Yeast has long been a friend to human substance abusers. These masterful microbes, among the first fungi domesticated by humans, can take simple sugar from any number of sources and, like magic, ferment it into ethanol. Soon, though, yeast could be used to generate other, more illicit substances, bringing us one step closer to the possibility of homebrewed smack.
A paper published today in Nature Chemical Biology details a novel process for replicating poppy’s opiate-producing chemical pathways by genetically modifying good ol' Saccharomyces cerevisiae. That technology could lay the foundation for low-cost drug discovery, potentially producing anti-cancer therapeutics, antibiotics, and other narcotics. The only hitch: With the right opioid-producing yeast strains, it would also be easier to create morphine, heroin and other drugs at home---no Walter White-level smarts required. Just call it Breaking Bread. No, wait, Brewing Bad.
“Right now, you would need a background in synthetic biology and genetics to overcome the challenges to produce the right kind of yeast,” says John Dueber, a bioengineer at UC Berkeley and lead author on the study. “It is not an imminent threat. But if a strain made for licit purposes got out, then all that would be required is knowledge of brewing beer to ferment it into morphine.”
Though a relatively young industry, synthetic biology has made huge leaps in recent years. With some genetic tweaks, yeast and algae can now make fuel, flavoring, and scent. But the rapid pace of synbio development has led some researchers to tap the brakes and discuss the implications of their work.
Genetic techniques have always provoked interesting ethical and regulatory questions: Gene-drive technology and human germline modification come with the allure of eradicating invasive species and eliminating genetic diseases, but they also have the potential to upend natural selection and change human genes in unexpected ways. Now, the possibility of yeast-derived opiates poses a new set of challenges for drug regulators. “I haven’t seen anything quite like this before,” says Kenneth Oye, MIT tech policy expert and co-author of an op-ed published alongside the study.
Though genetically-modified yeast have the potential to create novel and illicit drugs, opiate-producing strains could provide enormous benefits. Humans have cultivated opium poppies for thousands of years and, today, we still process the plants for natural opiates like morphine and semi-synthetic opiates like oxycodone. But relying on poppies has downsides. Few countries permit growing the plants for medicinal use, meaning that damage to even one area’s crop impacts drug production worldwide, and poppy farming has led to deforestation. Plus, of course, there’s the pesky issue of illicit heroin production.
Perhaps most compelling, though, is that manipulating synthetic pathways in poppies is difficult, making it nearly impossible to create safer, less-addictive opiates. Yeast, on the other hand, is incredibly easy to alter. “It’s hard to add or subtract genes into the plant, and plants grow very slowly,” Dueber says. “Whereas, we can easily put in different DNA and change combinations of genes in yeast—and yeast can double every two hours.”
This isn't the first time researchers have taken steps toward using yeast to create opioids. Last year, Christine Smolke and her team at Stanford announced that they had reprogrammed yeast with genes from both poppies and bacteria that live on the plant's stalks to, eventually, make semi-synthetic opioids. (Because Smolke’s engineered strains will bypass morphine to produce higher value opioid compounds, it can’t be converted to heroin.) And, last month, a PLOS One article co-authored by Concordia University’s Vincent Martin outlined different synthetic steps toward morphine using yeast.
Piggybacking on some of this research and enlisting Martin’s help directly, Dueber and his colleagues used the cells that create vibrant colors in sugar beets to develop a biosensor that could identify the enzyme tyrosine hydroxylase in yeast. Mutating that enzyme allowed the fungus to convert glucose into reticuline—a chemical that’s just a hop, skip, and a jump away from codeine, morphine, and other benzylisoquinoline alkaloids.
While it might seem early to worry about the possibility for homebrewed opioids, Dueber predicts that a strain could carry out all the stages of opioid production in as little as a couple of years. He points to the surprising speed of his own work as a case study: Thanks to improvements in biochemistry and his colleagues' work in the field, Dueber was able to complete some of the most critical technical work toward synthesis in just six months.
Dueber thinks it's important that scientists and policymakers start considering the possibilities now, before the science gets ahead of regulations. “We didn’t want the final strain to be made and then tell the public that [homebrewing] was a possibility,” he says.
Oye proposes that the next steps should be voluntary, convincing technologists to make yeast less appealing for illegal use by generating strains that can only spit out less-addictive drugs, or ones that are finicky and difficult to maintain outside a lab. He also said regulators may enforce watermarking yeast DNA so illicit use can be traced to specific labs---and hopefully dissuade someone from casually grabbing a sample of yeast and brewing morphine in their kitchen.
Still, some, like Smolke, are not convinced homebrewing is a threat. The yeast strain would need to be highly engineered and would require "very specialized and highly controlled fermentation equipment and conditions, which are not readily available to nonspecialists," she wrote in an email. "Putting such highly engineered yeast strains into a homebrew kit would not get you very much opiates to make it worthwhile."
For now, it's still easier for you to access morphine by dumping a bunch of poppy seeds into your homebrew. But that doesn't mean regulators should be complacent. Homebrewed, yeast-derived opiates are a possibility, but the right equipment and the right science in the hands of a well-funded drug operation will make them a certainty. There is always potential for abuse, Smolke says, and we should responsibly develop an alternative to our poppy-based supply chain to address illegal markets, high costs, and other issues.
As for Dueber’s team, they have completed seven of the 15 steps for the poppy's opioid-producing pathway and are working to piece together the full process. “At this point the illicit danger is concrete,” Dueber says. “It’s easy to see exactly what molecules would be harmful, whereas the benefits are immense and, I think, will be well worth it.”
