NEWS TRENDS ANALYSIS :: THE OBSERVATORY Snyder, the Stanford W. Ascherman,


MD, FACS, Professor in Genetics, and Professor of medicine Philip Tsao, PhD, are co-senior authors. Genetics instructor Sai Zhang, PhD, and neu- roscientist Jonathan Cooper-Knock, PhD, a Stanford visiting scholar and lecturer at the University of Sheffield, share lead authorship. The researchers used two large data sets to unpack the genetics behind severe COVID-19. The first data set contained genomic information from healthy human lung tissue. The data helped identify gene expression in 19 different types of lung cells, including epithelial cells that line the respiratory tract and are the first defense against in- fection. (Gene expression is the process by which certain genes are switched on to make RNA and proteins.) Other data came from the COVID-19


Host Genetics Initiative, one of the larg- est genome-wide studies of critically ill coronavirus patients. The researchers looked for genetic clues in the data — DNA mutations, called single nucleotide polymorphisms — that might indicate if someone is at a higher risk for severe COVID-19. They tracked whether some mutations occurred more or less often in COVID-19 patients with severe disease. Mutations that continued to appear,


or were notably absent, in the patients who developed severe COVID-19


suggested those variations might be behind the infection’s severity. To verify whether the suspicious mutations might in fact increase odds for severe COVID-19 infection, the re- searchers performed a genome-wide search in lung tissue for the muta- tions from patients critically ill with COVID-19 and from healthy people. “We did this for the 19 lung cell types,” Zhang said. Although it was clear which mutations were most likely to convey risk for severe disease, the researchers still didn’t know which genes were af- fected by the mutations. So the team worked backward, using molecular clues to decipher the region of the genome in which the mutation occurred and, fi- nally, narrow the region down to specific genes. “Then we had our final gene list associated with COVID-19 severity.” “When you’re studying the genetic basis of disease, you’re trying to pinpoint regions in the genome that are respon- sible,” Snyder explained. The research- ers also wanted to know which types of cells harbored faulty gene expression. Through their machine learning tool, they determined that severe COVID-19 is largely associated with a weakened response from two well-known im- mune cells — natural killer (NK) cells and T cells. “NK cells and a subtype called CD56bright are the most important,” Cooper-Knock said. “T cells rank second.”


Elderly COVID-19 patients at greater risk


When COVID-19 began surging around the world in early 2020 and physicians were confronting a deadly disease they knew little about, scientists at the University of Minnesota’s Institute on the Biol- ogy of Aging and Metabolism (iBAM) swung into action to help, according to a news release.


“Early in the pandemic it became very clear that certain people were at greatest risk—the elderly, people with diabetes, and people with obesity,” says Laura Niedernhofer, Professor of Biochemistry in the Medical School and Director of iBAM. “And one com- mon thread between those groups? They all have increased levels of senescent cells.” Senescent cells are aging cells that have stopped dividing but haven’t died. According to Niedernhofer, the burden of senescent cells in our body doubles with every decade of life.


“Senescent cells drive inflamma- tion, and that inflammation then puts you at greater risk for disease and aging,” explains iBAM Associate Director Paul Robbins, also a Professor of Biochemistry in the Medical School. “If you have a perfectly healthy, robust immune system, your body clears these cells for you. But as we age, our immune response wanes and stops clearing these cells effectively.” What if there were a drug that


could help clear senescent cells and slow the onset of not just the aging process, but of the many diseases associated with aging, such as heart disease, cancer, type 2 diabetes, and Alzheimer’s disease?


That question led Niedernhofer and


Robbins, working with colleagues at the Mayo Clinic, to become the first scientists to describe a new class of drugs called senolytics in 2015. More recently, they’ve shown that fisetin, a


natural antioxidant found in various fruits and vegetables (apples, straw- berries, onions, and cucumbers, for example), successfully clears senes- cent cells. “We do have preliminary data [indi-


cating] that fisetin clears senescent cells in humans,” says Niedernhofer, “and there are now many clinical trials underway to study it further.” When COVID-19 struck, iBAM scien-


tists quickly geared up to see whether the senolytics they were developing to promote healthier aging could also be used to treat the viral infection caused by SARS-CoV-2.


“The excitement around senolytics as a COVID-19 treatment has been growing,” says Camell, “since the group’s results were published in the prestigious journal Science.” Clinical studies are under way in Minnesota to evaluate the success of treating COVID-19 patients with senolytics.


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NK cells, which you’re born with and are the body’s first line of defense against infection, are known for their ability to destroy viruses and cancer cells. NK cells also help produce a range of immune system proteins called cytokines, Cooper-Knock said. “CD56bright cells are like the gen- eral directing the war. They mobilize other immune cells, telling them where to go and what to do. We found that in people with severe coronavirus infection, critical genes in NK cells are expressed less, so there’s a less robust immune response. The cells aren’t doing what they’re supposed to do,” Cooper-Knock explained. Snyder likened COVID-19 risk genes to harmful variants of the BRCA genes that predispose some people to breast and ovarian cancer. “Our findings lay the foundation for a genetic test that can predict who is born with an increased risk for severe COVID-19,” he said. “Imagine there are 1,000 changes in DNA linked to severe COVID-19. If you have 585 of these changes, that might make you pretty susceptible, and you’d want to take all the necessary precautions.” “The drugs bind to receptors on the NK cells and trigger them to have a more robust response,” he said. Trials of NK cell infusions for severe COVID-19 are underway.


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