Towards ecologically-realistic genetic mosquito population control strategies for disease elimination

The ‘shifting’ method of genetically modifying vectors that does not require any input of novel genetic material into populations will be discussed. Updated advances will include modelling of this method to explore its feasibility and new estimates of effective population sizes of natural populations of Aedes aegypti. It will be proposed that this ‘natural’ method of genetic control is not mutually exclusive of ‘synthetic’ approaches that employ transgenic methods. Hybrid programmes could take advantages of each approach. A prime goal of any such programme should be to minimise the genetic perturbation of natural populations.  

Time permitting, the question ‘Why is Aedes aegypti the primary vector of almost all arboviruses affecting humans?’ will be asked and answers proffered. 

Professor Jeffrey Powell, Yale University, USA

Professor Jeffrey Powell, Yale University, USA

Professor Powell began working on Aedes aegypti as an undergraduate student at Notre Dame under George B. Craig in 1967. He obtained a PhD under the supervision of Theodoius Dobzhansky. Since 1972 he has been on the faculty of Yale Univeristy. His area of expertise is population genetics and evolutionary biology.

The increasing evidence over the last 50 years of a striking degree of genetic and bionomical heterogeneities among and within species of the Anopheles gambiae complex has definitively made clear to the scientific community that malaria vector control strategies need to account for these cryptic genetic discontinuities to ensure their efficacy. This is particularly true in the case of genetic control strategies that are being developed to reduce or replace malaria vectors. 

Professor della Torre will focus on the two most recently diverged members of the complex – A. gambiae  and A. coluzzii – and show novel genomic and ecological data suggesting that the same process of genetic adaptation to environmental and anthropogenic changes that is believed to have driven historical diversification of the A. gambiae complex continues to act within them, likely altering epidemiologically important attributes. Professor della Torre will first show how genetic, behavioural, and ecological components interact in a complex way to modulate the strength of reproductive isolation across Africa, and then describe the genomic signatures of this dynamic process. She will then focus on the area of high hybridisation between the two species at the far-west of their range, and present novel data suggesting that extensive introgressive hybridisation occurring particularly in the coastal region is leading to a locally selected hybrid form which appears to be more resilient against introgression of medically-important loci and traits than inland populations. Overall, these data point to a very dynamic, site-specific and ongoing process of intra-specific sub-structuring within the two major Afrotropical malaria vectors, and highlight the need to monitor these ongoing process and its impact on epidemiologically important attributes, such longevity, fecundity, parasite susceptibility, host seeking behaviour.

Professor Alessandra della Torre, Sapienza University of Rome, Italy

Professor Alessandra della Torre, Sapienza University of Rome, Italy

Professor Alessandra della Torre is Associate Professor of Parasitology at University of Rome SAPIENZA, where she graduated in Biological Sciences and got a doctorate in Microbiology and Epidemiology. She coordinates the Medical Entomology group which is focused on Afrotropical malaria vectors – with particular reference to bionomics, population genetics, genomics of the Anopheles gambiae complex, having a primary role in highlighting intra-specific genetic sub-structuring leading to the recognition of a new species of the complex, A. coluzzii – and autochthonous and invasive mosquito vectors of human and zoonotic diseases in Europe – with particular reference to bionomics of Ae. albopictus and development/optimisation of monitoring/control tools. Professor Alessandra della Torre’s research activities are carried out in partnership with several European and international groups, including groups from malaria endemic countries, in the frame of projects funded by European Community and NIH. She is also a member of the Partner Working Group of the ‘Anopheles gambiae 1.000 genome’ which is providing to the scientific community a very powerful tool for describing A. gambiae and A. coluzzii population structure and history, and for conducting genome-wide association studies of vector traits relevant for local malaria epidemiology.

Existing malaria control interventions have been very successful in reducing the burden of disease, but still hundreds of thousands die every year, and new tools are likely to be needed to eliminate the disease. Recent progress in molecular biology offers the potential for a new platform for malaria control based on genetic manipulation of the mosquito vectors. Some of the many genetic approaches that have been proposed will be reviewed, focussing in particular on those using sequence-specific nucleases, and some of the population modelling that aims to predict the impact of alternative strategies.

Professor Austin Burt, Imperial College London, UK

Professor Austin Burt, Imperial College London, UK

Austin Burt is Professor of Evolutionary Genetics at Imperial College London. In 2003 he proposed that enzymes that recognise and cut specific sequences of DNA could be used to control pest populations, and since 2005 he has been Principle Investigator of a research consortium developing this idea to control the mosquitoes that transmit malaria, with particular attention to sub-Saharan Africa. Target Malaria is a not-for-profit consortium that currently includes over 100 individuals at 14 institutions across 3 continents (www.targetmalaria.org).

