As Lyme disease continues to cast a shadow over New Englanders’ outdoor expeditions, MIT researchers are planning to fight the disease using gene editing. As part of the Mice Against Ticks project, they plan to identify genes that make white-footed mice immune to the bacteria that cause Lyme disease, and then insert these immunity genes into thousands of mice and release them on small, largely uninhabited islands. Greater immunity in mice would reduce transmission of the Lyme bacteria to the ticks that bite them, and then to humans. If the project works, it could be expanded to Martha’s Vineyard, Nantucket, and even the mainland.
Pro: Why this MIT researcher wants to genetically engineer mice
By Kevin M. Esvelt
The epidemic of Lyme disease is an ecological problem of our own making: we have inadvertently altered our environment to maximize the number of infected ticks. The question today is whether we should consider altering the genomes of wild animals to undo that mistake.
If so, we should find the most minimal intervention that might solve the problem. We should actively invite suggestions, concerns, and guidance from interested local communities who know their own environments best. And we should initially observe the effects on mostly uninhabited islands.
That’s exactly what my colleagues and I aim to do with Mice Against Ticks, a community-guided project working to prevent tick-borne disease through genome editing.
The current Lyme disease epidemic is the unanticipated result of our desire to live near trees. The Northeast is more wooded today than it’s been for millennia, but our forests are fragmented by houses and roads. Fragmented forests benefit three species:
Black-legged “deer” ticks, which feed three times in their lifetimes, enough to acquire and transmit to other animals the pathogens that cause Lyme and other diseases.
Deer, each of which can host thousands of adult ticks that will collectively lay millions of eggs.
White-footed mice, which are better at acquiring and transmitting tick-borne pathogens than any other animal.
By changing the environment to benefit ticks, deer, and mice, we’ve inadvertently supercharged the cycle of tick-borne disease transmission, creating a positive feedback loop: more ticks create more opportunities for transmission. More deer mean more ticks. And more mice mean more infected ticks.
In principle, we could throw that cycle into reverse by immunizing white-footed mice against Lyme disease. Of course, trapping and vaccinating all of the mice in the woods would be impossible. But it is possible to harness immunity genes that some white-footed mice naturally acquire the same way people do: when exposed to a new pathogen, the immune system evolves new genes that flag the enemy for destruction. By isolating the most effective Lyme resistance genes evolved by some white-footed mice, combining and editing them into the genome so they can be passed on to descendants, and releasing sufficient engineered mice into the woods, we could gift nearly all mice living in an area with strong inborn resistance to tick-borne disease.
Mice Against Ticks will live or die by the three cautionary guidelines outlined earlier:
Make the smallest possible change that could solve the problem. Since some mice already evolve anti-Lyme resistance genes naturally, just like all mice do when vaccinated, gifting local mouse populations with the same kind of immunity should minimize unintended consequences.
Seek advice from people who may know more. Science works by inviting others to challenge ideas. I believe the term “others” should include people beyond the scientific community, especially those who live in potential early adopter communities. The more skeptical you are, the more we want to hear why.
Start small and see what happens before scaling up. Many people across the country would like to put an end to Lyme disease tomorrow, but it would be premature to begin immunizing mice everywhere. It’s better to start with reversible trials on well-studied and sparsely populated islands that are small enough to remove all of the edited mice and reintroduce wild mice if necessary.
Our team approached the communities of Nantucket and Martha’s Vineyard in 2016, before we performed any experiments in the lab, to invite community guidance on whether and how to proceed. Were people interested enough for us to begin research, knowing that the benefits would be many years away and might eventually require releasing 100,000 genome-edited mice into the woods? Remarkably, the answer was a resounding “yes.” But
when asked whether we should stick as close as possible to what’s already found in nature, even if that makes the intervention slower, less effective, and requires more mice to be released, people were, and are, divided. Conversations over the years suggest that an apparent majority prefer that we err on the side of simple and natural when possible.
How well our approach works — and whether there will be any ecological side effects — can’t be known until we test it. That’s why we’ll need federal and state regulators to carefully examine the mice and approve field trials on the small, mostly uninhabited islands that have already volunteered for the privilege. Independent ecologists will evaluate the trial results and report to the communities of Nantucket and Martha’s Vineyard, which will decide whether or not to proceed using their own systems of governance. If effective, the same resistance genes could be used for disease prevention on the mainland.
We expect to continue to learn from residents about what is and isn’t important to them, and also about what we should be watching for and designing for. We’ve already had citizens point out potential outcomes we hadn’t anticipated that might change how communities decide to introduce resistance. It’s possible that we might come across something that fundamentally challenges public support for the project. If so, we walk away: your environment, your call.
My personal hope is that the Mice Against Ticks model, in which researchers openly approach communities before beginning experiments and agree to be guided by a steering committee of local residents, will become the gold standard for all research intended to engineer wild organisms and introduce them into the shared environment.
