Can Gene-Edited Mice in Nantucket Kill Lyme Disease?

Biotech researchers at MIT want to battle Lyme using CRISPR. What could go wrong?

This story is part of “Tickpocalypse,” a multi-part special report.

The island of Nantucket, the popular summer destination off the coast of Cape Cod, Massachusetts, is home to about 11,000 people year-round — and millions of ticks.

When infected with a strain of bacteria called Borrelia burgdorferi, those ticks can transmit Lyme disease to humans. And Lyme, which can cause everything from fever and headaches to muscle pain and arthritis, symptoms that can linger for years if the disease isn’t treated in time, is on the rise. About 300,000 people are estimated to contract the disease every year in the United States, and that number is expected to skyrocket, driven by a dramatic increase in the tick population. On Nantucket and nearby Martha’s Vineyard, the incidence of Lyme and other tick-borne diseases is among the highest in the country.

“Approximately 50% of people who grew up here have had an acute Lyme episode at least once in their life,” says Roberto Santamaria, the director of the island’s health department.

To stop the spread of the disease, Kevin Esvelt, an evolutionary biologist at MIT, is proposing an unorthodox approach: Lyme-resistant mice. In the lab, the team is using the gene-editing tool CRISPR to edit the genes of white-footed mice, the primary carriers of the Lyme bacterium, so that they can’t be infected in the first place.

In a series of public and town hall-style meetings beginning in 2016, Esvelt — who likes to refer to Lyme as the natural disaster of the Northeast — and his team have met with community members on Nantucket and then Martha’s Vineyard to present the idea and get feedback. The islands’ boards of health have given the green light for the project to move forward, but the communities will still have a final say in whether or not the resulting mice will be released there. For now, Esvelt’s team is figuring out how to engineer the mice and how many mice would need to be released to show that the approach works. They’re also considering two private islands for an initial field trial, which would need to be conducted even before the engineered mice can be released on Nantucket or Martha’s Vineyard.

“We want to take an existing form of mouse immunity that only a few mice have, make it stronger, and give it to all of the mice,” Esvelt says. “We think it would be the smallest possible change that would solve this problem.”

Many people associate deer with tick-borne diseases. And they’re a big part of the problem. A single deer can play host to up to a thousand ticks at a time. Nantucket has a lot of deer — more than 50 per square mile, according to Massachusetts’ deer harvest data. Deer were first brought to the island in the 1920s, and the population has since exploded.

But deer don’t actually transmit Lyme to ticks. Instead, ticks get infected with it when they feed on infected rodents like the white-footed mouse. Then, when they bite a human or other animal, they pass on the pathogen. “If we were to immunize all of the mice so they couldn’t carry these pathogens, then we could disrupt the transmission cycle and prevent most cases of tick-borne disease,” Esvelt says.

Plus, he says, the white-footed mouse is a better candidate for genetic engineering than the tick is. For one, mice can start reproducing at between eight and 10 weeks of age. Ticks take two years to mature before they can lay eggs. That means in a mouse population, an engineered trait would spread much faster than in ticks. And, as Esvelt puts it, “no one wants us dropping millions of genetically engineered ticks.”

Instead, he wants to take advantage of a natural immune response that some mice already have. These mice make antibodies that help stop the invading pathogen, which is introduced when ticks feed on their blood. Esvelt wants to boost this immunity and give it to more mice to see if he can reduce the chance of ticks spreading the disease.

Right now, he and his team are isolating these antibodies from mice and identifying which ones will fight Lyme and other tick-borne pathogens. Then, they’ll use CRISPR to edit the mice’s genomes so their liver cells produce the antibodies from birth.

Once the modified mice are made, it will be the job of Sam Telford, Esvelt’s collaborator and a tick researcher at Tufts University, to expose them to Lyme-infected ticks in the lab. If the gene editing works, and the mice don’t get infected with the Borrelia burgdorferi bacterium, the next step would be to release a couple thousand of these engineered mice into an area on a private island. Once the engineered mice mate with wild mice, they’ll pass on the immunity to the next generation.

“The assumption is that the fewer infected ticks, the fewer cases there will be.”

So far, residents have been receptive to the project. That may have to do with the burden of Lyme disease on the islands. Both islands also have long traditions of New England-specific town hall democracy.

Telford, who has been studying mice on Nantucket and Martha’s Vineyard for 30 years, is currently scouting for a site for an initial field trial, which would need to last at least two years. This initial release would involve a small, private island, that’s relatively uninhabited, to make sure the technology works as designed. If anything goes wrong, Telford claims they could trap and remove the modified mice. To have the best chance of spreading the immunity, he says the modified mice would need to be released in the spring. “After the long winter, the mouse population is at its lowest. That’s when you would want to do any sort of introduction,” he says.

