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Scientists Concerned, as Researchers Get Closer to Engineering Yeast for Morphine

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5/5,
  1. Beenthere2Hippie
    poppy.gif 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 home brews 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 hydrocondone, 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. yeast.gif 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 deoxygenase, 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.

    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 already is 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 home brewed 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 home brew (or tea),” she says.

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

    Original Source

    Written by: Robert F. Service, May 18, 2016, Science Magazine

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  1. Healer
    Re: Home-Brew Heroin Is Coming And May Democratize Drug Markets

    I'm sure a lot of people would still make large batches of opium/morphine with this home brew method and redistribute on the black market. This knowledge isn't going to be wide spread by the regular heroin user. I can easily see drug dealers learning this method and selling to their current clients. A lot of people will probably not bother to do this on their own even if they find out about it. This just seems like something that will end up pumping more drugs into the market. You cant expect every drug user to stumble upon these methods.

    So if I understand this correctly anybody can pickup this yeast to make their desired drug? If I can read about how they did this than I would understand a bit better. What would be stopping the DEA from stopping suppliers from selling this stuff?
  2. 5-HT2A
    Home-Brew Heroin Is Coming And May Democratize Drug Markets

    [IMGR="WHITE"]https://drugs-forum.com/forum/attachment.php?attachmentid=44309&stc=1&d=1432679990[/IMGR]When it comes to producing drugs like heroin and cocaine, science is on the verge of a revolutionary breakthrough that could disrupt traditional drug markets by making it possible for anyone to produce their own. Researchers working with genetically engineered yeasts are rapidly advancing toward the point where all it would take is some humble fungi and a home-brewing kit.

    Professor John Dueber at the University of California at Berkeley leads a team of researchers who have created a yeast that produces S-reticuline, the main precursor of some 2,500 molecules, including opium. Their results were just published in the journal Nature Chemical Biology.

    Other groups of researchers have been working on the beginning, middle, and end stages of the process needed to make opiates from S-reticuline. In theory, combining the research efforts could create an opiate-producing yeast tomorrow; in practice, it's likely to take a while longer.

    Still, progress is accelerating.

    "The field is moving much faster than we had previous realized," Dueber told The New Scientist, adding that he now thought a morphine-making yeast was now only two or three years away.

    Once high-yield morphine-producing yeasts are developed, anyone who got ahold of them could use them to make morphine at with their own home-brewing kit, Dueber said. And it wouldn't take much—perhaps a few milliliters—to get you high.

    "It's probably as simple as that," he said. "The beer would have morphine in it."

    Other researchers are doing similar work with tropane alkaloids, a family of compounds that includes cocaine. Because researchers still don't fully understand certain steps the coca plant takes to make the alkaloids, cocaine-making yeasts are further away, but there is no reason that a coke-yeast can't be produced once the mechanism is understood.

    "Indeed, someone could potentially produce cocaine in yeast," conceded biochemist Peter Facchini of the University of Calgary in Canada.

    The implications for drug markets and drug prohibition are enormous. If home-brewed drugs became widespread, suppressing them would become an even more futile task than it already is. Similarly, the availability of cheap, home-produced drugs would undercut traditional drug producers and traffickers, removing or reducing a primary source of funding for guerrillas, terrorists, and other non-state actors dependent on drug crops to finance their wars and revolutions.

    "It would be as disruptive to drug enforcement policy as it would be to crime syndicates," said Tania Bubela, a public health researcher at the University of Alberta in Edmonton, Canada. "It may force the US to rethink its war on drugs."

    "If I were a member of a criminal syndicate, I would not like this very much," said Kenneth Oye, a political scientist at the Massachusetts Institute of Technology.

    In Dueber's words, the availability of biosynthetic drug-producing yeasts would "democratize" drug production. Individuals or small groups could make them locally, without the chemical expertise needed, for example, to make methamphetamine.

