New research paves the way for cannabinoids without cannabis
marijuana becomes increasingly mainstream — the legal cannabis market is estimated to reach $166 billion by 2025 — the potential for cannabis to change numerous industries from health to food is great. The future of cannabis may feature production facilities that have more in common with a craft beer brewery than a grow house — and leave out the plant altogether.
In a paper published today in the peer-reviewed journal Nature, biochemists at the University of California, Berkeley report what some cannabis industry experts are describing as a breakthrough in biosynthetic cannabinoid production. By using genetically modified yeast, the Berkeley scientists were able to convert simple sugars into the active chemical compounds in marijuana: tetrahydrocannabinol (THC) and cannabidiol (CBD). The scientists made THC and CBD — the chemicals that get users high and which have supposed medical benefits — without the marijuana plant.
The research could help make these compounds — which are produced in relatively low quantities by the plant — much cheaper and more widely available for medicinal and recreational use, potentially bypassing some of the common constraints for the traditional marijuana market, including sky-high energy needs and a complex, ever-shifting legal landscape.
“It’s an idea that many companies have been working on, but I’ve never seen anything so thorough,” says Daniele Piomelli, director of the University of California, Irvine’s Institute for the Study of Cannabis, who was not involved in the research. “It appears like a very substantial step forward.”
Over the last few years, biosynthesis — the process of producing complex molecules within living cells — has quietly gained ground as a way to satisfy the booming demand for nonsmokable cannabinoid products, like THC-laced snacks and CBD-infused oils. A handful of American and Canadian companies have begun to file patent applications for cannabinoid-producing yeast, E. coli, and other easily-manipulated microorganisms, usually keeping their research a secret to maintain their business advantage.
But Samuel Banister, a chemist at the University of Sydney’s Lambert Initiative for Cannabinoid Therapeutics, who was also not involved in the research, says the Nature paper is the first public disclosure of the full process needed to make yeast produce cannabinoids at commercially-viable levels. He believes the work could also pave the way for yeast to synthesize some of the other cannabinoids besides THC and CBD, of which there are over a hundred, that could be promising for medical applications but are only found in cannabis plants at low levels.
The new research from the Berkeley scientists centers on the identification of a cannabis enzyme that can be transferred into yeast DNA so that it metabolizes sugar into cannabinoids instead of alcohol and carbon dioxide. Thanks to a large public database of cannabis DNA, scientists had identified dozens of potential candidates for this enzyme. But few are compatible enough with yeast DNA that they can produce large volumes of cannabinoids without side effects that damage the final product.
“You’re asking a yeast cell to make something it doesn’t normally make,” says Banister. “There’s always the chance it might be toxic or have other downstream effects on the viability of the cell.”
“It’s as easy as brewing beer.”
Jay Keasling, the biochemist at Berkeley who led the research, says his team tested dozens of options before finding the right combination of enzyme genes. Yeast is a good host organism, Keasling says, because its DNA is thoroughly documented and because it’s already in wide use for other commercial applications like beer-making and wine-making.
“It’s as easy as brewing beer,” says Keasling. “You feed the yeast sugar, it grows and replicates, produces the THC, and secretes it outside the cell so that it’s floating in the sugar water that the yeast is growing in. It comes in high concentrations, and then we purify it away and you’re left with a very pure white powder.”
Keasling filed a patent for this method back in 2017, and has since been hammering down the science and working with a Bay Area biotech startup, Demetrix, to bring the process from the lab into commercial production. Over the next few years, the company hopes to bring the cost of production below $1,000 per kilogram, far below the cost of chemically-synthesized cannabinoids (tens of thousands of dollars per kilogram) or cannabinoids extracted from a plant (more than $5,000 per kilogram), according to Jeff Ubersax, the company’s CEO.
Biosynthesized cannabinoids aren’t yet being produced commercially by any company. And some of Demetrix’s competitors remain skeptical that Keasling’s approach is much different from what others are cooking up behind the scenes.
“They’re showing how these pieces will all go together, which is cool, but I don’t know that I would describe it as a breakthrough,” says Kevin Chen, CEO of Montreal-based Hyasynth Bio, which recently received a $7.6 million investment from the Canadian cannabis distributor OrganiGram to speed up the rollout of its own biosynthetic cannabinoids. “Everyone is in the research stage, so it’s hard to say who will have the first product out.”
Ronan Levy, chief strategic officer of another Demetrix competitor, New Mexico-based Trait Biosciences, says his company’s preferred approach is to find ways to induce a cannabis plant to produce cannabinoids in every one of its cells, rather than only those in the “tricone” (better known as the “bud”), where it grows naturally.
“Instead of trying to find other organisms, why not figure out how to expand on what the plant can do?” he says. “Yeast is definitely interesting, we just don’t think it makes the most sense.”
“So you have a yeast that makes THC. Do you schedule this yeast?”
It’s unclear whether biosynthesized cannabinoids would be subject to the same legal restrictions as plant-derived compounds, since federal law applies to the plant and not necessarily to the cannabinoids in it. Cannabis researchers are subject to tight restrictions on where they can procure samples, and the Food and Drug Administration has approved only one CBD-based drug, Epidiolex, for childhood epilepsy.
“So you have a yeast that makes THC. Do you schedule this yeast?” says Piomelli, referring to the Drug Enforcement Administration’s drug classification system. “We haven’t seen the law at work enough to conclude, case by case, what will work. The legal landscape on cannabis is so confusing that almost anything goes.”
Either way, biosynthesis is poised to change the way we think about getting high.
“We don’t make insulin from animals anymore, and the plant won’t be the way forward for industrial production of cannabinoids,” says Banister. “If big corporations want to move into the cannabis space, I think they will be moving in this direction.”