Daisy-chain gene drives: The role of low cut-rate, resistance mutations, and maternal deposition.

The introgression of genetic traits through gene drive may serve as a powerful and widely applicable method of biological control. However, for many applications, a self-perpetuating gene drive that can spread beyond the specific target population may be undesirable and preclude use. Daisy-chain gene drives have been proposed as a means of tuning the invasiveness of a gene drive, allowing it to spread efficiently into the target population, but be self-limiting beyond that. Daisy-chain gene drives are made up of multiple independent drive elements, where each element, except one, biases the inheritance of another, forming a chain. Under ideal inheritance biasing conditions, the released drive elements remain linked in the same configuration, generating copies of most of their elements except for the last remaining link in the chain. Through mathematical modelling of populations connected by migration, we have evaluated the effect of resistance alleles, different fitness costs, reduction in the cut-rate, and maternal deposition on two alternative daisy-chain gene drive designs. We find that the self-limiting nature of daisy-chain gene drives makes their spread highly dependent on the efficiency and fidelity of the inheritance biasing mechanism. In particular, reductions in the cut-rate and the formation of non-lethal resistance alleles can cause drive elements to lose their linked configuration. This severely reduces the invasiveness of the drives and allows for phantom cutting, where an upstream drive element cuts a downstream target locus despite the corresponding drive element being absent, creating and biasing the inheritance of additional resistance alleles. This phantom cutting can be mitigated by an alternative indirect daisy-chain design. We further find that while dominant fitness costs and maternal deposition reduce daisy-chain invasiveness, if overcome with an increased release frequency, they can reduce the spread of the drive into a neighbouring population.

Treating intrusive memories after trauma in healthcare workers: a Bayesian adaptive randomised trial developing an imagery-competing task intervention.

Intensive care unit (ICU) staff continue to face recurrent work-related traumatic events throughout the COVID-19 pandemic. Intrusive memories (IMs) of such traumatic events comprise sensory image-based memories. Harnessing research on preventing IMs with a novel behavioural intervention on the day of trauma, here we take critical next steps in developing this approach as a treatment for ICU staff who are already experiencing IMs days, weeks, or months post-trauma. To address the urgent need to develop novel mental health interventions, we used Bayesian statistical approaches to optimise a brief imagery-competing task intervention to reduce the number of IMs. We evaluated a digitised version of the intervention for remote, scalable delivery. We conducted a two-arm, parallel-group, randomised, adaptive Bayesian optimisation trial. Eligible participants worked clinically in a UK NHS ICU during the pandemic, experienced at least one work-related traumatic event, and at least three IMs in the week prior to recruitment. Participants were randomised to receive immediate or delayed (after 4 weeks) access to the intervention. Primary outcome was the number of IMs of trauma during week 4, controlling for baseline week. Analyses were conducted on an intention-to-treat basis as a between-group comparison. Prior to final analysis, sequential Bayesian analyses were conducted (n = 20, 23, 29, 37, 41, 45) to inform early stopping of the trial prior to the planned maximum recruitment (n = 150). Final analysis (n = 75) showed strong evidence for a positive treatment effect (Bayes factor, BF = 1.25 × 106): the immediate arm reported fewer IMs (median = 1, IQR = 0-3) than the delayed arm (median = 10, IQR = 6-16.5). With further digital enhancements, the intervention (n = 28) also showed a positive treatment effect (BF = 7.31). Sequential Bayesian analyses provided evidence for reducing IMs of work-related trauma for healthcare workers. This methodology also allowed us to rule out negative effects early, reduced the planned maximum sample size, and allowed evaluation of enhancements. Trial Registration NCT04992390 ( www.clinicaltrials.gov ).

Mechanistic modelling of within-mosquito viral dynamics: Insights into infection and dissemination patterns.

Vector or host competence can be defined as the ability of an individual to become infected and subsequently transmit a pathogen. Assays to measure competence play a key part in the assessment of the factors affecting mosquito-borne virus transmission and of potential pathogen-blocking control tools for these viruses. For mosquitoes, competence for arboviruses can be measured experimentally and results are usually analysed using standard statistical approaches. Here we develop a mechanistic approach to studying within-mosquito virus dynamics that occur during vector competence experiments. We begin by developing a deterministic model of virus replication in the mosquito midgut and subsequent escape and replication in the hemocoel. We then extend this to a stochastic model to capture the between-individual variation observed in vector competence experiments. We show that the dose-response of the probability of mosquito midgut infection and variation in the dissemination rate can be explained by stochastic processes generated from a small founding population of virions, caused by a relatively low rate of virion infection of susceptible cells. We also show that comparing treatments or species in competence experiments by fitting mechanistic models could provide further insight into potential differences. Generally, our work adds to the growing body of literature emphasizing the importance of intrinsic stochasticity in biological systems.

