Vector-borne diseases continue to impose a considerable burden of mortality and morbidity on many populations. Chemical-based control of the vectors has substantially reduced this burden, but it seems clear that other tools and interventions will be necessary to eliminate and eventually eradicate these diseases. Genetic control measures have for decades been discussed as potentially offering an independent line of attack that would help get us over the finish line, and in the last few years much progress has been made in reducing the various ideas to practise. A key development has been proof-of-principle demonstrations of synthetic gene drive systems in both model organisms (Drosophila) and malaria-transmitting mosquitoes (Anopheles). Gene drive is a process of preferential inheritance whereby a gene or genetic element is transmitted at a greater-than-Mendelian rate from one generation to the next, potentially allowing it to increase from rare to common in a population in just one or two dozen generations. Considering that many vectors have generations times of a month or less, this is fast enough to be useful for public health interventions. To take perhaps the most daunting example, there are too many malaria-transmitting mosquitoes in sub-Saharan Africa to hope to control them by inundation, but with gene drive we can think about much smaller releases and allowing this natural process to amplify impacts.
The papers in this themed issue highlight the transitions taking place as the science moves from proof-of-principle demonstrations to the development of constructs that could actually be released and do some good. As already mentioned, the efficiency of gene drive approaches comes from the fact they can spread of their own accord – analogous, in many ways, to conventional biological control agents. It is therefore possible that unintended release from an insectary could lead to unintended spread, and due attention must therefore be paid to proper containment. As Adelman et al. note, there is a long history of developing appropriate facilities and protocols for containment of exotic species and infectious agents, and much that the gene drive community can learn from this past experience. They particularly emphasise the key role of Standard Operating Procedures (SOPs), which are formal documents describing how activities such as entering or exiting a facility, inspecting it, disposing of waste, or specific experimental manipulations should be done, and which are worked out between the researchers and the appropriate institutional review board (IRB).
Another lesson to be learnt is the importance of knowing in some detail exactly what one is aiming to develop, and of being able to recognise it when it has been done. As Carballar-Lejarazú & James note, another document, a Target Product Profile (TPP), is very useful in this regard, listing the various criteria that must be met in order to declare that a particular construct looks promising enough to take to the next stage of development, and eventually into deployment. Mathematical and computer modelling will necessarily play a large role in predicting field impacts from lab data, and therefore in defining the so-called go/no-go thresholds for moving forwards.
As mentioned, there is a long history of chemicals being used for malaria control, both drugs against the parasite and insecticides against the vector, and there is an equally long history of parasites and mosquitoes evolving resistance to these chemicals. It will be crucial for those developing genetic approaches to consider and mitigate the possible evolution of resistance against these new tools, and it is reassuring to see researchers even at this early stage grappling with this issue. In their overview of gene drive technology for malaria control, Hammond & Galizi give an excellent discussion of the current state-of-play with resistance management, and of ideas for preventing, or at least retarding, its evolution.
A successful genetic intervention must not only perform as expected in the mosquito (e.g. distort sex ratios or block parasite development), it must also be acceptable to the appropriate regulators, and desired by the public or society at large. Because genetic approaches to vector control give area-wide control, issues of governance and ethics are somewhat different than with individualised interventions like drugs or vaccines (though the most basic precepts, such as the paramount importance of safety, still hold). Najjar et al. review the current state-of-the-art in stakeholder engagement for area-wide vector control programmes, and argue, reasonably, it should be early and fulsome.
This issue also includes a 4-way discussion of various issues surrounding gene drive technologies among experts in ecology, governance, and ethics. Reassuringly, there is broad agreement across a number of topics, including the principle that the people most likely to be affected one way or another by a release should have the larger role in deciding whether it takes place. In the context of African malaria, it is therefore very much to be welcomed that the New Partnership for Africa’s Development (NEPAD) has been holding a series of meetings for regulators to learn about gene drive technologies even now, well before a field-ready construct has been developed, and hopefully other jurisdictions will follow their lead.
Together, the contributions in this special issue reflect the growing realisation that novel genetic approaches to vector-borne diseases may no longer be decades in the future, and we had best get prepared.
Faculty of Natural Sciences, Department of Life Sciences, Imperial College London
[email protected]
Andrea Crisanti
Faculty of Natural Sciences, Department of Life Sciences, Imperial College London
Editor-in-Chief, Pathogens and Global Health