Using the age-old idea of employing yeast to convert sugar into alcohol, researchers have formulated key steps using which sugar-fed yeast can be turned into a microbial factory to churn out therapeutic drugs including morphine, antibiotics and possibly even anti-cancer drugs.
Researchers have been trying to imitate the complex 15-step chemical pathway in the poppy plant to enable production of therapeutic drugs by using microbes in lab for over 10 years, but one of the major hurdles was to find a way wherein the entire process from start to finish can be finished by using just one microbe – E. coli or yeast.
This is exactly what a research team led by bioengineers at the University of California, Berkeley, has done in their latest study, published in journal Nature Chemical Biology. UC Berkeley bioengineer John Dueber teamed up with microbiologist Vincent Martin at Concordia University in Québec to overcome this hurdle by replicating the early steps in the pathway in an engineered strain of yeast. Researchers were successful in synthesizing reticuline, a compound in poppy, from tyrosine, a derivative of glucose using the engineered yeast.
The idea is simple – researchers wanted to imitate the fermentation process wherein yeast is fed glucose and at the end of the process the resultant compound is the target therapeutic drug.
Dueber, the study’s principal investigator and an assistant professor of bioengineering says: “With our study, all the steps have been described, and it’s now a matter of linking them together and scaling up the process. It’s not a trivial challenge, but it’s doable.”
Plants showed the way
Researchers have been looking at poppy plant pathway and Benzylisoquinoline alkaloids, or BIAs, – the class of highly bioactive compounds found in the poppy. Researches have been paying particular attention to the trail in the BIA pathway that leads to the opiates, such as codeine, morphine and thebaine, a precursor to oxycodone and hydrocodone, all of which are controlled substances. Researchers say that different trails will lead to the antispasmodic papaverine or to the antibiotic precursor dihydrosanguinarine.
Though one of the options is to genetically engineer the poppy, but researchers including study lead author William DeLoache, a UC Berkeley Ph.D. student in bioengineering, say that moving the BIA pathway to microbes dramatically reduces the cost of drug discovery and the best bit is that the DNA of yeast can be easily manipulated and tuned to quickly test the results.
The researchers found that by repurposing an enzyme from beets that is naturally used in the production of their vibrant pigments, they could coax yeast to convert tyrosine, an amino acid readily derived from glucose, into dopamine.
With help from the lab of Concordia University’s Vincent Martin, the researchers were able to reconstitute the full seven-enzyme pathway from tyrosine to reticuline in yeast.
“Getting to reticuline is critical because from there, the molecular steps that produce codeine and morphine from reticuline have already been described in yeast,” said Martin, a professor of microbial genomics and engineering. “Also, reticuline is a molecular hub in the BIA pathway. From there, we can explore many different paths to other potential drugs, not just opiates.”
Regulators need to pay attention
Researchers note that their study may make homebrewing of drugs a reality and hence call upon regulators and law enforcement officials to pay attention.
Dueber notes that homebrewing of controlled substances could be possible in just about two years and regulators should utilise this time to think about policies to address this area of research.
“The field is moving surprisingly fast, and we need to be out in front so that we can mitigate the potential for abuse”, Dueber added.
Or they could just legalise the poppies and we could do it even better and safer!