Back in 2019, researchers published a new method in the journal Nature using genetically modified yeast to produce the cannabinoids THC and CBD. Now several businesses think this method may hold the key to manufacturing and studying rare cannabinoid compounds that would be too difficult and expensive to produce by traditional agricultural methods.
For the consumer, the benefits are high-quality, low-cost CBD and THC: you get exactly what you want from yeast,” said Jay Keasling, a UC Berkeley professor of chemical and biomolecular engineering and of bioengineering and a faculty scientist at Lawrence Berkeley National Laboratory. “It is a safer, more environmentally friendly way to produce cannabinoids.”
Cannabis and its extracts, including the high-inducing THC, or tetrahydrocannabinol, are now legal in 10 states and the District of Columbia, and recreational marijuana – smoked, vaped or consumed as edibles – is a multibillion-dollar business nationwide. Medications containing THC have been approved by the Food and Drug Administration to reduce nausea after chemotherapy and to improve appetite in AIDS patients.
CBD, or cannabidiol, is used increasingly in cosmetics – so-called cosmeceuticals – and has been approved as a treatment for childhood epileptic seizures. It is being investigated as a therapy for numerous conditions, including anxiety, Parkinson’s disease and chronic pain.
But medical research on the more than 100 other chmicals in marijuana has been difficult, because the chemicals occur in tiny quantities, making them hard to extract from the plant. Inexpensive, purer sources – like yeast – could make such studies easier.
Plus, he added, there is “the possibility of new therapies based on novel cannabinoids: the rare ones that are nearly impossible to get from the plant, or the unnatural ones, which are impossible to get from the plant.
Now researchers have turned to yeast to do something more improbable: manufacturing the cannabis compounds CBD and THC. By loading brewer’s yeast with genes from the cannabis plant, they’ve turned the miracle microbes into cannabinoid factories. It’s a clever scheme in a larger movement to methodically pick apart and recreate marijuana’s many compounds, to better understand the plant’s true potential.
The process goes like this. Two different yeasts produce either THC or CBD, depending on what kind of enzyme they carry. Importantly, both carry the cannabis genes that produce CBGA. “CBGA is this kind of central cannabinoid that’s the mother of all the other cannabinoids,” says UC Berkeley chemical engineer Jay Keasling, coauthor on a new paper in Nature detailing the technique.
Using Yeast to Produce Cannabinoids
Led by principal investigator Jay Keasling, synthetic biologists at UC Berkeley found a way to genetically engineer brewer’s yeast to produce the primary active ingredients in cannabis: THC and CBD.
Yeast are naturally adept at converting sugar into alcohol. To coax the yeast into producing cannabinoids instead of alcohol, the researchers inserted more than a dozen genes into the yeast genome including many copies of genes used by the cannabis plant to synthesize cannabinoids. The resulting yeast strains could be fed sugar and, in turn, create large quantities of specific cannabinoids.
This method of cannabinoid production has several major benefits when compared to extraction from the cannabis plant.
· Less time: it may take months for a cannabis plant to reach maturity, but a batch of yeast can be grown in about a week.
· Less space: a large scale yeast operation only requires a fraction of the space of a similarly productive cannabis grow operation.
· More sustainable: cannabis cultivation requires heavy resource usage, including lighting, ventilation, water, and pesticides. Producing cannabinoids from yeast is much less energy and resource intensive.
Yeast: The Key to Rare Cannabinoids?
Despite the benefits, it may still be difficult to outperform cannabis plant yields for THC and CBD. That’s because THC and CBD are the most abundant cannabinoids—the plant produces these compounds in large quantities. However, yeast has the potential to truly shine when it comes to more rare and novel cannabinoids.
There are over 100 cannabinoids that occur naturally in the cannabis plant but only in very small quantities. This makes them hard to extract and even harder to study. The amounts required for pharmaceutical research would be prohibitively expensive using traditional plant extraction methods. As a result, research exploring the therapeutic properties of these cannabinoids has made little progress.
Yeast production solves this problem by enabling the production of large amounts of specific cannabinoids beyond THC and CBD. Aside from THC and CBD, Keasling and his colleagues were also able to produce the naturally occurring but less abundant cannabinoids THCV (tetrahydrocannabivarin) and CBDV (cannabidivarin).
They also found that yeast as well as the enzymatic steps required for making cannabinoids were quite flexible. This means researchers could design yeast strains to produce both rare and completely novel cannabinoids with medically useful properties.
Co-opting yeast metabolism
To achieve the production of cannabinoids in yeast, the group engineered the biosynthetic pathway. This began with establishing a pathway for the initial intermediate, olivetolic acid.
Olivetolic acid, together with the mevalonate pathway intermediate geranyl pyrophosphate (GPP) are the precursors to Cannabigerolic acid (CBGA). CBGA is the core cannabinoid from which others are derived. This conversion is performed by geranylpyrophosphate:olivetolate geranyltransferase (GOT).
Namely, CBGA is the precursor to tetrahydrocannabinolic acid (THCA) and cannabidiolic acid (CBDA) in addition to several of their cannabinoids. GPP was produced by introducing an expression cassette encoding the Enterococcus faecalis genes and overexpression of the native mevalonate pathway gene.
Hexanoyl-CoA, the precursor to olivetolic acid, was produced by an additional heterologous biosynthetic pathway using genes from several bacteria and the cannabis plant itself. Alternatively, hexanoic acid was used as a substrate for the enzyme endogenous acyl activating enzyme (AAE), which converts hexanoic acid into hexanoyl-CoA.
Where can I buy THC producing yeast?
They don’t exist outside of research labs trying to scale the process up to commercial/industrial size. It’s important to note that the yeast have to be fed cannabinoid precursors (sometimes other cannabinoids like CBG actually) to make desires cannabinoids.
It’s a complicated multi step process that requires experience and knowledge across multiple scientific disciplines. When one does get yeast to produce a desired cannabinoid, those cannabinoids still must be extracted, separated and purified from a bunch of stinky yeast.