A CRISPR–Cas9 gene drive targeting doublesex causes complete population suppression in caged Anopheles gambiae mosquitoes

A CRISPR–Cas9 gene drive targeting doublesex causes complete population suppression in caged Anopheles gambiae mosquitoes

A team of researchers led by Dr. Andrea Crisanti at Imperial College London claim to have found a way to eradicate the world’s population of mosquitoes along with the dreaded diseases that the mosquitoes carry.  In a research article titled “A CRISPR–Cas9 gene drive targeting doublesexcauses complete population suppression in caged Anopheles gambiaemosquitoes,” Crisanti et al. describe using gene editing techniques to eradicate the Anophelesgambiaemosquito population in particular, but conclude that the same techniques can be used to successfully eradicate mosquitoes of all types – and with them, malaria and the other parasites they carry.

Mosquitos of the Anopheles genus can be found all over the world except in Antarctica.  The femaleAnophelesmosquito transmits malaria by biting an infected person and then passing along the parasite to the next person it bites.  Malaria is a blood-transmitted disease, which means one cannot contract it from mere casual contact with another person.  Because it is transmitted through the blood, one can contract it from a contaminated transfusion or needle.  Nonetheless, mosquitoes are primarily to blame for the spread of malaria infection.

Because of the mosquito’s ubiquity and notoriety, scientists over the centuries have researched ways to stop the transmission of mosquito-borne diseases.  The scientists whose research preceded Crisanti’s came up with numerous practical techniques that ultimately were of limited utility, including skin sprays to repel mosquito bites and mosquito coils that produce strong mosquito-repellent smoke when lit up.  While creative, these measures hardly made a dent in the incidence of mosquito-related illnesses.

In their work, Dr. Crisanti and his team used gene editing to eliminate entire populations of Anopheles gambiaemosquitoes in the lab. The team tested their technique on the femaleAnopheles gambiae mosquitoes because of their unique role in transmitting malaria.  Crisanti et al. altered part of a gene called doublesex, which determines whether an individual mosquito is male or female, and this allowed the scientists to block reproduction in the female mosquitoes.  Crisanti’s team reported that “the CRISPR–Cas9-targeted disruption of the intron 4–exon 5 boundary aimed at blocking the formation of functional AgdsxF did not affect male development or fertility, whereas females homozygous for the disrupted allele showed an intersex phenotype and complete sterility.”  Kyros Kyrou, Andrew M Hammond, Roberto Galizi, Nace Kranjc, Austin Burt, Andrea K Beaghton, Tony Nolan & Andrea Crisanti. A CRISPR–Cas9 gene drive targeting doublesex causes complete population suppression in caged Anopheles gambiae mosquitoes.  Nature Biotechnology.  2018; 36: 1062-1066.

The Crisanti team’s article in the journal Nature Biotechnology reports that caged populations of the Anopheles gambiaereached total collapse within seven to eleven generations.  This approach falls within a species of genetic engineering known as gene drive, which involves technologies that spread a gene or particular suites of genes through a population.  The researchers used the gene editing technique known as CRISPR (Clustered Regularly Interspaced Short Palindromic Repeats) to modify a part of the doublesexgene that is responsible for female development.  Males that carried the modified gene showed no changes, and neither did female mosquitoes with one copy of the modified gene.  Crucially, however, female insects with two copies of the altered gene showed both male and female characteristics in that they did not bite and did not lay eggs.

As the modified gene spread female infertility, the caged populations eventually died out.  As with all technologies, this one was not risk-free.  Previous attempts to use this approach with mosquitoes ran into problems.  The mosquitoes developed a resistance to the genetic modification because the targeted genes developed natural mutations that allowed them to continue functioning and these mutations were then passed down to the mosquitoes’ offspring.  However, thedoublesexgene is said to be highly conserved, which means that random mutations are for the most part lethal to the organism.  In this way, the scientists were able to get around a potential source of resistance and prepare to test the technique on larger populations of mosquitoes in real-world settings where competition for food and other ecological factors could affect the outcome.  Dr. Crisanti stated that “there is still more work to be done both in terms of testing the technology and larger lab base studies and working with affected countries to assess the feasibility of such an intervention.  It will still be at least five, ten years before we consider testing mosquitoes with gene drive in the wild.  But now we have some encouraging proof that we’re on the right path.  Gene drive solutions have the potential one day to expedite malaria eradication by overcoming the barriers of logistics in resource-poor countries.”

The Crisanti team’s research article is intended for audiences ranging from doctors and researchers to students and charitable/philanthropic organizations that fund such research.  The research appears to hold significant promise because it attacks the problem at its core by manipulating the genetic makeup of female mosquitoes to prevent them from biting people and laying eggs.  Mosquito-related diseases may not seem as big a deal in the United States as in other parts of the world where millions of people die from such diseases each year.  As tiny and harmless as it might seem, the mosquito is considered the deadliest insect in the world.  The World Health Organization (“WHO”) estimates that nearly half of the world’s population is at risk of contracting malaria.  According to the WHO, there were roughly 212 million malaria cases and an estimated 429,000 malaria deaths worldwide in 2015 alone.  World Health Organization.  https://www.who.int/features/factfiles/malaria/en/.

The Crisanti team’s research holds particular value for fellow researchers who are currently developing vaccines or medications to treat existing diseases transmitted by Anopheles gambiaemosquitoes, potentially unleashing new levels of research funding from major philanthropic organizations and even private enterprise.  As a relatively new strain of research, it no doubt still has many obstacles to overcome. For example, the ultimate goal should be the eradication of mosquito-related diseases, not of the mosquito population itself.  After all, mosquitoes serve an important function in the survival of freshwater creatures.  Mosquito larvae serve as a food source for fish and other small creatures in ponds and other freshwater sources.  

With that caveat, the Crisanti team’s research seems comprehensive and reliable and could go a long way towards eradicating mosquito-borne diseases and saving millions of lives in the long run.  Everything I’ve learned in this Microbiology class about biotechnology and genetic engineering, specifically transformation, enabled me to understand how the introduction of foreign DNA into the Anopheles gambiaemosquito can alter its morphology to destroy its reproductive capabilities.  I believe this research is worth pursuing because the stakes for the long-term health of the human race are simply too high to ignore.