Genetically engineering the first malaria-proof mosquito

Malaria kills a million people every year and infects 250 million more. The best way to prevent malaria is to stop mosquitoes from transmitting it – and we've just genetically engineered mosquitoes that are completely incapable of spreading the disease.

The new breed of malaria-proof mosquitoes is the creation of entomologists at the University of Arizona. They managed to alter the mosquito genome so that it was immune to Plasmodium, the single-celled parasite that spreads malaria. The team hopes to ultimately replace all wild mosquitoes with these lab-bred populations.

Lead researcher Michael Riehle doesn't minimize how ambitious their project is:

"If you want to effectively stop the spreading of the malaria parasite, you need mosquitoes that are no less than 100 percent resistant to it. If a single parasite slips through and infects a human, the whole approach will be doomed to fail."

Riehle and his colleagues created the malaria-proof mosquitoes by building a genetic construct that could be inserted into the insect's genome. By placing this construct in mosquito eggs, the subsequent generation passed the new information onto their descendants, and it soon became pervasive throughout the population.

But what does this genetic construct do? It works upon one of the biochemical pathways in the cells of the mosquito. The new information alters a signaling enzyme known as Akt so that is always on and sending its message throughout the cell. That message is critical in immune response, and the result is basically a super-charged immune system that can repel any parasite, including Plasmodium. Akt also decreases the lifespan, which helps in malaria control because only the oldest mosquitoes can actually transmit the disease.

The early results are astonishing. When the team fed malaria-infested blood to the mosquitoes, not a single animal became infected with Plasmodium. That's unheard of in the wild, and frankly far more than Riehle had expected to see:

"We were surprised how well this works," said Riehle. "We were just hoping to see some effect on the mosquitoes' growth rate, lifespan or their susceptibility to the parasite, but it was great to see that our construct blocked the infection process completely."

As many as 250 million people contract malaria every year, and about a million die from the disease. Those who die are mostly children, and about 90% of the fatal cases occur in Sub-Saharan Africa. Even these numbers might be underreported, according to RIehle, which only makes the task of stopping the disease even more urgent. The good news is that the only way malaria can spread is through the bite of what's known as a "vector" – a mosquito from the genus Anopheles. About a quarter of all Anopheles species are major carriers of the disease.

The Plasmodium parasite is ingested by female mosquitoes when they feed on the blood of an infected organism. The parasite then works its way out of the mosquito's digestive system toward the salivary glands. Although most of the Plasmodium is wiped out, enough survives the journey to build up an army of thousands of new parasitic cells. When the mosquito next feeds on an animal, a few of these new cells, known as sporozoites, are transmitted into the victim's bloodstream. The mosquito unwittingly transmits about forty of these parasites, but it only takes a single sporozoite to give the victim malaria.

There are no malaria vaccines that work well or provide long-lasting protection. A few vaccines are currently in clinical trials, but all of them are known to be severely flawed. Even if the perfect vaccine came along, distributing it to those who need it most would be a logistical nightmare. Eradicating the source of the disease is thought to be the better option.

Riehle explains what that would take:

"The eradication scenario requires three things: A gene that disrupts the development of the parasite inside the mosquito, a genetic technique to bring that gene into the mosquito genome and a mechanism that gives the modified mosquito an edge over the natural populations so they can displace them over time."

He readily admits that they still don't know how to accomplish the third step, but they have already solved the first two problems. For now, the mosquitoes remain in the lab with zero chance of escape. But the fact that they have already achieved 100% protection against Plasmodium bodes well that they will soon figure out how to replace the wild populations with lab-bred, malaria-proof counterparts, and with this step make malaria a thing of the past.

[PLoS Pathogens]