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Asante
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Psychedelics produced from GM yeasts - what's your opinion?
#5323478 - 02/21/06 10:23 AM (18 years, 1 month ago) |
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Preliminary Feasibility Study for The Biological Production of L-Dopa, Mescaline and Tryptamines by Intact Recombinant Yeast Cells Using Only Common Amino Acids as Precursors to Bioenzymatic Synthesis
Overview I intend to present here a culling of existing and proven laboratory techniques for the recombinant transformation of microorganisms to the purpose of their production of pharmaceutical compounds which at the present time are only being made via organic syntheses using legally restricted and costly chemicals, and chemical procedures both difficult and dangerous to utilize for the layman not extensively trained in traditional organic synthetic methods. Genetically transformed yeasts and e. coli cultures are currently harnessed on an industrial level to make such varied compounds as human insulin, opiates (see references) and cytokines and other immunological artifacts. There is every reason to believe that provided with a moderately equipped recombinant genetics lab and the use of these proven techniques, that yeast cells could be made to produce in high yield tryptamines such as DMT and psilocybin, mescaline and other drugs. I chose to start with tryptamines and phenethylamines as they are simple molecules, which are almost identical to their biosynthetic precursors: the ubiquitous amino acids tryptophan and tyrosine. THC, LSA, and other restricted compounds could also be made in this fashion, but with much, much greater difficulty as they are very much more complex molecules and their biosynthesis is not explored in great detail at this time. With such a recombinant yeast (and I chose yeast over e. coli due the simplicity of yeast culture, i.e., bread and brewing techniques considered-- and also due to the total lack of pathogenicity of cervesia yeasts in general and the fact that yeasts are eukaryotic) all an untrained layman would need to produce these compounds in a pure yield would be: one transformed yeast cell, a bucket, warm water, sugar, amino acids and 12 hours-- and simple acid base extraction techniques to separate the pure psychedelic compounds from the waste materials. Even given theoretical restrictions on amino acids such as those currently imposed on tryptophan, these amino acids are present in almost all living tissue and could be obtained from such. The yeast would utilize its foreign dna inserts to code enzymes that would biochemically substitute the molecular groups that create mescaline or DMT from their amino acid precursors as part of the transformed yeast's metabolic routine. It is not unrealistic to expect a gram or two of pure material from such a 'brewing' effort, in theory--and perhaps more with the use of a pH balanced, aerated fermentation chamber. In addition, several useful pharmaceuticals could potentially be made by precursor strains of such a yeast, including L-DOPA, a valuable medicinal compound. L-DOPA is one hydroxyl group (one cactus enzyme) away from tyrosine; it is one further aromatic hydroxyl group and three methyl groups and a decarboxylation away from mescaline. A yeast transformed with only one of the cactus enzymes would produce L-DOPA. I hold out the potential to royalties from such an organism to a prospective funding agency as another reason to support this project: biologically manufactured L-DOPA would be hundreds of times less costly than that which is currently made by pharmaceutical companies using expensive traditional methods which, unlike enzymatic synthesis, create a toxic waste stream. Bioenzymatic synthesis is totally clean and extremely efficient. Also enzymes almost always produce a single enantiomeric species, though that is not a consideration here.
Considerations The following techniques would most easily produce tryptamines, as DMT is created from tryptophan by the work of only two enzymes: one enzyme decarboxylates the L-alkylaminocarboxy chain to an ethylamino chain which is then N-methylated by the second enzyme. The decarboxylation gene is already known and commercially available, and would also work with the alkylamine chains of tyrosine and phenylalanine. The second enzyme would have to be isolated by reverse cloning of fungal mrna into cdna, which would be tagged with synthetic linkers, methylated and inserted into a restricted plasmid appropriate for a yeast strain. A third enzyme would be required for DMT to psilocin, a 4-hydroxyl transferase. Transforming the yeast cell with the ligated plasmid dna and foreign vector dna is actually the easiest and simplest step of the entire process: it can be accomplished with electroporation or cheap and simple chemical methods employing buffering agents and lithium acetate (see references). The bulk of the work is involved in identifying the appropriate reading frame for the cloned mrna to cdna fragment which codes a single enzyme for a specific chemical transformation, again two such genes in the case of tryptophan to N-methyltryptamine --and in choosing appropriate marker genes to identify the transformed vs. wild type cells. Somewhere between three and possibly five unkown genes will have to be characterized and inserted for a yeast to produce mescaline from tyrosine ( not including the known decarboxylation enzyme gene) so it is a more difficult transformation to attempt by far. But I have other reasons to consider as an initial project in this area the choosing of mescaline over DMT or psilocin. First, the mrna to get the reverse cloned cdna is easily obtainable from the semi-legal and widely available "San Pedro" cactus, T. pachanoi, which typically produces 12% mescaline from its dry weight. It is not feasible to use restricted genomic dna, as it is almost impossible to know where to begin a reading frame, or if a restriction site lies in the desired frame. Mrna clones only for the active enzymes involved in the current metabolism of the plant or other organism, and it can be relatively easily cloned back into double stranded cdna which is easily inserted in a plasmid with the appropriate promoters and markers (see references). My main reason for not choosing tryptamines to work with initially is not a technical one, as I have shown the tryptamines to be more technically simple. It is the legal issue and unwillingness to deal with Schedule I fungal materials that I am concerned with. And while it would also be possible to use semi-legal DMT plant sources for such a transformation, I have had great difficulty obtaining such materials in a fresh condition at any affordable cost. And there is the L-DOPA side reaction to consider, which will only come from working on the mescaline synthetic route. The L-DOPA synthesis could also be used as a factor to legitimize the research, on the road to perhaps an understated goal of mescaline synthesis.
