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“What would you say, if I told you I was going to stop by your house this weekend and release some mosquitoes?”
Dave Burbank
Dave Burbank

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Controlling diseases such as malaria, zika, and West Nile may amount to controlling the mosquito’s sex life, releasing genetically altered mosquitoes to manage the mating, blood-meal, egg-laying relationship—long-term research in Laura Harrington’s lab.
Dave Burbank
Dave Burbank

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“I’m pretty optimistic about genetic control,” Harrington says. “You release the males that don’t feed on blood anyway, so you’re not adding to the risk of transmission.”
Dave Burbank
Dave Burbank

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In the U.S. the Asian tiger mosquito—a vector for dengue, yellow fever, and zika in other parts of the world—is the potential threat.
Dave Burbank
Dave Burbank

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Cornell received a $10 million grant from the Centers for Disease Control and Prevention to establish the Northeast Regional Center for Excellence in Vector Borne Diseases.
Beatrice Jin; Dave Burbank
Beatrice Jin; Dave Burbank

Mosquitoes—the Sex of the Matter

by Caitlin Hayes

The mosquito is one of the deadliest animals worldwide, according to the World Health Organization. They transmit diseases such as malaria, dengue, yellow fever, chikungunya, West Nile virus, and zika. They’re responsible for millions of deaths each year, and the strategies to control outbreaks are limited, even in the United States.

When Laura C. Harrington, Entomology, was a graduate student doing fieldwork in Thailand, she experienced the danger and suffering first-hand, contracting malaria and dengue. The malaria made her so delirious she thought she was being euthanized, a fevered hallucination that referenced her job in a veterinary clinic as an undergraduate. She was hospitalized for both infections, traveling many miles from northern Thailand to Bangkok to get treatment for dengue.

“It’s what really influenced me, disappointed and inspired me—knowing that there were a lot of people who couldn’t get their kids to a hospital like I was in for dengue treatment,” Harrington says. “It was a big source of guilt for me. I felt there’s got to be something better that can be done.”

For Harrington, that something better is improving control of the vectors of transmission. At Cornell and field sites around the world, she and her team study aspects of mosquito biology and behavior, often overlooked, which can be exploited to control vector populations and disease transmission.

The Mosquito’s Mating Habits

Reproduction is a potential vulnerability in mosquitoes’ lifecycle. “We feel strongly that the mating system represents an ideal target for mosquito control,” Harrington says.

In most species, the females’ need for a blood meal increases after mating. The males do not feed on blood, but the females need it to develop their eggs. “We’ve noted these marked differences in females after she mates or after we inject the male’s seminal fluid,” Harrington says. “It definitely affects her feeding biology, and we’re exploring that now, trying to figure out if it makes her take larger or more frequent blood meals, which of course is important for transmission.”

Harrington’s group, in collaboration with the lab of Mariana F. Wolfner, Molecular Biology and Genetics, is also investigating ways to exploit this juncture in the lifecycle, with a particular focus on the male’s seminal fluid. By genetically altering the male mosquito, its semen could be made into a weapon, stopping the female from mating or reproducing. For example, over- or under-expressing certain molecules that are transferred to the female, the semen could prevent the female from mating again. It could prevent the female’s oviduct from relaxing in order to lay her eggs. The semen could even be made poisonous, by over-expressing a scorpion toxin. This has been done in fungi but not yet in mosquitoes.

“We feel strongly that the mating system represents an ideal target for mosquito control.”

Harrington’s lab is looking into a number of promising alterations, using CRISPR/Cas9 to knock out certain genes in order to understand their function in males, as well as a few receptor genes in females. They’re also partnering with Lena Kourkoutis’ lab, Applied and Engineering Physics, to image the structure of the sperm cell and how it changes once it enters the female reproductive tract. Targeting the process of capacitation, which may enable sperm to fertilize, could be a focus for control as well.

“I’m pretty optimistic about genetic control,” Harrington says. “You release the males that don’t feed on blood anyway, so you’re not adding to the risk of transmission.” She is also hopeful about species-specific insecticides, which would only target vector species.

