Drastic attempts to thwart the spread of Covid-19 have left a lot of scientific research at a standstill. As researchers and participants avoid unnecessary face-to-face contact, most clinical research is off the table.
But not all research can be put entirely on hold—particularly when it involves animal models. The scientists who study Alzheimer’s in mice are among those who have had to find ways to keep their research going.
These aren’t just any mice: They’ve been bred and genetically edited to have mutations that make them more likely to develop Alzheimer’s-like traits as they age. They’re immensely valuable in the fight to develop effective treatments for the common form of dementia; losing them would mean losing years of research into the disease.
Scientists who create these mice have had to implement a form of triage: The less-developed lines will simply be kept alive and well until more personnel can be back in the lab to breed, edit, and study them further. For the lines that teams deem more critical, scientists are finding ways to continue research so they won’t lose their progress.
Modeling Alzheimer’s disease is a daunting task. As far as scientists know, Homo sapiens are the only creatures on the planet to develop the plaques of amyloid, tangles of tau, and brain inflammation associated with the disease. Chimps seem to develop some of the characteristics of the disease when they reach old age—but they don’t progress to the full onslaught of neurodegeneration. Other species simply don’t seem to experience it at all.
Mice don’t develop Alzheimer’s, exactly, but scientists have been able to come up with mouse models that mimic aspects of disease, since their neurological and vascular systems are similar enough to humans’. For the past two decades, Alzheimer’s mouse models were genetically modified to have mutations on only one of three genes, explained Gareth Howell, a neuroscientist at The Jackson Laboratory in Maine. In humans, these same mutations all but guarantee that they’ll develop the disease in their 30s, 40s, or 50s.
But this dominantly-inherited form of Alzheimer’s makes up just 1% of the estimated 50 million cases worldwide. The field of Alzheimer’s research has been pock-marked with failures after failure of clinical trials—in part, researchers now believe, because the models weren’t telling them the full story.
The pathways to develop late-onset Alzheimer’s disease—the more common form of the disease, which develops after age 65—develops differently than the dominantly-inherited form. Scientists don’t know which combinations of mutations ultimately lead to Alzheimer’s in humans, especially because other factors, like diet and exercise, can tip the scales to lead to Alzheimer’s disease. But that’s exactly what they’re trying to figure out in mice.
For the past five years, scientists at The Jackson Laboratory, Indiana University, the University of Pittsburgh, the University of California at Irvine, and Sage Therapeutics have been developing mouse models that account for several genetic risk factors at once. Together, these groups make up MODEL-AD, a consortium created in 2015 by the US National Institute on Aging. (Conveniently, it stands for the Model Organism Development and Evaluation for Late-Onset Alzheimer’s Disease).
Creating these mouse models has taken a lot of expertise and time. First, scientists have to use Crispr to edit mouse embryos to insert one mutation at a time. Then, the mouse has to reach reproductive age—about five or six weeks—before being bred with another mouse with the same mutation to guarantee that its pups will carry it. Those embryos have to be genetically modified to insert another risky genetic mutation—and on and on the cycle goes, for several generations, until the mice carry up to four risky mutations. The whole process can take multiple years.
Which is why it’s so important to keep these lines alive—at bare minimum—as labs are shut down. Between the Indiana University Labs and Jackson Labs in Maine, researchers have dozens lines of mice, and both groups have animal lab facilities where technicians are considered essential enough to go in and properly feed, clean, and provide water to the mice “on the shelf,” or available for future studies. So far, the staff have been able to manage taking care of all the lines in these facilities.
But while the years-long breeding process won’t likely be interrupted, the ongoing research involving these lines probably will. “The big labor comes in aging and phenotyping,” says Bruce Lamb, a neuroscientist who heads up the development of the MODEL-AD mouse models at Indiana University.
At four months, 12 months, 18 months, and 24 months, researchers see if the mice show some of the characteristics of Alzheimer’s in humans—like certain proteins in their blood, or the aggregation of amyloid and tau in their brain. By 24 months, murine models are about the equivalent of a person in their 80s or 90s. At this point, researchers can also do post-mortem analyses on their brains—just like they would for people who have donated their bodies to research.
Although each research group has decreased their in-lab staff to avoid any possible spread of Covid-19, they’re hoping that they can keep a separate list of personnel who are permitted to go in and perform, in isolation, some of the basic phenotyping tasks at some of those critical ages, if necessary. In some cases, the groups have decided not to take data in some of the middle stages in the models’ lives at 12 and 18 months.
The only work that has been truly delayed is the creation of totally new lines, or lines that have just started out and need to continue to be genetically modified. “That’s the frustrating bit—we’re not starting those experiments,” says Howell.
In the meantime, the group still has papers to write and grants to apply for. The goal is that the required lockdown to stop Covid-19 will be over in time to get back to lab work before any of the oldest models have died, so they can collect all the data they need—without losing the time it took to develop them.