In your experience, how can the tools of biotechnology be used to combat pathogens transmitted by mosquitoes, such as the Zika virus?

Well that is a very broad question, and of course there are a huge number of possibilities. Probably any vaccine that people try to develop against Zika will be a recombinant vaccine as indeed the leading candidate dengue vaccines are. In other words, genetically engineered virus vaccines will be one application of biotechnology. If we restrict ourselves to insects specifically, then there are a number of ways that we can use insect genetic engineering or synthetic biology to tackle the spread of infectious diseases. The two main strategies that have emerged are:

Firstly using modified insects to try to reduce the number of pest insects in a population, so populations suppression, which really is the same goal as people have attempted to achieve by environmental management e.g. insecticide spraying. This is the same kind of thing, to have fewer mosquitoes so there are less insects biting and less transmission. But genetic methods have the possibility of being much more specific and targeted and environmentally friendly. The delivery agent in all these things is a modified mosquito which you will release and it will do two things. First of all, it will look for the wild females for you if you release modified males in a way that a chemical insecticide won’t do.  And then you will also have the specificity that the males will only mate with females of the same species, and not affect other mosquito species let alone butterflies and all the other benign and harmless insects that are around in the environment. Again it is hard to get that exquisite species specificity from a chemical insecticide, or indeed any other control method. Now if you were in a situation where the disease was being transmitted by a large number of vector species or more generally if you were a farmer whose crop was being eaten by a whole host of pest species, you might prefer something more broader spectrum than a dozen or so species specific interventions. So this species specific intervention, which I think is very good from an environmental point of view is a feature of this type of approach, so it will make it more attractive in some settings and less relevant in others. In malaria, of course the transmission is more complicated and so there are more species involved – or at least different species in different areas – than dengue, chikungunya, Zika, which are all primarily transmitted by one species of mosquito, Aedes aegypti and in some cases with involvement to an unknown extent by other species such as Aedes albopictus. And so population suppression is one strategy and it has a familiar outcome.

The other strategy, which is perhaps less familiar, is so called population replacement, which is essentially trying to spread genes into the wild population using technology that would make mosquitoes less harmful without actually killing them, so make them less able to transmit a particular pathogen. The closest analogy would be like ‘vaccinating’ the whole mosquito population in some ways, because the mosquitoes will still be there, and they will be biting people, but will no longer be able to transmit the disease. There are many number of reasons why vaccinating the whole population of mosquitoes won’t work, but it has been done with rabies by trying to vaccinate wild dogs, badgers etc. with a live engineered rabies vaccine. So this is the closest analogy we have to illustrate the concept. The way we actually go about doing this is making a strain in the lab, and genetically modifying it so it won’t transmit the disease and release these mosquitoes into the wild population.

For population suppression, the gene we are trying to release will have some huge fitness cost associated with it. So the mosquito will mate with one insect and then it will disappear, so it is a self- limiting method and these are attractive in terms of controllability because the modification will disappear quite quickly unless you maintain it. On the other hand it won’t persist in the environment, which is good from that point of view, but from an applied point of view you might want them to hang around longer. Now in the case of these refractory genes, the genes that are not going to kill the insect but are going to stop the disease being transmitted, you really need most of the mosquitoes to be carrying them. And you want it to hang around in the environment quite a long time and you don’t want them to disappear rapidly. The parasite (e.g. dengue or malaria) does not do much damage to the mosquito because the parasite depends on them for transmission, so the mosquito does not need to be resistant to them. Therefore making the mosquitoes resistant to the parasite is not much of a dampener because it will not harm them at all, first of all, and the gene needs to be carried by all of the mosquitoes when in fact only a small proportion of the mosquitoes carry the parasite. Overall, it is highly unlikely that they will be able to make a transgene that will have a net benefit to the mosquito simply by making them resistant to dengue. That means it is likely that the cost associated with other modifications almost certainly will have a net fitness cost and so tend to disappear from the wild population, which is rather opposite of what you want if you want it to hang around at high frequency – and maybe increase in frequency – in the wild population. Now of course, if you were actually vaccinating mosquitoes, that would not hang around and you will have to go around doing it each time e.g. like when you vaccinate people, and you have to keep on vaccinating new babies each year etc. The idea that you have to keep on doing this entirely consistent with what you do at the moment e.g. with Sterile Insect Release. Now there is a possibility that we might be able to get away from that and have something that will propagate itself.

Now, I say that in terms of vaccines we have rather shied away from that because, well – can you imagine an infectious vaccine? There were some suggestion to move to that but by and large we choose not go down that route. But the case of mosquito-born diseases might be different and certainly there are genetic schemes, so called gene drive systems, which are predicted to be able to spread themselves though wild populations despite not inferring any individual fitness benefit but by biasing inheritance in their favor. Such systems have received a lot of attention recently, although we have been talking about them since the 60’s or even earlier, but recent developments particularly in nuclease based systems and CRISPR applications have lead to some recent papers which suggest that this can work, in relatively short timescales, for spreading genes through wild populations and that the proposed targets are primarily major malaria vectors.

