Noam A. Cohen, MD, PhD
Noam A. Cohen, MD, PhD, has dedicated the better part of the last two decades of his career to studying the role the nose plays in identifying and defending against bacteria that could cause sinusitis. Soon after the first cases of COVID-19 were diagnosed in Greater Philadelphia in March 2020, Dr. Cohen, the Ralph Butler Endowed Professor for Medical Research at the Perelman School of Medicine at the University of Pennsylvania, reached out to Susan Weiss, PhD, Vice Chair of the Department of Microbiology at the Perelman School of Medicine and Co-Director of the Penn Center for Research on Coronaviruses and Other Emerging Pathogens, and asked if she'd like to collaborate on experiments exploring how SARS-CoV-2 infected human nasal cells. She replied quickly: Yes. She also wanted to look at other coronaviruses her lab had been studying.
In the course of his pre-pandemic research, Dr. Cohen had been collecting cells from the noses of consenting Penn Medicine patients and veterans treated at the Philadelphia VA Medical Center and saving them in liquid nitrogen storage. He estimates that he has cells from about 1,000 noses. With those he selects for experimentation, Dr. Cohen and his team remove the cells from storage, place them in an incubator, and, "with a lot of care and a bunch of science," they're able to grow them into the multiple different cell types that line the inside of a human nose.
For these early-pandemic experiments, they grew the cells, then brought them to Dr. Weiss's lab. Here they were infected not only with SARS-CoV-2, but also MERS (Middle East Respiratory Syndrome) and other coronaviruses that cause the common cold.
Dr. Cohen admits, half-jokingly, he was motivated to do the experiments merely as a means to keep his lab open. During the early months of the pandemic, only those that were performing COVID-19-related research were permitted to continue without interruption. But then they began noticing something interesting, or so they thought.
"The cells from certain individuals got really infected with SARS-CoV-2, while the cells from other individuals didn't get as infected," Dr. Cohen says. "What we were basically looking at was how much virus each one of these cultures, these petri dishes, was producing, and there were huge differences."
They realized that what they were observing reflected what was playing out around the world. Some were infected with COVID-19 and never realized it because they were asymptomatic, while others were becoming seriously ill and dying at alarming rates.
Around this time, in October 2020, a paper was published by the New England Journal of Medicine (NEJM). The researchers studied 3,815 people in Italy and Spain – two of the countries hardest hit by the first wave of COVID-19. Of these, 1,610 were diagnosed with COVID-19 and respiratory failure. Researchers observed the same behavior that Drs. Cohen and Weiss had, and they came up with a potential explanation for it.
The key to deciphering COVID-19 is in the nose?
The researchers behind the NEJM paper categorized study participants based on the severity of their COVID-19 respiratory compromise. They then performed a genome-wide association study (GWAS), which is used to "identify genomic variants that are statistically associated with a risk for a disease or a particular trait," according to the National Human Genome Research Institute (NHGRI). Once these variants are identified, they're generally used to pinpoint nearby variants that contribute directly to the disease or trait, the NHGRI says.
Through their GWAS, they identified what they came to believe is a gene cluster that potentially predisposes those who have it to severe COVID-19. They also suspected that blood type plays a role. Dr. Cohen says that part "didn't make any sense to me." But the gene cluster did, especially once his longtime collaborator, Danielle R. Reed, PhD, Associate Director of the Monell Chemical Senses Center in Philadelphia, took a closer look at the genes in question and one of them turned out to be "highly expressed in the cells in the nose," as he puts it.
Nasal Cells Grown In Culture
The nucleus of each cell is stained blue. The hairlike structures that sweep the mucus out of the sinuses are stained green and the cells infected with SARS-CoV-2 are stained red. This is 48 hours after adding the virus to the cultures.
"The nose is the gatekeeper to the lungs, and what happens in the nose may contribute to what happens in the whole body," Dr. Cohen says. "It's a respiratory disease and it gains entry to the body through the nose. The initial infection is in the nose. That's why we have the high rate of smell loss. So we need to try to understand what's happening with this virus in the nose as we try to figure out why some are getting super-sick, and others are asymptomatic."
Dr. Cohen wasn't just collecting nose cells for 15 years, he also had genetic profiles of the patients themselves. Turning to their database, he and his team filtered for those who had this genetic cluster, then pulled these cells from storage, along with those from a sampling of patients who do not have the cluster. They grew both sets of cultures and then, once they were mature, moved them to Dr. Weiss's lab where they were infected with COVID-19.
"Lo and behold, the cells that came from the patients who had the genetic risk factor got much more infected and were producing a lot more virus at 24 and 48 hours after infection compared to the ones who didn't have the risk factor," Dr. Cohen says. "So we thought that maybe we had a mechanism, a gene, that was enriched in the nose that, at least in an in vitro cell-based assay correlated to the kinetics of the viral biology – how fast the virus got into the cell, how fast the virus replicated, how fast the virus got out of the cell, then reinfected the neighboring cells. This was starting to make sense."
Further supporting the hypothesis – that what's happening in the nose dictates the course of the infection – the gene in question isn't expressed much in the lungs, Dr. Cohen says.
A perplexing mystery is solved – possibly
Over the coming months, the theory gathered even more momentum in the headlines that came to dominate our screens. While epidemiologists publicly fretted that COVID-19 would ravage Africa because of its subpar healthcare systems, the reality produced a different result. The first wave of infection appeared to be just as widespread as it was in most countries, but the mortality rate in many African countries remained relatively low by comparison.
The outbreak in India was a sharp contrast. Hospitals were quickly overwhelmed, and thousands were dying every week for a roughly two-month period in mid-2020.
Dr. Cohen says the gene cluster provides a potential answer to both scenarios.
"It turns out that Africans don't have this risk factor. At all," he says.
Following the publication of the NEJM paper, researchers used publicly available datasets to look at the prevalence of this genetic risk factor around the world. The highest concentrations appear to be among those with roots in India and Bangladesh. In fact, from the limited data available, Bangladeshi people have the highest rate of any population, at 25 percent.
Through his own research, Dr. Cohen estimates the gene cluster's prevalence among American Caucasians is one percent, which, he says, correlates with mortality rates in the United States. As of this writing, in mid-October 2022, there have been more than 95.5 million confirmed cases of COVID in the US and more than one million deaths officially attributed to the virus, according to the World Health Organization. That puts the mortality rate at 1.1 percent.
The next phase of his research is to try to determine what, exactly, this gene that's highly expressed in the nose does once it's exposed to COVID-19. His working hypothesis is this: When the virus gets into a cell, the gene appears to play a role in how it exits the cell.
However, because of the low prevalence of the gene among his collection of nose cells, the research is at a standstill until he can develop a broader and more diverse selection of participants. A recently secured grant from the National Institutes of Health should enable Drs. Cohen and Weiss to continue their progress in the coming months.
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