Progress Paused
Scientists Describe Research Reboot After Covid Shutdown
Imagine laboring many months toward a rare goal. All the planning, all the prep work and your team finally finds itself poised, with the objective within reach, when suddenly the journey is halted in its tracks. That’s how one longtime intramural scientist describes NIH’s recent 13-week lab shutdown due to the global coronavirus pandemic.
“It’s like climbing Mount Everest,” said senior investigator Dr. Charles Venditti, who heads NHGRI’s organic acid research section. “It’s just a long, long struggle, just trying to get to base camp. And then when you get there, the team has to coordinate to go for the summit. The summit is the sort of major accomplishment we try to achieve for a scientific program. Usually, it’s a manuscript or a set of experiments that are going to make a major advance…Well, a lot of us were at base camp. Then came covid, and we had to just stop everything. Now we’re just dwindling; we can’t have everybody come in and we can’t have the team assembled. It’s been difficult for us to keep our projects advancing in the laboratory. No one knows when we’re going to come back full speed and that really affects our ability to get our science to the top of Mount Everest. The covid pause has introduced a major, major setback.”
Shutting Down
Beginning Mar. 20, to reduce the risk of coronavirus transmission, NIH shut down all but mission-critical functions in all its laboratories and facilities nationwide. More than 3 months later, on June 22, the first labs—those with specific functions that could not be performed elsewhere and designated “Group A”—began returning to physical worksites under strict safety guidelines and with significant restrictions.
Days later, several scientists in Group A described the unprecedented period from a researcher’s perspective.
Like Venditti, staff scientist Dr. Dave Kupferschmidt of NINDS’s integrative neuroscience section was at a crucial moment when the shutdown was announced.
“Our lab had to shut down experiments just as projects were beginning to crest,” he said. “Technical details of many experiments had recently been streamlined and we were about to enter a particularly productive phase. Our experiments also require complex breeding of various transgenic mice and often last 6-7 months from start to finish. The shutdown meant that we couldn’t advance these projects enough in time to present meaningful stories at [virtual] conferences that many of us were poised to attend.”
His lab, which studies the neural circuit basis of normal and disordered cognition, had several initiatives underway when NIH entered lockdown mode.
“Many of these projects involved long-term neuronal recordings from mice with genetic mutations relevant to schizophrenia as they performed tests of cognitive function,” Kupferschmidt explained. “Others involved monitoring and manipulating the activity of discrete neuronal populations in the mouse brain to study how their connections might be altered to counteract disordered connectivity seen in our disease-related models.”
In-person work stoppage came at an inopportune time for NHGRI’s Dr. Mike Erdos, too. He’s a staff scientist in NIH director Dr. Francis Collins’s lab.
“I was one of the last people in the lab at the time of closure because I had a new instrument, with an engineer on site, being installed,” Erdos said. “We have not gotten to use it yet. The install was completed on Mar. 19. Mar. 20 was our first official shutdown day. We have two major projects in the lab—understanding the molecular genetics of type 2 diabetes pancreatic function using single-cell analyses and development of potential therapeutics to treat the premature aging Hutchinson-Gilford progeria syndrome (HGPS).”
Biggest impact
Research chemist Dr. Rob Robey of NCI’s Laboratory of Cell Biology, where NIH deputy director for intramural research Dr. Michael Gottesman is chief, also experienced “sudden progress interruptus.”
“One of the most frustrating things about shutting down was lost time on a project that started getting really interesting just before Covid-19 hit,” he shared. “We work on drug resistance in cancer and we had done RNA sequencing on a cell line that had been selected for resistance to a drug we have been studying. We had some candidate genes that we were exploring as potential resistance mechanisms and one of my colleagues sent me a paper that implicated one of the genes we had been looking at—a real ‘Aha!’ moment—just about a week before we had to shut down. Even worse, the gene is poorly characterized, so there are only a handful of papers about it on PubMed. So for 3 months I could only dream up experiments and not actually do any of them—very frustrating for a scientist in general, but even more so in this instance. I am making progress on this now, but the 3 months lost is just annoying.”