A theoretical model for host-controlled regulation of symbiont density.

There is growing empirical evidence that animal hosts actively control the density of their mutualistic symbionts according to their requirements. Such active regulation can be facilitated by compartmentalization of symbionts within host tissues, which confers a high degree of control of the symbiosis to the host. Here, we build a general theoretical framework to predict the underlying ecological drivers and evolutionary consequences of host-controlled endosymbiont density regulation for a mutually obligate association between a host and a compartmentalized, vertically transmitted symbiont. Building on the assumption that the costs and benefits of hosting a symbiont population increase with symbiont density, we use state-dependent dynamic programming to determine an optimal strategy for the host, i.e., that which maximizes host fitness, when regulating the density of symbionts. Simulations of active host-controlled regulation governed by the optimal strategy predict that the density of the symbiont should converge to a constant level during host development, and following perturbation. However, a similar trend also emerges from alternative strategies of symbiont regulation. The strategy which maximizes host fitness also promotes symbiont fitness compared to alternative strategies, suggesting that active host-controlled regulation of symbiont density could be adaptive for the symbiont as well as the host. Adaptation of the framework allowed the dynamics of symbiont density to be predicted for other host-symbiont ecologies, such as for non-essential symbionts, demonstrating the versatility of this modelling approach.

Life history and the evolutionary loss of parental care.

Parental care has been gained and lost evolutionarily multiple times. While many studies have focused on the origin of care, few have explored the evolutionary loss of care. Understanding the loss of parental care is important as the conditions that favour its loss will not necessarily be the opposite of those that favour the evolution of care. Evolutionary hysteresis (the case in which evolution depends on the history of a system) could create a situation in which it is relatively challenging to lose care once it has evolved. Here, using a mathematical approach, we explore the evolutionary loss of parental care in relation to basic life-history conditions. Our results suggest that parental care is most likely to be lost when egg and adult death rates are low, eggs mature quickly, and the level of care provided is high. We also predict evolutionary hysteresis with respect to egg maturation rate: as egg maturation rate decreases, it becomes increasingly more costly to lose care than to gain it. This suggests that once care is present, it will be particularly challenging for it to be lost if eggs develop slowly.

Catastrophe risk can accelerate unlikely evolutionary transitions.

Intelligent life has emerged late in Earth's habitable lifetime, and required a preceding series of key evolutionary transitions. A simple model (the Carter model) explains the late arrival of intelligent life by positing these evolutionary transitions were exceptionally unlikely 'critical steps'. An alternative model (the neocatastrophism hypothesis) proposes that intelligent life was delayed by frequent catastrophes that served to set back evolutionary innovation. Here, we generalize the Carter model and explore this hypothesis by including catastrophes that can 'undo' an evolutionary transition. Introducing catastrophes or evolutionary dead ends can create situations in which critical steps occur rapidly or in clusters, suggesting that past estimates of the number of critical steps could be underestimated. If catastrophes affect complex life more than simple life, the critical steps will also exhibit a pattern of acceleration towards the present, suggesting that the increase in biological complexity over the past 500 Myr could reflect previously overlooked evolutionary transitions. Furthermore, our results have implications for understanding the different explanations (critical steps versus neo-catastrophes) for the evolution of intelligent life and the so-called Fermi paradox-the observation that intelligent life appears rare in the observable Universe.

Incorporating effects of age on energy dynamics predicts nonlinear maternal allocation patterns in iteroparous animals.