But Esvelt says the team is likely a few years away from an initial field trial. That would require approval from federal regulators, the Massachusetts Department of Fish and Game, and approval from landowners. A release on Nantucket and Martha’s Vineyard won’t be considered until after a field trial, and even then, Esvelt and his team say they won’t move forward unless a majority of the islands’ citizens agree.

In both Nantucket and Martha’s Vineyard, residents have been able to give input on the project, dubbed Mice Against Ticks, offering feedback on the design of the mice, for example, as well as the release strategy. Joanna Buchthal, a graduate student in Esvelt’s lab and the project manager, says this approach means the technology may change based on the communities’ input.

“I think people are far more likely to embrace a technology if they’re involved in the development and have the opportunity to ask questions early and often,” she says.

Santamaria says the researchers’ openness about their work is what led the Nantucket board of health to move forward with the project. “We were blown away by the idea of open science,” he says.

Esvelt first asked residents if they even wanted white-footed mice that were genetically engineered to fight tick-borne disease and, if so, what exactly the mice should be resistant to — Lyme disease or ticks in general. Residents said they’d ideally want the white-footed mice to be resistant to both Lyme disease and ticks. So, that’s what Esvelt’s group hopes to accomplish.

The level of impact the modified mice would have on the burden of Lyme disease on the island is unknown, Telford says, because researchers don’t have good predictive models. “The assumption is the fewer infected ticks, the fewer cases there will be.” But that hasn’t been shown in practice yet.

Over the past few years, the team has been posting updates about the project and video recordings of its public presentations online so that anyone can read and view them. Ultimately, Esvelt says, the communities will vote on whether or not to use the technology. “You can decline to be affected by our work.”

Carolyn Neuhaus, a bioethicist at the Hasting Center who studies gene editing, says the idea of allowing communities to make decisions about their local ecosystems is not new. But as scientists explore the use of genetic engineering tools like CRISPR to change the environment, public engagement will be important since “people can’t meaningfully opt out of things that happen in shared spaces.”

As more of these technologies are developed, Neuhaus says scientists need to be open to criticism and new perspectives and make sure they involve communities and people with a vested interest in environmental issues, including indigenous populations.

For now, many residents on Nantucket and Martha’s Vineyard use permethrin, a type of insecticide, to ward off ticks. Both islands also have venison donation programs to encourage more deer hunting. Hunters can donate venison they don’t want to a food pantry.

But there’s a desire for high-tech solutions, including renewed interest in developing a Lyme disease vaccine after the only approved one was pulled from the market by the manufacturer in 2002 due to fears of perceived side effects (the vaccine was released around the time a now-debunked study suggested a link between vaccines and autism), negative media attention, and low demand. GlaxoSmithKline, the maker of the vaccine — called LYMErix — said that even though cases of Lyme were on the rise, sales for the vaccine dropped from about 1.5 million doses in 1999 to a projected 10,000 doses in 2002. The National Institutes of Health says early research into other Lyme vaccines for humans is in the works, but it could be some time before one is ready for market. Other researchers have sequenced the tick genome in hopes of revealing weak spots in its genetic code and figuring out a way to disrupt the transmission of the pathogen.

One worry among Nantucket and Martha’s Vineyard residents is that Esvelt’s idea could upset the natural ecological balance of the island. Buchthal says one of the biggest concerns people have had is the number of modified mice that will need to be introduced and how that might affect homeowners and businesses. Buchthal says they would release no more than 2,000 mice for an initial field trial, but the number will probably be much smaller.

Enid Haller, executive director of the Lyme Center of Martha’s Vineyard, remains skeptical of Esvelt’s plan. “I’m torn about it,” she says. “Part of me feels like it might be a good answer to bring the tick population down. I think it would probably make a dent. For me to embrace it, I’d want to know if tampering with nature that way long-term is safe.”

Haller was diagnosed with Lyme disease in 2009, but says she had symptoms for several years before that. Both her husband and adult daughter also suffered debilitating side effects for years before getting diagnosed with the disease. If Lyme disease isn’t treated early, its effects can linger for months or years in some patients.

For that reason, Haller is more concerned about people who are already infected with Lyme disease. “I think prevention is important, but I think treatment should be at the top of the list,” she says. “There are a lot of sick people that aren’t getting treated right now.”

Esvelt’s team knows the project will take years to come to fruition if it works at all. As Telford sees it, the modified mice are just another tool in fighting Lyme disease.

For Esvelt, the project is just as much about the process as it is about the science. “Our long-term goal,” he says, “is to enable every community to make its own decisions about their shared environment.”

This story is part of “Tickpocalypse,” a multi-part special report.