EXPERT REACTION: Mozzies knocked out with gene drive

This is an interesting development in the potential use of gene drive systems to suppress pest populations.

In particular, the authors target the essential doublesex gene that is involved in the sex determination pathway and needed for normal development of males and females. A construct was developed that prevents females developing normally and results in them producing a sharply reduced number of viable eggs.  This construct could be driven through the population, and importantly appears to be stable so far – it has proven resistant to the rapid evolution of genetic variants that stop the gene drive acting.

Importantly, the work shows that there is a very rapid decrease in egg number in population cages such that populations of Anopheles mosquitoes eventually collapse.

It remains to be seen if the same phenomenon can be reproduced in large cages designed to represent field populations more closely where there is a greater chance of mutations arising that prevent the gene drive from operating properly.

Nevertheless, at least in the short term, the experiments show that it is possible to produce a stable drive to suppress populations of mosquito disease vectors.  

In this study, scientists created a new gene drive that disrupts development of female malarial mosquitoes (Anopheles gambiae) and causes their caged populations to crash.

Andrea Crisanti’s group at Imperial College, UK has used CRISPR technology to create a mutation in a gene (doublesex) that prevents normal development of biting females but does not affect harmless male mosquitoes.

By linking the mutation to a CRISPR-based machinery that ensures it is transmitted nearly 100 per cent of the time, the mutation quickly spreads through a population, turning more and more females into intersex mosquitoes that can’t bite and reproduce.

The heavy hit on egg production was enough to cause total collapse of experimental caged populations in less than a year.

This is not the first gene drive for suppression of malarial mosquitoes that Crisanti’s group has created, but the doublesex construct seems much more resilient to mosquitoes developing resistance to it, and this is what gives hope it might work in the field.

Field trials are indeed the ultimate test for the efficacy of suppression gene drives, but the releases of such GM mosquitoes are met with heavy regulatory constraints and public skepticism.

An important breakthrough happened this August, when Burkina Faso’s national biosafety authority granted permission to release 10,000 non-gene-drive GM Anopheles mosquitoes, as a first step towards eventual rollout of the gene drive constructs like Crisanti’s.

Exciting and hopeful times in fight against malaria are ahead.

Novel approaches to mosquito control are critical if we are to reduce the burden of mosquito-borne disease. Traditional approaches to controlling mosquitoes, especially the use of insecticides, is becoming less effective as key mosquitoes involved in outbreaks of disease are becoming resistant to our commonly-used insecticides.

As malaria is still responsible for killing over half a million people every year and making hundreds of millions of people sick, new technologies are required to battle mosquito-borne disease.

While gene drives have shown great potential in the past, laboratory studies have demonstrated that resistance in mosquitoes to these approaches developed in much the same way that they’re beating our commonly-used insecticides.

This new research, however, opens new potential applications of this strategy and provides support for researchers to pursue field-based studies. No such resistance to this approach was shown in these newly published laboratory studies.

By releasing laboratory-reared, genetically-modified mosquitoes into the field, they can crash the local mosquito populations by reducing the proportion of fertile female mosquitoes. It is a tantalising prospect that collapsing mosquito populations may substantially reduce the transmission of mosquito-borne pathogens.

This latest research demonstrates great potential for future management of malaria in many parts of the world, especially Africa.

However, adapting this approach to Australian mosquito-borne disease may face many challenges. Australia is free of malaria but thousands of people fall ill following mosquito bites each summer.

Unfortunately, there are many different types of mosquito, found in many different types of environments, that drive outbreaks of mosquito-borne disease here.

The release of genetically modified mosquitoes is still a long way off but perhaps in the future it will be an additional tool available to local health authorities in reducing the public health risks associated with our local mosquitoes.

CRISPR-based Gene drive technology consists of accelerating the spread of a defect in important genes in insects or mammals to eradicate deadly infectious diseases such as malaria or Zika virus infection or to eradicate animals that have become a pest.

While the first attempts using gene drives in malarial mosquitoes showed early signs of success, resistance to the gene drive occurred so rapidly that it compromised any attempts to eradicate malaria or Zika virus infection using CRISPR-based gene drives. The reasons are a poor control of how the gene drive spreads, and previous attempts targeted genes which were too essential for the modified mosquitoes to survive.

To overcome this problem of resistance to gene drives, a team in UK targeted a gene essential for sex determination but not for survival called doublesex in mosquitoes, and they better controlled the delivery of the CRISPR gene drives, making it more efficient.

As a result, the researchers noted a rapid and efficient spread of the drive and did not observe any resistance to CRISPR gene drives in malarial mosquitoes, achieving the collapse of the entire mosquito population.

Overall, this proof of principle study is a significant advance of CRISPR-based gene drive technology, showing some promise on malaria control and eradication. However, prior to this, a more thorough study is required to assess the real efficacy of this CRISPR-based gene drive technology in malarial mosquitoes.