アメリカの研究チームは、酵母を利用した新たな麻薬（モルヒネやコデインなど）の合成法を確立しつつあると報告しました。これまで、合成初期に必要な酵素（L-チロシンをL-DOPA（ドーパミンの前駆体）に変換する酵素）が知られておらず、微生物に作らせることは困難でした。今回、研究チームは独自のセンサーを開発することで新たに酵素を同定し、遺伝子を改変した酵母に「麻薬の一歩手前の物質（S-レチクリン）」を合成させることができたとしています。あと1段階で麻薬に変換できるため、ブドウ糖を原材料にして生産する道が開けると考えられます。論文は5月19日付けのNATURE CHEMICAL BIOLOGYに掲載されました。
An enzyme-coupled biosensor enables (S)-reticuline production in yeast from glucose,William C DeLoacheet al., Nature Chemical Biology (2015) doi:10.1038/nchembio.1816.
Prof Paul Freemont
Co-Director of the EPSRC Centre for Synthetic Biology and Innovation, and Co-Director of the UK Innovation and Knowledge Centre for Synthetic Biology (SynbiCITE), Imperial College London
“This study represents a growing trend in the emerging field of synthetic biology, which aims to develop a framework for the systematic engineering of living systems for useful purposes based on our ability to read and write DNA. One major aim is to develop sustainable biomanufacturing processes such that complex natural products like morphine can be manufactured more efficiently, cheaply and safely. Such processes would also lead to the possibility of further development of more effective pain-killers.
“Although this study and others represent an important landmark in achieving this, it throws open the whole debate on how such biomanufacturing processes can be safely regulated and also the need to engage with a wide array of stakeholders. This is due in part to the drive in the synthetic biology field to make biotechnology more accessible to non-experts, which has led to the rapid growth of amateur biologists or DIY-bio enthusiasts. Synthetic biology has also captured the imagination of thousands of undergraduate students worldwide, who compete annually in the Internationally Genetically Engineered Machine competition or iGEM. With the widespread availability of digital biotechnology it is possible that non-experts and less-trained researchers could replicate such experiments, although they are still quite technically demanding.
“It is important to note I think that information for the chemical synthesis of illegal drugs has been available on the web or in the literature for some time with easy to follow recipes that in some cases can be followed by non-experts. For new biomanufacturing processes like those described in these publications, I can envisage a series of safety features that could be engineered into specific production strains that would prevent their use outside of a controlled and regulated environment. I could also imagine new DNA watermarks that could be introduced into production strains that would immediately allow the identification of such strains. There are already existing regulatory barriers to obtaining the necessary pieces of synthetic DNA from DNA synthesis companies that would be required to construct such production strains.
“I welcome the commentary by Oye et al as it provides a framework to initiate a wide debate on how these new biomanufacuring applications can be safely regulated and utilised for the wider good.”
Prof Paul Freemont: “I am employed by Imperial College London as a professor. I hold grant funding from the major RCUK funding agencies including BBSRC, EPSRC, Innovate UK and also charity funding from CRUK and the CF Trust. I am a board member of the MRC MCMB funding panel and recently chair of the Diamond Scientific Advisory Committee. I am a Fellow of the Society of Biology and the Royal Society of Medicine. I am Co-founder and Co-Director of the EPSRC Centre for Synthetic Biology and Innovation & the UK Innovation and Knowledge Centre for Synthetic Biology (SynbiCITE- Imperial College London, www.imperial.ac.uk/syntheticbiology, www.synbicite.com). I am also head of the Section of Structural Biology in the Department of Medicine at Imperial College London. I am co-founder and equity holder of two start companies – Equinox Pharma Ltd which specialises in computational drug discovery, and LabGenius Ltd which specialises in optimisation of industrial protein produ!
ction. None of these companies have any interest in the biomanufacturing of pharmaceuticals or chemicals.”
Prof Christopher Voigt
Department of Biological Engineering, Massachusetts Institute of Technology
"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."
Prof George M. Church/ Prof Robert Winthrop
Harvard Medical School/Health Sciences and Technology, Harvard and MIT
"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
"The Nature Chemical Biology 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/ Dr William J. Perry
Fellow in International Security, Center for International Security and Cooperation (CISAC)/ Stanford University
"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."
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