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    Basic medical research took a hit during the pandemic. It might take years to recover

    COVID-19-related shutdowns and restrictions halted studies for cancer, diabetes, and more, threatening scientific progress. Can researchers make up for lost time?

    A scientist experimented in the laboratory

    At this time last year, researchers at Massachusetts General Hospital (MGH) and Boston Medical Center were all set to recruit breast cancer survivors in a clinical trial designed to improve long-term outcomes for Black women afflicted with the disease.

    Researchers in the nation’s largest long-term study of brain development and child health were planning to collect saliva samples from 12,000 youths around the nation to measure such things as hormonal changes that drive puberty.

    And a team led by Gregory Germino, MD, at the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) in Maryland had just launched a study to see if inactivating a specific gene in mice might slow the development of polycystic kidney disease.

    Instead, the breast cancer trial halted its enrollment launch, the adolescent development study never got its saliva samples, and the kidney disease experiment stopped breeding the mice it needed. Each study has resumed, but impediments remain and recovery moves slowly.

    The same is true for countless medical research projects around the country, as collateral fallout from the pandemic — including restrictions at labs, shortages of supplies, and fears among participants of contracting COVID-19 from research procedures — continues to hamper experiments, trials, and longitudinal studies that do not focus on COVID-19.

    “In some cases it’s going to take years” to bring projects back to where they were before the pandemic, says George Weiner, MD, director of the University of Iowa Holden Comprehensive Cancer Center in Iowa City, which does lab and clinical research.

    It remains to be seen what research will be severely affected and for how long; many projects are back up to speed after minor delays. But some academic medicine leaders worry that the nation stands to lose significant ground on medical research in the coming years.

    No one has been able to simply flip a switch and pick up where they left off” when labs and other facilities closed or severely curtailed activities as the pandemic surged in the spring of 2020, three of those leaders recently wrote in the Hill, a news site covering Congress and the presidency. “The pandemic threatens to erode our nation’s scientific progress.”

    Nonetheless, researchers and administrators at institutions around the country are working hard to make up for lost time.

    Empty slots at clinical trials

    “People are still skittish.”

    That’s how Weiner describes one of the biggest barriers to fully resuming clinical trials at Holden, especially in trials designed for prevention and early detection of disease. When people weigh the benefit of being screened for diseases against the risk of contracting COVID-19 at a clinical trial site, many opt to stay home.

    Wariness is one reason that many clinical trials not related to COVID-19 are recovering slowly from shutdowns caused by the pandemic.

    “Most clinical studies had to stop recruiting new participants and defer in-person follow-up visits,” says Germino of the NIDDK.

    At the Johns Hopkins Institute for Clinical and Translational Research (ICTR) in Baltimore, enrollment in clinical trials dropped by more than 70% between March and August of 2020, according to Director Daniel Ford, MD, MPH. The Penn Medicine Abramson Cancer Center in Philadelphia reports that nearly 90% of its clinical trials suspended enrollment last spring.

    At the ICTR today, clinical trial enrollment (including in COVID-19 trials) stands at about 75% of where it was a year ago, Ford says. He calls participant reluctance “a major barrier.”

    The reluctance varies greatly by the type of trial. While many trials that provide experimental therapies for people seeking treatment against confirmed diseases have reached their enrollment targets — such as those at the Abramson Cancer Center — trials that enlist people who might be at risk of a disease still lag. For example: At the ICTR, a randomized drug trial aimed at preventing dementia struggles to recruit elderly participants.

    “They’re saying, ‘I think I’ll wait a couple of months to join that trial,’” Ford says. Considering COVID-19’s particularly severe impact on older people, he says, “That seems perfectly rational.”

    Recruitment for the breast cancer study at MGH was paused when the Boston hospital halted observational research in March 2020, according to Erica Warner, ScD, MPH, an assistant professor at Harvard Medical School and project director of the Harvard/MGH Center on Genomics, Vulnerable Populations, and Health Disparities. The project restarted last fall with redesigns, including enrolling and observing participants remotely, Warner explains. She says the trial has enrolled 37 women and she expects to soon reach its target of 50.

    Trial leaders expect to attract more participants as vaccinations help the nation gradually resume in-person gatherings. But at Holden, Weiner speaks for many when he observes, “We’re not back to normal yet.”

    Limits in the labs

    “Our research was delayed pretty much by a year.”

    That assessment by Melanie Mormile, PhD, associate dean for research at the Missouri University of Science and Technology (Missouri S&T) in Rolla, reflects a common estimate among many lab directors.

