Stanford team converts lowly yeast to medicine
STANFORD >> For millenniums, humans have harnessed yeast to brew beer. Now, in the latest advance in the fastmoving field of “synthetic biology,” a Stanford team is enlisting the lowly fungus to do so much more.
On Monday, the Stanford scientists announced that they have coaxed genetically altered yeast to create not sugar, as nature intended, but noscapine, a nonnarcotic cough suppressant whose only viable natural source is opium poppies.
Their success brings us one step closer to the day when cells become a faster, safer and better pipeline for applications in medicine and industry.
The field is building on what ancient cultures have always known: Plants such as opium poppies have molecules with many valuable medicinal properties. But these molecules are designed to help plants, not us, so they make only small quantities. And obtaining medicinal compounds from plants is hard, time-consuming and potentially dangerous.
The poppy takes a full year to mature. And while noscapine itself is harmless, the poppies’ illicit poten-
tial requires costly controls and restrictive regulations. Moreover, the plants can be legally grown only in a concentrated geographical area.
“The challenge has been how to access and unlock that potential,” said chemical engineer Christina Smolke, who led the team of scientists.
The team’s solution: Don’t use the whole plant — just its most special genes.
Into a yeast cell, they inserted 25 gene sequences from the poppy, as well as from other bacteria and even rats. This essentially swapped out the yeast cell’s original operating system for a lab-designed one.
The bioengineered yeast can spew out substantial amounts of noscapine in three or four days. Although the drug is not approved in the U.S., the natural version 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. Preliminary studies show it has potential as a cancer drug with less toxicity to healthy cells than currently available chemotherapies.
This strategy is the basis of a molecular assembly line that could be used
to make any natural compound, Smolke said, leading to cheaper, faster, better and more reliable medications. The research is published online in the April 2 Proceedings of the National Academy of Sciences.
“We can build a mechanism that makes molecules more efficiently and faster than nature,” said Smolke, a professor of bioengineering. “Also, we could make molecules that we don’t find in nature, with enhanced value, by modifying them slightly.”
Smolke has created a Menlo Park-based company called Antheia to commercialize the technology. Patents are held by Stanford. Other members of her team included Yanran Li, a former postdoctoral scholar who is now at UC Irvine, and postdoctoral scholar Sijin Li.
Genes are the operating instructions for enzymes, which create proteins that build complex substances. They serve as the instruction manual that is buried inside every organism — its software, in a sense.
Synthetic biology is different from genetic engineering, which simply inserts a whole gene from one organism into another.
“Syn biologists” are engineers who build gene sequences and assemble them, using made-to-order parts from gene foundries, much as industry orders up
cast and machined metal parts. Then they replace the natural genes with a manmade version.
To produce noscapine, Smolke’s team typed out the desired gene sequences on a computer. These gene sequences were custom ordered from a commercial gene synthesis company.
Then Smolke’s team tinkered with the different gene sequences so they’d all get along with each other.
The sequences were stitched into the yeast’s chromosome. This was no small feat: The genes had to be oriented perfectly, and inserted into the correct spot.
It’s challenging to jumpstart life. While almost any scientist can type out gene sequences, order the genes and then assemble them, it’s far tougher to get the genes to collaborate on what you want them to do.
Two years ago, Smolke and her team used a similar but simpler process to make two opioid compounds.
What’s remarkable about Smolke’s work is its success in transferring complex metabolic pathways into microbes, synthetic biologist Jens Nielsen of Chalmers University of Technology in Goteborg, Sweden, told the journal Science in 2015.
“This is a major milestone,” he said.
Biotechnology policy expert Kenneth Oye of the Massachusetts Institute of Technology told Science:
“It shows this field is really moving fast.”
Yeast also is being enlisted to make a lifesaving malaria drug, after bioengineering by Emeryville’s Amyris Biotechnologies. The drug’s ingredient used to be extracted from a shrub that grows wild in various African countries.
A Swiss company makes yeast-made vanillin, the main component of vanilla, and is working on saffron. Other labs are testing the ability of engineered cells to create synthetic fuel and moisturizers for cosmetics.
An international team led by the Institute for Systems Genetics at New York University is dedicated to synthesizing the entire yeast genome. This means replacing each of yeast’s 16 chromosomes with a fabricated sequence of 12.5 million genetic letters.
Someday, yeast could be fully customizable.
“With this technology, you are not limited to reconstruct or copy what nature gives you,” Smolke said. “We take inspiration from nature’s molecules, but improve upon them.
“This technological platform,” she said, “opens up broad sweeps of new and different medicinal compounds.”