Homeless in Arizona

Sadly the opiate drugs,just like marijuana have been demonized by the government to justify it's insane war on drugs.

If people would review the facts they would see that opiate drugs are no where near as dangerous as alcohol, tobacco or meth.

Yes, opiates are addictive just like tobacco. And you can overdose on opiates. But opiates don't cause other health problems like alcohol and tobacco do.

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Home-Brewed Morphine Is Around The Corner

May 19, 2015 6:10 PM ET

Michaeleen Doucleff

Making morphine — or heroin*, for that matter — isn't easy. You have to know a bunch of fancy chemistry to synthesize the drug from scratch. Or you have to get your hands on some opium poppies and extract morphine from the flowers' milky juice.

The latter is tougher than it sounds. Sure, the beautiful flowers grow across millions of acres around the world. But farming and trading poppies are tightly regulated both by laws and by drug kingpins.

In the end, very little morphine makes its way to poor countries. So even patients recovering from major surgery or suffering from deadly cancers often go without pain relief in the developing world.

But what if yeast could brew morphine from sugar? You know, the way yeast ferments grapes and grains into wine and beer? The little critters would eat up sugar and turn it into the drug. A shot of this home brew could be as powerful as a pill or two.

That day is approaching faster than scientists thought.

After seven years of research at four top labs, scientists have figured out all the steps needed to create yeast that brews opiates.

This week bioengineers at the University of California, Berkeley report the last missing link in the chemical pathway to make morphine in yeast.

Now the pieces just need to get connected up and inserted into one yeast strain, says John Dueber, who led the study. "It's not going to be easy to do that," he says. "But if a talented lab focused on the goal, we're looking at about two to three years."

Then "it could be relatively easy to brew morphine," Dueber says.

And then the imagination goes wild: Backyard brewing operations could make kegs of narcotics. DIY morphine kits could ship directly from Mexico. And morphine cocktails could pop up at sketchy tourist destinations around the world.

That's definitely not what Dueber had in mind while working on the genetically modified yeast. Instead, he wanted to make one of the building blocks of morphine (called S-reticuline). This molecule can be transformed into thousands of potential drugs, he and his team write this week in the journal Nature Chemical Biology.

"Because we can reprogram the yeast easily," Dueber says, "we might be able to make better cancer therapies, antibiotics or opiates that aren't so addictive."

But Dueber and his colleagues are concerned about the repercussions of the home-brewing technology. He thinks it's not too early to map out regulations for the narcotic-making microbes.

Several prominent political scientists agree. The designer yeast is likely to be more useful for drug cartels than pharmaceutical companies, Kenneth Oye at the Massachusetts Institute of Technology and his colleague wrote Monday in a commentary for Nature.

Pharmaceutical companies already have a cheap, steady supply of opium from legal poppy farms in India, Turkey and Australia. "That [supply] chain will be hard to disrupt," The New York Times points out. "Thousands of small farmers, their bankers and equipment suppliers depend on the sales, and they have political clout just as American corn farmers do."

But drug cartels have to smuggle poppies out of southeast Asia, Afghanistan and Mexico. And they would probably be happy to cut out this dangerous step and simply brew heroin at production facilities in Europe and North America, Oye and his colleagues note.

And of course, the technology could open the door for small-scale operations that fly under regulators' radar. "In so doing, it could dramatically increase people's access to opiates," Oye and colleagues write.

Such changes could make the U.S.'s current problem with heroin worse. But in developing countries, where analgesics are scarce, small-scale opiate production could be a help.

Right now genetically engineered yeasts make a whole array of useful compounds, from perfume scents and food flavors to malaria drugs and vitamins. Companies can grow, buy and trade the critters as they wish.

Oye and his colleagues want the government to regulate some of these organisms the way they regulate dangerous bioweapons, such as anthrax and smallpox. For instance, allow only certain labs to grow the yeast, make it so the microbes require special food to grow on, and tag the critters with unique DNA so officials can track them.

*Heroin is simply morphine with two extra acetyl groups attached. Making it from morphine requires some acetic acid, or vinegar, and basic synthetic chemistry skills.

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Breaking news and analysis from the world of science policy

Engineered yeast may soon duplicate the biochemical pathways that have long made opium poppies a source of widely used drugs, including heroin.

