Combating Zika with genetically engineered mosquitoes: Hope or hype?

As the Zika outbreak continues in the Americas, methods of controlling the mosquitoes that spread the virus by using genetic engineering have gained attention. In addition to the engineered mosquitoes made by British biotech company Oxitec and currently being used by the Brazilian city of Piracicaba, gene drive systems have been suggested as a way to suppress populations or prevent mosquitoes from carrying the virus. But how realistic is it for these new technologies to be an effective control measure against the spread of Zika?

 

Dr. Thomas W. Scott, Distinguished Professor of Entomology and Epidemiology, University of California, Davis (webpage):

Expertise: The ecology, epidemiology, and prevention of vector-borne disease.

“Results from field trials in Brazil for Oxitec’s existing genetically engineered mosquitoes are encouraging. The big challenge for this approach is logistics. How do you scale this system up to the huge areas and cities that need to be treated? I have not seen a clear, convincing answer to this critical question. And there are other questions: is the cost-effectiveness of this approach within reach of governmental budgets? And how sustainable will it be over broad geographic areas and densely populated modern mega-cities?

“Creating gene drive systems has been one of the key road blocks for genetic strategies of mosquito-borne disease control. New results using the CRISPR-Cas9 system are very encouraging, but they are currently lab based. It would be a gamble, and one I would not be comfortable taking, to start releasing CRISPR-modified mosquitoes into natural settings without a series of properly designed incremental studies that assess how well it performs in the field. Circumstances in the field are well know to be very different from well controlled lab settings, and can produce unexpected results.  Prior to use in a public health system we need to know from rigorous, properly designed studies how well a gene drive system in mosquitoes would work at preventing human infection and disease. To do this correctly, takes time and careful evaluation. Rushing to field application would be risky business.

“Overall, some of these techniques could hypothetically be used to eliminate diseases by making the mosquito species on which the diseases depend go extinct. But there are caveats. Removing some species could open a niche for others to occupy, and the result of that change are hard to predict. Another big question is whether elimination of a mosquito species is feasible. There are probably a few species we could eliminate with huge budgets and teams of people, but for the species that constitute the biggest public health problems I’m doubtful that with current tools eradication is feasible. Hopefully genetic strategies will evolve in their design and impact so that they can be effectively deployed for disease prevention in the future.”

 

Dr. Anthony James, Distinguished Professor, Microbiology & Molecular Genetics, University of California, Irvine (webpage):

Expertise: Molecular biology of insect vectors of disease, genetics of vector competence, malaria, dengue fever.

“Over a decade has past since the Oxitec mosquitoes were developed for population suppression. Improvements on that design could be made by using gene drives that would promote better efficacy and shorter times to impact. New strains could be made in less than a year but would need to be and tested in a phased program for efficacy and safety. The testing and scale-up would take 2-3 additional years, including meeting the regulatory requirements and necessary public engagement to get community consent to test them.

“Both Aedes aegypti and Aedes albopictus are not native to the Americas so eliminating them is a form of bioremediation. Gene drive technologies are the best and safest chance of getting elimination, with the fewest anticipated non-target effects and are a realistic solution for targeting specific problems; in this case, transmission of viruses (dengue, Chikungunya and Zika) by the major invasive Aedes species.”

 

Dr. Marcelo Jacobs-Lorena, Professor, Malaria Research Institute, Johns Hopkins Bloomberg School of Public Health (webpage):

Expertise: Mosquitoes as vectors for the malaria parasite, genetic modification of mosquitoes.

“There are two broad strategies to control the transmission of pathogens by mosquitoes. One strategy is population reduction by killing the mosquito, and the other strategy is population replacement by modifying the existing mosquitoes. This distinction is important because any population reduction strategy will leave an empty biological niche behind. If we kill those mosquitoes the biological niche is usually left in-tact, so when the intervention stops the mosquito population comes back rapidly. On the other hand, with a population replacement strategy the biological niche is still filled with the modified mosquitoes that are unable to transmit the pathogen.

“Presently there is no genetic engineering technology available to make a mosquito resistant to a virus, so only population reduction strategies can be applied. Besides insecticides, the other population reduction strategy is to use genetically engineered mosquitoes like those made by Oxitec. This strategy has worked extremely well, but one limitation is that in order to be effective you have to release enormous numbers of mosquitoes, in vast excess of the existing population. That is perfectly feasible if enough political and economical will is available, and this strategy should be explored.

“Another extremely promising population replacement approach is introducing the bacterium Wolbachia into mosquitoes. Pilot studies have shown beyond any doubt that mosquitoes that are infected with Wolbachia are poor transmitters of dengue virus. Although it has not been shown, I would predict that it is quite likely that Wolbachia will also impair transmission of Zika virus as well. Wolbachia exist naturally in other mosquito species and introducing them to Aedes mosquitoes has the big regulatory advantage of not involving genetic modification. This strategy deserves more support and attention since it has the advantages of population replacement and could be a promising solution within 2-5 years.

“Regarding gene drives, in principle they are a way to introduce genes into mosquito populations. To my knowledge, no gene has been identified which can stop the progression of virus infection in the mosquito but gene drives could be used for population reduction. From a scientific point of view, in 2-5 years gene drive technology could be ready for field introduction but the big ‘if’ is the regulatory aspect and there is quite a bit of public opposition to genetically engineered organisms in nature.”

