Thursday, May 21, 2015

Poppy yields not only a powerful narcotic, but a door to medicinal leap forward

The painkiller itself, which poppy plants already supply cheaply and with great virtuosity, isn't always the prize; one of its precursors, an alkaloid called (S)-reticuline, can produce about twenty-five hundred other compounds, some of which are thought to have anticancer, antispasmodic, or antibiotic effects.

Humans have been farmers for thousands of years, and as a result we have been drinkers of alcohol, the product of yeast and sugar fermentation.
Wild yeast was the first microorganism that we domesticated, more than ten millennia ago.
But archaeologists believe that we have been harvesting the gum of opium poppies for even longer.
Across a broad swath of the Middle East and Asia, our ancestors tapped, dried, boiled, and consumed the poppy pod’s sticky secretions.
Dale Dutcher's photo.The flower provided one of the first medicinal substances known to humanity, as well as a potent high.
But not even the Romantic poets, ensconced in their stately pleasure-domes and out of their minds on "smack" heroin, could have imagined what a paper published today in the journal Nature Chemical Biology describes: turning yeast, a simple fungus, into a narcotics lab to rival the poppy.
Genetically modified yeast can synthesise morphine and semisynthetic opioid pharmaceuticals, researchers in the US have shown today.
This could obviate the need to grow opium poppies, reducing security concerns and the resulting regulatory hurdles, as well as the costs of chemically synthesising some of the synthetic opioids.
To produce opiates, the poppy relies on a complicated fifteen-step metabolic pathway that first evolved in the plant’s wild ancestors and has been refined over centuries by drug-hungry gardeners.
For a decade, laboratories around the world have been adapting poppy DNA for use in yeast, designing their own strains of the fungus with the ability to turn sugar, its preferred food, into the chemical precursors to morphine.
(The painkiller itself, which poppy plants already supply cheaply and with great virtuosity, isn't always the prize; one of its precursors, an alkaloid called (S)-reticuline, can produce about twenty-five hundred other compounds, some of which are thought to have anticancer, antispasmodic, or antibiotic effects.)
Last summer, the Stanford University scientist Christina Smolke caused a stir by announcing that she and her colleagues had created an engineered yeast that could perform the final few steps in the long process of making morphine.
Today’s paper, a collaboration between two labs—one at Concordia University, in Quebec, led by Vincent Martin, and the other at the University of California, Berkeley, led by John Dueber—fills in some earlier steps.
For the first time, a single yeast cell can be used to cook up bespoke morphine from scratch.
Despite the seeming complexity of the task, the science moved quickly—“much more quickly than our average paper,” Dueber said.
What he had imagined would take several years took a matter of weeks, and with that speed came a growing sense of alarm.
“We were like, ‘Oh wow, this is really happening,’ ” he said.
“And I don’t think people are ready for it yet.” In the United States, the Drug Enforcement Administration monitors the movement of controlled substances in and out of labs, but no provision exists for the organisms that are capable of making those substances.
Meanwhile, the federal government’s policy around what is called dual-use research of concern—scientific advances that could be exploited for ill—applies only to viruses and other pathogens.
Already aware of this regulatory vacuum, and of the possibility that their work could be misused, both Dueber and Martin sought outside consultation, Dueber from Kenneth Oye, the director of M.I.T.’s Program on Emerging Technologies, and Martin from the bioethicist Tania Bubela.
As the scientists prepared their paper for print, Oye, Bubela, and one of Oye’s colleagues, the political scientist Chappell Lawson, wrote one of their own, to be published at the same time.
In their comment, which appears today in the journal Nature, Oye, Bubela, and Lawson point out that the risk of yeast-based morphine is not that it will destroy the legal opium-poppy industry, which is overseen by the International Narcotics Control Board, but that it could put illicit opiate production into the hands of many more people, at a much smaller scale.
Whereas you have to be an Afghan warlord to grow fields of opium poppies and an organic chemist to refine their sap, with a designer yeast strain in hand, Dueber said, “you just have to be able to brew beer to synthesize morphine.”
Bubela speculates that mom-and-pop morphine shops could undercut the Mexican drug cartels that currently dominate the wholesale illegal heroin market.
(Heroin is synthesized from morphine, though it is usually several times more potent.)
“It’s possible the cartels might be more upset about this new technology than law enforcement,” Oye, an economist by training, told me, only half joking.
But he and Bubela agree that such increased access would inevitably result in a greater number of addicts.
For that reason, their paper contains a strong call for regulation, including increased lab security and new legislation that targets drug-secreting organisms.
They also recommend that their colleagues in the lab engineer wimpier strains of yeast, or ones with unusual nutritional needs that make them harder to raise at home.
Oye and Dueber, both cognizant of the fine line between voicing concern and crying wolf, are at pains to point out that at least two years’ worth of hard science lies between the aspiring drug lord and his closet bioreactor.
(Dueber also noted that, without the accompanying commentary, a paper titled “(S)-Reticuline Production in Yeast from Glucose” would have been unlikely to create much of a buzz.)
Neither man believes, however, that the Nature commentary’s recommendations will be enacted in full, or even that they are enough to prevent someone misusing the technology.
“Eventually, this will happen,” Duebner said. “I just think we want to be prepared for that eventuality.”
The value that this strain of yeast offers as a platform for drug discovery is worth the risk, he argues—as long as scientists are smart about it.
Last November, at the iGEM Giant Jamboree, an annual competition in genetic engineering, Edward You, an agent with the F.B.I.’s Biological Countermeasures Unit, used a scenario involving morphine-producing yeast—he called it “baking bad”—to argue that the field of biology must make an attitude shift, from “Do no harm” to “Not on my watch.”
At the time, You’s story line was speculative; seven months later, it isn’t.
“The technology is moving pretty freaking quickly,” Oye told me.
“You end up pulling your hair out, frankly.” The F.B.I. agent agreed. “I don't think we can keep up, which is why scientists have to be empowered to regulate themselves,” he said.
With advances in our ability to redesign living organisms occurring at a pace that leaves policymakers trailing far behind, it seems that the best we can hope for is a head start on our future anxieties.
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