The Rise of Franken-Cannabinoids?

cannabis geneticsIn the near future, the CBD, THC or other cannabinoids you consume in edibles or medications may not be derived from cannabis at all, but grown in a laboratory.

Kevin Chen, CEO and co-founder of Hyasynth Bio, describes the Montreal-based start-up as "focused on engineering strains of yeast to produce the active compounds of cannabis without having to grow plants."

Hyasynth is one of several such firms with high hopes for "bio-synthesis" of cannabinoids. Since its founding in 2014, Hyasynth has raised $12 million in investment, the bulk of it coming from New Brunswick's Organigram, one of Canada's leading licensed producers of cannabis.

"We're still in the research and development stage, but we hope to sell to companies bringing CBD to market," Chen says. "We expect to see food and beverage companies get into this. There are several advantages to industrial fermentation, including efficiency gain, especially with larger scale production. It's a lot faster and easier for a higher yield."

He notes that lactic acid, citric acid (vitamin C) and many antibiotics are already produced by this method.

The technology was first pioneered in the 1970s, especially by the San Francisco-based Genentech, to produce insulin—which was previously extracted from pig pancreases, a very inefficient method by contemporary standards. Today, the process begins with gene-splicing—taking human DNA and placing it into a bacterium, from which the insulin can then be produced.

"Similarly, we're putting a cannabis gene into yeast," Chen explains. "In the mapping of the cannabis genome over the past 20 years, researchers have been identifying the genes responsible for producing cannabinoids. That research is publicly available, so we don't have to actually handle cannabis ourselves. We are getting the genes for the enzymes that are responsible for its production, and we add it to the yeast genome. These genes are made synthetically, and arrive in the mail as a small tube of clear liquid."

For instance, CBDA synthase and THCA synthase are lab-produced enzymes that stimulate production of CBDA and THCA, which are respectively the precursors to CBD and THC.

Chen says companies in the US, China and elsewhere around the world are "synthesizing genes from individual nucleic acids, the sub-units of DNA."

Chen emphasizes that "the CBD we produce is not different from that derived from plant extraction. We are using an engineered yeast to produce the stuff, but the end product is not modified."

What is unique is the process. "We are developing our own patent portfolio and have made several submissions so far. Two of our applications are published," Chen says. 

"We are developing a proprietary process for the production of cannabinoids. Our IP portfolio will include many different aspects of that process, including unique aspects of our yeast strains that we've developed."

There is obvious market potential for this in edibles, which are just now poised to take off in Canada. Edibles have been legal under Canada's medical marijuana program since 2015 pursuant to a Supreme Court decision, and became legal for the adult-use market under Health Canada regulations that took effect last year. So while the industry in the United States is still waiting on the FDA to approve use of CBD in edibles and medications, in Canada this sector is set for fast growth.

However, unlike in the US, CBD is only available at licensed cannabis dispensaries in Canada. And THC edibles are generally freely available in US states that have legalized, while they are just now about to hit the market in federally legalized Canada.

"In every market we have to do an analysis," says Chen. "More regulators are catching up with the technology. In Canada, all cannabinoids are treated the same under law no matter how they’re derived. We are actively analyzing whether it would be legal in US."

Pursuant to Canada's 2018 Cannabis Act, all cannabinoids are now regulated by the provinces with oversight from Health Canada's Controlled Substances and Cannabis Branch, as opposed to the federal Office of Controlled Substances, which relinquished the oversight it had maintained under the Controlled Drugs and Substances Act.

As for the enzymes used to initiate cannabinoid production, Chen calls this a "baby step in the process" not restricted under either US or Canadian law. "The gene is not treated as a controlled substance," he says.

Legal complexities notwithstanding, these products are certainly headed to market both sides of the US-Canadian border in the near future.

Big Bud looks beyond actual bud
Organigram's 2018 $10 million investment deal with Hyasynth is one of several like deals recently reported, in both Canada and the US as well as Europe.

Also in 2018, Toronto's giant licensed producer Cronos Group announced a strategic partnership with Boston-based Ginkgo Bioworks, which is likewise pursuing cannabinoid production through fermentation. The Canadian Press put the deal at $22 million.

Cronos chief executive Michael Gorenstein told the Canadian Press last April that the partnership will focus on "rare cannabinoids," which are "economically impractical" to produce at scale through "traditional cultivation and extraction."

Also named as pursuing this method are Vancouver-based InMed Pharmaceuticals and Amyris of Emmeryville, Calif. Ginkgo Bioworks and Amyris both hold US patents on producing cannabinoids from yeast.

These companies may soon be joined by Demetrix, founded by UC Berkeley researcher Jay Keasling and led by former Amyris executive Jeff Ubersax. As TechCrunch reports, Demetrix last year received an infusion of $50 million from Horizons Ventures, the Hong Kong firm backed by real estate billionaire Li Ka-shing, and Tuatara Capital, a Manhattan-based fund that invests in the legal cannabis industry.

The proximity of the University of California's most prestigious institution (as well as the very cannabis-friendly local culture) promises to make East Bay a research hub in this sphere.

At least one European company is also on track with this methodology. Last year Farmako of Frankfurt applied with the European Patent Office for worldwide rights to a micro-organism it has developed for the production of cannabinoids from sugar. The engineered bug, dubbed Zymomonas cannabinoidis, is a modified version of Zymomonas mobilis, the bacteria used in production of tequila. As Digital Journal notes, the genes responsible for production of alcohol were removed and replaced with genes from the cannabis plant—and the malaria parasite, of all things.

