Could gene editing be the answer to the spread of mosquito-borne diseases such as the Zika virus and dengue fever?
A newly discovered master-switch gene may give humans the advantage in the centuries-old insect wars — and the ability to fight the bugs in a less costly, more effective way.
That’s the good news from an entomologist and a biochemist at Virginia Tech, whose gene-editing breakthrough is outlined in a review, published today in the journal Trends in Parasitology.
Co-authors Zach N. Adelman, PhD, associate professor of entomology, and Zhijian Tu, PhD, professor of biochemistry, believe their discovery of a male-determining factor in mosquitoes, combined with the gene-editing system CRISPR-Cas9, could potentially force mosquito populations to produce fewer females and more males.
Female mosquitoes are the transmitters of Zika, yellow fever, malaria, Chikungunya, and dengue fever.
The Zika virus and other dangerous diseases are spread by just one of the world’s 3,500 species of mosquito, Aedes aegypti or Asian tiger mosquito, common in the United States.
How to “Nix” Female Mosquitoes
Adelman’s and Tu’s discovery of the first male-determining factor, also known as M factor, in mosquitoes is called Nix. It was reported in May 2015 in a high-profile study in the journal Science.
The researchers found that when Nix was expressed in female embryos, it generated the development of internal and external male genitalia.
Scientists have had success with recent attempts to control dengue fever genetically by releasing sterile, transgenic mosquitoes, the researchers’ report said.
But the methods used are expensive and impractical because they require long-term insect releases and are difficult to accomplish on a large scale.
The Virginia Tech scientists have uncovered a better way to fight the deadly insects.
“A more effective and less costly approach might be to drive maleness genes with the CRISPR-Cas9 system,” Tu told Healthline. “This has shown promise as an easy, efficient, and precise approach to introduce mutations at virtually any genomic site of interest in a wide range of organisms, including mosquitoes.”
‘Mosquitoes are just like us. They have two copies of each of their chromosomes,” Adelman added in a Healthline interview. “Adding in the Nix gene should force all of the mosquitoes to develop as males.”
Using current methods, each generation of sterile mosquitoes must be reared in a factory and released. Males are physically separated from females in the factory.
“With the 'driving maleness genes' method, females do not need to be sorted in the factory, because you have all males,” Adelman said. “When you use an approach where the Nix males are also fertile, for each generation you rear in the factory you could get many generations producing all males in the wild.”
CRISPR Is the Final Ingredient
The Nix gene by itself, however, will still only be passed on to half of the offspring. The scientists will need to use CRISPR-Cas9 to break the chromosome that doesn't have Nix, he said.
“Cells are very good at fixing broken chromosomes,” Adelman said. “And in this case they will use the Nix-containing chromosome as a guide to repair the broken one. The result is each chromosome will now contain Nix, instead of just one. Thus, most progeny will be male in each generation.”
“It became clear to us that Nix is a strong candidate for the male-determining factor because it is only found in males,” Tu said. “It is expressed early during development before sex is determined, and its sequence indicates a potential function in regulating key players in sex determination.”
The scientists demonstrated that Nix is the first male-determining factor in mosquitoes by showing that it’s both “required and sufficient” to initiate male mosquito development, he added.
In the next stage, Adelman and Tu will test their hypothesis.
They believe if they integrate one or a few key male-determination genes (such as Nix) into the autosomes (chromosomes unrelated to sex), it will be sufficient to reduce the number of female mosquitoes either by conferring female-lethality or turning females into fertile or sterile males.
Adelman said “there is still plenty of technical detail to work out” — including obtaining local support for field-testing the technology — before they can apply their discovery in the field.
How Nix Works is a Mystery
At the moment, it’s still unclear how Nix controls sex determination in mosquitoes, Tu said, and whether M factors are conserved across species that transmit different diseases.
He added that the effectiveness and long-term stability of CRISPR-based gene-drive systems in mosquitoes remain unknown.
“This new approach is likely more efficient than classic sterile-insect techniques to achieve population reduction and to control disease, because male-bias is sustained over many generations,” Tu said. “The approach would still ultimately be self-limiting because local populations can crash due to an insufficient number of females, which could eliminate the engineered Nix gene from the environment.”
Their work has been supported by two exploratory grants from the National Institute of Allergy and Infectious Diseases at the National Institutes of Health. This month they received two more grants from the same agency to continue their research on sex-determination and related applications in both Aedes aegypti and Anopheles stephensi (carrier of malaria in India, South Asia and the Middle East).
While their research could have extraordinary influence on global health, the scientists are concerned about the ethics of releasing genetically-modified organisms into the environment.
“We take these concerns very seriously,” Adelman said. “Publishing our views on the technology now, when there are still a number of years before any potential trials, should help bring all of the arguments into the public sphere with enough time to have an informed discussion.”