Technique and Protocol Several of the obstacles I have faced in planning this project have revolved around ways to avoid extra expenses while not contaminating the integrity of the process. Traditional molecular biology laboratories utilize freely much expensive equipment such as computerized DNA synthesizers and analytical equipment. Barring that perhaps some of this could be borrowed, I propose that possibly much of the project could be done with more tedious and time consuming, but far less expensive methods. For example, rather than using radiolabeled synthetic oligionucleotide probes based on purified enzyme analysis to identify the correct cdna fragments that clone a specific enzyme gene, perhaps cdna fragments could simply be inserted at random (after adding synthetic linkers and methylation to avoid a restriction site within the reading frame, and also making it easy to identify and recover the vector dna from the e. coli for insertion into yeast ) and the resulting pools of bacteria subdivided and tested until a strain is identified that performs a single enzymatic task. Growth and lysis of these strains after large scale culture would be used in place of polymerase chain reaction artificial amplification of the cdna. It may be unavoidable to utilize some pcr amplification of the extracted mrna, as it is typically isolated as a very small sample. Some unusual options may be open in the case of mescaline: the aromatic hydroxylase activities of many bacteria are under intense scrutiny right now in general for the search for bacteria capable of degrading toxic waste. I have found one such gene described (see references) but it specifically will not work here as it does not recognize phenylalanine as a substrate and has very low activity with tyrosine. There are probably other bacterial genes already recognized that could 3,5 hydroxylate the aromatic ring of tyrosine. As with standard chemical procedures, once a ring has one hydroxyl present this will catalyze the formation of further hydroxylations. The human gene which converts the hydroxy free phenylalanine into 4-OH phenylalanine (aka tyrosine) requires a cofactor, tetrahydrobiopterin, a relative of folic acid. In general, the cofactors required for bioenzymatic synthesis (as opposed to cell free enzymatic synthesis) are often present (NADP, NADH and various metal ions are common examples) in the cell. But it is distantly possible that one or more of these enzyme cofactors will be required to be cloned also. Two hydroxylase genes will have to be isolated from the cactus to complement the 4-hydroxyl group present in tyrosine. The already known decarboxylase gene will be easy to transform, as it is identified and characterized. This leaves the three methyl groups to transfer to the 3,4,5 hydroxyl intermediate. It is possible that either one enzyme will transfer a methyl to each of these groups to make 3,4,5 trimethoxyphenethylamine (mescaline) --but it also possible that three different enzymes methylate these aromatic hydroxyls. This brings the total of unknown genes to be cloned from cactus mrna to a possible high of five, and a possible low of three. The above is a slightly simplified overview of the process, leaving out routine details of constant analyisis of the progress of transformation through agarose gel electrophoresis, and nmr confirmation of target structure at every point. The references I have included will fill in those gaps. This is a preliminary report, and I was rushed to get it together by the 1st, May when the board of the Heffter Organization meets. More detail can and will be provided, if necessary.
