A Way to Brew Morphine Raises Concerns Over Regulation

By DONALD G. McNEIL Jr.MAY 18, 2015

All over the world, the heavy heads of opium poppies are nodding gracefully in the wind — long stalks dressed in orange or white petals topped by a fright wig of stamens. They fill millions of acres in Afghanistan, Myanmar, Laos and elsewhere. Their payload — the milky opium juice carefully scraped off the seed pods — yields morphine, an excellent painkiller easily refined into heroin.

But very soon, perhaps within a year, the poppy will no longer be the only way to produce heroin’s raw ingredient. It will be possible for drug companies, or drug traffickers, to brew it in yeast genetically modified to turn sugar into morphine.

Almost all the essential steps had been worked out in the last seven years; a final missing one was published Monday in the journal Nature Chemical Biology.

“All the elements are in place, but the whole pathway needs to be integrated before a one-pot glucose-to-morphine stream is ready to roll,” said Kenneth A. Oye, a professor of engineering and political science at M.I.T.

Yeast cells on this Petri dish are producing the pigment betaxanthin, which researchers used to identify key enzymes in the production of benzylisoquinoline alkaloids, the metabolites in the poppy plant that could lead to morphine, antibiotics and other pharmaceutical agents. Credit William DeLoache/UC Berkeley

This rapid progress in synthetic biology has set off a debate about how — and whether — to regulate it. Dr. Oye and other experts said this week in a commentary in the journal Nature that drug-regulatory authorities were ill prepared to control a process that would benefit the heroin trade much more than the prescription painkiller industry. The world should take steps to head that off, they argue, by locking up the bioengineered yeast strains and restricting access to the DNA that would let drug cartels reproduce them.

Other biotech experts counter that raising the specter of fermenting heroin like beer, jokingly known among insiders as “Brewing Bad,” is alarmist and that Dr. Oye’s proposed solutions are overkill. Although making small amounts of morphine will soon be feasible, they say, the yeasts are so fragile and the fermentation process so delicate that it is not close to producing salable quantities of heroin. Restricting DNA stifles all research, they argue, and is destined to fail just as restrictions on precursor chemicals have failed to curb America’s crystal meth epidemic.

A spokesman for the Drug Enforcement Administration said his agency “does not perceive an imminent threat” because no modified yeast strain is commonly available yet. If that happens, he said, D.E.A. laboratories would be able to identify heroin made from it.

An F.B.I. agent who has been following the yeast strains since 2009 said he was glad that the debate was beginning before the technology was ready and before lawmakers moved to restrict it.

“We’ve learned that the top-down approach doesn’t work,” said Supervisory Special Agent Edward You, who said he coined the “Brewing Bad” term and had held workshops for biotech students and companies. “We want the people in the field to be the sentinels, to recognize when someone is trying to abuse or exploit their work and call the F.B.I.”

No scientific team has yet admitted having one strain capable of the entire sugar-to-morphine pathway, but several are trying, and the Stanford lab of Christina D. Smolke is a leader. She said she expected one to be published by next year.

No one in the field thought there should be no regulation, she said, but suggestions that home brewers would soon make heroin were “inflammatory” because fermenting manipulated yeasts “is a really special skill.” Implications of research like hers should be calmly discussed by experts, she said, and Dr. Oye’s commentary “was getting people to react in a very freaked-out way.”

Robert H. Carlson, the author of “Biology Is Technology,” said restrictions were doomed to fail just as Prohibition failed to stop the home brewing of alcohol.

“DNA synthesis is already a democratic, low-cost technology,” he said. “If you restrict access, you create a black market.”

What is considered one of the last important missing steps, a way to efficiently grow a morphine precursor, (S)-reticuline, in brewer’s yeast, Saccharomyces cerevisiae, was published in Nature Chemical Biology on Monday by scientists from the University of California, Berkeley, and Canada’s Concordia University.

Photo

Kenneth A. Oye, a professor of engineering and political science at the Massachusetts Institute of Technology, said that drug-regulatory authorities are ill-prepared to control a process that can create heroin’s raw ingredient. Credit Stuart Darsch

The leader of the Berkeley team, John E. Dueber, said it was not trying to make morphine but 2,500 other alkaloids for which reticuline is a precursor, some of which might become antibiotics or cancer drugs.

Nonetheless, he said, since he realized his research has implications for the making of morphine, he sent his draft paper to Dr. Oye, suggesting the debate become more public.

One crucial question is whether the technology is of more use to the pharmaceutical industry or drug cartels. Dr. Oye argues it is the latter.

Companies are always seeking painkillers that create less addictive euphorias or do not paralyze breathing muscles, and having a predictable process they could tweak would be useful, but they already have a cheap, steady supply of opium from India, Turkey and Australia, where poppies are grown legally by licensed farmers.

That chain will be hard to disrupt. Since the 1960s, when it was created to convince Turkey to crack down on heroin, the International Narcotics Control Board has set quotas. Thousands of small farmers, their bankers and equipment suppliers depend on the sales, and they have local political clout just as American corn farmers do.

Also, pharmaceutical companies can already synthesize opiates in their labs. Fentanyl, a painkiller 100 times as powerful as morphine, is synthetic, as is loperamide (Imodium), an antidiarrheal opiate.

Heroin sellers, by contrast, must smuggle raw materials out of lawless Afghanistan, Laos, Myanmar and Mexico. Their supply lines are disrupted when any local power — from the Taliban to the United States Army — cracks down. Brewing near their customers would save them many costs: farmers, guards, guns, planes, bribes and so on.

One frightening prospect Dr. Oye raised was how viciously drug cartels might react if Americans with bioengineering know-how started competing with them. Gunmen from Mexican drug gangs have taken control of many secret marijuana fields in American forests.

His commentary suggested several possible steps to prevent misuse of the technology. The yeasts could be locked in secure laboratories, worked on by screened employees. Sharing them with other scientists without government permission could be outlawed.

Their DNA could be put on a watch list, as sequences for anthrax and smallpox are, so any attempt to buy them from DNA supply houses would raise flags. Chemically silent DNA “watermarks” could be inserted so stolen yeasts could be traced. Or the strains could be made “wimpier and harder to grow,” Dr. Oye said, perhaps by making them require nutrients that were kept secret.

Agent You said he did not want to comment on Dr. Oye’s suggestions, but was glad a threat had been identified by scientists before it was a reality, adding, “If this occurred across the board, it would make the F.B.I.’s life a heck of a lot easier.”

A version of this article appears in print on May 19, 2015, on page D1 of the New York edition with the headline: Makings of a New Heroin. Order Reprints| Today’s Paper|Subscribe

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