But the only viable source of noscapine is opium poppies. Many tons of noscapine are extracted annually from the plant, which takes a full year to mature. While noscapine itself is harmless, the poppies’ illicit potential requires costly controls and restrictive regulations. The plants can be legally grown only in a concentrated geographical area. Half of all poppies produced for noscapine are in Australia, and the rest are mostly in India, France, Turkey and Hungary, making global noscapine output subject to local environmental events and to varying soil and nutrient conditions. In addition, naturally occurring noscapine must be thoroughly separated from numerous molecular companions, narcotic and otherwise, that don’t occur in yeast.

The yeast Smolke’s group bioengineered can spew out substantial amounts of noscapine in three or four days. The investigators achieved this result by stitching three separate sections of the noscapine biosynthesis pathway into a single yeast strain.

Initially, noscapine output was meager, Smolke said. “Traditionally, we’ve gotten our medicines from the natural world, mainly from plants. 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,” she said. “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.”

Every enzyme catalyzes its own limited set of chemical reactions. So, the synthesis of complex chemicals requires a whole assembly line of different enzymes working in concert with one another, ideally with each enzyme in the production chain generating just enough of its given intermediate product to keep the next one busy. As with a factory conveyor belt, too little activity, or too much, at any point can jam up the line. Enzymes need energy supplies, too, and some of them require the assistance of additional molecules that may abound in the organism they come from, but not necessarily in a yeast cell.

Soldiers on Mars

“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 entailed, among other things, splicing in rat genes that direct the production of dopamine, a key intermediate in noscapine synthesis. Dopamine’s production in plants is poorly understood, but because of dopamine’s importance as a crucial chemical in the animal nervous system, the enzymes responsible for its production in mammals have been studied intensively.

This is a technology that’s going to change the way we manufacture essential medicines.

The scientists used CRISPR, a gene-editing tool, to alter inserted genes so that the enzymes for which they coded would work most efficiently amid the exotic acidity, osmotic character and chemical composition of their new home. They also souped up the yeast’s production of a chemical whose levels would have otherwise been too low to sustain robust noscapine production.

“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.”

Stanford’s Office of Technology Licensing holds pending patents on intellectual property associated with the findings in this study.

Other Stanford study co-authors are former graduate student Aaron Cravens, PhD, and former postdoctoral scholars Kate Thodey, PhD, and Isis Trenchard, PhD, now both at Antheia.

The study was funded by the National Institutes of Health (grant AT007886) and Novartis Institutes for Biomedical Research.

Antheia Inc., a biotechnology company based in Menlo Park, California, that Smolke co-founded in 2015, has licensed the technology from Stanford and is now working to commercialize noscapine production in yeast. Smolke is Antheia’s chief executive officer.

Smolke is an investigator at the Chan-Zuckerberg Biohub and a member of Stanford Bio-X and of the Stanford Neurosciences Institute. She also is a faculty fellow at Stanford ChEM-H.

Stanford’s Department of Bioengineering, which is jointly managed by Stanford’s School of Medicine and School of Engineering, also supported the work.