Rough Summary of Technique (see references attached for details)
1.extraction of active mrna from fungus or cactus 2.cloning of mrna into cdna clones or possible use of mrna/cdna hybrid strands 3.attachment of synthetic linkers to cdna fragments 4.methylation ofcdna fragments 5.restriction of plasmid using sites corresponding to synthetic linkers 6.ligation of plasmid and vector dna using T4 ligase 7.transformation of e. coli pools with ligation plasmid and identification of marker genes on plasmid (typically antibiotic resistance) 8.subdividision of e. coli pools until single unknown genes are characterized by expression products 9.lysis of expanded pools 10.extraction and restriction of plasmids and agarose gel separation of fragments 11.ligation of characterized fragments to yeast plasmid 12.sequential transformation of yeast cells (see references) 13.selection of transformed yeast clones
Costs I have not had time to run every detail of the cost of such a project, and much depends on the availability of borrowed equipment and technical expertise, as I have no current lab access beyond some organic equipment. Also much could be purchased used, saving considerably. I have previously mentioned some methods which could save money at the expense of time. The bulk of the costs are tied up in the high end microfuge and centrifuge required, Sorval type rotors capable of 12,000 g. It may be possible to substitute a slower centrifuge used for longer spin periods. Also, other minor items will be needed such as a shaker and gel electrophoresis kit. I have also not looked into pre-prepared kits specifically designed for recombinant engineering. The inorganic chemicals and antibiotics and restriction enzymes will also be costly. I have been given an estimate of from $10,000 to $15,000 for the whole project by an expert in the field. None of these techniques are in the least speculative. They are the tried and proven workhorse tools of standard molecular biology. Only the application remains.
References Nucleotide sequence and over-expression of morphine dehydrogenase, a plasmid encoded gene from Pseudomonas putida M10. J Biochem, 290, 539-544 A M Hailes and N C Bruce (1993) The biological synthesis of the analgesic, hydromorphone : an intermediate in the metabolism of morphine by Pseudomonas putida M10. Appl Environ Microbiology, 59, 2166-2170 G W W Cameron and N C Bruce (1993) Towards enginering pathways for the synthesis of analgesics antitussives. Ann N Y Acad Sci, Vol 721, 85-89 G W W Cameron, K N Jordan, P J Holt, P B Baker, C R Lowe and N C Bruce (1994) Pathway Engineering for the biological synthesis of analgesics and antitussives. Conference Proceedings on Applied Catalysis, Biotechnology '94, UK Institute of Chemical Engineers, pp 50-52 N C Bruce and M T Long, (1994) Biological production of semisynthetic opiates using genetically engineered bacteria. BioTechnology vol 13, 674-676 N C Bruce and M T Long (1995) Engineering microbial transformation pathways for the synthesis of morphine alkaloids. Trends in Biotechnology, 13, 200-205 M T Long, A M Hailes, G W Kirby and N C Bruce (1995) Morphinone reductase : characterization, cloning and application to biocatalytic hydromorphone production. Ann N Y Acad Sci, In Press A M Hailes, C E French, D A Rathbone and N C Bruce (1996) Engineering pathways in E. Coli for the synthesis of morphine alkaloid analgesics and antitussives Ann N Y Acad Sci, In Press D A Rathbone, P-J Holt, C R Lowe and N C Bruce (1996) also Towards the redesign of morphine dehydrogenase with improved properties, same authors and reference. "Molecular Cloning : a Laboratory Manual" by Maniatis, Fritsch and Sambrooke, Academic Press, 1989
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koppie
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Re: Psychedelics produced from GM yeasts - what's your opinion? [Re: Asante]
#5323643 - 02/21/06 11:04 AM (18 years, 1 month ago) |
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I say go for it! Then we can start a free yeist ring!
Brew your own DMT! As easy as making beer or wine... Genesplicing in underground high tech biolabs sounds very tempting. Every day life feels more like living in a cyberpunk novel.
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giz
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Re: Psychedelics produced from GM yeasts - what's your opinion? [Re: koppie]
#5323652 - 02/21/06 11:07 AM (18 years, 1 month ago) |
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intresting read
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Shdwstr
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Re: Psychedelics produced from GM yeasts - what's your opinion? [Re: Asante]
#5323687 - 02/21/06 11:16 AM (18 years, 1 month ago) |
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Quote:
Wiccan_Seeker said:
Rough Summary of Technique (see references attached for details)
1.extraction of active mrna from fungus or cactus 2.cloning of mrna into cdna clones or possible use of mrna/cdna hybrid strands 3.attachment of synthetic linkers to cdna fragments 4.methylation ofcdna fragments 5.restriction of plasmid using sites corresponding to synthetic linkers 6.ligation of plasmid and vector dna using T4 ligase 7.transformation of e. coli pools with ligation plasmid and identification of marker genes on plasmid (typically antibiotic resistance) 8.subdividision of e. coli pools until single unknown genes are characterized by expression products 9.lysis of expanded pools 10.extraction and restriction of plasmids and agarose gel separation of fragments 11.ligation of characterized fragments to yeast plasmid 12.sequential transformation of yeast cells (see references) 13.selection of transformed yeast clones
Whoo Hoo.... Time to scrape some mould from the old breadbox, break out the double boiler, and start cooking.... shouldn't take me more than a hour or so.