This optimism comes with a note of caution, however, because there’s a lot of work to do, including outreach to communities where mosquitoes or insecticides would be disseminated. “What would you say, if I told you I was going to stop by your house this weekend and release some mosquitoes?” Harrington says. “It requires a lot of trust.”

Who’s Attracted to Whom

Harrington’s group also studies how mosquitoes are attracted to each other in the first place. Her lab made breakthroughs when they discovered that male and female Aedes aegypti mosquitoes, the vector for dengue and yellow fever, change the frequency with which they flap their wings when they come into close proximity. They perform a kind of mating duet the team called harmonic convergence. The findings were reported in Science in 2009.

With former student Lauren Cator, PhD’11 (Imperial College), Harrington is continuing to probe the implications of this behavior and whether the male’s ability to harmonically converge is a signal of fitness to the female. One student in Harrington’s lab will be looking at the link between a male’s ability to harmonically converge and the robustness of its immune system. It’s possible that females use the quality of buzzing in the males to determine the strongest, healthiest genetic partner.

If this is true, it’s important that any genetically altered males are able to harmonically converge. “These knockout mosquitoes are not great because their fertility is going to be low. If females can sense that they’re not very sexy, they’re out of tune, then they’re not going to mate with them, and the project won't work,” Harrington says. “With colleagues at Harvard, we’re actually finding that indeed, one of the mutants has this diminished ability to converge harmonically.”

These detailed biological behaviors are often overlooked when genetically altered mosquitoes are released in the field, Harrington continues. “Before any kind of release, it’s really important to understand how effective they’re going to be.”  

Potential Outbreaks in the United States, Asian Tiger Mosquitoes

Closer to home, Harrington’s group is tracking what could become a vector for outbreaks in the United States—the Asian tiger mosquito. An invasive species introduced to the United States in the 1980s, the Asian tiger mosquitoes lay their eggs in manmade containers, tires or shipping bins, all over the world. The embryos can stay dormant for six months or more, until the conditions are right for hatching. The scariest thing about the species is that they’re excellent vectors of disease.

“In other parts of the world, they’re very important in the transmission of dengue, yellow fever, and zika,” Harrington says. “In New York state, they’ve been found infected with West Nile virus, and they’re very important in heartworm transmission in dogs. In the laboratory, at least, they’re known to transmit 20 or more different viruses that affect human and animal health. It’s actually the best overall mosquito vector of viruses.”

The species has already spread throughout the southeastern United States and is moving north. PhD student Talya Shragai is tracking this expansion, working with Cornell’s Cooperative Extension to enlist the help of gardeners in New York State. She’s trained groups to trap mosquitoes and their eggs, giving her a much broader sampling effort than she could accomplish herself.

Shragai is also exploring the types of containers the mosquitoes are breeding in and how they adapt to cooler temperatures, with an eye toward limitations in the species that scientists can exploit.

Northeast Regional Center for Excellence in Vector Borne Diseases

The United States has been spared from major mosquito-borne disease introductions, with the exception of West Nile, but recent cases of zika in Florida and Texas are a reminder of our vulnerability. Amidst a broad effort to better prepare the United States, the Centers for Disease Control and Prevention (CDC) awarded Cornell a $10 million grant to establish the Northeast Regional Center for Excellence in Vector Borne Diseases, which Harrington directs. This is one of four CDC grants, awarded in 2017, to universities to develop regional centers.

Cornell’s center has three goals. The first is to train the next generation of public health entomologists, with a new master’s program to begin in 2018 and to add courses to the Master’s in Public Health program in the College of Veterinary Medicine. The second aim is to create a regional research community in the Northeast, promoting and providing support and infrastructure for collaboration. The third is to find solutions that can be applied in the near-term.

While Harrington is excited about all of these goals, her personal passion is teaching and training. “The rewards for me are really about the students, giving them what I have so they can be better than I ever could be,” she says. “Cornell’s a really great place for this. There’s a lot of talent and a certain intellectual buzz that you don’t find other places. It’s not something we have control over, it happens or it doesn’t. But the fact that we have it here is really special.”