    Yeast-based drug makers also would have a much easier time coming up with ingredients. Unlike the tightly controlled precursor chemicals used in traditional drug-manufacturing processes, the only ingredient needed for the yeasts is sugar.

    by Phillip Smith

    May 25, 2015

    Source:
    http://www.alternet.org/drugs/home-brew-heroin-coming
  3. CaptainTripps
    Once it is proven that this can be done, it will be done. The amount of money involved in this is staggering. But organized criminal organizations, some of which are even backed by governments have the kind of money necessary. It is one thing to invest in the possibility of creating an easy way to produce opiates, but it is quite another to invest in finding the way to do something you know has been done. It is like anything else, once the science is developed, the technology will follow. But that probably wont even be necessary, the theft of intellectual property is very common place these days. Who needs a team of scientists when all you need is a good hacker? Or how about a "leaker" someone on the inside who decides to either sell or give this information away? I could easily see someone who might give this technology to the world on the premise that homemade opiates could end the terrorism that the heroin market supports. Or even as a way to help end the war on drugs.

    The thing to remember is that it may be very difficult to produce the yeast to begin with, but replicating it should not be difficult. As I see it the war on drugs in the western world is going to come down to this. There will be two categories of drugs, those easy to produce and those difficult to produce. Those that are easy to produce will be legalized in some form or another, those that are difficult to produce (or difficult to transport from producing countries to consuming countries) will remain illegal.

    The drug warriors are going to have to pick their battles as the public is tired of pissing money down a rat hole. It is becoming clear that some drugs just cant be stopped and this war is not worth fighting on an indefinite basis with little or no chance of success.
  4. lkt004
    You could engineer it to require very specific growth requirements that would deter the average home microbiologist but it's not hard to figure out growth requirements. And unless you have bioreactors in the tens of thousands of liters you wouldn't bother, it's not as simple as "plate out the yeast, drink the morphine".

    And it would take several lifetimes of home microbiologists/chemists to pull this off, there would be hundreds working on this project using the most sophisticated equipment available.
  5. Rob Cypher
    you need genetically altered yeast; surely that is not something that the average "shake and bake" meth chef could pull off, either in creating or possessing. Sounds like you would still need access to a proper lab, like you do for LSD.
  6. Beenthere2Hippie
    I, too, am interested in what someone with a good working knowledge of chemistry thinks the likelihood of such a thing actually happening. I've asked a friend/member with a strong knowledge of chemistry his opinion but haven't heard back yet. It is quite a numbing thought.
  7. assassoid
    Re: Home-Brewed Heroin? Scientists Create Yeast that can Make Sugar into Opiates

    Wow. They can take all the measures imaginable to protect science as this from "falling into the wrong hands" but it will happen.. eventually . I know nothing of phytochemistry , but I wonder if independent chemists can figure this out so it can be public domain eventually ?
  8. hookedonhelping
    Home-Brewed Heroin? Scientists Create Yeast that can Make Sugar into Opiates

    [IMGR="white"]https://drugs-forum.com/forum/attachment.php?attachmentid=44227&stc=1&d=1432060568[/IMGR]
    Home-brewed heroin? Scientists create yeast that can make sugar into opiates
    Researchers have managed to reproduce the way poppies create morphine in the wild, but warn that the technology needs urgent regulation


    Home-brewed heroin could become a reality, scientists have warned, following the creation of yeast strains designed to convert sugar into opiates.

    The advance marks the first time that scientists have artificially reproduced the entire chemical pathway that takes place in poppy plants to produce morphine in the wild.

    Scientists warned that the findings could pave the way for opium poppy farms being replaced by local morphine “breweries” and called for urgent regulation of the technology. In theory, opium brewing would be no more difficult to master than DIY beer kits, raising the possibility of people setting up Breaking Bad-style drug laboratories in their own homes.

    Tania Bubela, a public health professor at the university of Alberta and co-author of a commentary on the research in the journal Nature, said: “In principle, anyone with access to the yeast strain and basic skills in fermentation could grow morphine-producing yeast using a home-brew kit for beer making.”

    The team behind the advance have stopped one step short of linking together the entire chemical chain within a single easy-to-brew yeast strain, and announced a self-imposed moratorium on the work to allow law enforcement agencies and regulators time to catch up.