 

Dr. Max J. Scott, Professor of Entomology, North Carolina State University (webpage):

Expertise: genetic pest management, developing transgenic “male-only” strains of insect pests for genetic control programs.

“Oxitec’s approach is promising but it will be a challenge to scale to larger areas, as was faced by the screwworm program in the United States which eradicated the insects by using ionizing radiation to sterilize large numbers of screwworms which were then sent out into the wild. There is one major difference between Oxitec’s approach and using radiation to create sterile insects: the multiple dominant lethal mutations induced by ionizing radiation make it very difficult for insects to develop resistance because the mutations occur at random. In fact, no resistance has not been observed in over 50 years of the screwworm program. Oxitec’s approach relies on one gene for lethality and is not 100% dominant. I think there is a potential for resistance to develop to Oxitec’s strain. 

“CRISPR/cas9 gene drives systems are very new and their development has been rapid. The approach is promising but it is early days. More testing and development in the lab is needed.”

 

Dr. Bruce Hay, Professor of Biology, California Institute of Technology (webpage): 

Expertise: Developmental biology and genetics, including developing transgenic mosquitoes that lack the ability to transmit pathogens such as malaria, dengue fever and chikungunya.

“Oxitec’s technology can be scaled up. It is largely a question of money, will and a lack of fear about something new. I think of Oxitec’s technology as akin to the invention of the seatbelt. Seatbelts are a really simple, pretty much foolproof way of preventing death. They won’t prevent every death, but the mechanism of action is so well understood that there is simply no biologically plausible mechanism by which it could go wrong. In the same way, Oxitec mosquitoes won’t eradicate every mosquito but nor will there be any unpredictable side-effects.

“Gene drives are still in their infancy, in several ways. First, genes that mosquitoes could carry to prevent infection are still being developed. Good progress is being made, but the ideal genes do not quite exist yet. Second, the gene drive technologies, while promising, are also still in early stages of development. Recent reports demonstrate exciting progress. But if you look closely at the details they also show that gene drive as currently implemented fails. This does not mean it won’t work, but just that we are still in the early stages of development. It will be very interesting to see how these technologies improve in terms of evolutionary robustness (ability to keep driving in large populations containing extensive genetic diversity) over the next year or two. All the stars are aligned in terms of technology development for gene drives in mosquitoes, so I would expect to see a lot of progress.

“The bottom line with respect to species elimination is that we have lived with rats, lice, fleas, and mosquitoes for ever. We can win the disease battle through public health measures that break the infection cycle of the pathogen without eliminating the host (rats, fleas, mosquitoes etc). Genetic technologies will be used in targeted ways to break the cycle of infection without eradicating animal species.”

 

Dr. Gregory Lanzaro, Professor, Department of Pathology, Microbiology and Immunology, University of California, Davis (webpage):

Expertise: population genetics of insect vectors of human and animal diseases.

“With respect to Aedes aegypti, the mosquito responsible for transmission of Zika, I believe that the Oxitec mosquitoes could be deployed anywhere right away. It’s important to keep in mind that this mosquito is very limited in its ability to disperse, especially in the urban environments it typically inhabits. So I think the best assessment is that the Oxitec mosquitoes could effectively be used to suppress A. aegypti within cities where its control is desirable.

“Gene drive systems are very close to field trials. My assessment is that the lab work for the initial constructs are very near completion. I’m sure research will continue to make improvements, but the existing systems are pretty much ready. I would guess, barring legal/regulatory obstacles, we will see a field trial in 2 or 3 years.

“I would very much be in favor of the application of gene drives for reducing or eliminating vector borne diseases. The system developed by the groups at UC San Diego and UC Irvine are population replacement strategies, so will not eliminate mosquito species, only alter them so they cannot transmit pathogens, in this case malaria parasites. In the end the mosquitoes will still be there.

“As far as eliminating species, as some have suggested for A. aegypti, I do not believe there would be a significant environmental impact. Firstly, A. aegypti was eradicated from large parts of South, Central America and the Caribbean in the 1960’s-70’s and there were no major issues with the environment noticed. Secondly, A. aegypti is not native to the New World and it seems the environment here did just fine before this mosquito was introduced by man from Africa. Finally, I think it is safe to say that we are doing more damage to the environment by using insecticide-based strategies to control these mosquitoes.

“The alternative – doing nothing – is not acceptable. Diseases transmitted by A. aegypti, notably dengue and yellow fever, have resulted in horrific epidemics impacting hundreds of thousands of people. The emergence of diseases like chikungunya and Zika will continue to threaten public health as long as we tolerate the presence of mosquito vectors in our midst.”

 

Declared interests (see GENeS register of interests policy):

Dr. Thomas W. Scott: “I collaborated with Oxitec in a research project that studied a different genetically modified strain of Aedes aeypti than OX513C. Our collaboration ended during 2013. I serve on the Vector Control Advisory Group (VCAG) for the World Health Organization (WHO), which serves as an advisory body to WHO on new forms of vector control for malaria and other vector-borne diseases. Oxitec submitted an application to VCAG during the time that I was on the committee.”

Dr. Anthony James: “No financial conflicts of interest. However, I do work on gene drive technologies.”

No further interests declared.

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