California researchers say the world may be just one genetic tweak away from human-to-human transmission of the H5N1 bird flu virus — a worrisome mutation that could open the door to widespread human infections and possibly even a pandemic, according to some experts.

In a study published Thursday in the journal Science, Scripps Research Institute biologists determined that a single mutation of the hemagglutinin protein — the “H” in H5N1 — could transform a virus that has so far sickened or killed mostly birds and cows into a pathogen that targets cells in human beings.

The finding comes amid a growing number of H5N1 outbreaks among California dairy cows, as well as a state-ordered recall of raw milk products. Since the virus began infecting the nation’s dairy stock in March, infectious disease experts have warned that unprotected contact between dairy workers and infected cows could enable the virus to evolve in a manner that threatens humans.

Now, Scripps researchers suggest the path for such a genetic change may be much shorter than state and national health officers anticipated.

“This really surprised us,” said study coauthor James Paulson, a biochemist and molecular biologist. This one mutation “satisfies a requirement for transmission,” he said.

Richard Webby, director of the World Health Organization’s Collaborating Center for Studies on the Ecology of Influenza in Animals and Birds, said the study’s finding countered prevailing thought on the virus — specifically, that it would take multiple mutations for the virus to pose a threat to humans.

“This will likely cause a stir,” said Webby, who is also a researcher in the department of infectious diseases at St. Jude Children’s Research Hospital in Memphis, Tenn., and was not involved in the Scripps research.

“I think most of us thought it would probably need more than one change,” Webby said.

Yoshihiro Kawaoka, a virologist at the University of Wisconsin-Madison and the University of Tokyo, called the Scripps teams’ finding a “significant discovery” and said it was “critical because, given the mutation rate of influenza viruses, one in every 10,000 particles of the bovine H5N1 virus could carry this mutation.”

That means the potential emergence of an H5N1 virus “that can recognize human receptors is closer than we may have thought,” he said.

Several months ago, Paulson and coauthor Ian Wilson, a Scripps structural biologist, decided they’d investigate the current H5N1 strain, and see what it would take for it to cause a human pandemic.

Paulson is an expert in researching where and how different influenza viruses bind to cells when they enter a host. Wilson studies the structure of influenza virus proteins.

The scientists began their research by accessing a global influenza database and locating the genetic sequence for A/Texas/37/2024 — the strain of H5N1 bird flu found in a Texas dairy worker.

They then examined the hemagglutinin proteins, or spikes, on the outer surface of the virus, since those enable it to latch onto the cell membrane of its host. Animals such as birds and humans have different docking stations on their cells — known as sialic acid receptors. In order for a flu virus to open a door into a cell and begin replicating, it needs just the right spike, or key.

Although more than 50 humans have been infected by H5N1, many of these cases involve dairy workers who were likely sprayed in the eyes and nose with milk from infected cows. Researchers postulate that repeated exposure of this sort allowed the virus to push into the cells — a brute force entry more than a lock-picking.

Ordinarily, person-to-person transmission of a flu virus “is mainly through the air from droplets from a sneeze or cough, which contains very little virus,” Paulson said. “In this context, the virus needs to be able to recognize human-type receptors to bind to cells in the human airway in amounts sufficient to cause infection.”

In order to figure out what it would take for the virus to gain the right docking equipment to unleash a human pandemic, Paulson, Wilson and their team looked at previous flu outbreaks that had jumped the bird-human divide, including the influenza outbreaks of 1918, 1957, 1968 and 2009 — as well as some earlier research.

They “selected a number of positions” on the hemagglutinin protein “to mutate, one at a time” with amino acids they knew had been implicated in previous pandemics.

Then they attempted to bind these altered “H” proteins with human and bird receptor analogues.

Lo and behold, when they switched a glutamine to a leucine at position 226, it no longer bound to the bird receptors, but instead exclusively to those of humans.

Paulson said it was especially interesting because this mutation had occurred before in earlier strains of H5N1, including one from around 2010 — but “at that time, that single mutation was not sufficient to change receptor specificity. So, the unexpected thing is that virus has changed in subtle ways — evolved, if you will — so that now that single mutation does change the receptor specificity.”

Although the researchers demonstrated that it was possible for the virus to become a threat to humans with just one genetic change, that does not mean nature will follow that specific path. A multitude of factors can influence the evolution of an organism, and they are not easily predicted. This may be why the virus has not yet gained the ability to widely infect humans, some say.

“Despite more than 50 human infections with bovine H5N1, we have not seen evidence of this virus adapting to humans on a larger scale,” Kawaoka said. “This suggests that … additional mutations are likely required for the virus to become fully transmissible between humans.”

Paulson acknowledged that the “context of the total biological picture is extremely important.”

He said the research focused on just “one property that is important for the virus to be successful when adapting to a new host,” but there are others that may also be important.

For instance, H5N1 in the past was known to cause severe respiratory disease. But recently, it’s mostly been associated with conjunctivitis and only occasionally with mild, upper respiratory disease in people.

“Why is that? I don’t think anybody knows,” Paulson said.

What is known is that the virus is moving swiftly through a variety of species around the globe — with ample opportunity to mutate and adapt.

As of Thursday, the Centers for Disease Control and Prevention had confirmed H5N1 infections in 58 people: 35 as a result of working with infected dairy cows, 21 from infected poultry, and in two cases, the source is unknown.

In addition, 707 dairy herds across 15 states have also been infected. And in just the last 30 days, 23 commercial poultry farms in California have come down with the virus — affecting more than 5.6 million birds.