Patented genetically modified cannabinoids coming?
THC has already been synthesized for pharmaceutical use in the US. There are two brands on the market, Marinol and Syndros, that use a synthetic THC compound called dronabinol. It was approved by the FDA in 1985, primarily for treatment of the wasting syndrome in AIDS patients (by stimulating the appetite) and alleviating nausea caused by chemotherapy. A third FDA-approved drug, Cesamet, also prescribed for chemo patients, contains a compound known as nabilone that has a similar structure to THC. But these are chemically synthesized, while the focus of the new research is on biosynthesis.

It's the possibility of new biological compounds, that mimic cannabinoids actually found in cannabis but are nonetheless unique enough to be patented, that holds particular promise for the industry's future.

Kevin Chen told Project CBD that Hyasynth has already produced "novel cannabinoids that aren't found in the cannabis plant."

Jeff Chen (no relation), executive director at the UCLA Cannabis Research Initiative, similarly told Green Entrepreneur last year that while you can't patent that plant, "these novel compounds are able to be patented, and [scientists] are able to modify the molecules for different ailments."

Actually, the patenting of cannabis plant strains is also underway—to the alarm of many small-scale growers. But claims to patentable "novelty" will be far less ambiguous with new chemical compounds.

Carly Bader, analyst for the microbial team at Denver-based AgriScience Labs, notes one way that the legal restrictions incentivize creation of modified cannabinoids.

As Bader explained to Project CBD: "You could modify these chemicals in such a way that it doesn’t act in a different way, it has the same analgesic effect, for instance—but the molecule has an extra ring structure. The extra ring structure is inert, but it makes it not THC or not CBD. So it lets you skirt around the law, because there's no genus cannabis involved."

But she also notes that only plant-derived cannabinoids provide the "full spectrum" effect. "You can isolate CBN, CBG or CBC. But there's this idea that these things work together, so purity may not be best when it comes to producing the effect you want."

On the other hand, this technology could become critical if demand grows for these rare cannabinoids. "The plant would never make a high enough concentration of these cannabiniods for the health benefits to be clinically relevant. One of our clients is making a topical with 500 milligrams of CBN per gram. Now, they are using plant-derived CBN, but it take a lot of plants and a lot of effort to produce."

CBN, she notes, is also in a legally ambiguous category. "It is not listed as a controlled substance but can be considered an analogue of THC," Bader says.

"It is not always clear or precise whether a particular chemical structure is legal," Bader elaborates. "After so many years of prohibition, we're kind of working in the opposite way with cannabis—we've made this plant legal in certain states, and now have to determine what else is legal. When I was researching cholera toxin, nobody was withholding it from me. Whereas with cannabis, we're moving from an atmosphere in which there was no federal funding, it was all illegal, to trying to strip these laws and allow the research to happen."

"Whether it's law or stigma, it's an obstacle to getting into this field," Bader sums up. "I had to take a big breath before I got involved because I knew it would place me on a certain spectrum. But now I'm proud to be involved and helping to advance science and public health."

Is there a dark side?
Such idealism, however, will doubtlessly be contrasted by a deep wariness in some quarters. 

Much of the current apprehension about genetically modified organisms in food and agriculture is misplaced. Too often, the emphasis has been on the possible health hazards of GMOs (often derided as "Frankenfoods"), for which there is actually little evidence. This allows biotech boosters to dismiss the critics, while both sides overlook potential adverse social impacts of the technology—for which there actually is pretty solid evidence.

A commentary on the website of the Thai Cannabis Corporation, dedicated to advancing the nascent cannabis industry in the Southeast Asian nation, expresses some forebodings about what lab-grown cannabnoids could mean for growers of the good old-fashioned plant, and especially in the developing world.

The commentary draws an analogy to vanillin, the organic compound that gives vanilla its flavor. It is of course found in the plant, but today lab-synthesized vanillin supplies more than 99% of the global demand for vanilla flavoring. And that of course means that less than 1% is supplied by extracts from farmed vanilla. Most of that 1% today comes from Madagascar—and growing vanilla is a rough life. Notes the commentary: "After Madagascar was recently hit by cyclones and drought, the cost of farmed vanilla extract shot up... yet Madagascar's farmers remain poor."

The Thai Cannabis Corporation predicts: "Just as with vanillin, artificial THC, CBD, CBG, etc. are likely to be 'good enough' to satisfy 99% of global demand. All of the world's cannabis farmers will be fighting over the remaining 1% of global demand, and only the world's best cannabis farmers, in its poorest developing nations, will survive… if you call extreme poverty 'surviving.'"

The commentary even foresees biosynthesis eventually developing to the point that it could actually mimic the full-spectrum effect: "Chemists are very likely to be able to blend artificial cannabinoids, terpenes, and flavonoids into an imitation extract that's subjectively indistinguishable from, and as effective as, the extracts from the very best farmed Gorilla Glue, Jack Herer, Charlotte's Web, or any other cannabis strain."

Which could certainly spell eventual disaster for cannabis growers.

Hyasynth's Kevin Chen, asked for thoughts on this critique, offers: "One brief counterpoint is that cannabinoids have immense potential as pharmaceuticals, while vanilla does not. Scale and consistency are important when considering the pharmaceutical supply chain, which is partly why the insulin story is so successful... I think most people agree that cannabis is a unique scenario, and also that having access to high-quality and low-cost medicine is a good thing."

It's a truism that technology often proves a double-edged sword, holding out promise as well as peril. Certainly, followers of the cannabis industry would do well to closely watch the developments in corporate biotech labs from Montreal to East Bay to Frankfurt.

This story first ran Feb. 28 on Project CBD

Image via Project CBD


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