Opiates Coming to a Yeast Culture Near You

October 23, 2015 | Sarah Tse

yeast colonies (Saccharomyces cerevisiae) mutants on an agar plate
Photo credit: Rainis Venta/Wikipedia (CC BY-SA 3.0)

Scientists have genetically engineered yeast to produce opiates for pharmaceutical drugs, but some fear the technology could get out of hand.

We can thank yeast for some of the most important innovations in human history: alcohol, bread, and Marmite. These microscopic fungi are also good for a few other trivial things, like expanding our knowledge of cell biology and producing medicinal insulin and biofuels. The next breakthrough in harnessing the powers of yeast for human profit is opiate production.

SEE ALSO: Yeast Engineered to Produce Cannabinoids

Opiates are the class of painkillers naturally produced by the opium poppy, Papaver somniferum. The sticky latex that seeps out of poppy seed pods contains morphine, codeine, and thebaine, which are all processed for medicinal use. Although we have selectively bred the plants to make latex with higher opiate contents, growing enough poppies to meet medicinal demands still requires a lot of land, labor, and processing. The few countries allowed to grow opium poppies are heavily regulated, in an attempt to thwart the illegal drug trade that uses opium to make heroin.

Poppy pod
The profitable poppy pod. Photo credit: KGM007/Wikipedia

We’ve already wrangled yeast into producing other useful compounds that were hard to extract from their natural sources. In the twentieth century, we had to purify insulin from the pancreatic extracts of cows and pigs, until scientists figured out how to genetically engineer yeast to turn them into “biofactories.” Now the microbes can produce insulin through their normal metabolic processes—that is, the chemical reactions and mechanisms they carry out on a daily basis. So what’s stopping us from using yeast to manufacture any compound we might need?

Opiates are built through a complex pathway of reactions, each step requiring different molecular machines (“enzymes”), helper molecules, and raw materials—few of which are naturally produced by yeast. It took a few years, but a team at Stanford University finally worked out the entire laborious system by which the opium poppy synthesizes thebaine, the precursor for drugs like codeine and oxycodone.

The next step was to give yeast the tools to follow all these steps. The team edited the yeast’s DNA to include instructions for building each one of the enzymes and helper molecules. This involved splicing in the DNA for 21 different enzymes, isolated from plants, mammals, bacteria, and yeast. The completed pathway can convert sugar (naturally-produced in yeast) into thebaine, modeled on the fermentation routine held so dear by bakers, brewers, and vintners.

Even after transplanting this new opiate pathway into the yeast DNA, the team encountered obstacles. Yeast, like all organisms, don’t want to waste time or resources making things they don’t need. Scientists had to address each step of the pathway to make it hyper-productive, which would get around the inherent inefficiency of biological processes. This involved tinkering with the yeast’s fundamental metabolic framework, as well as refining the new genes they had added so that the yeast could properly express them.

Finally, researchers successfully cajoled the yeast into synthesizing thebaine. Of course, it will take another few years for the Stanford team to scale up each cell’s yield and make the process commercially viable. Once they’ve ironed out the details, the researchers hope that their yeast-produced opiates will use 500 times less land than poppy-produced opiates.

But in a world where chemistry teachers set up meth labs in their basements, this breakthrough has provoked concerns about abuse. It’s easy enough to obtain a starter kit for home-brewing beer, so home-brewed heroin seems a very real and terrifying possibility. These fears are especially valid in light of recent increases in heroin and painkiller addiction. The Stanford team anticipated these concerns and conducted an additional experiment where they placed the engineered strain under typical home-brew conditions.

Luckily, the yeast only produced negligible amounts of a precursor to thebaine—thebaine itself was not produced. Even if someone managed to replicate lab settings, thebaine needs additional processing before it can function as a street drug. The researchers are confident that careful monitoring and communication with government regulators as they continue to refine the production process will prevent its corruption. If all goes as planned, this process could revolutionize the pharmaceutical industry by opening the door to less costly drug discovery and experimentation. Oh yeast, what would we do without you?

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