‘This is confusing the hell out of us.’ No one knows how Omicron originated, but scientists have theories

A lab technician used a single channel pipette dropper at a Testaro COVID-19 laboratory in the Dunkeld suburb of Johannesburg, South Africa.Waldo Swiegers/Bloomberg

When the Omicron variant emerged last month, scientists were shocked to find it had 50 genetic changes, many of which pose a threat to human health. Where did this strange and menacing viral beast come from?

Just as no one knows whether Omicron will overpower vaccines or how quickly it will spread in the United States, its origins remain a mystery. But experts have theories.

The most popular holds that Omicron evolved within a single individual with a weak immune system. Another theory suggests it took shape unnoticed in a population where there was little vaccination or testing. A third hypothesis posits that the virus, after originally leaping from animals to humans, jumped back into animals and formed mutations that went on to infect people.

“If we know where this came from, we’re in a better position to prevent it from happening again,” said Dr. Jeremy Luban, chair in AIDS research at the University of Massachusetts Medical School. For example, if variants are developing within immunocompromised people, that points to the critical need to ensure that such people, and all those they come in contact with, are fully vaccinated. And better understanding how microbes spill from animals to humans and back may help protect us from the next virus to emerge from the animal kingdom.

In the early months of the pandemic, most experts weren’t worried about the virus mutating. They saw about two mutations a month, rarely of any significance to human health.

“Then, in the fall of 2020, all anyone could talk about was these variants,” Luban said. “Why until the fall of 2020 was the virus seemingly remaining static, then all of a sudden there was this explosion of mutations that were clinically relevant?”

Studying the virus genome, Luban and his team noticed in March 2020 that a mutation labeled D614G was increasing in frequency, and worried about what that meant. Now he thinks it might be the mother of all mutations.

“It’s the foundation upon which the others exist,” he said. In the laboratory, he showed that without D614G, the Alpha variant, first discovered in the United Kingdom in September 2020, was no longer functional.

“There may be a general principle here,” Luban said. “In order for certain mutations to be viable, there first has to be some other enabling mutation. And we suspect that D614G is just one of several.” Why did the virus mutate little at first, and then suddenly begin cranking out Alpha, Beta, Delta and more? It could be because “it took the virus a while to acquire these enabling mutations,” Luban said.

And when Omicron burst upon the scene last month, its surprising number of mutations may have been made possible by several of these enablers, likely including D614G.

Most scientists suspect that Omicron evolved within the body of one person whose immune system was weakened by HIV, cancer treatment, drugs that suppress the immune system, or other factors.

A weakened immune system can be a favorable setting for the proliferation of harmful mutations — errors that occur in the genes of a virus when it replicates. Mutations happen randomly and typically don’t enhance the virus’s effectiveness. When a virus acquires a mutation that gives it an advantage, it’s purely by luck.

But Omicron came out armed with a huge number of mutations seemingly tailored to enable fast spread among people. That suggests it evolved in an environment where something more than chance was at play, said Mark Zeller, staff scientist at the Scripps Research Institute. The number and type of mutations suggest “a different evolutionary process than just normal transmission in a community.”

And that environment could be the body of an immunocompromised person. It was already known that the virus could linger for a long time in such people. A 2020 study at Brigham and Women’s Hospital had followed an immunocompromised individual who harbored the virus for 152 days.

If this theory is correct, we’ll never know who hosted Omicron’s evolution. But scientists envision the virus replicating for months within this person, learning ways to evade the faltering immune system. Eventually it spread to someone else, and onward from there.

Dr. Yonatan Grad, assistant professor of immunology and infectious diseases at the Harvard T.H. Chan School of Public Health, offers a subtly different hypothesis: Rather than developing in someone who is severely immunocompromised, the variant might have formed in a person whose immunity waxed and waned, such as someone going through cycles of chemotherapy.

In this scenario, the virus would have been exposed to the person’s antibodies but never fully eliminated. Each time the virus made a copy of itself, the versions that could resist the person’s antibodies were more likely to survive.

Another theory holds that the variant developed undetected among people in a place where little vaccination, testing, or genomic sequencing was being conducted. (Southern Africa, where Omicron was first detected, would not meet this definition: The region has sophisticated viral surveillance systems. Although vaccination rates are low, it’s not known whether the virus originated there.) “It could be the virus has been infecting a lot of people, and over a year and half of spreading person to person, it steadily acquired new mutations,” Luban, the UMass researcher, said.

Grad considers that “extremely unlikely, given the extent of mixing among peoples.”

And the animal theory?

It has fewer adherents, but many consider it plausible. “There is a long history of viruses jumping from animals to people,” Luban said. SARS-CoV-2, the formal name for the pandemic coronavirus, is believed to have originated in bats. “We know it jumps from animals to humans. We know it can get mutations in the animal and jump to people,” he said.

SARS-CoV-2 has been found in dogs and cats and on mink farms. Zoos have reported cases in lions and tigers, snow leopards, gorillas, and, just a few days ago, hippos. It’s widespread among white-tailed deer in the Midwest and Northeast, and genomic studies show that the virus has spilled over into the deer population multiple times.

But no one knows how the virus travels between humans and deer, who don’t have a lot of close contact. It could be an intermediary animal that interacts with both people and deer, like dogs, but no one has evidence to confirm that.

“This is confusing the hell out of us,” said Marc C. Johnson, professor of molecular microbiology and immunology at the University of Missouri School of Medicine.

There is other suggestive evidence lending credence to the animal-to-human theory. Johnson said that his studies of wastewater from New York City found samples of SARS-CoV-2 with mutations that had never been detected in virus samples from people. The mutations included changes that enable the virus to evade antibodies. And these versions of the virus were so prevalent that they most likely did not come from a single patient, Johnson said.

One possible explanation is that the mutations originated in animals whose feces got into the sewer system, perhaps dogs, cats, or rats.

That’s not to say that the variants found in New York’s sewers are related to Omicron. Rather, they suggest that Omicron may have developed in a similar way. “I think these are independent viruses that evolved under similar conditions,” Johnson said. “Omicron has a lot of things in common with these lineages from New York City.”

But Zeller notes that even if the virus mutated by spreading among animals, it would have had to then suddenly jump to a human. “That seems less plausible to me,” he said.

In the end, Zeller said, when it comes to the origins of Omicron, “We don’t know and I’m not sure we’ll ever find out.”