Scientists Bioengineer Medicine Using Yeast

Monday, April 2, 2018

Scientists Bioengineer Medicine Using Yeast

Bioengineers have used CRISPR, the gene-editing tool, to make noscapine, a cough suppressant, and potential cancer drug, that occurs naturally in opium poppies, in brewer's yeast.

In a landmark study in the field of synthetic biology, Stanford University bioengineers have figured out a way to make noscapine, a non-narcotic cough suppressant that occurs naturally in opium poppies, in brewer's yeast.

"We're no longer limited to what nature can make," claims Christina Smolke, PhD, professor of bioengineering at Stanford University. "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."

"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."

"This is a technology that's going to change the way we manufacture essential medicines," said Smolke.

In research published in the journal Nature, they team inserted 25 foreign genes into the one-celled fungus to turn it into an efficient factory for producing noscapine. Many of the inserted genes came from the poppy, but several came from other plants and even from rats.

All the genes were recipes for enzymes, working together, that could build complex substances from simple starting materials.

The researchers also modified some of the plant, rat and yeast genes, as well as the medium in which the yeast proliferates, to help everything work better together. The result was a tremendous 18,000-fold improvement in noscapine output, compared with what could be obtained by just inserting the plant and rat genes into yeast.

Noscapine has been widely used since the 1960s as a cough medicine throughout Asia, Europe and South America, as well as in Canada, Australia and South Africa. Preclinical trials also indicate potential for noscapine as a cancer drug with less toxicity to healthy cells than currently available chemotherapies.

So far,  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. Also, 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.

"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.

"Our work also enables the supply of many pathway intermediates and derivatives for structural confirmation and further investigation," state the study authors.

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.

SOURCE  Stanford Medicne

By  33rd Square