Microbes envelop a universe all their own just beyond our vision, but they are in constant influence of our lives. We’re all familiar (as humanity has been for centuries) with beer, wine, and liquor and the term “fermentation”. Microbes also give us delicious cheeses, yogurts, and Kombucha. They supply us with isolated production of vitamins and helpful organic acids without chemical combinations that produce dangerous side products. What can’t they do?!
As surprised as Alexander Flemming was in 1928 when his experiment was pocked with patches of inhibited growth (the birth of Penicillin), we should no longer be surprised by or underestimate the power of fungi and microbes. The microbial production of compounds for industry has been around for an extremely long time, and today we’re going to discuss the eventual combination of two of my favorite topics: microbes and cannabinoids.
We’ve touched on the synthesis of cannabinoids in previous posts, but as a refresher, the most well-known cannabinoids (CBD, THC, CBC, and their acidic counterparts) are produced within Cannabis s. enzymatically from the mother of all cannabinoids, a.k.a., Cannabigerolic Acid (CBGa) and Cannagerovarinic Acid (CBGVa). Enzymes are key to lowering the energy requirements of producing chemical compounds. They are utilized for a vast array of abilities and found throughout all living organisms great and small. They work like machines, changing one chemical or compound into another. As an example, Bakers Yeast does this by using enzymes to break down fermentable sugars such as maltose into glucose and further into carbon dioxide and ethanol causing the dough to rise and become fluffy and light. Cannabis s. uses enzymes similarly to break and combine GPP, Malonyl-CoA, Hexanoic Acid, and Olivetolic Acid into CBGa and CBGVa. CBGa is enzymatically manipulated again to create CBDa, THCa, and CBCa, along with their -varin counterparts (CBDVa, THCVa, CBCVa). So how does this relate to microbes other than just general usage of enzymes?
This is where synthetic biology comes into play. Synthetic biology is the redesigning of organisms for useful purposes by engineering them genetically to have new abilities. Sounds like science fiction, right?! Well, it’s not far from it. The modern-day laboratory is set in the perfect time to do this with the declining costs of DNA synthesis, bioinformatics, and expanding databases of the genetic makeup of all living things. Synthetic biology has been the basis of cleaner, easier, and frankly safer access to many things. Saccharomyces cerevisiae used commonly in beer and bread production has been “taught” and changed to produce morphine and other alkaloids. Escherichia coli now helps with the production of insulin for use in those with diabetes. Now, E. coli, S. cerevisiae, Y. lipolytica, and K. phaffii are all candidates to produce cannabinoids.
By recoding a tiny part of the genetics found within the blueprints for these microbes’ enzymes, they now have the ability to manipulate precursor compounds such as olivetolic acid (or even sugar!) into CBGa/CBGVa or directly into other cannabinoids. Not only does this open the doors for the extraction of cannabinoids without the use of flammable ethanol or butane, but it also would allow for the production of minor cannabinoids at much higher rates than they are produced in the cannabis plant originally. We’ve talked previously about the 114 or more cannabinoids produced by the Cannabis plant, but almost all of them are known in structure only; they are produced in such small quantities that scientists know they exist and what they look like, but not much more. Until recently, CBG was known to exist as a precursor to CBD/THC/CBC and now we have plant genetics allowing for high extraction of CBG and thus clinical studies related to the possible benefits and medical effects/differences from that of CBD and THC. What could be learned from an at-present nearly unknown cannabinoid such as cannabicitran (CBT), cannabicyclol (CBL), or even higher amounts of tetrahydrocannabivarin (THCV), or cannabidivarin (CBDV) than can be produced in the plant?
Production of cannabinoids by microbial means also leads to other benefits to the environment. We would no longer need huge swaths of land and water to produce Cannabis s. plants - the same volume of cannabinoids could be grown in a moderate industrial laboratory the size of a small brewery. There would be much less concern for the proper disposal of huge amounts of ethanol or alkanes (butane, propane, etc.) from the extraction process as many of these "chassis" microbes can be grown in nutrient-rich water or on sustainable agar mats. Synthetic biology could even make cannabinoids better - esterification or similar processes and additions could lead to CBD being just as effective but also water-soluble without the use of massive ratios of surfactants, or not as susceptible to the p-450 enzyme in humans that leads to the quick loss of bioavailability.
Great strides have been made in the production and use of cannabinoid rich Cannabis plants and efficiency has only gotten better on extraction and post-processing, but the future holds many possibilities and microbes are well on their way to being a big part of them.
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