    “We’re certainly not aiming for the illicit drugs market, that’s for sure,” said Vincent Martin, a microbiologist at Concordia University in Québec and co-author. “We realised that we’re entering into a brave new territory here. Me and my collaborators felt that various regulatory bodies should be consulted and talked to and we should build a consensus of how to take this forward.”

    The findings, published in the journal Nature Chemical Biology, mark a turning point in efforts that have been made for more than a decade to replicate in microbes the 15-step chemical pathway in the poppy plant.

    Scientists had previously succeeded in reproducing the second half of the chemical pathway, but the initial conversion of glucose to a compound called reticuline had proved a sticking point. The latest study cracks this problem for the first time by inserting genes from the poppy plant, sugar beet and a soil-dwelling bacteria into yeast.

    Several existing yeast strains are available that can turn reticuline into morphine, and the scientists said that combining the two halves of the process was now feasible – although they have not yet attempted this final step.

    “What you really want to do from a fermentation perspective is to be able to feed the yeast glucose, which is a cheap sugar source, and have the yeast do all the chemical steps required downstream to make your target therapeutic drug,” said John Dueber, lead author and a bioengineer at the University of California, Berkeley. “With our study, all the steps have been described, and it’s now a matter of linking them together and scaling up the process. It’s not a trivial challenge, but it’s doable.”

    He predicted a timeline of a “couple of years, not a decade” for the reliable production of controlled drugs by sugar-fed yeast.

    Being able to synthesise opiates in the laboratory raises the possibility of engineering new therapeutic forms of the drug, designed to be less addictive, more powerful or longer lasting, for instance.

    “It creates a platform for finding new chemical structures that could have a lot of potential benefits,” said Martin.

    However, it also raises concerns about the yeast falling into the wrong hands. In their commentary, Bubela and colleagues at the Massachusetts Institute of Technology (MIT) call for urgent regulation of the technology warning that it could lead to an alternative system for current criminal networks, particularly in North America and Europe, where the drugs are in high demand. “Because yeast is so easy to conceal, grow and transport, criminal syndicates and law-enforcement agencies would have difficulty controlling the distribution of an opiate-producing yeast strain,” the authors write. “All told, decentralised and localised production would almost certainly reduce the cost and increase the availability of illegal opiates - substantially worsening a worldwide problem.”

    Future strains of morphine-producing yeast could be designed to have unusual nutrient requirements as a biocontainment measure, Bubela suggests. Such strains should also be kept in bio-secure facilities in the future, with similar safeguards to those used by researchers working with anthrax or smallpox.

    Globally, more than 16 million people use opiates illegally. The drugs come from the misuse of prescription pain medications and from illegally cultivated poppy crops in countries such as Afghanistan, Laos and Mexico.

    “The time is now to think about policies to address this area of research,” said Dueber. “The field is moving surprisingly fast, and we need to be out in front so that we can mitigate the potential for abuse.”

    Martin said the team had no plans to complete the chain until regulations were in place to do so safely. “If this is something that we shouldn’t do, let’s talk about it now,” he added

    http://www.theguardian.com/science/...ntists-yeast-that-can-make-sugar-into-opiates
    5/18/2015
  9. TheBigBadWolf
    Re: Scientists: Home heroin-making technology could exist within a 'couple of years'

    Design new less addictive opiates?

    Muhahahaha!, so to say.

    This is sounding as true as the stories I recently heard about a guy with a long white beard.

    Did not BAYER back then develop the non- addictive heroin? Was not the codones and morphones developed aiming there?
    That's about the lamest pretext I be heard in a while.

    The poppy growers are the biggest of cost factors for natural and semi-synthetical opioids. Those could be cut out be feeding glucose to yeast, I think.

    Anyone with me?

    BBW
  10. Rob Cypher
    Scientists: Home heroin-making technology could exist within a 'couple of years'

    Home-brewed heroin could become a reality, scientists have warned, following the creation of yeast strains designed to convert sugar into opiates.

