April 2, 2019

UCalgary-based team takes big step toward producing safer, less expensive pain-killing medications

Research led by biochemist Peter Facchini widens path to microbial production of pharmaceutical opiates

Imagine if we had pain-killing prescription drugs as effective as morphine, codeine and oxycodone, but without the addictive and potentially fatal side-effects.

What if such drugs could be produced relatively inexpensively, making them available to the 95 per cent of the global population that currently has no access to costly opiate medications?

Now, in a new study, a team of University of Calgary-based scientists has taken another big step toward being able to produce — in engineered yeast — safer, less expensive synthetic opioid pharmaceuticals. The team has discovered a previously unknown gene, and the corresponding enzyme, that plays a critical role in biosynthesizing morphine production in the opium poppy plant.

The enzyme, called neopinone isomerase, or NISO, adds a crucial piece to our understanding of opiate biosynthesis in opium poppy, says Dr. Peter Facchini, PhD, professor of plant biochemistry in the Department of Biological Sciences in the Faculty of Science.

The team also found that inclusion of the NISO enzyme dramatically improves the performance of yeast engineered to produce pharmaceutical opiate alkaloids, such as codeine and morphine, as well as valuable compounds used to make drugs for treating opioid dependency and overdose.

“Engineered yeast-based fermentation systems will eventually replace opium poppy plants as our commercial source for opiate painkillers and the drug naloxone, which saves countless overdose victims,” Facchini says.

Last year, Facchini and the research team discovered another previously unknown enzyme, called thebaine synthase (THS), which plays a vital role in catalyzing production of thebaine — the gateway compound to all pharmaceutical opiates — in opium poppy.

“THS and NISO each confer improvements to the product yields in engineered yeast strains by orders of magnitude that are compounded when combined, which paves the way to commercial production levels of opiates,” he says.

The team’s new study, “Neopinone Isomerase is Involved in Codeine and Morphine Synthesis in Opium Poppy,” is published in Nature Chemical Biology, a journal in the top-ranked Nature series.

Peter Facchini says yeast-based production will give Canada and the rest of the world a more stable and scalable supply of opiates.

Peter Facchini says yeast-based production will give the world a more stable supply of opiates.

Riley Brandt, University of Calgary

Solving the puzzle of opiate production

For the last three years, Facchini and his research team have been using strains of engineered yeast to identify and characterize a family of proteins, called PR10 proteins, involved in the "metabolic machinery" that enables opium poppy to make opiates. These proteins make up about one-third of the plant’s latex — the famed “milk of the poppy.”

“A couple of biosynthetic reactions can indeed occur spontaneously, but we’ve proven they’re not just left to chance in the plant,” Facchini says. “There is an enzyme in each case that makes sure you get the correct opiate product rather than mostly unwanted metabolic byproducts.”

The team used a wide range of methods and techniques, from genome sequencing and protein biochemistry, to yeast metabolic engineering and genome editing technologies.

The use of engineered yeast strains enabled the team to detect the byproducts (which have never been detected in the plant), determine which proteins or enzymes are involved in each step of converting the byproducts to opiates, and then utilize these enzymes to increase production of the high-value opiates in the engineered yeast.

In just three years, the researchers have been able to increase opiate production in engineered yeast strains by 10,000 times. Facchini says they are now within two to three years of achieving commercial-level production.

The team has discovered — and is in the process of publishing on — other key components of the opiate biosynthesis process that will make further huge differences in increasing opiate production via fermentation of engineered yeast, he notes.         

New company targets commercial production

Most of the research has been conducted by senior scientists working under contract for Epimeron Inc., a five-year-old Calgary-based biotechnology firm created to commercialize technology developed in Facchini’s UCalgary laboratory.

“Epimeron is now in the final stages of going public on the Canadian Securities Exchange, via agreements with Makena Resources Inc. and BioCan Technologies Inc., in a combined new company to be named Willow Biosciences Inc.,” says Joseph Tucker, CEO of Epimeron and executive chairman of Willow Biosciences.

Willow Biosciences, to be based in UCalgary’s new Life Sciences Innovation Hub, will continue efforts to commercialize the fermentative production of pharmaceutical opiates in engineered yeast, along with medical cannabinoids.

Facchini, who will serve as Willow Bioscience’s chief scientific officer, says yeast-based production will give Canada and the rest of the world a more stable and scalable supply of opiates, while avoiding the inherent problems of morphine derived from opium poppies being diverted to heroin.

“This engineered system also has the potential to yield new, improved and — importantly — less addictive opiate pain-killing medications,” Facchini says. “The opium poppy has been our source of these painkillers for 7,000 years. It’s time for the plant to plan for retirement.”

Major funding for the new study was provided by Epimeron, either directly or through a contract with the University of Calgary, and by the National Resources Council of Canada’s Industrial Research Assistance Program.