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Shredding the X chromosome: Wiping out female malaria-bearing mosquitos could halt disease

Scientists genetically modify mosquito responsible for spreading malaria so bugs produce mostly male offspring

June 27, 2014
An Anopheles gambaie mosquito

Female Anopheles gambaie mosquitos, like this one, can spread malaria when they bite humans.

Photo by James Gathany / CDC file

As summer heats up, the high-pitched whine of mosquitos thrums more frequently in our ears. For many around the world, that drone isn't just a nuisance, it signals life-threatening danger: malaria. Spread primarily by one group of mosquitos known as Anopheles, the malaria parasite infects more than 200 million people every year and kills more than 600,000, most of them children.

In a study released June 10 in the journal Nature Communications, researchers from Imperial College London and Fred Hutchinson Cancer Research Center demonstrated a technique that could wipe out that disease-carrying bug by engineering male mosquitos that father mostly male offspring.

The researchers made highly precise genetic tweaks in the mosquito species responsible for malaria’s spread in Africa, Anopheles gambaie. In laboratory tests, the engineered bugs could wipe out mosquito populations in just six generations, or six to 10 weeks. In four out of five tests using cages of non-mutated Anopheles mosquitos, introducing the modified bugs crashed the populations, leaving too few females to sustain growth.

The modification causes production of a protein in mosquito sperm that “shreds” the X chromosome, meaning the modified mosquitos produce mainly Y-containing sperm and, as a result, the bugs father more than 95 percent male progeny. Reducing the number of females serves as a double-pronged attack against the spread of malaria because only female mosquitos bite and without enough females, the malaria-bearing species would die out.

This technique is the first of its kind, said Fred Hutch protein engineer Dr. Barry Stoddard, one of the study authors. Although the engineered insects won’t be released into the wild anytime soon, they have the potential to eradicate malaria in a more targeted and environmentally safe manner than conventional techniques. Current efforts to control malaria involve either widespread pesticide use that kills all mosquito species as well as other insects, or draining wetlands where mosquitos thrive, which can devastate all wetland species.

“This is not intended to, nor would it ever, wipe out (all) mosquitos,” Stoddard said.

There are more than 3,000 known mosquito species around the world, the majority of which don’t carry disease, and the researchers’ technique is designed to only affect one of those species. Mosquito-eating predators will still have abundant food sources if Anopheles gambaie is eradicated.

An idea decades in the making

Scientists theorized nearly 50 years ago that distorting sex ratios could effectively wipe out pest populations, but this study is the first time that theory has successfully been put into practice. Researchers at Imperial College London, led by Drs. Nikolai Windbichler and Andrea Crisanti, came up with the idea to use endonucleases, proteins that act like molecular scissors to cut DNA at specific sites, to chew up mosquitos’ X chromosomes.

Eight years ago, they garnered funding from the Bill & Melinda Gates Foundation for the project and asked Stoddard, an expert on endonucleases, to help design the specific protein that could eradicate Anopheles gambaie. Stoddard and his team design custom endonucleases with the potential to target and correct human genetic defects that lead to chronic and life-threatening diseases, such as cystic fibrosis and sickle cell disease, or incurable viral infections such as HIV and hepatitis B.

“Barry and his colleagues in Seattle are second to none when it comes to expertise in the structural biology of endonucleases,” said Windbichler, one of the senior authors of the study.

It turned out that an endonuclease that naturally occurs in slime molds, which Stoddard has studied since the mid-1990s, targets a precise DNA sequence that studs the X chromosome — and only that chromosome — of Anopheles gambaie. The researchers introduced the endonuclease gene into male mosquitos and Stoddard’s group engineered the endonuclease to act only during the narrow window of sperm formation. Sperm are generated from a male cell that bears both an X and a Y chromosome, and normally, an extra cell division results in an equal mix of sperm cells carrying only an X or only a Y.

In the engineered mosquito, “you want this endonuclease to be expressed and you want to it to just shred, just absolutely chew to pieces any X chromosomes,” Stoddard said. With few X chromosomes remaining at the end of sperm formation, the fathers produce almost exclusively Y sperm. The genetic change is also heritable, meaning the engineered mosquitos’ male offspring will also only produce Y sperm and continue to spread the trait.

Promising start, important tests still to come

Stoddard stresses that although their initial tests were successful, these engineered mosquitos won’t be released into the wild for several years. The tests performed in the published study used laboratory-bred Anopheles gambaie, an important first demonstration of the technique’s power. Next the researchers will test the engineered strain’s ability to crash natural mosquito populations.

They plan to repeat the cage tests using wild mosquitos gathered in four African countries with varying levels of malaria: Burkina Faso, Mali, Kenya and Uganda. Following those experiments, they’ll need to perform safety tests, namely to ensure that the engineered gene won’t spread beyond the target mosquito species.

It’s also not known how fast or far wild mosquitos travel, so the researchers are not yet sure how many release sites would ensure that their engineered strain could wipe out malaria-bearing insects in an entire region or country. All in all, field tests of the modified mosquitos in the wild are at least two years away, Stoddard said.

Preventing malaria while sparing innocent species

Although he knows that genetically modified organisms may give pause to some, Stoddard says that because their approach is so specific to a single mosquito species, it has the potential to eradicate malaria with little to no other effects on the environment or humans.

“I truly believe this is not dangerous whatsoever,” he said, “especially in contrast to the alternatives, which is to do nothing at all and watch people die, or use pesticides or dredge wetlands. This is vastly superior in terms of environmental damage. The point is to spare thousands of species of mosquitos while eradicating one species.”

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Rachel Tompa is a staff writer at Fred Hutchinson Cancer Research Center. She joined Fred Hutch in 2009 as an editor working with infectious disease researchers and has since written about topics ranging from nanotechnology to global health. She has a Ph.D. in molecular biology from the University of California, San Francisco and a certificate in science writing from the University of California, Santa Cruz. Reach her at rtompa@fredhutch.org.

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