About a month ago, researchers and policymakers started fretting about a nightmare scenario for drug enforcement: the possibility that the impending invention of morphine-producing yeast could make it easy for many people to start manufacturing highly addictive opiates.
"Home brew" narcotics, they warned, could be on the way.
The timeliness of the worries was underscored Thursday, when researchers in England and Australia announced that they had discovered a long-sought gene in poppies that is crucial to the production of morphine in the plants -- and could help scientists finish engineering morphine-making yeast.
The development, reported in the journal Science, fills a gap in researchers' understanding of the biochemistry of poppies that could help scientists fine-tune and manufacture painkillers and other useful poppy-derived compounds.
That could lead to safer and more effective therapies. But it could also smooth the way for people to start producing morphine on their own -- perhaps even at home, much as hobbyists use yeast to brew beer or make wine -- expanding and localizing opiate production and getting more people hooked on drugs like heroin.
"There are still some technical challenges, but this is a possible security threat," said supervisory special agent Edward You of the biological countermeasures unit of the FBI's Weapons of Mass Destruction Directorate.
Before the release of the new study, said senior author and University of York biochemist Ian Graham, researchers had already catalogued the genes driving the multistep process of converting glucose to morphine in poppies -- except for one intermediate link in the chain: the gene that directs conversion of a chemical called (S)-reticuline into another called (R)-reticuline.
To identify that gene, Graham and colleagues from the University of York and GlaxoSmithKline in Australia introduced random mutations into hundreds of poppy plants, eventually finding three plants that did not produce morphine but did accumulate (S)-reticuline, suggesting that they might have mutations in the gene that allows the crucial conversion to (R)-reticuline to take place.
The three plants all turned out to have mutations in one particular gene, which the scientists later confirmed to be the one they were seeking. They named the gene "STORR," for (S)- to (R)-reticuline.
From a scientific standpoint, Graham said, STORR is interesting because it's actually two genes fused together. (That may be part of the reason why it took researchers so long to find it, he noted.) The discovery has practical applications, too. Graham's lab, for instance, is looking for ways to breed poppies to produce anticancer agents and designer painkillers.
"Now that we've discovered this step we can develop poppy plants and use breeding approaches to make bespoke varieties of poppies that make different molecules," he said.
Having a handle on STORR also affects yeast-based opiate manufacture, Graham acknowledged, because now scientists can try to use the gene to tailor the organisms.
"The publication of this gene provides the missing link for the production of morphine in yeast -- there's no doubt about it," Graham said. "I think it's only a matter of time before there is a proof-of-concept demonstration in yeast that this can happen."
The prospect that biologists might soon develop morphine-making yeast had people buzzing about "home brew" opiates last month, when a different team of researchers published a study in the journal Nature Chemical Biology that described how they engineered yeast to perform another portion of the process that converts glucose to morphine.
MIT political scientists Kenneth Oye and J. Chappell H. Lawson and University of Alberta School of Public Health professor Tania Bubela wrote a response to that study in the journal Nature in which they urged regulators to work preemptively to prevent abuse.
For example, scientists might want to stop short of designing a single strain of yeast to perform the entire conversion, Oye said in an interview, or they might engineer a "DNA watermark" to facilitate tracking.
"Maybe you want to do this in a wimpy yeast strain -- one that's fussy, harder to cultivate," he said. "But all of these technical steps should be done beforehand. Afterwards, it's too late."
Oye, Lawson and Bubela thought the researchers most likely to publish research on the missing step were a team in Calgary, Alberta. They didn't know about Graham's work and certainly didn't expect the announcement to come barely a month later, Bubela said on Wednesday.
"You can see how quickly the technical challenges are being overcome, even faster than we anticipated," she said, adding that it would be difficult for regulators to keep tabs on all research, all the time. "It speaks to the fact that policymakers need to get ahead of the technology."
Jeff Comparin, director of the Drug Enforcement Administration's laboratory in Dulles, Va., said that until a specific yeast strain that could make morphine becomes commonly available, his agency "doesn't perceive an imminent threat."
He added, however, that the DEA was monitoring research developments -- and that if heroin producers and traffickers did eventually decide it was worth their while to use the new approach, any heroin produced by yeast-morphine was expected to be easy to distinguish from traditionally sourced varieties.
"We would immediately recognize this type of heroin coming into the market," he said.
The FBI's You, whose unit works with the scientific community to get researchers thinking about unanticipated outcomes of their work, said he had been encouraged that researchers had initiated the conversation in this case.
"It isn’t often that you see scientists proactively calling out something like this. That’s what makes it remarkable," he said. "We have an opportunity to capture these complications and mitigate them."
Doing so would safeguard beneficial research efforts, he added.
In the meantime, there's plenty of work to be done before yeast is synthesizing morphine at any kind of scale, said UC Berkeley bioengineer John Dueber, lead author of the study in Nature Chemical Biology, who praised the new study as a "solid addition to the scientific literature."
Dueber said he thought the challenge of increasing efficiency and combining everything onto a single yeast strain was "considerable, but I think accomplishable in a few years."
As part of their experiment, Graham and his team did introduce STORR into yeast to demonstrate that the gene can produce the same enzymatic activity there that it triggers in plants.
The scientist said he wasn't interested in developing yeast-based production methods for opiates.
But he, too, thought getting regulatory controls in place ahead of time might be a good idea.
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