Some research elements can be stored, of course, but the loss of time—particularly with outside collaborators, and for early-career trainees and students—is harder to quantify and recoup.
“As we have learned from government shutdowns in the past, everything can be brought down to some level—cell lines frozen, experiments ceased—which we did for a number of ongoing experiments,” NHGRI’s Erdos said. “However, not everything can be brought to a halt. We have valuable mouse experiments in our mouse model for progeria with a very encouraging DNA-editing treatment that has been going on for over a year that continued through the sequester. One HGPS bone development cell culture experiment was in the middle of a 30-day differentiation [phase], which was able to be completed during the sequester. We also had one very detailed collaborative experiment with the New York Stem Cell Foundation that we were able to get to a stopping point, but then everything required freezing down.”
“I had to freeze all my cell lines down,” agreed Dr. Darawalee Wangsa Zong, NCI research biologist in the Genetics Branch. “A few of my colleagues had single-cell cultures growing and it was difficult for them to freeze those down. One of my experiments needed to be finished ASAP since my collaborator was waiting on just that one result before publishing. I managed to finish the experiment one day before we shut down.”
At NIH since 2004, she’s 1 of 19 people in that lab; half the staff consists of students.
“Our lab works with different types of cancer, particularly that of colon, breast and cervix,” Wangsa Zong said. “I was working on two projects of my own, but since our lab specializes in spectral karyotyping, we also have many outside collaborations that were put on hold.”
Senior investigator Dr. Daniel Reich of NINDS conducts studies of multiple sclerosis, including neuroimaging, pathology, biomarkers and RNA sequencing.
“Fortunately, we had no experiments that were lost,” he said. The major impact of the shutdown was “loss of ability to do our normal clinical studies—mostly natural history studies in multiple sclerosis—and our nonhuman primate studies, which require teams of people working together over a several-month period.”
Creative Safekeeping
Some labs found innovative ways to preserve what they could.
“I am fortunate to work with a very talented and creative group of scientists, and when it was clear that a shutdown was imminent, we worked hard to ensure a creative continuity of operations even if we couldn’t be on site,” explained NINDS staff scientist Dr. Ben Free. “We were lucky to have not lost any valuable reagents. We were able to transition the synthesis of some analogs to an overseas contract research organization that remained open as an essential business. The company then synthesized compounds under our direction so they would all be ready for us to test upon return to the lab.
“Furthermore,” he explained, “we were able to contract to another commercial research organization to run some selectivity testing on some lead compounds. This is an example of how we were able to continue some laboratory operations with the help of industry partners. This greatly prevented loss of time and resources as this portion of our work was able to continue and be highly productive.”
NCI senior associate scientist Dr. Art Shaffer said he “typically does daily experiments to move our lymphoma research forward. We do lots of benchwork experiments that we try to translate quickly to the clinic with our associated Clinical Center team…We do a fair amount of cell culture experiments that tend to run for weeks. We froze what we could, but some things in-progress were lost, probably about three-fourths of what we were doing. We were also stymied by not being able to do any mouse work. We need to test drug combinations to treat cancer in mice, and that was not approved to move ahead. Much like a budget shutdown, 1 week lost equals 3 weeks to restore/revive. That means we’ve got 9 months of work ahead to recover to the point where we were in March, assuming everyone can come back every day soon.”
Unrecoverable: Time, Experiences
Erdos lamented what can’t be recovered. “The biggest impact is losing the day-to-day interaction and discussions with our colleagues in the lab. Focusing while working home alone is a good thing, but much creativity comes from intangible thought interactions with other curious minds that lead to innovative and productive developments in research.”
Venditti thought of people and their families who schedule appointments up to a year in advance to visit NIH, and who couldn’t come during shutdown.
