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Scientists engineer yeast to turn sugar into hydrocodone

Stanford team members, from the left are: postdoctoral researcher Isis Trenchard, associate professor of bioengineering Christina Smolke, chemistry graduate student Stephanie Galanie and research associate Kate Thodey. (Rod Searcey)
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Over the past several months, scientists from around the world have published bits and pieces of a fascinating feat: In an effort to create pain medication components like hydrocodone -- the main ingredient in the pain killer Vicodin -- without the help of poppies, scientists have engineered simple baker's yeast to synthesize these medicinal compounds from sugar. One by one, labs figured out how to get the yeast to turn A into B, and B into C, Y into Z, and so on and so forth.

Now, for the first time, researchers at Stanford University have done it from start to finish. In a paper published Thursday in Science, they report the successful synthesis of hydrocodone from sugar, thanks to genetically engineered yeast.

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"There's certainly been a lot of activity in the field recently," senior study author Christina Smolke, an associate professor of bioengineering at Stanford, told The Post. Smolke has been working on this process for a decade -- since she started her lab at Stanford -- and remembers a time when most thought that replacing farmed poppies with a lab-grown drug source would be impossible.

Now the field is full of contenders, but Smolke's lab has the distinction of crossing the finish line first. Their engineered yeast can produce hydrocodone in just three to five days.

"We essentially put DNA into the yeast cells that give it the instructions to build a chemical assembly line process that ends with the medicines we want," Smolke said. After reading the "instructions" in its DNA, the cell will produce protein molecules that can take sugar from the environment, break it down, and rebuild it into the drugs -- in the same general way that yeast usually breaks sugar down and turns it into alcohol.

"This represents an elegant confirmation that it is feasible to engineer a pathway for production of morphinans such as thebaine into yeast," Ian Graham of the University of York, who published an unrelated study that identified the gene used by poppies to create precursors to pain medication, told The Post.

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But the marathon isn't really over. Smolke's yeast — which contains 23 engineered genes from plants, bacteria and rats — is capable of making a direct conversion from sugar to hydrocodone, as well as from sugar to thebaine, a precursor of opioid compounds that would essentially take the place of poppies in the production of pain medication, but would still requite refinement. But it doesn't make much of it.

For now, you'd need 4,400 gallons of the bioengineered yeast to get a single dose of pain medication.

"It's definitely the case that no one could take these strains now and use them for commercial production, or abuse them for nefarious purposes," Smolke said. "You could get more of these compounds from eating a poppy seed bagel. You really could."

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But as Smolke and her colleagues -- and the many other labs tackling the process — work on making the conversion more efficient, the process could make pain medications more readily available in parts of the world where poppies aren't reliable. The World Health Organization estimates that 5.5 billion people have little or no access to pain medications.

Some have expressed concern that this engineering could lead to "home-brewed heroin," where addicts and dealers could make illegal opioids the same way DIYers currently brew their own beer. For now, Smolke says, this isn't possible. Her team actually conducted a second study, which is available online, where they showed that typical home-brew conditions couldn't successfully produce opioids.

"It is of course important to be aware of the potential for abuse of this technology and to put safeguards in place that prevent abuse," Graham said. "The demonstration that the engineered strain does not produce thebaine under home brew conditions is reassuring, but cannot be relied on in itself to safeguard against abuse."

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And things will obviously get more complicated as the yeast strain is made to be more efficient and less fussy. Smolke and her colleagues hope that as the technology progresses, they and other researchers can be part of the policy-making process to help keep it in good hands -- but given that heroin abuse is on the rise in the United States, the eventual abuse of the technology seems almost inevitable.

But in addition to making pain medication more accessible to those who do need it, the yeast could one day make addiction less of a problem.

"In our view, the major benefit from this family of research projects will be in production of redesigned opiates that are safer and less addictive than current products," Kenneth Oye, an MIT professor who holds a point position in political science and engineering systems, told The Post.

Oye penned a Nature op-ed on the subject of regulating these yeast strains back in May. He's still concerned about the possible missuses of this feat of bioengineering, but he has no trouble seeing the benefits. Pharmaceutical companies are always looking to make opioid medications that are less dangerous and addictive, he said, and yeasts are easier to modify to suit our wishes.

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Smolke agrees, and creating novel opiates is one of her lab's next big targets.

"When poppies make morphine, we're kind of stuck with what the poppy makes," Smolke said. "It hasn't evolved to make ideal medicines for humans. It's evolved to do what's best for the poppy."

Using yeast, she said, they can make compounds tailored to humans -- not flowers.

"And there's no reason to think this should stop with pain medication," Smolke said. In fact, a simpler strain of bioengineered yeast is already used to produce the anti-malarial drug artemisinin, which is traditionally made from a plant as well. Now around one third of the world's supply of the drug is created using the yeast assembly line.

To make artemisinin, you only need to engineer six new genes into baker's yeast. Smolke's strain features 23 alterations.

That jump in complexity gives a tantalizing taste of just how much is possible with the simple yeast, and there's no telling what medications might one day benefit from some similarly finagled fungus.

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