Iteroparous parents face a trade-off between allocating current resources to reproduction versus maximizing survival to produce further offspring. Parental allocation varies across age and follows a hump-shaped pattern across diverse taxa, including mammals, birds and invertebrates. This nonlinear allocation pattern lacks a general theoretical explanation, potentially because most studies focus on offspring number rather than quality and do not incorporate uncertainty or age-dependence in energy intake or costs. Here, we develop a life-history model of maternal allocation in iteroparous animals. We identify the optimal allocation strategy in response to stochasticity when energetic costs, feeding success, energy intake and environmentally driven mortality risk are age-dependent. As a case study, we use tsetse, a viviparous insect that produces one offspring per reproductive attempt and relies on an uncertain food supply of vertebrate blood. Diverse scenarios generate a hump-shaped allocation when energetic costs and energy intake increase with age and also when energy intake decreases and energetic costs increase or decrease. Feeding success and environmentally driven mortality risk have little influence on age-dependence in allocation. We conclude that ubiquitous evidence for age-dependence in these influential traits can explain the prevalence of nonlinear maternal allocation across diverse taxonomic groups.

Common mechanisms explain nitrogen-dependent growth of Arctic shrubs over three decades despite heterogeneous trends and declines in soil nitrogen availability.

Heterogeneity has been observed in the responses of Arctic shrubs to climate variability over recent decades, which may reflect landscape-scale variability in belowground resources. At a northern fringe of tall shrub expansion (Yuribei, Yamal Peninsula, Russia), we sought to determine the mechanisms relating nitrogen (N) limitation to shrub growth over decadal time. We analysed the ratio of 15 N to 14 N isotopes in wood rings of 10 Salix lanata individuals (399 measurements) to reconstruct annual point-based bioavailable N between 1980 and 2013. We applied a model-fitting/model-selection approach with a suite of competing ecological models to assess the most-likely mechanisms that explain each shrub's individual time-series. Shrub δ15 N time-series indicated declining (seven shrubs), increasing (two shrubs) and no trend (one shrub) in N availability. The most appropriate model for all shrubs included N-dependent growth of linear rather than saturating form. Inclusion of plant-soil feedbacks better explained ring width and δ15 N for eight of 10 individuals. Although N trajectories were individualistic, common mechanisms of varying strength confirmed the N-dependency of shrub growth. The linear mechanism may reflect intense scavenging of scarce N; the importance of plant-soil feedbacks suggests that shrubs subvert the microbial bottleneck by actively controlling their environment.

Potential use of gene drive modified insects against disease vectors, agricultural pests and invasive species poses new challenges for risk assessment.

Potential future application of engineered gene drives (GDs), which bias their own inheritance and can spread genetic modifications in wild target populations, has sparked both enthusiasm and concern. Engineered GDs in insects could potentially be used to address long-standing challenges in control of disease vectors, agricultural pests and invasive species, or help to rescue endangered species, and thus provide important public benefits. However, there are concerns that the deliberate environmental release of GD modified insects may pose different or new harms to animal and human health and the wider environment, and raise novel challenges for risk assessment. Risk assessors, risk managers, developers, potential applicants and other stakeholders at many levels are currently discussing whether there is a need to develop new or additional risk assessment guidance for the environmental release of GD modified organisms, including insects. Developing new or additional guidance that is useful and practical is a challenge, especially at an international level, as risk assessors, risk managers and many other stakeholders have different, often contrasting, opinions and perspectives toward the environmental release of GD modified organisms, and on the adequacy of current risk assessment frameworks for such organisms. Here, we offer recommendations to overcome some of the challenges associated with the potential future development of new or additional risk assessment guidance for GD modified insects and provide considerations on areas where further risk assessment guidance may be required.

Life history, mating dynamics and the origin of parental care.

Parental care, mating dynamics and life history co-evolve. Understanding the diversity of reproductive patterns found in nature is a major focus of evolutionary ecology research. Previous research suggests that the origin of parental care of eggs will be favoured when egg and adult death rates and juvenile survival are relatively high. However, the previous research that explored the link between care and life history did not account for among-species variation in mating dynamics. As mating dynamics are generally expected to influence care, we explore, theoretically, the life-history conditions (stage-specific rates of maturation and survival) that favour parental care across three mating scenarios: reproductive rate (1) is unaffected by males (assuming that some males are present), (2) increases as male abundance increases or (3) decreases as male abundance increases. Across scenarios, all forms of care were most strongly favoured when egg and adult death rates, juvenile survival and female egg maturation rates were relatively high. When reproductive rate was unaffected by male abundance or increased as male abundance increased, as we might expect in systems in which females are mate-limited, all forms of care were most strongly favoured when male egg maturation rate (i.e. the rate at which male eggs develop, mature and hatch) was moderate or high. When greater male abundance inhibited reproduction, which might occur in systems with intense male-male competition, all forms of care were most strongly favoured when male egg maturation rate was low-to-moderate. These results suggest that life history affects the evolution of parental care, and sex-specific life history can interact with mating dynamics to influence the origin of care.

