When the dreaded announcement came, Sandeep Datta, PhD, understood the need but worried about the potential impacts: scientific progress suspended, young researchers’ careers stalled, the mice gone.
To combat the spread of COVID-19, Harvard Medical School on March 13 ordered a halt to lab work not related to the disease, with narrow exceptions. Datta’s lab there stopped several projects observing how mice behave in response to sensory inputs to their brains, like odor; the researchers hoped to gain insights into such human ailments as Alzheimer’s disease. Although more than 20 people are assigned to the lab, these days just one staffer at a time comes in to monitor a two-year-old longitudinal study that the school allowed to continue on a scaled-down basis.
“New science has stopped,” Datta says.
As for the mice: The lab euthanized 80% of its stock, Datta says, so researchers don’t risk their health by having to staff the laboratory to maintain the colonies. Restocking those colonies will take weeks or months.
Harvard University, where some research has been halted and some continues, reflects scenarios playing out at university labs across the country after campuses shut down to stop the novel coronavirus transmission. Leaders overseeing labs have been wrestling with unprecedented questions, starting with how to decide what research continues and what does not.
“We’re not making value judgments between one research program and the next,” says Colin Duckett, PhD, vice dean for basic science at Duke University School of Medicine. “But to keep our researchers safe, we have to reduce how many can come to work — and that’s forcing us to make some really hard decisions.”
Still unanswered: How will suspended projects resume? How will the researchers get paid? What happens to students whose theses and dissertations, due in months, rely on findings from research that stopped? How can sidelined researchers spend their time constructively now?
In early March, Duckett guided Duke’s labs in developing contingency plans to shut down most or all of their projects if required. “Our goal is to have zero cases of infection in our research labs,” he wrote.
On March 17, the school sent a message to its labs: “All laboratory PIs [principal investigators] should begin to activate their wind-down plans effective now.”
Duke’s criteria for shutting down lab work are typical of those developed by other medical schools. The simplest decisions involved two types of projects: Those focused on the coronavirus could continue, while no new projects unrelated to the virus could start.
“Our goal is to have zero cases of infection in our research labs.”
Colin Duckett, PhD
Duke University School of Medicine
The pain points for researchers have been the many projects in the middle — ongoing experiments not related to the virus. In those cases, the decisions rest on what it would take to restart the project and whether the project would still be scientifically valid. Duckett puts it this way: “Is your research going to be viable when we come back out of this? And how little can you do [in the meantime] to ensure viability when we come back out of this?”
The answers are fairly straightforward for some projects, such as those that examine microorganisms.
“You can freeze your cell lines down, you can grow up your bacteria and yeast very quickly,” says Etty “Tika” Benveniste, PhD, senior vice dean for basic sciences at the University of Alabama at Birmingham (UAB) School of Medicine.
For many of those projects, staff are allowed in the labs as little as possible to carry out the minimum activities required to keep a suspended project viable, such as making sure bacteria remain frozen.
Maintenance isn’t so simple for projects involving animals.
Suspending animal-based research can pose significant challenges of science, time, and money. Benveniste points to longitudinal studies that require observations on animals as they age, as tumors progress, or as treatments show impact. At Virginia Commonwealth University School of Medicine, Michael Donnenberg, MD, senior associate dean for research and research training, notes, “We have quite a few opiate studies involving mice that had been on a certain diet for long-term study,” with observation points from 30 days to more than 90 days.
At those and other universities, some long-term animal studies have continued, with researchers scheduling individual visits to labs and remaining there for as little time as possible. At Harvard, for example, one researcher is allowed to visit the Datta lab to monitor a longitudinal study on a cohort of mice that started at their births and has run for more than two years. The data they collected in the past will be of little use without the collection of more data, Datta says; suspending the project would be equivalent to shutting it down and starting over.
In addition, labs that provide core services and equipment, such as freezing specimens in liquid nitrogen, are operating on an as-needed basis at many universities to support the research that remains.
With most projects shut down, however, a question looms throughout the labs: What to do with the mice?
Labs around the country have collectively euthanized thousands of mice in order to protect staff from having to come to the labs to care for them. “Most labs that are animal intensive have really reduced their colony sizes greatly,” says Benveniste at UAB.