The evolution of insecticide and drug resistance and the complexity of vectorial system have seriously challenged standard public health approaches to control malaria and to date, alternative measures are desperately needed. New control approaches envision using engineered mosquitoes to suppress or to replace existing populations. Another approach that may be effective is based on conventional sterile male release. However, availability of these tools does not necessarily guarantee ultimate success. A major concern is that presence of reproductive barriers will reduce the spread of the genes of interest between subpopulations. A second concern is the possibility that laboratory adapted mosquitoes will not be able to compete for mates in the wild. Success will depend on understanding patterns of effective mosquito reproduction that are relevant to transgene spread. Most population models assume that all individuals have the same reproductive success, which probably is not the case. The most plausible natural circumstance is variation in the competitiveness of males to acquire a mate as well as assortative mating — the tendency of certain phenotype to mate with one another — yet these phenomena have been little studied in mosquitoes. Field and large outdoor cage studies designed to dissect the mating biology and characterise essential factors that enhance mating competitiveness in mosquitoes are needed to provide a foundation for predicting the potential utility of genetic control. Here, some of the key practical questions that are essential to translate transgenic or sterile males technological advance into improved malaria control in the field will be addressed.

Dr Aboulaye Diabate, Institut de Recherche sur les Sciences de la Santé, Burkina Faso

Dr Aboulaye Diabate, Institut de Recherche sur les Sciences de la Santé, Burkina Faso

Diabate Abdoulaye is a vector ecologist. He received a PhD degree from the University of Montpellier and spent four years as a postdoc fellow at NIH in the US. His research activities proceed along two different but complementary directions. First, it involves insecticide resistance and its management; and second, it focuses on population biology, ecological studies on phenotypic variation within and between populations of mosquitoes, and analyses of its genetic and environmental sources. He is particularly interested in mosquito male biology and related transgenic and sterile male approaches to control vector diseases. He has been an invited speaker in several prestigious universities including Harvard University. He is the recipient of the Royal Society Pfizer Award 2013, and was awarded the Grand Challenges Star in Global Health Grant and the MRC/DFID African Leader Scheme grant. Currently he is the group lead of the Vector Biology Department at IRSS, Bobo Dioulasso, Burkina Faso.

Aedes aegypti and Aedes albopictus are not only the most important vectors of dengue, chikungunya, and Zika viruses but also the world’s most invasive mosquito species. Because of their widespread distributions and similar ecological requirements, the two species frequently encounter one another, leading to potential competitive interactions. Despite this, most predictive spatial distribution models do not account for the effects of such interspecific competition. Outcomes of interactions depend on both local environments and the genotypes of competitors. In the common circumstances where invasions result in their co-existence, habitat segregation favours the predominance of domesticated A. aegypti in urban areas and of A. albopictus in vegetated zones. Examples of competitive displacements of A. albopictus by A. aegypti are confined to urbanised environments. Massive competitive displacements that led to local extinctions of A. aegypti by A. albopictus have been documented in southeastern USA and Bermuda. These rapid displacements are believed to be caused by asymmetric reproductive interference, known as satyrization. Larval resource competition favouring A. albopictus may act synergistically with satyrisation, or alone to achieve slower outcomes, such as habitat segregation during co-existence. Resistance to satyrisation evolves rapidly in A. aegypti and is retained in all Florida populations of this species in sympatry with A. albopictus. Different outcomes may prevail in other co-existence contexts, e.g., where A. aegypti are represented by the feral ssp. formosus, or where male A. albopictus are inefficient satyrs. Genetic control planning should include awareness of the potentials for competitive displacements and the evolution of antagonistic phenotypes.

Professor L. Philip Lounibos, University of Florida, USA

Professor L. Philip Lounibos, University of Florida, USA

Professor Lounibos is a broadly trained biologist (PhD Harvard, 1974) who has conducted research for over fifty years on aspects of mosquito ecology, behaviour, and evolution. Although no longer working on genetic control, while employed in the 1970s by ICIPE in Kenya Professor Lounibos directed the first field trials of chromosome translocations for control of Aedes aegypti. Since 1977 he has been employed at the Florida Medical Entomology Laboratory, which became part of the University of Florida several years after his arrival. Professor Lounibos’ current academic appointment of Distinguished Professor is in UF’s Department of Entomology, where he also teaches and supervises graduate students. For the past twenty years, mosquito invasion biology, especially the causes of competitive displacements, have been central to Professor Lounibos’ research pursuits.

Ecological factors are likely to be critical in successful application of genetic control strategies, including movement dynamics and use of the landscape, and factors affecting population dynamics such as mortality rates and competitive interactions. Models provide tools for integrating the effects of many factors, but it is not feasible to include all factors in every model. Models focusing on genetic control strategies may not include ecological details, while models focusing on pathogen transmission, other control strategies, or population dynamics likely do not include genetic control strategies. However, many types of models can be useful in the discussion about genetic strategies. Considering the factors included, available data, and effects on the outcomes of different models can provide information about important ecological aspects that may influence outcomes of genetic control strategies, and highlight areas requiring additional data for parameter estimation. Models of mosquito-borne viruses will be used to illustrate how differences between mosquito species can influence transmission dynamics and need to be considered in developing control strategies. Mosquito movement across a landscape likely influences the success of control strategies. Models of mosquito movement in simplified landscapes will illustrate how landscapes affect spatial distribution and potential efficacy of different control strategies.

