Yeast engineered for making morphine one step closer, raising concerns over ‘home-brew’ opiates

An elusive step in genetically engineering yeast to manufacture opiates from glucose has been achieved by researchersCombined with previous studies which have demonstrated other steps of the process, the new study published in Nature Chemical Biology brings the possibility of an engineered yeast strain that produces painkillers like morphine much closer. Cautioning that this opens the door for production of ‘home-brewed’ opiates, experts have called for “fast and flexible regulation to protect the public and the research community” in a commentary published in Nature.

The following researchers gave their take on the study.

 

Dr Christopher Voigt, Professor, Department of Biological Engineering, Massachusetts Institute of Technology (webpage)

Expertise: synthetic biology, systems biology, genetic circuit design, developing and applying genetic circuits to problems in biotechnology.

“The claims are well supported by the research. This work overcomes the key bottleneck in the pathway. The downstream steps to morphine and other products have been shown and it would be straightforward to combine the pathways.

“However, moving to large scale production still has many hurdles. It is necessary to increase the titers significantly. They report ~100 ug/l (of the intermediate – the final pharmaceutical product is not shown). Considering a dose of morphine is 30 mg, this means that 300 liters of yeast would have to be grown for one dose. (Again, they haven’t shown the final product so this is extrapolating from the intermediate).

“Moving to higher production would also require metabolic engineering, strain development, and bioprocess scale-up. All are of which are well within reach and just a matter of turning the crank on the science.

“As the commentary suggests, it is going to be possible to ‘home-brew’ opiates in the near future. Yeast can be consumed, of course, so there would no need to separate the product. Imagine if the pathway were improved so that a glass of yeast culture grown with sugar on a windowsill provided the 30 mg dosage needed. This is well below the titers typical for industrial production.

“There are many approaches that are being developed to prevent the use of a strain outside of a defined environment. None that I know of could be applied off-the-shelf to this problem. A more challenging problem is that one would not have to obtain the safeguarded strain. The information in this paper, combined with DNA synthesis, could be readily applied to rebuild the strain without ever gaining access to the physical DNA or strain from the authors.”

 

Dr George M. Church, Robert Winthrop Professor of Genetics, Harvard Medical School; Professor of Health Sciences and Technology, Harvard and MIT; Founding member, Wyss Institute for Biologically Inspired Engineering at Harvard (webpage):

Expertise: genome engineering, synthetic biology, personal genomics, sequencing.

“The methods and results described in the DeLoache et al. Nature Chemical Biology study look well executed and clear. Many pharmaceuticals are already made by yeasts and bacteria at high yield commercially. This sort of metabolic engineering optimization is fairly straightforward. Once the recipe is published it becomes very easy to reproduce it — something that any DIYBIO user could do.

“The concerns in Oye et al. are quite justified. The proposed regulations are not likely to hinder legitimate research or education. I pointed out the need for active surveillance of Synthetic biology in 2004: A Synthetic Biohazard Non-proliferation Proposal (http://arep.med.harvard.edu/SBP/Church_Biohazard04c.htm). Such safeguards have been implement by the International Association of Synthetic Biology and the International Gene Synthesis Consortium as noted by Oye et al. Potent pharmaceuticals (not just psychoactive ones) are potentially toxic — accidentally or intentionally.”

 

Dr Keith Tyo, Assistant Professor, Department of Chemical and Biological Engineering, Northwestern University (webpage)

Expertise: synthetic biology, using knowledge of microbial metabolic networks to increase production of a given metabolite, methods to modify existing environmental detection sensors in yeast to detect new analytes.

“The Nature Chemical Biological report by Dueber and colleagues describes an impressive chemical feat of biosynthesizing opiate molecules from abundant sugars. The ability to use biosynthesis to generate new opiate derivatives that are less less addictive is quite promising.

“In the analysis by Oye, et al., the opiate-producing yeast is, rightly so, characterized as an organism that is a threat to public health, because it could be used for decentralized synthesis of illicit drugs. Because the opiate-yeast is a threat to public health, it is reasonable to treat it like many other infectious pathogens (malaria, TB, etc). Existing biosecurity policy has been effective to date with containing these pathogens, though, no doubt, bad actors would desire access to the pathogens to use against the public. In analogy to highly virulent pathogens, genetic engineering research on yeast opiate metabolism can be carried out with well established safe guards, and the knowledge produced from this research would benefit public health by potentially discovering new less-addictive narcotics.