Repertoire analysis of γδ T cells in the chicken enables functional annotation of the genomic region revealing highly variable pan-tissue TCR gamma V gene usage as well as identifying public and private repertoires.

BACKGROUND: Despite increasing interest in γδ T cells and their non-classical behaviour, most studies focus on animals with low numbers of circulating γδ T cells, such as mice and humans. Arguably, γδ T cell functions might be more prominent in chickens where these cells form a higher proportion of the circulatory T cell compartment. The TCR repertoire defines different subsets of γδ T cells, and such analysis is facilitated by well-annotated TCR loci. γδ T cells are considered at the cusp of innate and adaptive immunity but most functions have been identified in γδ low species. A deeper understanding of TCR repertoire biology in γδ high and γδ low animals is critical for defining the evolution of the function of γδ T cells. Repertoire dynamics will reveal populations that can be classified as innate-like or adaptive-like as well as those that straddle this definition. RESULTS: Here, a recent discrepancy in the structure of the chicken TCR gamma locus is resolved, demonstrating that tandem duplication events have shaped the evolution of this locus. Importantly, repertoire sequencing revealed large differences in the usage of individual TRGV genes, a pattern conserved across multiple tissues, including thymus, spleen and the gut. A single TRGV gene, TRGV3.3, with a highly diverse private CDR3 repertoire dominated every tissue in all birds. TRGV usage patterns were partly explained by the TRGV-associated recombination signal sequences. Public CDR3 clonotypes represented varying proportions of the repertoire of TCRs utilising different TRGVs, with one TRGV dominated by super-public clones present in all birds. CONCLUSIONS: The application of repertoire analysis enabled functional annotation of the TCRG locus in a species with a high circulating γδ phenotype. This revealed variable usage of TCRGV genes across multiple tissues, a pattern quite different to that found in γδ low species (human and mouse). Defining the repertoire biology of avian γδ T cells will be key to understanding the evolution and functional diversity of these enigmatic lymphocytes in an animal that is numerically more reliant on them. Practically, this will reveal novel ways in which these cells can be exploited to improve health in medical and veterinary contexts.

Effects of maternal age and stress on offspring quality in a viviparous fly.

Many organisms show signs of deterioration with age in terms of survival and reproduction. We tested whether intraspecific variation in such senescence patterns can be driven by resource availability or reproductive history. We did this by manipulating nutritional stress and age at first reproduction and measuring age-dependent reproductive output in tsetse (Glossina morsitans morsitans), a viviparous fly with high maternal allocation. Across all treatments, offspring weight followed a bell-shaped curve with maternal age. Nutritionally stressed females had a higher probability of abortion and produced offspring with lower starvation tolerance. There was no evidence of an increased rate of reproductive senescence in nutritionally stressed females, or a reduced rate due to delayed mating, as measured by patterns of abortion, offspring weight or offspring starvation tolerance. Therefore, although we found evidence of reproductive senescence in tsetse, our results did not indicate that resource allocation trade-offs or costs of reproduction increase the rate of senescence.

The concomitant effects of self-limiting insect releases and behavioural interference on patterns of coexistence and exclusion of competing mosquitoes.

Aedes aegypti is the dominant vector of dengue, a potentially fatal virus whose incidence has increased eightfold in the last two decades. As dengue has no widely available vaccine, vector control is key to reducing the global public health burden. A promising method is the release of self-limiting Ae. aegypti, which mate with wild Ae. aegypti and produce non-viable offspring. The resultant decrease in Ae. aegypti population size may impact coexistence with Ae. albopictus, another vector of dengue. A behavioural mechanism influencing coexistence between these species is reproductive interference, where incomplete species recognition results in heterospecifics engaging in mating activities. We develop a theoretical framework to investigate the interaction between self-limiting Ae. aegypti releases and reproductive interference between Ae. aegypti and Ae. albopictus on patterns of coexistence. In the absence of self-limiting Ae. aegypti release, coexistence can occur when the strength of reproductive interference experienced by both species is low. Results show that substantial overflooding with self-limiting Ae. aegypti prevents coexistence. For lower release ratios, as the release ratio increases, coexistence can occur when the strength of reproductive interference is increasingly high for Ae. albopictus and increasingly low for Ae. aegypti. This emphasizes the importance of including behavioural ecological processes into population models to evaluate the efficacy of vector control.