Dr Cynthia Lord, University of Florida, USA

Dr Cynthia Lord, University of Florida, USA

Dr Lord’s research interests are in the ecology and epidemiology of vector-borne pathogens. Current projects include the role of multiple vector species in Aedes vectored arboviruses, factors influencing effective use of novel mosquito control methods, and how transstadial effects of the larval environment influence arbovirus transmission dynamics.

Dr Lord is an Associate Professor at the Florida Medical Entomology Laboratory, University of Florida. She received her BS in Zoology from the University of Vermont and her PhD in Ecology and Evolutionary Biology from Princeton University. Her doctoral research was on the seasonal population dynamics of the black-legged tick, combining field research and theoretical studies. She subsequently did post-doctoral research at the University of Notre Dame on the population dynamics of an invasive mosquito, and at the University of Oxford on African Horse sickness invasion and epidemiology.

Nearly 20 years into a successful global campaign against malaria, the disease still costs over 400,000 lives a year. As the campaign’s primary weapon was aimed against the mosquito, it is also a testimony for the resilience of this vectorial system. The genetic mosquito control promises to overcome limitations of our conventional measures of vector control by recruiting the vector reproductive drive as a weapon against itself. Trusting the mosquito to do its part might be naïve even without undesirable results. The complexity of the real world is not represented in a cage (even if named malaria-sphere), where the mosquito manifests only a fraction of its multi-faceted biology and personalities. Our knowledge of mosquitoes outside the lab is full of major unknowns, multiplying the uncertainty in predicting the spread of introduced genes within and between populations. Nobody has followed a single wild mosquito through a full night. We only guess where they take their sugar meals, mate, rest, how far they fly, how they persist though the months-long dry season? Current knowledge of the deme’s effective size, geographical dimensions, its boundaries, and the geneflow connecting different demes–are all questionable. Further, we don't know how fast they would counter our actions by mutation(s) in the introduced gene or in other genes whose function alters the outcome. Because we will never know all the answers, we could test the success of the genetic approach on a distant island or in a ‘developed country’ targeting a local vector, while at the same time, seek answers to high priority questions. Moreover, demonstrating a capacity to ‘recall’ an introduced gene and restore the previous genetic makeup would be key.

Dr Tovi Lehmann, National Institute of Allergy and Infectious Diseases, National Institutes of Health, USA

Dr Tovi Lehmann, National Institute of Allergy and Infectious Diseases, National Institutes of Health, USA

Dr Lehmann works in the Laboratory of Malaria and Vector Research, in the National Institute of Allergy and Infectious Diseases, National Institutes of Health, USA. He has been studying the ecology of African malaria mosquitoes integrating field and laboratory experiments. With colleagues he is currently investigating the mystery of malaria mosquito persistence through the Sahelian dry season, focusing on aestivation (dry-season diapause) and long-distance migration. Their inferences are based on mark-release-recapture experiments, spatio-temporal variation in vector density, aerial sampling of mosquitoes in the lower jet stream, seasonal changes in physiology, genetic variability in natural populations, tracking scent-tagged mosquitoes in shelters using sniffing dogs, among other approaches. Their results provide evidence for aestivation in A. coluzzii and wind-assisted long-distance migration in A. gambiae s.s. and A. arabiensis, both of which have important implications for understanding disease transmission as well as for malaria control.

Gene-editing and gene-drive techniques offer the possibility of imposing a genetic load on a mosquito vector population that reduces its density to a level at which it can no longer support disease transmission or itself goes extinct. The possibility of extinction distinguishes this form of vector control from most other interventions. This talk will consider the potential ecological consequences of removing a species from a community or driving its population to very low densities, with a particular focus on the African vectors of malaria. It will consider the possibility of relaxed competition leading to super-competent vectors or population rebound, and the risks of an empty niche being filled by other potentially more powerful vectors. It will also explore the possibility that removing a species from an ecological web will cause a perturbation that affects other members of community. The talk will finish by exploring how such eventualities should be considered in risk assessment and by regulators examining proposed releases of modified mosquitoes.

Professor Charles Godfray CBE FRS, University of Oxford, UK

Professor Charles Godfray CBE FRS, University of Oxford, UK

Charles Godfray is a population biologist with broad interests in science and the interplay of science and policy. He has spent his career at the University of Oxford and Imperial College London, and is currently Hope Professor of Entomology and Director of the Oxford Martin Programme on the Future of Food at Oxford. His research involves experimental and theoretical studies in population and community ecology, epidemiology and evolutionary biology. The two main current projects in his laboratory involve experimental studies of the interactions between aphids and their food plants, natural enemies and symbionts, and the control of malaria vectoring mosquitoes using novel genetic interventions. He is particularly interested in food security and chaired the Lead Expert Group of the UK Government Office of Science’s Foresight project on the Future of Food and Farming and is currently chair of Defra’s Science Advisory Council.