When the coronavirus began its furious march around the globe, leaving illness, death and suffering in its path, medical researchers urgently set out to understand the disease, known as COVID-19. Efforts to explain where it came from, how it affects people in such different ways and what can be done about it have produced more than 475,000 publications supported by about 26,000 organizations in 198 countries, according to the Dimensions COVID-19 database.

The scientific research that resulted in all those publications often begins with an observation. In the early days of the pandemic, Henry P. Barham, a 38-year-old ear, nose and throat doctor and researcher at Baton Rouge General, was operating three to four days a week, performing tracheotomies, and the removal of skull-based tumors, and some days did 30 nasal endoscopies – procedures that increased risk of exposure to COVID-19 through aerosolization, the broadcasting of viral particles. Despite their protective gear, some of his colleagues got the virus. Barham did not.

He was grateful, but perplexed. Why, he asked, wasn’t he getting sick?

The question kept him awake nights as he developed theories about why some people experience only mild symptoms, while others are hospitalized and still others die of the virus.

Barham specializes in rhinology, treating nasal and sinus problems. During his residency, he studied the T2R38 gene, otherwise known as the “supertaster” gene because it affects people’s ability to taste. The term, introduced in the 1990s by Yale psychologist Linda Bartoshuk, is something of a misnomer, since it doesn’t refer to those who have an abundance of taste buds, enabling them to detect notes of, say, cloves, mushrooms and forest floor in a pinot noir.

T2R38 confers only the ability to taste bitterness. Supertasters – and Barham is one – taste the bitterness in coffee or broccoli acutely. A person must inherit the T2R38 gene from both parents to be a supertaster.

The gene also plays a role in the immune system, which, in the midst of the pandemic seemed intriguingly relevant to Barham.

He hypothesized that supertasters were unlikely to develop severe symptoms of COVID-19. He thought that “tasters,” who have inherited the gene from only one parent, were likely to experience mild to moderate symptoms, and “nontasters” who had not inherited the gene were at a higher risk for severe symptoms and hospitalization.

Meanwhile, a friend in his early 40s got a serious case of COVID-19, but the man’s wife remained healthy. Barham wondered whether his friend was a nontaster and his wife a supertaster. He gave them a simple taste test involving strips of flavored paper, and his suspicion proved correct: His sick friend was a nontaster, his wife a supertaster.

People have an innate immune system – the one we’re born with – and an adaptive one, which evolves over time, learning how to fight pathogens based on what it has encountered in the past.

“When exposed to a novel virus like the coronavirus that causes COVID-19,” Barham says, “the strength of our innate immune system becomes paramount.”

The supertaster gene, T2R38, is part of that innate immune system. Its main functions are to create more hairlike filaments (cilia) to speedily sweep pathogens along; to increase production of mucosa, diluting the invaders; and finally, to create nitric oxide, which kills pathogens.

People’s perception of taste (coffee tasting very bitter, slightly bitter or not bitter at all, for example) has been known for over a decade to be associated with their immune response to respiratory infections and sinus infections – stronger perception of bitterness reflects stronger immunity. But past studies of this connection have focused on bacterial infections and inflammation, not viruses. Barham wondered whether taste receptors could be connected to the coronavirus.

In April 2020, Carol Yan, an otolaryngologist and head and neck surgeon at UC San Diego Health, published a study that concluded if patients have experienced loss of taste and smell, they are more likely to have COVID-19 than another type of infection. These findings fueled Barham’s conviction that the role of the supertaster gene in immunity to COVID-19 needed to be investigated.

“I was on fire,” he says, and read everything he could find on the supertaster gene.

In June 2020, he set out to test his hypothesis. Barham, Christian Hall, a fellow rhinologist, and Mohamed Taha, an otolaryngologist and research fellow, did a retrospective study – looking at 100 patients who earlier had tested positive for the coronavirus. They used the same test Barham had given to his friend and his wife: four small strips of paper placed on the tongue, one at a time, after which the patient rated the intensity of flavor from 1 to 10 (mildly bitter to intensely bitter, for example).

None of the 100 patients tested was classified as a supertaster. Seventy-nine patients had mild-to-moderate coronavirus symptoms and they were classified as tasters. And 21, who had been seriously ill and required hospitalization, were classified as nontasters. The study’s findings were published in August 2020 in the International Forum of Allergy & Rhinology.

These results were promising but because loss of taste and smell were common symptoms of the coronavirus, Barham and his team set out to create a study that would be able to account for those losses. As they put it in their study, it wasn’t clear whether a person’s supertaster status predicted the severity of COVID-19 or was a consequence of infection severity. They had to test people before they got COVID-19, and then again, afterward.

The study tested people for the absence of both prior and current coronavirus-related infection. They then took the paper-strip taste test, and a subgroup also supplied spit samples for genetic testing, which provides greater accuracy.

From July 1 through Sept. 30, 2020, they followed 1,935 patients and health-care workers who had been exposed to the coronavirus but had neither a previous nor current infection. Each was given the paper-strip taste test, and a subgroup also supplied spit samples

About half were classified as tasters, a quarter as nontasters, and a quarter as supertasters. During the follow-up period, 266 of the 1,935 people tested positive for the coronavirus. Nontasters, the researchers found in the study published last month, were far more likely to contract the disease and for their symptoms to last longer: an average of 23.5 days – compared to five days for supertasters and 13.5 days for tasters.

Nontasters were also far more likely to be hospitalized. Of the 55 study participants hospitalized, 47 (85.5 percent) were nontasters. Of the supertasters who tested positive, none needed to be hospitalized. These results indicated the accuracy rate for predicting severity of the disease based on a person’s taster status was 94.2 percent. Barham says the 5.8 percent discrepancy can be explained by the age of some of the participants. The mean age of tasters requiring hospitalization was 74 (the mean age of all participants was 45.5.), and supertasters’ ability to taste diminishes over time.

As with most scientific research, the implications of this work will require more time and study to be completely understood, as the researchers point out in their conclusion. Experts have varying opinions of what the results mean as pieces of the coronavirus puzzle are assembled.

“I think this is going to help unravel the mysteries of COVID-19, and eventually have clinical use,” said Amesh Adalja, senior scholar at Johns Hopkins Center for Health Security. “Lots of hospitals, for example, are coming up with scoring systems to decide: do I admit this patient to the ICU, or to the floor, or send them home? Immune profiling could be a way to help them make those decisions, but it’s going to take some time to change how people approach this.”

Catherine Blish, an infectious-disease specialist and professor of medicine at Stanford Medical Center, said she found the magnitude of the effect intriguing, referring to the difference in severity among supertasters and nontasters.

“I think it’s an important question to evaluate the role of this receptor,” and how it might be involved in development of disease, she said, “because the effects they saw in the JAMA study are pretty dramatic. Quite shockingly so.”

“But rigor was lacking as there was inadequate description of how patients were classified,” she said. “Therefore, it should be independently validated.”

The study focuses on predicting severity of the disease and should not influence prevention. Everyone, Barham says, should get vaccinated.

“Even supertasters, as they age, have the potential to get sick, especially if exposed to a high viral load,” he says. “So, they should be vaccinated, too.”

Barham says he hopes that what he and his team have discovered about the supertaster gene will help scientists to not only determine treatment for COVID-19 but also advance their understanding of the flu and other viruses. One of his goals is to see whether he can find ways to improve people’s innate immunity to all upper respiratory infections through the stimulation of T2Rs.

“The beauty of science is the more we find, the more we open up,” Barham says.