@article{okamoto_gould_lloyd_2016, title={Integrating Transgenic Vector Manipulation with Clinical Interventions to Manage Vector-Borne Diseases}, volume={12}, ISSN={1553-7358}, url={http://dx.doi.org/10.1371/journal.pcbi.1004695}, DOI={10.1371/journal.pcbi.1004695}, abstractNote={Many vector-borne diseases lack effective vaccines and medications, and the limitations of traditional vector control have inspired novel approaches based on using genetic engineering to manipulate vector populations and thereby reduce transmission. Yet both the short- and long-term epidemiological effects of these transgenic strategies are highly uncertain. If neither vaccines, medications, nor transgenic strategies can by themselves suffice for managing vector-borne diseases, integrating these approaches becomes key. Here we develop a framework to evaluate how clinical interventions (i.e., vaccination and medication) can be integrated with transgenic vector manipulation strategies to prevent disease invasion and reduce disease incidence. We show that the ability of clinical interventions to accelerate disease suppression can depend on the nature of the transgenic manipulation deployed (e.g., whether vector population reduction or replacement is attempted). We find that making a specific, individual strategy highly effective may not be necessary for attaining public-health objectives, provided suitable combinations can be adopted. However, we show how combining only partially effective antimicrobial drugs or vaccination with transgenic vector manipulations that merely temporarily lower vector competence can amplify disease resurgence following transient suppression. Thus, transgenic vector manipulation that cannot be sustained can have adverse consequences—consequences which ineffective clinical interventions can at best only mitigate, and at worst temporarily exacerbate. This result, which arises from differences between the time scale on which the interventions affect disease dynamics and the time scale of host population dynamics, highlights the importance of accounting for the potential delay in the effects of deploying public health strategies on long-term disease incidence. We find that for systems at the disease-endemic equilibrium, even modest perturbations induced by weak interventions can exhibit strong, albeit transient, epidemiological effects. This, together with our finding that under some conditions combining strategies could have transient adverse epidemiological effects suggests that a relatively long time horizon may be necessary to discern the efficacy of alternative intervention strategies.}, number={3}, journal={PLOS Computational Biology}, publisher={Public Library of Science (PLoS)}, author={Okamoto, Kenichi W. and Gould, Fred and Lloyd, Alun L.}, editor={Alizon, SamuelEditor}, year={2016}, month={Mar}, pages={e1004695} }
 @article{okamoto_langerhans_rashid_amarasekare_2015, title={Microevolutionary patterns in the common caiman predict macroevolutionary trends across extant crocodilians}, volume={116}, ISSN={["1095-8312"]}, DOI={10.1111/bij.12641}, abstractNote={Both extinct and extant crocodilians have repeatedly diversified in skull shape along a continuum, from narrow-snouted to broad-snouted phenotypes. These patterns occur with striking regularity, although it is currently unknown whether these trends also apply to microevolutionary divergence during population differentiation or the early stages of speciation. Assessing patterns of intraspecific variation within a single taxon can potentially provide insight into the processes of macroevolutionary differentiation. For example, high levels of intraspecific variation along a narrow-broad axis would be consistent with the view that cranial shapes can show predictable patterns of differentiation on relatively short timescales, and potentially scale up to explain broader macroevolutionary patterns. In the present study, we use geometric morphometric methods to characterize intraspecific cranial shape variation among groups within a single, widely distributed clade, Caiman crocodilus. We show that C. crocodilus skulls vary along a narrow/broad-snouted continuum, with different subspecies strongly clustered at distinct ends of the continuum. We quantitatively compare these microevolutionary trends with patterns of diversity at macroevolutionary scales (among all extant crocodilians). We find that morphological differences among the subspecies of C. crocodilus parallel the patterns of morphological differentiation across extant crocodilians, with the primary axes of morphological diversity being highly correlated across the two scales. We find intraspecific cranial shape variation within C. crocodilus to span variation characterized by more than half of living species. We show the main axis of intraspecific phenotypic variation to align with the principal direction of macroevolutionary diversification in crocodilian cranial shape, suggesting that mechanisms of microevolutionary divergence within species may also explain broader patterns of diversification at higher taxonomic levels.}, number={4}, journal={BIOLOGICAL JOURNAL OF THE LINNEAN SOCIETY}, author={Okamoto, Kenichi W. and Langerhans, R. Brian and Rashid, Rezoana and Amarasekare, Priyanga}, year={2015}, month={Dec}, pages={834–846} }
 @article{drury_okamoto_anderson_grether_2015, title={Reproductive interference explains persistence of aggression between species}, volume={282}, number={1804}, journal={Proceedings of the Royal Society of London. Series B}, author={Drury, J. P. and Okamoto, K. W. and Anderson, C. N. and Grether, G. F.}, year={2015} }
