Better Painkillers made with Yeast

Better Painkillers Designed with Yeast

In Carmel Valley, a charming, rustic village located 11 miles inland of Carmel-by-the-Sea, there are a score of Monterey County wineries and tasting rooms, convenient to Carmel Valley home dwellers and tourists alike. The yeasts cultivated from wild strains have fermented wine from grapes or leavened bread from flour for thousands of years. Now cutting-edge Stanford research has taken yeast into the laboratory and reengineered it to produce modern plant-based painkilling medications.

In a recent breakthrough after a decade-long effort, Stanford scientists reprogrammed the genetic machinery of baker’s yeast so that it could convert sugar into the opioid compound hydrocodone within three to five days. Producing the opioid so rapidly could potentially speed access to lower cost medicines, especially for impoverished countries. The techniques they developed and demonstrated for opioid pain relievers can be adapted to produce many plant-derived compounds to fight and treat chronic conditions such as high blood pressure and arthritis, infectious diseases, and cancers.

Hydrocodone like its chemical relatives morphine and oxycodone are opioids, members of a family of painkilling drugs sourced from the opium poppy. Like the process of making wine in Carmel Valley wineries, it can take more than a year to produce a batch of opioid medicines such as hydrocodone starting from opium poppies. After growing the poppies at licensed facilities, the plant material is harvested, processed, and then sent to pharmaceutical manufacturers, where the active drug molecules are extracted and refined into medicines.

Christina Smolke, PhD, Stanford associate professor of bioengineering is senior author of a report published in Science describing her team's work. When they started work a decade ago, many experts thought it would be impossible to engineer yeast to replace the entire farm-to-factory process, she said. Now, although the output is small, the experiment proves that bioengineered yeast can make complex, plant-based medicines.

Smolke's team is modernizing the process that began when plant-derived medicines were chewed or brewed into teas by our ancestors, or later refined into pills using chemical processes that extracted and concentrated the active ingredients. The team inserts precisely engineered snippets of DNA into cells such as yeast, reprogramming the cells into custom chemical assembly lines that produce medicinal compounds.

In order to create the cellular assembly line for hydrocodone, the Stanford team had to engineer 23 genes from other plants, bacteria, and even rats into the genome of baker's yeast. Previously, in order to prove that yeast biosynthesis was even possible, the team had used genetically engineered yeast to produce the antimalarial drug artemisinin from the sweet wormwood tree. The yeast-based artemisinin production required adding only six genes for the biosynthesis process. Over the last decade, about one-third of the world’s supply of artemisinin has successfully shifted to yeast-based biosynthesis and bioreactors.

Smolke described the biosynthesis development work for the opioid hydrocodone that followed as the most complicated chemical synthesis ever engineered in yeast.

The bioengineering team found and fine-tuned snippets of DNA from bacteria, other plants, and even rats that equipped yeast to produce all the enzymes necessary for the cells to convert sugar into hydrocodone.

The team had to discover a missing link in the basic science of plant-based medicines to get the yeast assembly line going. (S)-reticuline, a molecule that is a precursor to active ingredients with medicinal properties is produced by many plants, including opium poppies. In the opium poppy, (S)-reticuline is transformed naturally into a variant called (R)-reticuline, a molecule that starts the progression toward the plant-based production of molecules that can relieve pain.

Smolke’s team and two other labs independently discovered which enzyme reconfigures reticuline, but the yeast didn’t create enough of the opioid compound. So the Stanford team genetically tweaked the next enzyme in the process to boost production. They continued adding enzymes down the production path, including six enzymes from rats, in order to craft a molecule ready to plug pain receptors in the brain.

With both alcohol and opium, there is potential for misuse, and in their Science paper, the Stanford authors acknowledged that a new process to make opioid painkillers could multiply concerns about the potential for opioid abuse. However, the World Health Organization estimates that 5.5 billion people worldwide, more than half of humanity, have little or no access to pain medications. Smolke said that biotech production could lower costs and, with proper controls against abuse, allow bioreactors to be located where they are needed.

In addition to bioengineering baker's yeast to convert sugar into hydrocodone, the Stanford team also developed a second yeast strain that can process sugar into thebaine, a precursor to other opioid compounds. Bio-produced thebaine still needs to be refined through sophisticated processes in pharmaceutical factories, but it would eliminate the time delay of growing poppies.

The molecules that Smolke's team produced and the techniques they developed showed that it is possible to make important medicines using only yeast. If responsibly developed, such medicines can be made and provided fairly to all who need.

Smolke's team has patented their process, and in time to come, even residents of Carmel Valley homes may find these plant-based painkillers from lowly yeast alleviating their arthritis, high blood pressure or even cancer.