    A major factor has been restrictions on lab access. When university labs reopened after closing down for weeks or months during COVID-19 surges last year, they adopted rules about which students could return to the labs, how many people could be on site at once, and how far apart they had to remain. That has not only reduced researchers’ lab hours at many institutions but also makes it difficult or even impossible for people on the same project to work in the lab at the same time.

    At Missouri S&T, some students couldn’t return to the labs for six months, Mormile says. Among the projects that were delayed was one in which students were testing whether changes in pH levels can affect an organism’s resistance to antibiotics. They changed pH conditions in a lab-grown bacterium, measured the responses to antibiotics, and are finally wrapping up their results for publication, she explains.

    Lab access is easing as more people get vaccinated. Once in the labs, however, many researchers find their work hampered by supply shortages. COVID-19-related shutdowns and restrictions at businesses all over the world have disrupted global supply chains, leaving some basic materials — as well as specialized equipment — hard to get and often more expensive than a year ago.

    “Certain suppliers are running out of materials,” says Jackie Bader, PhD, a postdoc at Vanderbilt University Medical Center in Nashville, Tennessee. Bader finds herself hunting among multiple vendors to piece together even basic items she needs for experiments.

    The most common shortage is mice. During the shutdowns last year, many labs had to euthanize most of their mouse colonies because there weren’t enough staff on site to care for them.

    “That was a lot of loss,” notes Cameron Prigge, PhD, a postdoctoral researcher at Duke University School of Medicine in North Carolina.

    Labs are rejuvenating those colonies by purchasing and breeding mice — a steady but slow process. It is particularly sluggish for projects that demand a specific type of mouse, such as those that were genetically altered for the polycystic kidney disease experiment in Germino’s lab at the NIDDK. During one recent call with a collaborator, he says he was told, “You’re going to have to wait. Our colony has not come back” to where it was before the pandemic.

    With all these factors taken together, “The impact [of COVID-19] has been significant,” Germino says. “In many labs, including mine, we’re still not back to full engagement.”

    Gaps in longitudinal studies

    The Adolescent Brain Cognitive Development (ABCD) Study follows the health and development of 12,000 selected young people through annual collections of information via interviews, tests, brain imaging, and biological sampling. Funded by the National Institutes of Health (NIH), the project is carried out by scientists and child development experts at 21 medical and higher education sites around the country, including Children’s Hospital Los Angeles and the Medical University of South Carolina.

    COVID-19 forced the project to carry out some processes, like questionnaires and interviews, by phone and computer, according to ABCD Study Director Gaya Dowling, PhD, of the National Institute on Drug Abuse (NIDA). But the project could not replace the brain imaging and specimen collection (including hair, blood, and saliva) that is done when participants visit their project sites. When COVID-19 surged in the spring of 2020, the project paused those procedures for what many thought would be just a few months.

    “We hoped we could play catch-up a few months later” after the participating sites fully reopened, she says. “We were overly optimistic.”

    Because the two-year follow-up visits, which include the brain imaging scans, began in September 2018, the project had up-to-date scans on 7,500 youths by March 2020. As facilities gradually reopened last year and project organizers asked the remaining participants if they wanted to come in for their scans, about half said yes, according to Dowling.

    The specimen samples, however, are typically collected every year, and most of those were not collected in 2020, she says. The saliva is used to assess such things as substance use and hormonal development.

    “For a study of adolescent development, not being able to quantify pubertal hormones even in just one year is a real loss,” Dowling explains.

    As a result, there will be some gaps in the research data for the first full year of COVID-19. (The publicly available data sets are used by researchers around the world in publications and to help build their own studies.)

    Another large NIH project, the HEALing Communities Study, is beginning to recover from last year’s delays in launching strategies to research and combat opioid use disorder in four states. The project provided grants to universities and medical centers in Massachusetts, New York, Ohio, and Kentucky to spearhead community collaborations with a wide array of institutional partners, including hospitals.

    But many of those institutions closed or severely restricted activities during COVID-19 surges, so they couldn’t carry out their planned activities for the study. At the same time, hospitals were so overwhelmed by COVID-19 patients that they couldn’t train staff on the evidence-based practices that they had intended to initiate, such as starting patients on medication for opioid use disorder and connecting them to other services. “It wasn’t a time when they had the bandwidth” to launch new initiatives, says NIDA’s Redonna Chandler, PhD, director of the project.

    These and other research projects will eventually get back on track, while others might never fully recover. That could affect countless patients who hope for new treatments for their diseases.

    What remains to be seen is how much funding and staffing will be devoted to rebuilding research into those diseases, which the RISE Act in Congress attempts to partially address. As Ruben Mesa, MD, executive director of the Mays Cancer Center at UT Health San Antonio MD Anderson, observes, “Cancer is not on lockdown.”