Hacking the Skin Microbiome to Fool Mosquitos and Prevent Malaria

If you wanted to choose the perfect repellent to protect U.S. soldiers serving overseas in areas thick with mosquitos, where many people are sick from malaria, a number of questions would come to mind. Does it work? Is it safe? What will it cost? How does it smell and feel on your skin? Are there any environmental impacts?

Missing from that list is the one question you would never ask because it’s the one thing no current commercial repellent can ever seem to offer: Will it afford long-lasting protection—say for 14 straight days? Even the most concentrated bug sprays you can buy today won’t last much more than a few hours, let alone two weeks.

But that’s exactly the question officials at the U.S. Defense Advanced Research Projects Agency (DARPA) have been asking, and they recently launched a new program dubbed “ReVector” to find answers.

Malaria and the military

Militaries everywhere have had to deal with rampant infectious diseases since the dawn of time. Smallpox, cholera, typhoid, tuberculosis, and dysentery often claimed more victims than battles in past centuries, and malaria was historically one of the worst. It infected more than half a million American soldiers in World War II alone.

The U.S. military has fought malaria and mosquitos for more than a century, especially after a team in Cuba led by U.S. Army Captain Walter Reed discovered in 1900 that mosquitos spread infectious diseases. Over the 20th century, the Pentagon pioneered mosquito control methods, funded research into treatment and vaccines, field-tested insecticides like DDT, and helped develop the frontline repellent DEET.

Malaria is still a military problem, however, and over the last decade there have been typically several dozen cases of malaria among U.S. military members each year. One issue is that the DEET repellents wear off, forcing soldiers to reapply—often difficult in the field—and to carry the extra bulk of bug spray cans.

The olfactory cues from your skin microbiome guide female mosquitos to their mark.

That’s why DARPA launched ReVector, which seeks to design a longer-lasting repellent that will prevent mosquito bites for up to two weeks after a single application by temporarily modulating the skin microbiome—the naturally occurring, complex community of symbiotic microbes living on the skin, similar to the microbiomes found in other parts of the body, like the gut.

“You are totally covered with microbes—you have hundreds of species of bacteria, viruses, fungi living on your skin right now,” says Linda Chrisey, a DARPA program officer for ReVector. “They are an integral part [of] keeping you safe from infection and protecting you from other environmental insults.”

DARPA announced two separate contracts late last year as part of this effort. They awarded a $6.5 million, 18-month initial-phase contract under ReVector to a consortium made up of Ginkgo Bioworks, Azitra, Florida International University, and Latham BioPharm Group. They also awarded a $3.2 million, 18-month initial-phase contract to a second group, led by Michael Fischbach at Stanford University, Chris Voigt at MIT, and Omar Akbari at the University of California, San Diego.

Tinkering with the odor plume

Blame the bacteria on your skin for your smelly gym socks. The microbes sit there in their tiny commensal communities day after day, metabolizing your sweat, gulping up the other secretions from your body, releasing volatile compounds, and ultimately producing the major molecular component of your particular body aroma. And the olfactory cues from your skin microbiome guide female mosquitos to their mark.

“What we’re trying to do is to alter the skin microbiome to prevent the mosquitos from recognizing us,” says Matthew DeGennaro, a professor at Florida International University who is partnering on the contracts led by Ginkgo Bioworks.

There are a swarm of engineering challenges with this approach, like how to get bacteria from a bottle onto the skin, how to get it to take up residence, and how to make sure it only lasts for a few weeks.

Different mosquito species have different preferences for people we don’t fully understand.

Safety is another issue. “We have gone out of our way to build safety checks into our plan,” Fischbach said in an email. “Needless to say, any candidate therapeutic applied to a human needs to go through a process overseen by [the U.S. Food and Drug Administration] to ensure safety.”

One of the great unknowns involves the insects themselves. There are lots of different mosquitos that transmit diseases to humans, including at least seven distinct species of Anopheles gambiae, all of which spread malaria in human populations. Will a repellent work equally well on all of them? And what about the other mosquito species that also spread diseases, like the dengue, Zika, and yellow fever transmitting Aedes aegypti, or the common “house” mosquito Culex pipiens, which is known to spread West Nile virus?

Different mosquito species have different preferences for people we don’t fully understand, said biologist María José Ruiz López, a postdoc at Doñana Biological Station in Seville, Spain, in an email. López is not involved in either of the DARPA-funded projects, but she recently wrote a review article on mosquito behavior and interactions with the skin microbiome.

“While we are modulating the skin microbiome to prevent the bite of, let’s say, Anopheles mosquitos, we might be favoring the bite of other species, such as Aedes or Culex,” she says.

Another challenge is that each person’s microbiome is the unique product of many overlapping factors: gender, genetics, occupation, grooming habits, neighborhood, etc. Experts think these differences account for why mosquitos are more attracted to some people than others, but it may be difficult to find a single solution that works for everyone.

Nevertheless, researchers like DeGennaro remain optimistic. “I feel very good about it working because we’re striking at the heart of where odor is generated,” he says.

He says he has spent years studying mosquito olfaction and neurogenetics and dreams about making a lifesaving perfume that will prevent people from getting sick from mosquitos.

“I never imagined it would be a bacteria,” he says, “but it looks like it might be.”