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Bioengineered Opiates Don't Require Poppy Plants

Bioengineered yeast is poised to be the world's new supplier.
Image: Hanneliese/Shutterstock

Opiate drugs are on their way to being fully synthesized. Drug makers will no longer have to rely on a plant, the same basic organism that's delivered narcotics to humans since the Neolithic, for the most basic raw materials of opiate painkillers. Fields of flowering poppies are out, and bioengineered microorganisms are in, at least according to a new paper published in Nature Chemical Biology, which describes a new method of producing opiates with help from a genetically tweaked version of regular baker's yeast.

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The world's legal opium stores currently come from tightly controlled facilities in a small pool of countries: Australia, France, Hungary, India, Spain, and Turkey. It takes about 2,000 tons yearly to produce the needed compounds, according to the Drug Enforcement Administration, which isn't very much. It is however a system fraught with supply inefficiencies and insecurity, according to the new study's authors, led by Stanford bioengineering professor Christina Smolke. They note that while the United States is far and away the largest consumer of opiates, it has no production capabilities of its own.

"Agricultural production of drugs generally suffers from susceptibility to climate and disease, a single annual growing season, low alkaloid content in the plant body, need for extraction by chemical processing, and social and political factors related to the potential for illicit use," Smolke et al explain in their paper. So flowers are ripe for replacing.

It takes around 17 steps to get from the opium plant to the sorts of opiates found on pharmacy shelves. Oxycodon, for example, starts as codeine, one of the basic constituents of opium, and then goes through a chemistry gauntlet of oxidation and methylation before it becomes a crucial precursor called thebaine (a chemical step that, within the plant, occurs before the morphine itself, so refinement is kind of reversing the natural process).

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At this point, our future-drug can branch out in a few ways, becoming possibly oxymorphone or buprenorphine, with oxycodon being just another oxidation step and a final hydrogenation away. Phew.

Even morphine itself, a basic component of opium, goes through an extended series of steps: concentration, extraction, purification and repeat. For heroin, take morphine and cook it with acetic anhydride and then put the result through a few (sketchy) steps of purification.

Cut the processing effort and move production stateside, and the cost savings are obvious.

Smolke's process so far involves only the latter stages of opiate synthesis. Essentially, the researchers have modified the yeast genome in such a way that it behaves like a poppy, mimicking the steps undergone in the plant itself to convert thebaine to morphine. This process is obviously something that doesn't come naturally or easily to yeast cells, due to the very different structures of the plant organism and the yeast microorganism. The challenge is in reconstructing the optimal microenvironments for plant processes to occur, optimizing "spacial regulation" within the yeast.

Once these microenvironments are engineered in the yeast, more typical methods of microbal bioengineering can be used. "Standard optimization strategies for enhancing plant natural product biosynthesis in microbial hosts include optimizing codon usage, tuning enzyme expression and its timing, and redirecting host metabolism to increase supply of precursors and cofactors," the paper explains.

Next for Smolke and her team is further programming the yeast such that it can handle all of the steps involved in converting basic sugars into thebaine. At this point, all 17 steps will have been fully mimicked in engineered yeast cells, and we can expect the fully poppy-free results not long after. The advantage for drug makers over conventional field-grown opium is in efficiency and cost-effectiveness, Smolke told me. Makes sense: cut the processing effort and move production stateside, and the cost savings are obvious. Given the alarming growth of prescription painkiller usage, those savings might add up quickly.

Finally, we have to wonder about what effect this might have on the heroin market. Is there some future in which legal opiates all come from labs and heroin still comes from fields in Afghanistan? Smolke was circumspect, but offered that, "the microbial technology can be developed in a way that it is more secure and more difficult to divert to illegal use." Which still leaves our illegal poppy fields in operation, perhaps with less hope of ever going legit, and churning out ever-increasing volumes of poppy-derived opium. And with opium revenues accounting for some 60 percent of the total southern Afghanistan economy, a widely-exploitable synthetic represents a potent enemy.