We’ve got a poppy problem. The only way to make morphine, oxycodone, and other opiates is with the latex that oozes from opiate poppy seed pods. But if researchers and pharmaceutical companies have it their way, they'll soon be making those commercial drugs with little more than yeast and sugar.
Bioengineer Christina Smolke’s team at Stanford has been chipping away at the problem of how to churn out opioids using genetically engineered yeast for more than a decade. Today, they announced in the journal Science that they coaxed yeast to make the painkiller hydrocodone, as well as thebaine, an opiate alkaloid that can be converted to oxycodone, oxymorphone, and drugs that treat overdoses and substance abuse.
The Stanford team fed sugar to engineered yeast in a process not horribly different from making bread or beer. Except, of course, rather than leveraging the byproducts of alcoholic fermentation, their yeast spit out tyrosine, an amino acid precursor to opioids. With some extra engineering along the way, the yeast continued to develop small amounts of opioids. The process of cultivating common yeast to ferment beer and the Stanford opiate-producing method are also, understandably, very different. “In the case of the latter,” Smolke wrote in an email, “the cells are grown in enclosed bioreactors, that very precisely control stirring, aeration rates, nutrients, and other factors such as pH.”
Of course, if history has taught us anything, it’s that if a drug exists, someone will try to abuse it. It's like the Murphy's Law of getting high. And, as any brewer or baker will tell you, cultivating yeast is not particularly difficult. To that end, experts have warned about the possibility of yeast-grown, homemade smack. “These claims are relatively easy to test,” Smolke says, “and should be tested as we continue to engineer improved strains going forward.”
And Smolke’s team did just that, running a small study (available as a preprint here) comparing two engineered strains to the yeast that makes English ale. While the boozy yeast acted as a control in its fermentation bottle, the engineered strains didn't seem to do much at all. Neither produced thebaine, and only one of the strains produced a small amount of reticuline. Basically, if someone got their hands on the Stanford strains, it would take more than a basic home-brew kit to come up with much of anything.
And even if someone in the lab wanted to try their hand at making street drugs, the Stanford yeast strains produce thebaine and hydrocodone—unlike morphine, someone would need specialized skills and equipment to convert those byproducts to, say, heroin. “The question is, can a microbial-based supply chain be responsibly developed and implemented in a way where it reduces the potential of abuse of these compounds and the supply chain,” Smolke said in an interview for an article earlier this year about home-brewed opioids. “I believe that if responsibly developed, a microbial-based supple chain can actually address many of the challenges…including those with control, containment, [and] diversion to illegal markets.”
Scientists around the world have been leapfrogging and tag teaming their way toward solutions of their own. This development comes just months after news from UC Berkeley that modified yeast can create reticuline and research from The University of York that pieced together the final steps in the puzzle of how poppies produce opiates.
There’s a reason why researchers are racing to solve this problem: So few countries permit opium poppy farming that the supply chain is easily disrupted by crop failures and climate change. And, while some worry that yeast could be exploited by illicit drug-makers, the current system is alreadu infamous for fueling the drug trade.
Because manipulating synthetic pathways in poppies is so complex, it’s been close to impossible for researchers to develop safer, less-addictive alternatives to the drugs we rely on. Yeast could solve that problem. Smolke says the technology she and other researchers are working on could lay the foundation for low-cost discovery for anti-cancer therapeutics, antibiotics, and other pharmaceuticals and “will enable us to make and fairly supply medicines to all who need it,” she wrote.
Because the Stanford yeast only yield a small amount of opioids, next up is figuring out how to boost that to meet commercial needs. “I believe within two years, we'll see this technology ready to enter scale up and production,” Smolke says. Poppy farmers, get ready to be disrupted.
