Researchers engineer cough suppressant from yeast

April 5 (UPI) -- Scientists have developed a way to bio-engineer from yeast a non-narcotic cough suppressant that is being tested for cancer treatment -- and a process that potentially can change the way medicines are made.

Stanford researchers inserted 25 foreign genes, which came from the opium poppy, other plants and even rats, into the one-celled fungus. Their findings were published Monday in the Proceedings of the National Academy of Sciences.

These enzymes are proteins that work together and can build complex substances.

Noscapine is a non-narcotic cough suppressant that occurs naturally in opium poppies and is an ingredient in 14 cough medicines, including Coskap-N and Compress N.

"This is a technology that's going to change the way we manufacture essential medicines," Dr. Christina Smolke, professor of bioengineering at Stanford said in a press release.

She said the process needs a hundredfold improvement to be sold commercially, but most can be achieved by substituting large-scale bioreactors for simple laboratory flasks.

"Traditionally, we've gotten our medicines from the natural world, mainly from plants," Smolke said. "But the plants' molecular assembly lines have evolved to optimize the plants' survival, not to churn out buckets of one substance we humans want to get our hands on. Plus, we're putting them into our yeast strain, which is foreign turf. A yeast cell and a poppy cell have a lot in common, but in some respects they're as different as Earth and Mars."

Noscapine, which was discovered in 1930, has been widely used since the 1960s throughout Asia, Europe and South America, as well as in Canada, Australia and South Africa.

Also, preclinical trials show the drug has potential as a cancer drug with less toxicity to healthy cells than available chemotherapy.

Stanford researchers have engineered brewer’s yeast with over 30 enzymes from medicinal plants, microorganisms and mammals to enable rapid, fermentation-based production of a plant-derived cough suppressant and potential anticancer drug. Photo courtesy of Stanford Medicine News Center

But it is difficult to make, because it takes one year for the opium poppy plant to fully develop, and it can't be legally grown in a concentrated geographical area. Half are grown in Australia, with the rest mainly in India, France, Turkey and Hungary.

The bioengineered noscapine, however, can be manufactured in three or four days.

The poppies require costly controls and restrictive regulations because of their illicit potential. And the naturally occurring noscapine must be thoroughly separated from molecular companions, including narcotics. None of these properties occur in yeast.

The researchers had to work with a variety of complex chemicals that require different enzymes working in concert with one another.

"It's as if we're grabbing a couple dozen soldiers from different units, deploying them on Mars, and telling each of them, 'Now, not only am I putting you on Mars, but I want you to get some serious work done here, and I want you to work with these other soldiers you haven't worked with before -- many of them total strangers,'" Smolke said. "Good luck with that. We modified them to keep them in shape on this planet and to get along with one another better, and we nudged the yeast to help these enzymes grab the resources they need to get the job done."

That included rat genes that direct the production of dopamine, a key intermediate in noscapine synthesis.

The researchers used CRISPR, a gene-editing tool, to alter inserted genes.

"We're no longer limited to what nature can make," Smolke said. "We're moving to an age where we can borrow nature's medicine-manufacturing processes and, using genetic engineering, build miniature living factories that make what we want."

Smoke co-founded Antheia Inc., a biotechnology company based in Menlo Park, Calif., that has licensed the technology from Stanford and is now working to commercialize noscapine production in yeast.