requirement was also entirely unexpected, and less welcome. The future evolutionary trajectory of such a complex system may reveal additional surprises—positive or negative. However, it is a fallacy, sometimes called the nirvana fallacy, to compare actual things with idealised alternatives, for example the risks of future action with a hypothetical risk-free world. Both inaction and alternative actions have risks of their own. Nonetheless, it may be difficult both for regulatory authorities and the general public to compare the relatively well-known risks and hazards of inaction with the unknown aspects of a new technology, even when—as for genetic control—the technology seems likely to offer potentially large net benefits.

The above discussion has focused on genetic control methods alone. However, current control methods have some strengths as well as weaknesses; an optimal programme is therefore likely to integrate the best of current methods with new technology to achieve the goal of improved control. For example, short-term suppression by conventional methods is likely to be a desirable prelude to either sterile-male or refractory-insect methods as it will reduce the number of modified insects required to achieve a given effect.

As further tools become available, such as drugs and vaccines, this integrated vector management approach will naturally expand to integrated disease management—again using an optimal mix of available tools. In fact, after due consideration, national regulators in several countries have approved small-scale field trials as the next step in an incremental testing and scale-up process.

Several self-limiting and one self-sustaining genetic system have been tested in the field to date Hoffman et al. Public perception has generally been positive, though these are early days. Public response to genetic control, either in general or relating to specific applications, may vary considerably depending on a wide range of social, political, epidemiological, presentational, and cultural factors, of which the genetic element is only one; furthermore, this response may vary over time.

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Even for a well-established approach such as vaccination, participation rates are rarely as high as programme managers would wish, and scare stories such as that regarding MMR vaccine in the UK can still shake public confidence. However, regulatory and social factors, while crucial to the adoption of any new technology, are not the main focus of this review. OXA males were shown to have similar longevity and maximum dispersal to an unmodified comparator Lacroix et al. To our knowledge, each of these trials has been successful in accomplishing its experimental objectives, and in no case have any negative consequences to human health or the environment been identified.

One may anticipate that each of the programmes described above will develop further over the coming years, though there will doubtless be numerous technical, legal, and social challenges. In addition, one may anticipate that some of the many approaches at earlier stages of development will progress towards field trials and use.

In this regard one may particularly look to synthetic biology approaches to engineered refractoriness and gene drive systems—an approach that has been long heralded and where the daunting technical obstacles are slowly being overcome.