I'll let you know
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badchad
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Re: Psychedelics produced from GM yeasts - what's your opinion? [Re: Shdwstr]
#5324050 - 02/21/06 01:25 PM (18 years, 1 month ago) |
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Theoretically it sounds plausible.
However, in reality cloning of microorganisms to allow the synthesis of a protein isn't quite that simple.
I have several friends in microbiology/biochem. programs. Some have had some major problems creating truncated versions of proteins etc. I cannot speak firsthand however, and perhaps you are wiser than I on the subject.
-------------------- ...the whole experience is (and is as) a profound piece of knowledge. It is an indellible experience; it is forever known. I have known myself in a way I doubt I would have ever occurred except as it did. Smith, P. Bull. Menninger Clinic (1959) 23:20-27; p. 27. ...most subjects find the experience valuable, some find it frightening, and many say that is it uniquely lovely. Osmond, H. Annals, NY Acad Science (1957) 66:418-434; p.436
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koppie
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Re: Psychedelics produced from GM yeasts - what's your opinion? [Re: Asante]
#5324054 - 02/21/06 01:26 PM (18 years, 1 month ago) |
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So let me get this straight, first you are looking for materials to make a thermonuclear device, and now you're looking into the creation of mutant yeasts? Do we need to worry? Can I be a part of your plans for world domination? I don't need much territory, Australia would be just the right size.
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funnybunny
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Re: Psychedelics produced from GM yeasts - what's your opinion? [Re: badchad]
#5324090 - 02/21/06 01:39 PM (18 years, 1 month ago) |
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My dreams made true!
Quote:
Waiter! A jar of beerlocybin, please.
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ChuangTzu
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Re: Psychedelics produced from GM yeasts - what's your opinion? [Re: Asante]
#5324278 - 02/21/06 02:26 PM (18 years, 1 month ago) |
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DId that expert in the field give you any time estimates? I'd put it on a timescale of years even with expensive, top-of-the line equipment. That's a massive undertaking. Are you trying to get funding from Heffter?
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Asante
Omnicyclion prophet
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Re: Psychedelics produced from GM yeasts - what's your opinion? [Re: ChuangTzu]
#5325031 - 02/21/06 05:53 PM (18 years, 1 month ago) |
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Whoooah! In case I wasnt clear: this is an article I found online, not something I wrote myself.
I'm just looking for considerations and opinions, and hopefully to inspire someone.
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ChuangTzu
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Re: Psychedelics produced from GM yeasts - what's your opinion? [Re: Asante]
#5327084 - 02/22/06 03:09 AM (18 years, 1 month ago) |
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Yeah, that wasn't at all clear...
Maybe I'll try that when I'm rich and have tons of time on my hands. Otherwise, I'll wait until someone else figures out the needed sequences and have them made by these guys for $1.45/bp including free cloning. Even then, it's a shitload of work.
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Catalysis
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Re: Psychedelics produced from GM yeasts - what's your opinion? [Re: Asante]
#5329228 - 02/22/06 08:08 PM (18 years, 1 month ago) |
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I see several problems with this. Don't take this the wrong way but I am going to point out several flaws that I see for the sake of science.
First of all, I believe that the conversion of tyrosine to DOPA typically occurs in extracellular matrix. This poses a huge problem for DOPA biosynthesis and an even bigger problem if they expect to use DOPA as a precursor to other compounds in situ. DOPA "biosynthesis" has already been shown but it involves exposing tyrosine to immobilized mushroom tyrosinase.
Second, I have a big problem with this step.
8. subdividision of e. coli pools until single unknown genes are characterized by expression products
Aside from the fact that I have no idea what this means and it looks like it was written by a third grade student, how in the world does the author propose to isolate and analyze the expression products on his budget? NMR time is very expensive and they would need a lot of it. I also do not see how this protocol allows you to isolate single genes anyways, maybe I am missing something.
Third, this cannot be done without PCR equipment and reagents.
Also, if I were a reviewer, the author's reasoning for using yeast over E. coli due to pathogenicity would make me do a double take because E. coli is non-pathogenic.
I think that identifying and isolating DNA sequences corresponding to several unknown enzymes which may or may not exist is far more complicated than the author makes it out to be. In other words, I would never approve this proposal. The budget is low-balled even with the authors claims of being able to do this ghetto style(?!). Genetic work is extremely expensive and labor intensive even with highly sophisticated equipment.