Some of these systems we predict to spread through entire species and possibly also drive them to extinction. Is that a desirable outcome? Well, you can argue either way. On the one hand, you can say that humans have inadvertently driven many many species to extinction yet we have only deliberately eliminated two species – smallpox virus and the rinderpest virus, and to go from there to mosquitoes is quite a big step.

On the other hand, you can say mosquitoes are a major pest species, a very human adapted species – so an external parasite essentially – and it is hard to see that it has a significant role in the ecosystem, such that would we miss it if the species had completely gone. Some people can say that about mosquitoes in general, but that would be further than I would certainly be comfortable to go. But there are three and a half thousand named species of mosquitoes and we are only talking about one specific one, and nowhere are they the only species of mosquitoes in the area, even if you felt that there were things specifically dependent on mosquitoes. Though there are many mosquito-eating generalists, there aren’t many specialists that depend on them.

So I think I have argued it both ways and I am sure there are more arguments on both sides. My own personal preference though would be for more locally acting systems, which will affect a particular  population – short of an entire species. Although there may be cases where you would want to target an entire species, I think there will be many many more cases where you would want to do something with a particular pest population. Very often an invasive pest may be a problem where it has inadvertently moved to, but in its native area it may be less of a problem. For example, the Aedes aegypti population in California is a problem. It is actually native to Africa, but its non-African form is very adapted to biting humans, which is not universally true of African populations. So there is a case where maybe you want to eliminate A. aegypti in California but not in Africa.

Speaking about all these genetic control methods. In your experience, have they been evaluated and tested to the point where they are ready to be deployed on an operational basis at this point?

There is a huge range of proposed genetic control methods. Some of them are just ideas on pieces of paper and some of them are fully developed strains with field trial data and so on. So the answer there is enormously different depending on which control method you are talking about.

The only engineered mosquitoes that have been tested in the field are population suppression strategies, using engineered sterile male mosquitoes developed by Oxitec.  As you know, as the Research Director of Oxitec, I was involved with those, as were you, so there’s my conflict of interest. There have been 3 separate trials in the Cayman Islands, Malaysia and a whole series in Brazil. Now there is a trial in Panama. The trials have been very successful and in each case it is gradually increasing in scale, so I would say from my own perspective those are ready to use on a larger scale. So effectively operational use, if you like.

Whereas no other genetically engineered strain has been trialed. All of the gene drive systems have a lot of very good lab data but are some way off operational use. I am not sure we can anticipate field trials in the very near future for those.

So let’s say some of these methods, particularly the one developed by Oxitec could be close to being ready for operational use. What would it take, in your opinion, to actually reach that point? Like doing something similar to what happened in the 50s or 60s and partly the 70s in the eradication campaign of A. aegypti in the whole of the Americas. Are we at that point where we can think about large scale applications?

I think that technically that is perfectly feasible. Of course that program itself started off with a trial on a little island and went up to a larger scale and a larger scale and ended up as a continent-wide campaign. And I think that you can see that scale up and roll out for Oxitec’s technology, yes.

What would it take? Well, of course, funding and approval from regulators and the public. And that in turn depends on confidence on one sense or another in the regulations and the value in that it’s a worthwhile thing to spend money on. And I think that itself points to the careful incremental scaleup that is indeed what is going on at the moment. I don’t think anyone would jump from a field release that covered thousands or a few thousands of people to the whole of a big tropical city with tens of millions of people in it in a single step. So this incremental increase in scale is I think quite sensible. Now how fast that happens? Well that is an interesting social, political and commercial question and we will see.

This is especially interesting in view of the current Zika outbreak because you know as we speak, pregnant women are getting infected with Zika and their children are potentially being born with microcephaly, so that is something that local policy makers will have to weigh whether they should wait for another set of field trials or actually do something. There is a cost to waiting in a sense in terms of human life and suffering.  

As you point out, inaction is not neutral by any means. No more so than action and so I think it is a difficult question for politicians, who are not themselves familiar with this type of technology, to make a decision on. From my perspective, I know the technology very well and I don’t think that the technical factors related to the technology are a limiting issue in terms of when it can be rolled out.

More generally in new emerging diseases, like Zika, the drugs and vaccines are absolutely starting from scratch since there hasn’t been any work on them before. In terms of mosquito control, because it is transmitted by the same mosquito that spreads dengue and Chikungunya, you can control all these diseases by controlling the mosquito, which Oxitec technology aims to do.

My hope is that the Zika virus is going to give the final push for the policymakers to say that this is it, we need to get rid of this mosquito, in the face of a public health emergency declared by the WHO in terms of Zika virus. The virus might potentially affect Brazil economically and so it might be such a situation where they say this is it.

Yes, I think that’s right. The policymakers are in a difficult position in these circumstances and if we could bring forward new, more environmentally friendly  and more effective methods of mosquito control for the benefit of controlling not only Zika but chikungunya, dengue and other diseases, that would be some sort of silver linking in the very large problem that is Zika.