Insect-host control of obligate, intracellular symbiont density.

Many insects rely on intracellular bacterial symbionts to supplement their specialized diets with micronutrients. Using data from diverse and well-studied insect systems, we propose three lines of evidence suggesting that hosts have tight control over the density of their obligate, intracellular bacterial partners. First, empirical studies have demonstrated that the within-host symbiont density varies depending on the nutritional and developmental requirements of the host. Second, symbiont genomes are highly reduced and have limited capacity for self-replication or transcriptional regulation. Third, several mechanisms exist for hosts to tolerate, regulate and remove symbionts including physical compartmentalization and autophagy. We then consider whether such regulation is adaptive, by discussing the relationship between symbiont density and host fitness. We discuss current limitations of empirical studies for exploring fitness effects in host-symbiont relationships, and emphasize the potential for using mathematical models to formalize evolutionary hypotheses and to generate testable predictions for future work.

Combining refuges with transgenic insect releases for the management of an insect pest with non-recessive resistance to Bt crops in agricultural landscapes.

Reinforcing the high-dose/refuge strategy with releases of transgenic insects has been suggested as a method for simultaneously managing agricultural pest populations and resistance to transgenic crops. Theoretical and empirical studies have shown that these approaches can work when deployed against closed populations and the assumptions of the HDR strategy are met. However, field-evolved resistance is often linked to non-recessive resistance or refuge non-compliance, and pest management regimes are likely to take place at the landscape-level. It is therefore important to understand how effective such strategies are when resistance is non-recessive, and how they could be employed in agricultural landscapes. We developed a spatially-explicit model to investigate the efficacy of strategies combining refuges with transgenic insect releases to manage a pest with non-recessive resistance in agricultural landscapes. We compared two release strategies, area-wide releases and localised releases targeted at population hotspots, and analysed the effects of refuge and release parameters on population and resistance dynamics. Area-wide releases reliably achieved landscape-level pest eradication. Localised releases also eradicated the pest when low release thresholds were combined with high release ratios, and maintained the pest at low densities when insufficient to achieve extinction. Reinforcing refuges with localised releases also greatly enhanced the probability of resistance extinction. However, when resistance remained in the population, localised releases prevented resistance from reaching fixation rather than greatly delaying or reversing resistance evolution. Our work indicates that combining refuges with simple release policies is effective for landscape-level pest suppression when the HDR assumptions are violated, but more nuanced release strategies may be required to enhance the benefits to resistance management.

Clonal hematopoiesis of indeterminate potential and its impact on patient trajectories after stem cell transplantation.

Clonal hematopoiesis of indeterminate potential (CHIP) is a recently identified process where older patients accumulate distinct subclones defined by recurring somatic mutations in hematopoietic stem cells. CHIP's implications for stem cell transplantation have been harder to identify due to the high degree of mutational heterogeneity that is present within the genetically distinct subclones. In order to gain a better understanding of CHIP and the impact of clonal dynamics on transplantation outcomes, we created a mathematical model of clonal competition dynamics. Our analyses highlight the importance of understanding competition intensity between healthy and mutant clones. Importantly, we highlight the risk that CHIP poses in leading to dominance of precancerous mutant clones and the risk of donor derived leukemia. Furthermore, we estimate the degree of competition intensity and bone marrow niche decline in mice during aging by using our modeling framework. Together, our work highlights the importance of better characterizing the ecological and clonal composition in hematopoietic donor populations at the time of stem cell transplantation.

Resilience: nitrogen limitation, mycorrhiza and long-term palaeoecological plant-nutrient dynamics.

Ecosystem dynamics are driven by both biotic and abiotic processes, and perturbations can push ecosystems into novel dynamical regimes. Plant-plant, plant-soil and mycorrhizal associations all affect plant ecosystem dynamics; however, the direction and magnitude of these effects vary by context and their contribution to ecosystem resilience over long time periods remains unknown. Here, using a mathematical framework, we investigate the effects of plant feedbacks and mycorrhiza on plant-nutrient interactions. We show evidence for strong nutrient controlled feedbacks, moderation by mycorrhiza and influence on ecological resilience. We use this model to investigate the resilience of a longitudinal palaeoecological birch-δ15N interaction to plant-soil feedbacks and mycorrhizal associations. The birch-δ15N system demonstrated high levels of resilience. Mycorrhiza were predicted to increase resilience by supporting plant-nitrogen uptake and immobilizing excess nitrogen; in contrast, long-term enrichment in available nitrogen by plant-soil feedbacks is expected to decrease ecological resilience.

