The report, published Wednesday in the journal Nature, comes three months after researchers posted an early version of the study that ignited a media firestorm, as well as confusion over who, exactly, funded the work and whether it required greater government oversight.
In a lab experiment, the researchers combined the spike protein of an early lineage of omicron with the backbone of the original strain that emerged in Wuhan, China. The work, though not significantly different from numerous other experiments, drew media attention and set off fears that such manipulation of the coronavirus could unleash a more dangerous variant.
Proponents of the work counter that this experiment was fairly routine for pathogen research, which often involves the creation of “recombinant” viruses that mimic what happens in nature. The experiment was conducted by researchers wearing many layers of protective gear inside a biosafety Level 3 laboratory at the university’s ultra-secure National Emerging Infectious Diseases Laboratory.
The purpose of creating such a “chimeric” virus, which the scientists dubbed Omi-S, was to try to understand which of the mutations in omicron might be responsible for making it seemingly less pathogenic — that is, less likely to create severe illness — than the original strain.
The chimeric virus grew just like omicron in cell cultures. Omi-S turned out to be only a little less pathogenic in mice than the ancestral strain, with 80 percent mortality rather than 100 percent. It was still deadlier than omicron.
The research showed that omicron’s heavily mutated spike protein plays a role in making the variant less pathogenic than the ancestral strain. But the behavior of Omi-S suggested to lead researcher Mohsan Saeed, an assistant professor of biochemistry at Boston University, and other co-authors of the study that there had to be something else contributing to the phenomenon.
The researchers kept experimenting, and now they claim to have found at least one missing piece of the puzzle: a mutation involving a protein called nsp6.
Unlike the spike protein studded across the surface of the coronavirus, nsp6 is a “nonstructural” protein, as its name suggests. Researchers point out that many proteins encoded by SARS-CoV-2 are not part of the mainframe of the coronavirus but instead interact with the host in ways that are often mysterious.
“The reason that paper is important, it’s the first time where there is another gene that is encoded by the SARS-CoV-2 virus that is shown to be involved in pathogenicity,” said Ronald Corley, chair of microbiology at Boston University Chobanian & Avedisian School of Medicine.
“That represents a target protein for therapeutics,” said Corley, who is not a co-author of the paper but until recently was director of the laboratory.
The research drew widespread attention in October after Saeed posted an early version of the study on the preprint server bioRxiv, where scientists have put thousands of early drafts of their coronavirus research in advance of formal peer review.
Critics of pathogen research have long contended that the field lacks adequate safety reviews and oversight, and that some experiments are far too risky to justify any potential increase in knowledge. The Boston University experiment was seen as an example of “gain of function” research, in which a virus is manipulated in a way that could make it either more transmissible or more pathogenic.
Corley and other defenders of the experiment countered that it actually made the ancestral strain less deadly in mice.
Complicating the debate was uncertainty over whether the National Institutes of Health had funded the experiment. The original preprint version cited NIH as one of the funding sources, but the university said the research was done independently. An NIH spokesperson later confirmed that the agency did not fund the work.
Robert F. Garry, a Tulane University virologist who was not part of the study, said in an email that more research on nsp6 must be done to understand its significance. He also dismissed the fears that such research is too dangerous.
“Just the fact that it passed peer-review should alert everyone to the fact that prior ‘concerns’ were overblown and alarmist,” Garry said.
The National Institutes of Health charged a biosafety review board early last year with revisiting all the guidelines and protocols for research on potential pandemic pathogens, as well as what is known as “dual-use research of concern,” in which research intended to benefit human health could also be weaponized.
The biosafety board has signaled that it will recommend broadening the definition of experiments requiring special review. The board will release its report in the coming weeks, according to NIH.