I could go on and on but I think I made my point. I have often thought about the viability of this but science is really not at the point where we can do this kind of metabolic engineering efficiently at a low cost. Maybe in 10 years or so.
Edit: Everyone should feel free to comment on my criticism. I don't know much about enzymatic synthesis so I may be wrong.
Edited by Catalysis (02/22/06 08:43 PM)
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Skeptikos
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Re: Psychedelics produced from GM yeasts - what's your opinion? [Re: Asante]
#5329511 - 02/22/06 09:02 PM (18 years, 1 month ago) |
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Several weeks ago I had a conversation with a fellow who ran a start-up pharmaceutical company (since sold to a major company) who is now working on research into bringing other drugs to market for some venture capitalists. He explained to me how they use yeast to manufacture a particular drug. They first isolated the gene sequence which is responsible for manufacturing the chemical wanted. They then bath the yeast cells in a certain chemical (sorry I don't remember the name) along with a quantity of the gene sequence. The chemical temporarily weakens the cell walls and allows the entry of the supplied gene sequence into the yeast. Some of the yeast may integrate the sequence into their own genome. Of these, some may start to produce the chemical. The hard part of this phase comes in culturing the yeast and trying to isolate those (if any) which have begun to manufacture the desired chemical.
He didn't think this was the hardest part of bringing a new drug to market, nor the most expensive part of bringing a drug to market. The most difficult process involves getting the proper trials done and testing both the safety and efficacy of the drug, first on animals, and then on humans. The vast majority of new drugs don't even make it past the animal testing phase. But this is an entirely different kind of drug.
-------------------- Sincerely, Skeptikos
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Catalysis
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Re: Psychedelics produced from GM yeasts - what's your opinion? [Re: Skeptikos]
#5329559 - 02/22/06 09:13 PM (18 years, 1 month ago) |
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Yeah its pretty cool. With bacteria, they heat shock them to bring them near death and the DNA enters as the cell membrane starts to break down. They put an antibiotic resistance gene in the DNA plasmid so you can grow them on antibiotic agar and only the transfected bacteria will survive.
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Skeptikos
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Re: Psychedelics produced from GM yeasts - what's your opinion? [Re: Catalysis]
#5329624 - 02/22/06 09:26 PM (18 years, 1 month ago) |
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Oh, he said one problem that crops up in genetic engineering like this is that the yeast may actually alter the chemical slightly, may make it levorotary instead of dextrorotary or otherwise change the structure of the molecule. This makes testing VERY important (and possibly deadly for the subject).
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Asante
Omnicyclion prophet
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Re: Psychedelics produced from GM yeasts - what's your opinion? [Re: Catalysis]
#5331239 - 02/23/06 11:04 AM (18 years, 1 month ago) |
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Quote:
Don't take this the wrong way but I am going to point out several flaws that I see for the sake of science.
Hey, I didnt write that one but if I had I'd be glad you did it the way you did.
Quote:
I believe that the conversion of tyrosine to DOPA typically occurs in extracellular matrix.
That would be the kiss of death as far as yeast is concerned unless you get really creative. ($$)
But the phenomenon is interesting. LSA-containing lettuce comes to mind, at lets say a hundred doses per head Harvest, dry & powder! Salvinorin-containing watermelons would be great too
But yes, it sounded too good to be true. Still, what would be needed?
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Asante
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Re: Psychedelics produced from GM yeasts - what's your opinion? [Re: ChuangTzu]
#5331241 - 02/23/06 11:06 AM (18 years, 1 month ago) |
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Wow! Chuang, that link of yours looks like something that escaped from a superhero comic. Synthetic genetics on demand... I love the 21th century
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Baby_Hitler
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Re: Psychedelics produced from GM yeasts - what's your opinion? [Re: Asante]
#5337287 - 02/25/06 07:47 AM (18 years, 1 month ago) |
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For some reason this makes me think of those liquid culture teks where you extract mycelium from big vats of media and extract psilocybin from it.
Maybe we could culture some M. hostilis root bark tissue.
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Re: Psychedelics produced from GM yeasts - what's your opinion? [Re: Asante]
#5339493 - 02/25/06 10:18 PM (18 years, 1 month ago) |
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You seriously haven't seen this type of shit? L-PAC. At least 5 successful home workups (40% return or greater off of starting materials) have been posted. Fuck, it's an industrial technique!
The problem with home or individual implementation is the equipment, as per normal. ALtho with recombinant techniques being what they are, it's just barely within reach of a sneaky well funded individual.
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