Coevolution influences the evolution of filial cannibalism, offspring abandonment and parental care.

Understanding evolutionary patterns of parental investment and care has been a long-standing focus in studies of evolutionary and behavioural ecology. Indeed, patterns of investment and care are highly diverse, and fully understanding such diversity has been challenging. Recently, several studies have highlighted the need to consider coevolutionary dynamics in studies of parental care, as parental care is likely to co-occur and co-originate with a range of other traits. Two traits that commonly co-occur with parental care are offspring abandonment (the termination of parental investment prior to full independence in offspring) and filial cannibalism (the consumption of one's offspring). Here, we use a mathematical framework to explore how co-occurrence and coevolution among care, abandonment and cannibalism can influence the life-history conditions under which care is expected to evolve. Our results suggest that in some cases, the evolution of parental care can be inhibited by offspring abandonment and filial cannibalism. In other cases, abandonment and filial cannibalism that benefits parents can promote the evolution of parental care. It is particularly interesting that behaviours that seem so contrary to care-that is, eating or abandoning one's young-can in some cases broaden the conditions under which care can evolve. In general, our findings highlight that considering co-occurrence and coevolutionary dynamics between two or more traits is essential to understanding the evolution of trait diversity.

Crystal toxins and the volunteer's dilemma in bacteria.

The growth and virulence of the bacteria Bacillus thuringiensis depend on the production of Cry toxins, which are used to perforate the gut of its host. Successful invasion of the host relies on producing a threshold amount of toxin, after which there is no benefit from producing more toxin. Consequently, the production of Cry toxin appears to be a different type of social problem compared with the public goods scenarios that bacteria usually encounter. We show that selection for toxin production is a volunteer's dilemma. We make specific predictions that (a) selection for toxin production depends upon an interplay between the number of bacterial cells that each host ingests and the genetic relatedness between those cells; (b) cheats that do not produce toxin gain an advantage when at low frequencies, and at high bacterial density, allowing them to be maintained in a population alongside toxin-producing cells. More generally, our results emphasize the diversity of the social games that bacteria play.

Insect pest control, approximate dynamic programming, and the management of the evolution of resistance.

Ecological decision problems, such as those encountered in agriculture, often require managing conflicts between short-term costs and long-term benefits. Dynamic programming is an ideal method for optimally solving such problems but agricultural problems are often subject to additional complexities that produce state spaces intractable to exact solutions. In contrast, look-ahead policies, a class of approximate dynamic programming (ADP) algorithm, may attempt to solve problems of arbitrary magnitude. However, these algorithms focus on a temporally truncated caricature of the full decision problem over a defined planning horizon and as such are not guaranteed to suggest optimal actions. Thus, look-ahead policies may offer promising means of addressing detail-rich ecological decision problems but may not be capable of fully utilizing the information available to them, especially in scenarios where the best short- and long-term solutions may differ. We constructed and applied look-ahead policies to the management of a hypothetical, stage-structured, continually reproducing, agricultural insect pest. The management objective was to minimize the combined costs of management actions and crop damage over a 16-week growing season. The manager could elect to utilize insecticidal sprays or one of six release ratios of male-selecting transgenic insects where the release ratio determines the number of transgenic insects to be released for each wild-type male insect in the population. Complicating matters was the expression of insecticide resistance at non-trivial frequencies in the pest population. We assessed the extent to which look-ahead policies were able to recognize the potential threat of insecticide resistance and successfully integrate insecticides and transgenic releases to capitalize upon their respective benefits. Look-ahead policies were competent at anticipating and responding to ecological and economic information. Policies with longer planning horizons made fewer, better-timed insecticidal sprays and made more frequent transgenic releases, which consequently facilitated lower resistance allele frequencies. However, look-ahead policies were ultimately inefficient resistance managers, and directly responded to resistance only when it was dominant and prevalent. Effective long-term agricultural management requires the capacity to anticipate and respond to the evolution of resistance. Look-ahead policies can accommodate all the information pertinent to making the best long-term decision but may lack the perspective to actually do so.