A study in the US trialling genetically modified gut bacteria in humans has had a potential escapee, after the microbe mutated.
The team of researchers at Stanford University undertook early clinical trials of a strain of a common gut bacterium, which they genetically engineered to help prevent kidney stones.
But the results of the trial, published today in Science, were mixed.
While the therapy was mostly successful in healthy volunteers, it didn't treat the underlying cause of kidney stones in people who suffered from the condition.
The bacterium also overstayed its welcome in two healthy volunteers, despite the scientists' best efforts to remove it.
Weston Whitaker, a Stanford University microbiologist who led the study, said all the protocols were followed, and "there were no specific reasons to worry about the health of individuals where the bacterium persisted".
"Many aspects of the technology worked surprisingly well, and we've clearly identified parts needing further development," Dr Whitaker said.
"I think we showed that there is promise in continuing this approach."
Sam Forster, a microbiologist at the Hudson Institute of Medical Research who was not involved with the research, said the findings showed both the hazards and potential of the technology.
"There are risks associated with these approaches but it's also an amazingly powerful technology and these types of studies provide a key fundamental understanding," Dr Forster said.
Genetically modifying gut bacteria
The researchers genetically modified a strain of bacterium called Phocaeicola vulgatus to carry the genes they were looking for.
"We chose Phocaeicola vulgatus because it is one of the most prevalent and abundant bacteria in the gut," Dr Whitaker said.
The team engineered the bacterium to have two new abilities: breaking up a compound called oxalate, which can cause kidney stones, and eating a compound called porphyran, which is found in seaweed.
Humans and most other gut bacteria can't process porphyran, so this gave the modified microbe a reliable source of food — as long as the trial participants consumed a porphyran supplement.
It also provided a handy way to get rid of bacteria once the experiment was over: trial participants could just stop taking porphyran. Or at least that was the theory.
After testing the modified microbe on mice and rats, the researchers ran two human trials — one with 39 healthy volunteers, and another with 20 volunteers who had a condition called enteric hyperoxaluria, where the body absorbs too much oxalate, causing frequent kidney stones.
The trial participants were either given a pill full of the bacterium or a placebo to swallow.
The researchers found the modified microbe could safely colonise healthy participants' guts, and reduce their oxalate levels.
And for most participants, the bacteria vanished after they stopped taking their porphyran doses.
But it lingered in four healthy people even when they'd dropped the seaweed supplements.
These study participants were treated with antibiotics, which successfully removed the modified microbe in two people — but it stayed put in the other two.
"It is possible our bacteria is still in those subjects," Dr Whitaker said.
While this is a novel situation, Dr Whitaker said there was no reason to be concerned.
"The genes, bacteria, and activities we introduced are commonly found in a healthy gut, so we considered this a relatively safe initial application," he said.
Bacteria mutated in the human gut
Engineered bacteria that stuck around in the gut in the healthy participants were successful because they mutated to eat foods other than porphyran.
So when the porphyran was removed, the gut bug just began eating something else.
The microbe also mutated to become less effective at degrading oxalate in some participants in the kidney stone group.
Bacteria are able to swap genes with each other, which gives them an extremely quick way to evolve new characteristics.
According to Dr Whitaker, the team knew it was possible the modified microbe could mutate but were "surprised it occurred" in the way it did, because it had been much less of an issue with lab studies or healthy volunteers.
Dr Forster said this was a known issue of working with bacteria.
"These bacteria exchange DNA all the time. And most of those exchanges are just as likely to be beneficial for us as detrimental to us."
"[DNA exchange] is not a characteristic of this strain or this technology, it's a characteristic of bacteria."
Interesting science has future applications
While this clinical trial was terminated by the team, both Dr Whitaker and Dr Forster were excited by the prospects this could provide in the future.
"While disappointing for the therapeutic outcome, I think there is some interesting science behind this, which is something we are following up on," Dr Whitaker said.
The Stanford team has now designed a new bacterial strain that has three essential genes, which he said would provide a "triple safeguard" against mutation.
The team is yet to test this new strain in patients, but when the researchers tested the bacteria in the lab, it was unable to bypass the protection provided by the addition of the genes.
Dr Forster said the paper highlighted how bacteria could be used to treat inflammatory gut disorders, and even gut cancers.
"In some cases there will already be species that can [be used as a therapy], and so there would be advantages to putting those natural species back in," he said.
"But in some cases … genetically modifying them provides a much more efficient way of providing that therapy."
"This paper is is a key step in that process."