 @article{okamoto_robert_gould_lloyd_2014, title={Feasible Introgression of an Anti-pathogen Transgene into an Urban Mosquito Population without Using Gene-Drive}, volume={8}, ISSN={["1935-2735"]}, DOI={10.1371/journal.pntd.0002827}, abstractNote={Background Introgressing anti-pathogen constructs into wild vector populations could reduce disease transmission. It is generally assumed that such introgression would require linking an anti-pathogen gene with a selfish genetic element or similar technologies. Yet none of the proposed transgenic anti-pathogen gene-drive mechanisms are likely to be implemented as public health measures in the near future. Thus, much attention now focuses instead on transgenic strategies aimed at mosquito population suppression, an approach generally perceived to be practical. By contrast, aiming to replace vector competent mosquito populations with vector incompetent populations by releasing mosquitoes carrying a single anti-pathogen gene without a gene-drive mechanism is widely considered impractical. Methodology/Principal Findings Here we use Skeeter Buster, a previously published stochastic, spatially explicit model of Aedes aegypti to investigate whether a number of approaches for releasing mosquitoes with only an anti-pathogen construct would be efficient and effective in the tropical city of Iquitos, Peru. To assess the performance of such releases using realistic release numbers, we compare the transient and long-term effects of this strategy with two other genetic control strategies that have been developed in Ae. aegypti: release of a strain with female-specific lethality, and a strain with both female-specific lethality and an anti-pathogen gene. We find that releasing mosquitoes carrying only an anti-pathogen construct can substantially decrease vector competence of a natural population, even at release ratios well below that required for the two currently feasible alternatives that rely on population reduction. Finally, although current genetic control strategies based on population reduction are compromised by immigration of wild-type mosquitoes, releasing mosquitoes carrying only an anti-pathogen gene is considerably more robust to such immigration. Conclusions/Significance Contrary to the widely held view that transgenic control programs aimed at population replacement require linking an anti-pathogen gene to selfish genetic elements, we find releasing mosquitoes in numbers much smaller than those considered necessary for transgenic population reduction can result in comparatively rapid and robust population replacement. In light of this non-intuitive result, directing efforts to improve rearing capacity and logistical support for implementing releases, and reducing the fitness costs of existing recombinant technologies, may provide a viable, alternative route to introgressing anti-pathogen transgenes under field conditions.}, number={7}, journal={PLOS NEGLECTED TROPICAL DISEASES}, author={Okamoto, Kenichi W. and Robert, Michael A. and Gould, Fred and Lloyd, Alun L.}, year={2014}, month={Jul} }
 @article{okamoto_amarasekare_petty_2014, title={Modeling oncolytic virotherapy: Is complete tumor-tropism too much of a good thing?}, volume={358}, ISSN={["1095-8541"]}, DOI={10.1016/j.jtbi.2014.04.030}, abstractNote={The specific targeting of tumor cells by replication-competent oncolytic viruses is considered indispensable for realizing the potential of oncolytic virotherapy. Yet off-target infections by oncolytic viruses may increase virus production, further reducing tumor load. This ability may be critical when tumor-cell scarcity or the onset of an adaptive immune response constrain viral anti-tumoral efficacy. Here we develop a mathematical framework for assessing whether oncolytic viruses with reduced tumor-specificity can more effectively eliminate tumors while keeping losses to normal cell populations low. We find viruses that infect some normal cells can potentially balance the competing goals of tumor elimination and minimizing the effects on normal cell populations. Particularly when infected tissues can be regenerated, moderating rather than completely eliminating the ability of oncolytic viruses to infect and lyse normal cells could improve cancer treatment, with potentially fewer side-effects than conventional treatments such as chemotherapy.}, journal={JOURNAL OF THEORETICAL BIOLOGY}, author={Okamoto, Kenichi W. and Amarasekare, Priyanga and Petty, Ian T. D.}, year={2014}, month={Oct}, pages={166–178} }
 @article{robert_okamoto_lloyd_gould_2013, title={A Reduce and Replace Strategy for Suppressing Vector-Borne Diseases: Insights from a Deterministic Model}, volume={8}, ISSN={["1932-6203"]}, DOI={10.1371/journal.pone.0073233}, abstractNote={Genetic approaches for controlling disease vectors have aimed either to reduce wild-type populations or to replace wild-type populations with insects that cannot transmit pathogens. Here, we propose a Reduce and Replace (R&R) strategy in which released insects have both female-killing and anti-pathogen genes. We develop a mathematical model to numerically explore release strategies involving an R&R strain of the dengue vector Aedes aegypti. We show that repeated R&R releases may lead to a temporary decrease in mosquito population density and, in the absence of fitness costs associated with the anti-pathogen gene, a long-term decrease in competent vector population density. We find that R&R releases more rapidly reduce the transient and long-term competent vector densities than female-killing releases alone. We show that releases including R&R females lead to greater reduction in competent vector density than male-only releases. The magnitude of reduction in total and competent vectors depends upon the release ratio, release duration, and whether females are included in releases. Even when the anti-pathogen allele has a fitness cost, R&R releases lead to greater reduction in competent vectors than female-killing releases during the release period; however, continued releases are needed to maintain low density of competent vectors long-term. We discuss the results of the model as motivation for more detailed studies of R&R strategies.