Researchers engineer brewer’s yeast to produce a complex drug that’s in short supply

The Future Summer 2018

Christina Smolke, PhD, says it took a lot of finesse to successfully engineer yeast so it can pump out sizable amounts of a cough suppressant that is found naturally in opium poppies and has potential anti-cancer properties.

“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,’” said Smolke, professor of bioengineering at Stanford. “Good luck with that.”

But, through ingenuity and new technology, researchers in Smolke’s lab figured out how to get cells of brewer’s yeast to make the complex compound, called noscapine.

Though noscapine is normally extracted from opium poppies, it is non-narcotic. Its medicinal value for suppressing coughs was discovered in 1930, and since the 1960s it has been used for that purpose around the world, including in much of Asia, Europe and South America.

More recently, the drug has been studied in mice for potential as a cancer drug — scientists believe it is less toxic to healthy cells than current chemotherapy treatments.

Tons of noscapine are extracted annually from opium poppies that are mostly grown in Australia, but also in India, France, Turkey and Hungary.

The cost is high and supply can be inconsistent, a result of strict opium crop regulations, a slow growing period — it takes a year for plants to mature — and the crop’s vulnerability to such environmental conditions as pests, bad weather and varying nutritional characteristics of the soil where it’s grown.

Bioengineered yeast from Smolke’s group, however, can inexpensively manufacture large amounts of noscapine in three or four days. Researchers succeeded by inserting 25 foreign genes — many from poppies, but several from other plants and rats — into a single strain of brewer’s yeast. All of those genes were recipes for enzymes — protein machines that, working together, can build complex substances from simple starting materials.

Using CRISPR, a gene-editing tool, the researchers altered some of the plant, rat and yeast genes, and the medium in which the yeast multiplies, to help everything work better together.

In other words, Smolke said, “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.”

The result was an 18,000-fold improvement in noscapine output when compared with what could be obtained by just inserting the plant and rat genes into yeast. “This is a technology that’s going to change the way we manufacture essential medicines,” Smolke said.

An additional hundredfold improvement will be necessary for commercial viability, but much of that can be achieved by substituting large-scale bioreactors for simple laboratory flasks, she said.

“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.”

A paper describing the research was published online April 2 in the Proceedings of the National Academy of Sciences. Smolke is the senior author. Stanford’s Office of Technology Licensing holds pending patents on intellectual property associated with the findings in the study.

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Bruce Goldman

Bruce Goldman is a science writer in the Office of Communications. Email him at goldmanb@stanford.edu.

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