    The advance marks the first time that scientists have artificially reproduced the entire chemical pathway that takes place in poppy plants to produce morphine in the wild.

    Scientists warned that the findings could pave the way for opium poppy farms being replaced by local morphine “breweries” and called for urgent regulation of the technology. In theory, opium brewing would be no more difficult to master than DIY beer kits, raising the possibility of people setting up Breaking Bad-style drug laboratories in their own homes.

    Tania Bubela, a public health professor at the university of Alberta and co-author of a commentary on the research in the journal Nature, said: “In principle, anyone with access to the yeast strain and basic skills in fermentation could grow morphine-producing yeast using a home-brew kit for beer making.”

    The team behind the advance have stopped one step short of linking together the entire chemical chain within a single easy-to-brew yeast strain, and announced a self-imposed moratorium on the work to allow law enforcement agencies and regulators time to catch up.

    “We’re certainly not aiming for the illicit drugs market, that’s for sure,” said Vincent Martin, a microbiologist at Concordia University in Québec and co-author. “We realised that we’re entering into a brave new territory here. Me and my collaborators felt that various regulatory bodies should be consulted and talked to and we should build a consensus of how to take this forward.”

    The findings, published in the journal Nature Chemical Biology, mark a turning point in efforts that have been made for more than a decade to replicate in microbes the 15-step chemical pathway in the poppy plant.

    Scientists had previously succeeded in reproducing the second half of the chemical pathway, but the initial conversion of glucose to a compound called reticuline had proved a sticking point. The latest study cracks this problem for the first time by inserting genes from the poppy plant, sugar beet and a soil-dwelling bacteria into yeast.

    Several existing yeast strains are available that can turn reticuline into morphine, and the scientists said that combining the two halves of the process was now feasible – although they have not yet attempted this final step.

    “What you really want to do from a fermentation perspective is to be able to feed the yeast glucose, which is a cheap sugar source, and have the yeast do all the chemical steps required downstream to make your target therapeutic drug,” said John Dueber, lead author and a bioengineer at the University of California, Berkeley. “With our study, all the steps have been described, and it’s now a matter of linking them together and scaling up the process. It’s not a trivial challenge, but it’s doable.”

    He predicted a timeline of a “couple of years, not a decade” for the reliable production of controlled drugs by sugar-fed yeast.

    Being able to synthesise opiates in the laboratory raises the possibility of engineering new therapeutic forms of the drug, designed to be less addictive, more powerful or longer lasting, for instance.

    “It creates a platform for finding new chemical structures that could have a lot of potential benefits,” said Martin.

    However, it also raises concerns about the yeast falling into the wrong hands. In their commentary, Bubela and colleagues at the Massachusetts Institute of Technology (MIT) call for urgent regulation of the technology warning that it could lead to an alternative system for current criminal networks, particularly in North America and Europe, where the drugs are in high demand. “Because yeast is so easy to conceal, grow and transport, criminal syndicates and law-enforcement agencies would have difficulty controlling the distribution of an opiate-producing yeast strain,” the authors write. “All told, decentralised and localised production would almost certainly reduce the cost and increase the availability of illegal opiates — substantially worsening a worldwide problem.”

    Future strains of morphine-producing yeast could be designed to have unusual nutrient requirements as a biocontainment measure, Bubela suggests. Such strains should also be kept in bio-secure facilities in the future, with similar safeguards to those used by researchers working with anthrax or smallpox.

    Globally, more than 16 million people use opiates illegally. The drugs come from the misuse of prescription pain medications and from illegally cultivated poppy crops in countries such as Afghanistan, Laos and Mexico.

    “The time is now to think about policies to address this area of research,” said Dueber. “The field is moving surprisingly fast, and we need to be out in front so that we can mitigate the potential for abuse.”

    Martin said the team had no plans to complete the chain until regulations were in place to do so safely. “If this is something that we shouldn’t do, let’s talk about it now,” he added.

    HANNAH DEVLIN
    THE GUARDIAN
    MAY 18, 2015

    http://www.rawstory.com/2015/05/sci...nology-could-spread-within-a-couple-of-years/