By Robert F. Service

18 May 2015 11:00 am

The opium poppy may soon meet its match. Researchers in the United States and Canada report today that they are closing in on a long-standing goal of engineering a complex suite of genes into yeast that would allow the microbes to synthesize morphine, codeine, and other medicines that have been harvested from poppies since before written history began. The new work holds out the prospect of being able to cheaply and easily produce widely used medicines with new capabilities and fewer side effects. At the same time, policy specialists worry that the new yeast strains could allow narcotics dealers to convert sugar to morphine or heroin as easily as beer enthusiasts create homebrews today.

“There really is potential for screwing things up,” says Kenneth Oye, a biotech policy expert at the Massachusetts Institute of Technology in Cambridge. “If you get the integrated pathway for one-pot synthesis of glucose to morphine, that’s not controllable if it gets out. You better darn well get on top of it before that happens,” says Oye, who offers several ideas for increasing oversight of the new biotechnology in a commentary released online today in Nature.

Morphine, heroin, and other opiates produced from poppies already wreak plenty of havoc. Some 16 million people worldwide use the drugs illegally. In the United States alone, nearly 14,000 people died from overdoses of heroin and other opiate pain relievers between 2010 and 2012, according to data compiled from 28 states by the U.S. Centers for Disease Control and Prevention. Oye says the concern is that those numbers could skyrocket if dealers and users can brew their own drugs.

Opiates belong to a class of compounds called benzylisoquinoline alkaloids (BIAs), which together with related families of molecules contains some 2500 known compounds. In addition to morphine, these include thebaine, a precursor to the pain relievers oxycodone and hydrocodone, as well as commonly used antispasmodic compounds, antibiotics, and anticancer agents. BIAs are complex, multiringed structures that are difficult and expensive to synthesize in a lab. Medicinal chemists have long sought an easier and cheaper route to making these compounds, in hopes that they might find new medicines. Health professionals have also sought versions that pose fewer side effects, such as risks of suppressed breathing and addiction that come with morphine. But so far engineering opium poppies to produce new compounds has proven difficult.

“Plants have slow growth cycles, so it’s hard to fully explore all the possible chemicals that can be made from the BIA pathway,” says William DeLoache, a Ph.D. bioengineering student at the University of California, Berkeley, and lead author of the new work on engineering yeast. “Moving the BIA pathway to microbes dramatically reduces the cost of drug discovery. We can manipulate and tune the DNA of the yeast and quickly test the results.” A long path

Efforts to insert the BIA pathway into yeast have been under way for the better part of a decade. But it’s a major challenge, says Vincent Martin, a microbiologist at Concordia University in Montreal, Canada, whose lab has been working on the project since 2009. Engineering yeast to produce morphine, Martin notes, requires adding genes to produce enzymes that carry out a chain of 15 separate chemical transformations. By contrast, one of synthetic biology’s greatest successes to date—the synthesis of the antimalarial drug artemisinin—required giving yeast the genes to carry out just five chemical steps.

In reengineering yeast to make BIAs, researchers typically divide the project up into two parts. In the first part, researchers splice in genes for enzymes that convert the amino acid tyrosine into an intermediate compound called S-reticuline; this step creates a key branching point that can lead to the synthesis of many different BIA compounds. One trail leads to morphine and codeine, while others lead to antibiotics and anticancer compounds. To create morphine, S-reticuline is first converted to a very closely related compound called R-reticuline, which is then transformed into thebaine and ultimately to morphine.

Last year, researchers led by Christina Smolke, a synthetic biologist at Stanford University in Palo Alto, California, reported that they had given yeast the enzymes needed to carry out the thebaine to morphine steps at the end of the second part of the pathway. And last month, Martin and colleagues reported in PLOS ONE that they had engineered yeast to complete all of the second-half steps moving from R-reticuline to morphine.

Meanwhile, the first part of the pathway has been harder to pull off in yeast. Going from glucose to tyrosine is easy: Yeast do that naturally. In 2011, researchers in Japan reported that they got the complete first half of the pathway to work in Escherichia coli bacteria, transforming tyrosine to S-reticuline. But to date that set of steps hasn’t worked well in yeast. The biggest roadblock has been the first step: converting tyrosine into a compound called L-Dopa. When the gene that directs that step is engineered into yeast, the bacterial enzyme works poorly at best, says Pamela Peralta-Yahya, a synthetic biologist at the Georgia Institute of Technology in Atlanta.

But John Dueber, a bioengineer at Berkeley; DeLoache; and their colleagues caught a break when they were working on a separate project to see whether L-Dopa was present in certain cells. The found that an enzyme, called DOPA dioxygenase, converted L-Dopa into a yellowish pigment. They quickly realized that they could use this enzyme as a color sensor to detect whether any other enzyme was able to convert tyrosine to L-Dopa.