This may not seem very important if scientists are just immunizing the neighborhood mice. But Mice Against Ticks is noteworthy for not using the most powerful technology available: a tool I helped to invent called gene drive, which is capable of single-handedly spreading engineered genes from just a handful of introduced organisms to the entire species.
Even if we differ on whether to release engineered Lyme-resistant mice into the woods, ensuring that ecological engineering proposals start small and invite community guidance is a project everyone can support.
Kevin M. Esvelt, an evolutionary engineer and assistant professor at the MIT Media Lab, is an inventor of CRISPR-based gene drive and a founder of the Mice Against Ticks project.
Con: Gene editing to stop Lyme disease: caution is warranted
By Allison Snow
When I first learned about Mice Against Ticks, I was shocked but also intrigued — shocked by the audacity of Kevin Esvelt’s plan to genetically engineer a mammal native to the United States, but curious about whether the project could prevent Lyme disease. The outcome of this radical intervention might influence how society views the acceptability of altering the genes of other animals, and perhaps even our own.
As an academic ecologist, I’ve spent the past three decades studying effects of genetically engineered organisms like Roundup-Ready crops on wild species. With the recent advent of the gene-editing technology known as CRISPR, biochemical engineers have bold, new aspirations that include tinkering with the genes of wild species in order to sculpt evolution, or even eradicate unwanted species from entire continents using a technique called gene drive.
Mosquitoes that carry malaria and other disease-causing pathogens are the focus of several gene-editing efforts. Now the white-footed mice of New England are another target. The persistence of Lyme disease depends on intricate ecological relationships among ticks, small mammals, and deer. Many researchers consider white-footed mice to be a major reservoir for Lyme disease because they harbor the bacteria that cause it, are very abundant, and are often bitten by black-legged ticks (deer ticks), which then infect people.
Esvelt and his collaborators hope to engineer mice to make them resistant to Borrelia burgdorferi, the microbe that causes Lyme disease. Their ultimate goal is to release thousands of these genetically engineered mice, first on largely uninhabited islands. If the experiment works, they could then replicate it on Nantucket and/or Martha’s Vineyard, and possibly the mainland — pending, of course, sufficient research progress, regulatory approvals, and public support.
Commendably, the team has sought comments and advice from residents of Nantucket and Martha’s Vineyard since 2016, and they are eager to obtain feedback from others during each stage of this ambitious, long-term project.
My main concerns about Mice Against Ticks center on how well independent ecologists and evolutionary biologists will be able to evaluate its long-term safety and likelihood of success. Once the genetically engineered mice are allowed to breed freely outdoors, it will be difficult — if not impossible — to recreate the original, non-engineered mouse populations if something goes wrong. Resistance genes that have been introduced by genetic engineering could persist indefinitely in wild mouse populations, so it’s essential that we understand and avoid possible risks well in advance of any planned releases.
The ecological effects of releasing genetically engineered mice into the wild could range from negligible to harmful. What if the genetically engineered mice turn out to be much more prolific or aggressive than their unaltered counterparts? Or what if other tick species and pathogens become more abundant following this intervention? Predicting the ecological effects of island-wide introductions of genetically engineered mice will be challenging, as I recently described in the journal BioScience.
Ecologists think of white-footed mice as a hub species because their populations affect, and are affected by, interactions within an interconnected network of many other species. These small creatures eat seeds, fungi, insects, and other invertebrates, and are in turn eaten by snakes, owls, hawks, bobcats, foxes, coyotes, and other animals. Although it’s simplistic to argue that there is an idealized balance of nature, we need to understand how all of these species can affect each other’s abundance, keeping in mind how often humans have caused harm by introducing wild animals and plants into novel situations. So it is clear to me that careful attention to possible unintended consequences of Esvelt’s proposal is warranted.
Another concern I have is whether the project can actually succeed. Will it lead to a measurable, long-term reduction in the numbers of the Lyme-infected ticks that transmit the disease to people? What if the introduced genetically engineered mice are inferior to local wild populations in their ability to survive, compete, and reproduce, causing the new resistance traits to be lost? Or could other reservoir species for Lyme disease — shrews, voles, rats, chipmunks, squirrels, and ground-foraging birds — sustain the Lyme transmission cycle perfectly well on their own? What kinds of ecological or epidemiological data would be needed to show that the intervention is working as intended, and how feasible are such studies? It’s important to consider these questions in advance to maximize the chance of success.
Related: Is ‘chronic Lyme disease’ real?
I am optimistic that concerns about this project can be taken into account as it moves forward and as ecologists and others continue to weigh in on expected benefits and risks. At this early stage, there is ample time for debate and research to answer key questions.
Although I’m inherently cautious about genetically engineering wild species, in some cases such interventions may be relatively safe, beneficial to human health, and worth the presumed risks. Perhaps this will be one of them.
Allison Snow is professor emeritus in the Department of Evolution, Ecology, and Organismal Biology at Ohio State University.