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Scientists Make Opioids From Bioengineered Yeast Instead of Poppies

Process takes only 3 to 5 days

It typically takes a year to produce hydrocodone from plants, but Dr. Christina Smolke, an associate professor of bioengineering at Stanford University, and her colleagues have genetically modified yeast to make it in just a few days.

The technique could improve access to medications in impoverished nations, and could later be used to develop treatments for other diseases, the researchers say. Writing in Science, they describe how they reprogrammed the genetic machinery of baker’s yeast so that these fast-growing cells could convert sugar into hydrocodone in just 3 to 5 days.

Hydrocodone and its chemical relatives, such as morphine and oxycodone, are opioids –– members of a family of painkilling drugs sourced from the opium poppy. It can take more than a year to produce a batch of medicine, starting from the farms in Australia, Europe, and elsewhere that are licensed to grow opium poppies. Plant material must then be harvested, processed, and shipped to pharmaceutical factories in the U.S., where the active drug molecules are extracted and refined into medications.

“When we started work a decade ago, many experts thought it would be impossible to engineer yeast to replace the entire farm-to-factory process,” Smolke said.

Now, although the output is small –– it would take 4,400 gallons of bioengineered yeast to produce a single dose of pain relief –– the experiment proves that bioengineered yeast can make complex plant-based medicines.

“This is only the beginning,” Smolke remarked. “The techniques we developed and demonstrate for opioid pain relievers can be adapted to produce many plant-derived compounds to fight cancers, infectious diseases, and chronic conditions, such as high blood pressure and arthritis.”

To get the yeast assembly line going, the Stanford team had to fill in a missing link in the basic science of plant-based medicines.

Many plants, including opium poppies, produce (S)-reticuline, a molecule that is a precursor to active ingredients with medicinal properties. In the opium poppy, (S)-reticuline is naturally reconfigured into a variant called (R)-reticuline, a molecule that starts the plant down a path toward the production of molecules that can relieve pain.

Smolke’s team and two other laboratories recently discovered which enzyme reconfigures reticuline, but even after the Stanford bioengineers added this enzyme into their microbial factory, the yeast didn’t create enough of the opioid compound. So they genetically tweaked the next enzyme in the process to boost production. Down the line they went, adding enzymes, including six from rats, in order to craft a molecule that emerged ready to plug pain receptors in the brain.

In addition to bioengineering yeast to convert sugar into hydrocodone, Smolke and her colleagues developed a second strain that can process sugar into thebaine, a precursor to other opioid compounds. Bioengineered thebaine would still need to be refined through sophisticated processes in pharmaceutical factories, but it would eliminate the delay of growing poppies.

“The molecules we produced and the techniques we developed show that it is possible to make important medicines from scratch using only yeast,” Smolke said. “If responsibly developed, we can make and fairly provide medicines to all who need them.”

Sources: Stanford University; August 13, 2015; and Science; August 13, 2105.

 

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