William DeLoache at UC Berkeley

An enzyme engineered into yeast allows researchers to see which microbes are making L-Dopa (yellow), a key step in the pathway to making opiates.

Next, they teamed up with Martin and his Concordia colleagues. The group tested an enzyme from sugar beets called a tyrosine hydroxylase. That beet enzyme was able to convert tyrosine to L-Dopa in yeast, in the process turning the petri dish yellow (see image, above), the team reports today in Nature Chemical Biology. They were able to increase the L-Dopa output by nearly threefold by randomly mutating versions of the enzyme and using their biosensor to track those that worked the best.

“It’s very nice work,” Smolke says. For now, she adds, the bacteria still produce higher yields of L-Dopa than the yeast. “But it sets the stage for being able to integrate these pathways in one organism,” Smolke says.

For now, the only missing step is being able to convert S-reticuline into R-reticuline, which links the first and second halves of the full pathway. But apparently that’s close at hand as well. Researchers at the University of Calgary have posted an abstract of a Ph.D. dissertation online that says they’ve identified a plant enzyme that carries out this S to R conversion, though the work has yet to be published. Once it is, researchers will be able to insert the gene in yeast, completing the full glucose to morphine pathway. “I think it’s doable within 2 to 3 years,” Dueber says. “This area is moving much faster than we thought.” Social and legal concerns

Given this speed, about a year ago Dueber and Martin reached out to Oye, asking if he would be willing to explore ideas for how the scientific community can prevent engineered yeast from exacerbating the illegal drug trade. In their Nature commentary, Oye and colleagues make several recommendations. First, they suggest that companies that now synthesize and distribute long stretches of DNA should consider carefully reviewing requests for the genes that code for key drugmaking components, and block suspicious requests. Such companies already undertake a similar process for gene sequences involved in microbes that could be used as bioweapons, and voluntarily report requests for such genes to law enforcement agencies.

Other possible measures would be to require researchers to engineer morphine producing yeast strains so that they also produce toxins unwanted by homebrewers, or inserting genetic watermarks into the strains to make them easier to track in the event that the strains fall into the hands of outsiders.

Although such measures may help deter criminals, any watermarking or toxinmaking genes could also be removed by a trained and skilled microbiologist, Martin notes. One other option for slowing the spread of the technology would be to request that journals not provide the full genetic details of any organisms that can complete the full transformation. (Dueber and Martin say they haven’t yet received any request to omit data.)

In the end, a new technology for producing morphine could have a profound impact on law enforcement agencies. But for now, agencies such as the FBI “aren’t recommending any specific regulatory measures,” says Edward You, a supervisory special agent for the FBI’s Weapons of Mass Destruction Directorate’s Biological Countermeasures Unit in Washington, D.C. But he says the FBI is already part of an interagency working group, which includes representatives from the National Institutes of Health and other research funding organizations, that is considering ways to keep modified yeast strands out of the hands of illicit drugmakers. And ongoing engagement with scientists and policy analysts “will definitely facilitate those discussions,” You says. “There is a window of opportunity here to negotiate the security issues.” Regulatory backlash?

Still, some researchers are concerned that hype over fears of homebrewed heroin could cause a harmful regulatory backlash. “I do believe that a thoughtful discussion of risks, opportunities, and regulatory needs is important with this technology,” Smolke says. However, she says she believes Oye’s commentary, for one, was “inflammatory.” The new technology could, in the long run, bring improvements over the existing poppy-driven drug trade and all the social ills that it brings, she and others note. Lab-derived drugs, for example, could be easier to nations to regulate, and reduce the environmental damage, social unrest, and violence associated with plant-derived drugs.

Smolke also emphasizes that researchers remain a considerable distance from putting together the full chain of chemical transformations needed for yeast to make morphine. And if and when that occurs, the organisms will still make only vanishingly small amounts of the drug. “In fact, it is more likely that a person could more easily access morphine by dumping a bunch of poppy seeds in their homebrew (or tea),” she says.

The question is, how long will this remain the case?

Posted in Biology, Chemistry, Health, Policy, Technology

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May 18, 2015

Home-Brewed Heroin

By Nicola Twilley

For as long as humans have been farmers, we have been drinkers. 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. 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, 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.

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 cook up 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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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.

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.