}, number={9}, journal={PLOS ONE}, author={Robert, Michael A. and Okamoto, Kenichi and Lloyd, Alun L. and Gould, Fred}, year={2013}, month={Sep} }
 @article{okamoto_robert_lloyd_gould_2013, title={A Reduce and Replace Strategy for Suppressing Vector-Borne Diseases: Insights from a Stochastic, Spatial Model}, volume={8}, ISSN={["1932-6203"]}, DOI={10.1371/journal.pone.0081860}, abstractNote={Two basic strategies have been proposed for using transgenic Aedes aegypti mosquitoes to decrease dengue virus transmission: population reduction and population replacement. Here we model releases of a strain of Ae. aegypti carrying both a gene causing conditional adult female mortality and a gene blocking virus transmission into a wild population to assess whether such releases could reduce the number of competent vectors. We find this “reduce and replace” strategy can decrease the frequency of competent vectors below 50% two years after releases end. Therefore, this combined approach appears preferable to releasing a strain carrying only a female-killing gene, which is likely to merely result in temporary population suppression. However, the fixation of anti-pathogen genes in the population is unlikely. Genetic drift at small population sizes and the spatially heterogeneous nature of the population recovery after releases end prevent complete replacement of the competent vector population. Furthermore, releasing more individuals can be counter-productive in the face of immigration by wild-type mosquitoes, as greater population reduction amplifies the impact wild-type migrants have on the long-term frequency of the anti-pathogen gene. We expect the results presented here to give pause to expectations for driving an anti-pathogen construct to fixation by relying on releasing individuals carrying this two-gene construct. Nevertheless, in some dengue-endemic environments, a spatially heterogeneous decrease in competent vectors may still facilitate decreasing disease incidence.}, number={12}, journal={PLOS ONE}, author={Okamoto, Kenichi W. and Robert, Michael A. and Lloyd, Alun L. and Gould, Fred}, year={2013}, month={Dec} }
 @misc{okamoto_grether_2013, title={The evolution of species recognition in competitive and mating contexts: the relative efficacy of alternative mechanisms of character displacement}, volume={16}, number={5}, journal={Ecology Letters}, author={Okamoto, K. W. and Grether, G. F.}, year={2013}, pages={670–678} }
 @article{grether_anderson_drury_kirschel_losin_okamoto_peiman_2013, title={The evolutionary consequences of interspecific aggression}, volume={1289}, journal={Year in evolutionary biology}, author={Grether, G. F. and Anderson, C. N. and Drury, J. P. and Kirschel, A. N. G. and Losin, N. and Okamoto, K. and Peiman, K. S.}, year={2013}, pages={48–68} }
 @article{legros_xu_okamoto_scott_morrison_lloyd_gould_2012, title={Assessing the Feasibility of Controlling Aedes aegypti with Transgenic Methods: A Model-Based Evaluation}, volume={7}, ISSN={1932-6203}, url={http://dx.doi.org/10.1371/journal.pone.0052235}, DOI={10.1371/journal.pone.0052235}, abstractNote={Suppression of dengue and malaria through releases of genetically engineered mosquitoes might soon become feasible. Aedes aegypti mosquitoes carrying a conditionally lethal transgene have recently been used to suppress local vector populations in small-scale field releases. Prior to releases of transgenic insects on a wider scale, however, most regulatory authorities will require additional evidence that suppression will be effective in natural heterogeneous habitats. We use a spatially explicit stochastic model of an Ae. aegypti population in Iquitos, Peru, along with an uncertainty analysis of its predictions, to quantitatively assess the outcome of varied operational approaches for releases of transgenic strains with conditional death of females. We show that population elimination might be an unrealistic objective in heterogeneous populations. We demonstrate that substantial suppression can nonetheless be achieved if releases are deployed in a uniform spatial pattern using strains combining multiple lethal elements, illustrating the importance of detailed spatial models for guiding genetic mosquito control strategies.}, number={12}, journal={PLoS ONE}, publisher={Public Library of Science (PLoS)}, author={Legros, Mathieu and Xu, Chonggang and Okamoto, Kenichi and Scott, Thomas W. and Morrison, Amy C. and Lloyd, Alun L. and Gould, Fred}, editor={Vasilakis, NikosEditor}, year={2012}, month={Dec}, pages={e52235} }
 @article{okamoto_amarasekare_2012, title={The biological control of disease vectors}, volume={309}, journal={Journal of Theoretical Biology}, author={Okamoto, K. W. and Amarasekare, P.}, year={2012}, pages={47–57} }