“Outside of bench research, the development of a scaled-up yeast-opiates process is most likely unattractive. The current amount of opiate the yeast produces would not be enticing for elicit drug production. To achieve attractive amounts of opiate would require substantial investment and expertise. Compare to other biosynthesized compounds (artemisinin, farnasene, 1,3-propanediol, etc.), $20 – $100 M investment is often required to engineer microbial catalysts to reach titers that would make sense for homebrew opiates. And even with this investment, only a small number of firms in the world would have the expertise to carry out the microbial engineering. If legal opiate production from poppy seed is already relatively low cost, no firm would investment in the yeast process.

“Finally, the operation of a yeast-opiate biosynthetic process has similar risks to other at-scale synthetic biology processes. Because the catalyst (yeast cell) is self-replicating, even stealing one cell from a competitor would allow a firm to produce the same compound. For non-opiate processes, the proprietary information in the production strain is a tightly held secret and measures are taken to ensure the strain is not taken. An opiate producing process would follow similar procedures, to ensure no one can steal the strain.

“In short, opiate-yeast presents challenges for public health, but fortunately not significantly different from other challenges we have faced. Small scale research can be handled analogously to infectious agents, investment in a commercially viable strain is unlikely, and deployment of a legal yeast-opiate process would require similar safeguards to biosynthetic production processes for other specialty chemicals.”

 

Dr. Megan J. Palmer, William J. Perry Fellow in International Security, Center for International Security and Cooperation (CISAC), Stanford University (webpage):

Expertise: societal aspects of biotechnology, best practices and policies for responsibly advancing biotechnology, biological safety and security, property rights, and governance.

“DeLoache et al.’s study is an example of a growing trend of technological advances to enable biology-based manufacturing. Biomanufacturing is envisioned as a means of producing a wide diversity of existing and novel compounds for use in materials, energy and health, not only pharmaceuticals. There remain significant uncertainties about the economic and security tradeoffs of the shifts in supply chains enabled through biomanufacturing, and what governance options, including regulations, will be viable and most effective.

“Oye et al.’s commentary highlights how production of controlled substances through biomanufacturing, such as opiates, poses additional layers of concerns. What is not included in this short comment is a detailed assessment and comparison of governance options of the current agricultural based production platforms versus biomanufacturing. The authors also do not substantiate claims regarding the technical barriers to achieving significant titers in a ‘home-brew’, which will impact the economic viability of both licit and illicit markets. Such detailed assessments are required to assess the regulatory needs called for in this article. There are risks of not acting quickly enough to adapt regulations during early technical development. Yet there are also risks of adopting regulations that fail to address the larger issues.

“The challenge for regulatory and technical communities will be to avoid reactive quick fixes, but instead swiftly create pathways to discuss, assess and act accordingly on the short- and long-term systemic challenges for shaping both licit and illicit use. It is unfortunate that the editorial framing of this article, especially the imagery, is inflammatory, laying a questionable groundwork for a more meaningful and holistic discussion of both benefits and risks. It is, however, heartening to see researchers proactively engaging in these discussions and welcoming more transparent debate. Exploring how the design of biotechnology impacts future governance options, and understanding the potential risks of the research process will be critical to managing the rapid pace of change in biotechnology. What is needed now is a thoughtful and nuanced discussion involving a broader group of researchers, industry, and regulators.”

 

References: 

An enzyme-coupled biosensor enables (S)-reticuline production in yeast from glucose‘ by DeLoache et al, published in Nature Chemical Biology on Monday, May 18 2015.

Regulate ‘home-brew’ opiates‘ by Oye et al, published in Nature on Monday, May 18 2015.

 

Declared interests (see GENeS register of interests policy):

Dr George Church: For a complete list of Dr Church’s Tech Transfer, Advisory Roles, and Funding Sources please see here.

Dr Megan J Palmer: Megan J Palmer an investigator of the NSF Synthetic Biology Engineering Research Center (SynBERC). Ken Oye and John Dueber are also SynBERC investigators.

No further interests declared.

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