“We have two natural history studies that are very, very active on rare metabolic disorders that affect mainly pediatric patients,” he explained. “Our laboratory does research to try and develop new treatments for these children. These are grave conditions and we are following hundreds of patients from all around the world, and for them, visiting NIH for an assessment is almost like an interventional clinical trial. Most of our patients are being treated with best intentions because there are no real evidence-based practices, as is typical for patients with rare disorders. Many of the children we take care of are managed with dietary protein restriction, cofactors and supplements. They’re teetering between health and illness. We often provide advice and guidance when they participate in our natural history studies.”
Reich, whose research also involves patients, agreed. “We aren’t open—we still can’t do our natural history studies, which is frustrating both to us and to the patients. We hope to be able to restart our nonhuman primate studies with Group B, but we’re nervous about how that will go.”
Regarding his lab’s work with animals, Venditti saluted the dedication and diligence of a technician who cared for the mice while everyone else teleworked. [See sidebar.]
“In addition to losing the ability to perform physical experiments,” Kupferschmidt noted, “we experienced a hit in our work efficiency as a result of the shift to telework. Our data analysis demands considerable computational power, and equipping ourselves for this capability from home unfortunately spanned a large chunk of the shutdown. All lab members and IT staff worked diligently to best facilitate this transition, but the massive scale of this shutdown created unforeseen hurdles and unavoidable backlogs.”
Considering next-generation scientists, Free observed, “One effect on our program was the lost opportunity and knowledge transfer for our trainees.” His lab had two postbaccalaureate IRTA fellows who had to leave the lab in the last days of the shutdown en route to graduate and medical school.
“These outstanding students were at NIH to learn hands-on application of science, designing and running experiments and contributing to overarching research projects,” he said.
Both students worked hard for 2 years, Free noted, only to have their projects rapidly cut short before they could see them through. “The [Office of Intramural Training and Education] did a fantastic job of providing resources for these trainees during the last few months to continue learning and being engaged, but the cut-off of the projects has been particularly tragic for them…We also had to cancel travel to two scientific conferences. These conferences, while extremely important for all scientists, are particularly valuable to trainees for cementing future relationships and furthering their careers. It was a shame that both conferences were canceled and the trainees who have since left the lab will not have the opportunity to make up those experiences.”
Daniel Bronder, an NCI predoctoral fellow, focuses on taking away the positive from the time away from the bench.
“[The forced downtime] offered the opportunity to take a step back from pipetting and reflecting on all the work I have done up to this point,” he said. “It has really provided me with an opportunity to take a more global look at the body of my work to scrutinize what I have got thus far and evaluate which experiments will be the most impactful to bring my story to completion. I also had the opportunity to start writing up the results of my work, so going forward I will be in a better position to slot results into place more easily.”
NCI research fellow Dr. Sarah Clatterbuck Soper reported, “Our lab is a combination wet/computational cancer genomics lab with a focus on osteosarcoma. I am mainly on the wet side, though I do some computational work. I study alternative telomere maintenance in osteosarcoma. I work in cell lines, so I was able to freeze down my work. While there has been a ramp-up process on return, it has been pretty smooth, basically just getting my cells going again. I should be able to begin collecting data again [soon]. It was perhaps comparable to taking a long vacation. While shut down, I was not able to move my ‘main’ wet lab project forward at all. That’s a big impact and obviously frustrating.”
Creating a New Normal
Free, whose lab studies development of new medications for dopamine-related neurological disorders such as Parkinson’s disease and psychosis, said he’s grateful that continuity of operations plans with industry partners allowed the scientists to “have compounds ready to go as soon as we were allowed back in the lab. It will take a few weeks to get our assays back up and running at anything near full capacity, but we are thankfully able to be productive right away. Schedule limitations have been a challenge, as we have had to think carefully about what assays we can feasibly get back online with any given personnel. We keep in very close daily contact and tweak our scheduling as necessary to ensure maximum workflow under the prescribed restraints necessary for a thoughtful and safe return.”
