Yeast is a type of microorganism commonly used to make bread, wine and beer. Now, a research team from Stanford University, CA, has steered it away from food and drink and applied it to the medical world, using yeast to make opioids.
Senior study author Christina Smolke, associate professor of bioengineering at Stanford, and colleagues publish their findings in the journal Science.
Opioids are the most widely used painkillers in the US. They work by attaching to opioid receptors in the central nervous system and gastrointestinal tract, reducing intensity of pain signals sent to the brain.
Types of opioids include hydrocodone, codeine, methadone, heroin and morphine, and they are sourced from the opium poppy.
According to Smolke and colleagues, it can take around 1 year to produce a batch of opioid drugs. The poppies must be harvested from farms in countries that are licensed to grow them – such as Australia and parts of Europe – and processed, before being shipped to pharmaceutical factories in the US. The active drug molecules are then extracted from the plant and made into opioid medications.
But could this time-consuming process be avoided if scientists were able to make opioids using yeast?
At present, plant-derived drugs are created using chemical processes that extract and concentrate the active compounds. But the Stanford team has developed a new approach to make opioids.
Researchers have already genetically modified yeast to produce artemisinin – a drug originally sourced from the sweet wormwood tree that is used to treat malaria – using biosynthesis. This involved adding engineered sections of DNA from six enzymes into yeast cells in order to reprogram them. The process has proved a success, with approximately one third of the world’s artemisinin now created using this approach.
However, Smolke and colleagues say the biosynthesis process they used to create opioids using yeast was much more challenging; it took 23 enzymes from plants, bacteria and rats to genetically modify the yeast in order to create hydrocodone.
“This is the most complicated chemical synthesis ever engineered in yeast,” says Smolke.
Opium poppies and some other plants produce a molecule called (S)-reticuline, which is naturally reformed into a variant called (R)-reticuline. This variant initiates the production of pain-relieving molecules.
The researchers added the enzyme that reconfigures reticuline to the yeast but found it failed to produce enough hydrocodone. As such, they genetically modified each subsequent enzyme in the reconfiguring process in order to increase hydrocodone production.
Adding the 23 modified enzymes to the yeast cells enabled the conversion of sugar – the main fuel source – to hydrocodone within 3-5 days. “Enzymes make and break molecules. They’re the action heroes of biology,” says study co-author Stephanie Galanie.
Using this process, the team was also able to create thebaine, a precursor to other opioid compounds. While thebaine developed in this way would still need to be processed in pharmaceutical factories, the researchers say it would speed up production by eliminating the need for poppy growth.
While opioids are effective pain relievers, they also play a key role in prescription drug abuse. In 2012, it is estimated that around 2.1 million people in the US had substance use disorders related to opioids, and the rate of accidental deaths from prescription painkillers has more than quadrupled in the country since 1999.
Smolke and colleagues admit that their new approach to opioid development may raise concerns about how it could impact abuse of the drug. They say that if the process were to be scaled up and put into use, it would need to be under tight regulation.
“We want there to be an open deliberative process to bring researchers and policymakers together,” says Smolke. “We need options to help ensure that the bio-based production of medicinal compounds is developed in the most responsible way.”
While opioids are highly abused drugs in the US, the Stanford team notes that there are still around 5.5 billion people around the globe who have limited or no access to pain medication.
They say the genetic modification of yeast into opioids could reduce the cost of the drugs and extend their reach to places where access to pain medication is low. What is more, they say their approach could be used to develop drugs to treat other conditions, such as arthritis, infectious diseases and cancer.
“The molecules we produced and the techniques we developed show that it is possible to make important medicines from scratch using only yeast. If responsibly developed, we can make and fairly provide medicines to all who need.”