But not always completely. Bradley Yoder, PhD, chair of the UAB School of Medicine’s Department of Cell, Developmental and Integrative Biology, says his lab is maintaining some mice colonies in hopes of again breeding those mice to restart suspended projects. “The lines are being maintained to hopefully maximize the numbers of mice for these experiments as quickly as possible,” says Yoder, whose research focuses on kidney disease. Still, he says, the shutdowns “will have a major impact on our productivity, probably for the next several years.”
Some labs have frozen embryos so they can rejuvenate their mouse strains later. Others will buy more mice and embryos from elsewhere. The Jackson Laboratory, a nonprofit biomedical research institution, is collecting mice from labs and freezing their sperm and embryos in order to preserve mouse strains for future research.
Whichever option a lab chooses, replacing the mice to restart experiments will take more time and money than growing yeast. “If you have a breeding colony that is producing, for drug testing, hundreds of a certain type of mice a week — to ramp that colony down to a few embryos and grow it back up to a productive colony takes weeks and weeks, and costs a lot,” says Curt Civin, MD, associate dean for research at the University of Maryland School of Medicine (UMSOM).
Lost science causes stress
“This has not made a lot of people happy,” Benveniste says of both the lab shutdowns and the denials by those in the decision-making chain, such as her, to requests for exceptions.
“I get requests from faculty — ‘I have this one experiment I need to do,’” Benveniste says. “I run a lab. I get it. But I have to say no because only the most essential research is allowed.”
The shutdowns “will have a major impact on our productivity, probably for the next several years.”
Bradley K. Yoder, PhD
University of Alabama at Birmingham Medical School
The shutdowns have caused a particular type of stress for graduate and postdoctoral students, whose research is foundational to their theses and dissertations, which are in turn critical for the start of their careers.
“All of these experiments have been stopped. The clock on their careers has stopped as well,” Datta says. “They’re justifiably anxious about how this will affect the science, and their ability to publish papers.”
Meanwhile, researchers are using their newfound spare time to analyze data and images they’ve collected, to read existing research, and to write articles, papers, and grant applications.
“All of us who work in research always have a hard drive filled with data waiting to be analyzed, and a paper waiting to be written,” Datta says.
Beth Sullivan, PhD, associate dean for research training at Duke, says some faculty there have told students, “You don’t have to wait until the last couple of months to write sections of your thesis,” even as they await final results from a suspended experiment.
However, the stress over suspended research extends beyond the due dates for papers. Critical scientific findings are being delayed and some might be lost for good.
“My research, from the experimental standpoint, has ground to a halt,” Sullivan says.
“A lot of what is on hold is what I would call our fundamental basic sciences,” Benveniste says. “That ranges from understanding how cells behave to what causes the transformation of cells into cancer. What are the underlying causes of Alzheimer’s disease and Parkinson’s? … We’re losing ground in fundamental discoveries.”
It’s not clear what ground will be made up, because no one knows what capacity funders or labs will have to reestablish research unrelated to the coronavirus after the shutdowns lift. Labs are using money from grants to continue paying researchers and faculty even as little lab work is being done. Who pays to finish those grant projects after the grant money is gone?
The National Institutes of Health (NIH) has said it will extend grant completion deadlines but has not promised money to cover costs. Four national organizations, including the AAMC, sent a letter to congressional leaders this month asking them to provide $26 billion in supplemental funds to the NIH and other major research agencies to help cover such costs related to the lab slowdowns and closures.
“We are deeply concerned that the people who comprise the research workforce – graduate students, postdocs, principal investigators, and technical support staff – and the future health and strength of the U.S. research enterprise, are at risk,” the letter says.
At UMSOM, Civin believes that the state of Maryland’s requirements for people to stay in place should be relaxed soon for a progressively increased number of researchers on selected projects, as they can be trained to use personal protective equipment correctly and maintain interpersonal distance by designating time periods for individuals to work in labs.
“Cancer is still going to kill more people than COVID-19 this year,” Civin says. “Don’t we want to get that research back up?”
In preparation for whenever that day arrives, research faculty are maintaining contacts with their teams through calls and video meetings and also reviewing new writing and data analysis.
“A lot of what concerns us now is, ‘How do we keep our labs together?’” says Datta, referring to his fellow principal investigators at other labs. “What can we do to support people who work in our labs? To prepare us to return? To keep everyone healthy now?”