Says Shaffer, “Jumping back in is impossible under the ‘Group A-B-C-D’ plan. We can only be at about one-third strength in the lab, which for us means you can’t be here every day. A typical lab week had been 6-7 days a week; now it’s only 3. Plus, NCI cores—sequencing, cell sorting, etc.—are not running at capacity, which also severely limits everything we can do.”
“There have been and will continue to be stages to our safe re-opening,” Kupferschmidt said of the lab led by principal investigator and NIMH director Dr. Joshua Gordon. “Currently only a few lab members are coming on site with any significant frequency. Mouse breeding is now being ramped up to re-derive our colonies of experimental mice. We hope to soon be able to restart the extended experimental clock on many of our lab’s projects.”
“Since I’m in charge of getting the lab supplies, etc., my first week or so involved taking inventory, getting the lab ready for everyone to return, [obtaining] masks, etc.,” Wangsa Zong noted. “We even had an equipment breakdown while we were away, so we’re trying to get that solved as well.”
Adjusting to a new covid-conscious climate, Erdos cautioned that “jumping right back in has the same caveats as shutting things down. Thawing cells and getting them to be conditioned for experiments again takes a little time. But it is necessary and also allows for us to get accustomed to the new regulations for distancing and safety. Being in the lab only about 50 percent of the time, and only one-third of the lab occupancy at any one time, requires extra attention to coordination and organization. Breeding animals for experiments also takes some lead time, about 2-3 months to get colonies back up to normal.”
“For us at least, things have been pretty smooth,” said Robey. “Everybody is hyper aware of wearing masks and keeping distance, I would say. It’s still a little awkward to share data in person—I actually made a PowerPoint file with recently acquired data and printed it out so my colleague and I could go over the data from a safe distance—but we all seem to be managing! Quite frankly, even though everybody is at one-third capacity, it still feels completely dead. I rarely see anybody in the halls; it’s just eerie.”
Those returning onsite should expect a very different workplace than they left. Auditoriums, shuttlebuses and cafeterias all are functioning on limited schedules, according to safety guidelines.
“Conference space will be utilized when NIH is at a phase where in-person meetings can be conducted safely either with proper physical distancing or because the pandemic has subsided,” said Brad Moss of the Office of Research Services. “Until such time, the use of remote conference capabilities continues to be the recommended method for conducting meetings at this time. ORS will continue to analyze the population on campus to see what food service operations we can open safely as additional groups return to work.”
An assessment of conditions followed the first wave of returnees. NIH director Collins announced on July 13 that Group B could return the week of July 20, which happened as scheduled. However, not all individuals within these groups have actually returned, despite the all-clear.
Sketch Amid Shutdown
Research Champion Immortalized
Dr. Charles Venditti’s NHGRI lab includes a translational research program that conducts natural history studies on rare metabolic disorders. A large part of their work involves breeding and treating very sick—and very valuable—mice. It’s a vital research component that is difficult to halt mid-stream—even when a pandemic unexpectedly comes calling. Fortunately, devoted animal caretakers like Darwin Romero, a Kelly contractor to NHGRI and Venditti lab mouse technician, rose to the occasion.
“Our mouse technician has just been an absolute hero for our research program,” Venditti said. “He’s in there saving our precious mice, even on weekends. Helping us with our critical gene therapy experiments. Acting as a missionary for our scientists to help them try to keep the science going remotely. It’s been amazing to see people step up and we’ve made real progress, despite the covid crisis, because of his efforts.”
So impressed with Romero’s work ethic was Venditti that his enthusiastic praise while teleworking inspired his youngest daughter, Livia, an artist, to render a portrait of the tech. The scientist plans to present the portrait to the aptly named science technician Darwin soon.
“Without the tireless efforts of our animal caretakers/vets and especially mouse technicians—like Darwin in this time of crisis—our precious animal disease models, and eventually the patients they help, would have been utterly decimated,” Venditti concluded.