Five genes identified as key targets for COVID-19 drug development

In the winter of 2020, as hospitals filled with the critically ill, a team of researchers faced a practical problem: there were far more potential treatments than time or resources to test them all. A study published in Nature that December offered a way forward—not by inventing new drugs, but by identifying which ones deserved to be tested first.

The work began in British intensive care units. Researchers from the GenOMICC consortium examined the DNA of 2,700 patients fighting severe COVID-19 across 208 ICU wards in the United Kingdom. They compared the genetic makeup of these gravely ill patients against healthy volunteers from other studies, looking for patterns in the code that might explain why some people descended into critical illness while others weathered the infection with milder symptoms.

What they found pointed to five genes: IFNAR2, TYK2, OAS1, DPP9, and CCR2. These genes operate in two distinct biological territories—one governing the body's antiviral defenses, the other controlling inflammation in the lungs. The differences in these genes between the ICU patients and healthy controls were not random. They suggested a mechanism: severe COVID-19 was not simply a matter of the virus overwhelming the body, but of the immune system itself becoming destructive. The damage to the lungs, the researchers concluded, came partly from the virus and partly from the body's own inflammatory response to it.

This distinction mattered enormously for treatment. Kenneth Baillie, the study's lead investigator from the University of Edinburgh, explained the stakes plainly: because only a handful of drugs could be tested at once in clinical trials, choosing the right ones first would save thousands of lives. The genetic findings provided a map.

The researchers discovered that reducing activity in the TYK2 gene appeared protective. A class of anti-inflammatory drugs called JAK inhibitors—including a medication called baricitinib—already produced this effect. Separately, they found that boosting activity in the IFNAR2 gene also seemed to offer protection, likely by mimicking the action of interferon, the antiviral proteins the immune system naturally releases. Drugs that stimulate interferon signaling, or that dampen harmful inflammatory pathways and reduce immune cell infiltration into the lungs, could potentially help the sickest patients.

But timing was critical. The researchers warned that these treatments would work only if given early in the disease, before the inflammatory cascade became irreversible. This meant that identifying which patients carried these genetic variants—and thus which ones might benefit most from targeted therapy—could become as important as the drugs themselves.

Baillie and his colleagues called for a fundamental rethinking of how COVID-19 trials were being run. Rather than testing drugs broadly across all severe patients, trials should focus on the specific antiviral and anti-inflammatory pathways the genetics had revealed. The message was urgent: large-scale clinical trials were needed immediately to test whether these targeted approaches would actually work in practice. The window for intervention was narrow, and the potential reward—thousands of lives saved through smarter drug selection—was too large to ignore.