The California poppy (top), rat, goldthread, bacteria, and opium poppy, among other organisms, contributed genes to the bioengineered yeast used to produce thebaine and hydrocodone. | Stephanie Galanie and Christina Smolke
After decades of work by scientists around the globe, researchers have genetically manipulated yeast to synthesize thebaine, an opiate substance that can be used to create many opioid drugs, and hydrocodone, a common semi-synthetic opioid drug.
Opioids are the most effective compounds used to treat millions of people who suffer from moderate to severe pain, including those in palliative care. The only current source of opioids is the opium poppy, Papaver somniferum, making production reliant on poppy farming. But the new manufacturing process could eliminate the need for farming and significantly reduce the time it takes to produce opioid compounds.
In their study published online in Science on 13 August, Christina Smolke of the University of Stanford and her colleagues successfully managed to engineer yeast to produce the enzymes required to create opioids, starting with sugar as the fuel source.
The scientists say there is still considerable work to be done before this process can be translated into practical commercial applications. While this study highlights the novel production of opioid substances through a microbial-based method, the current yield is miniscule. For example, the methods used in this paper produced less than a microgram of opioid compounds per liter. Using this technique to produce a single medical dose of hydrocodone, as used in Vicodin® (5 mg), would require thousands of liters of yeast fermentation broth.
With concerns about the potential uses of this research in mind, the research paper describing these results was specially reviewed by Science's editors, and Smolke and her co-authors say they are committed to open discussions about careful and responsible advancement of this research.
While yeast has been engineered previously to produce a variety of plant-based natural products, reconstructing the highly complex chemistry of opioids and their precursors has been a challenge. To produce the opioid precursor thebaine, the team engineered the yeast to express 21 enzymes from plants, mammals, and bacteria, as well as yeast. They also extended the pathway to express two additional enzymes to achieve production of hydrocodone.
The researchers were thrilled with the results. "This was the culmination of a decade of research for us," said Smolke. "An engineered biosynthetic pathway of this complexity had not been demonstrated before."
Smolke and her team of researchers learned to manipulate the yeast to produce the 20-plus non-yeast enzymes required for the cells to convert sugar to opioids. For example, the yeast cells were inefficient at reading the genetic instructions to process and concentrate a plant enzyme required to synthesize one of the compounds. The team had to rewrite these instructions so that the yeast processed this enzyme more like the plant cell it came from and increased its activity.
The scientists hope that their findings could eventually help stabilize the supply of opioids and be used to advance the discovery of new medicines for a broad range of different diseases and ailments.