Humans have been using yeast to produce the world’s most popular drug, alcohol, for millennia. Yeast has the natural ability to convert sugar into alcohol, as long as you starve it of oxygen. Consequently, we have used these biological factories to produce a wide variety of intoxicating beverages.
Using modern synthetic biology techniques, yeast can make more than just booze. Dr. Jay D. Keasling and his colleagues at the University of California, Berkeley have developed a way to use these organisms to produce CBD, THC and other cannabinoids.
This technology has the potential to make the production of cannabinoids cheaper, more efficient, and more sustainable. Currently, as many as 20 companies are working to produce these compounds in yeast.
Yeast-based cannabinoids are one of the first bioengineered cannabis technologies. However, researchers are developing other techniques using bacteria, enzymes, and genetically modified plants.
The application of advanced molecular biology techniques to the CBD and cannabis industry is still quite new. Nonetheless, industry leaders told CBD Hacker that products that depend on these technologies will be available in under two years.
Making Yeast Produce Cannabinoids
Making Yeast Produce CannabinoidsCultivators have been working to produce cannabinoids more efficiently for millennia. Since the cultivation of cannabis began over 4000 years ago, this plant has been gradually modified through selective breeding.
Like all domestic species, humans have taken the reigns of cannabis’ evolution through “artificial selection.” Growers have selected cultivars (or strains) for stronger fibers, greater medicinal properties, and more potent intoxication.
Genetically modified organisms have brought about a radical change to the way humans modify nature. The discovery and harnessing of the CRISPR/CAS9 system allows biochemists to move genes between completely unrelated species.
As with all new technologies, this advance has enabled wonderful, terrifying, and outright odd innovations. It has been used to produce drought-tolerant plants, glowing mice, and very recently, genetically modified humans.
Today, the agriculture and pharmaceutical industries rely heavily on GMOs, but the prohibition of cannabis has slowed the use of these technologies in cannabis plants. Today, the expansion of cannabis legalization has allowed this plant to enter the world of genetic modification — for better or for worse.
The Benefits of Yeast
Brewer’s yeast (Saccharomyces cerevisiae) is a popular organism amongst scientists. It grows rapidly and shares traits with human biology. Yeast happily grows in large vats, feeding on sugar and oxygen.
For these reasons, yeast is a popular “model organism” used in scientific research as an early test subject. It is the guinea pig for the guinea pigs.
Dr. Jason Poulos is the CEO of Librede, the first and only company with a US patent for producing cannabinoids in yeast. He described the many advantages yeast offers over plants.
Compared to agricultural production, yeast may be more environmentally and economically sustainable, Poulos said. Depending on the cannabinoid it is producing, using yeast may reduce costs by 10 to 100 times while generating a consistent, pure product.
Not only would this method eliminate supply chain variability, Poulos added, but it would lead to “no fertilizers, no pesticides, less land, less water, less energy, [and] faster production.”
While chemists produce most pharmaceuticals using synthetic chemistry from cheap starting materials, this is not always possible. Synthesizing cannabinoids in the traditional way is prohibitively expensive. Therefore, we must rely on enzymes (nature’s molecular chemists) to create these compounds.
Enzymes naturally do this job in the cannabis plant. Using genetically modified organisms to carry out chemical synthesis is called biosynthesis. This new technology promises to decrease the cost of production of many important chemicals.
Producing Trace Cannabinoids at Scale
In addition to THC and CBD, cannabis contains a multitude of other “trace” cannabinoids. These natural chemicals each have unique biological properties. Many may provide unique therapeutic benefits. Others have never been studied due to their rarity.
Producing cannabinoids through biosynthesis has an interesting benefit. It allows you to produce pure versions of uncommon cannabinoids. As Dr. Jim Bowie of UCLA said, “There are a wide variety of cannabinoids that might have medical uses, but they are too low in abundance to effectively extract from plants. … [W]e should be able to provide more affordable access to many more pure cannabinoids than is currently possible.”
In the cannabis plant, these compounds occur together at different ratios. In yeast, it is possible to produce one cannabinoid at a time. By feeding the yeast specific fatty acids, researchers control which cannabinoids they produce.
Dr. Poulus told us: “We make single isolated compounds. These can be mixed to mimic the exact ratio found in the cannabis plant.”
The “Unnatural” Cannabinoids
Cannabinoids (including CBD and THC) are any chemical that activates the cannabinoid (CB) receptors in the human body. Our body produces endocannabinoids, the natural activators of CB receptors.
Alternatively, plants produce compounds known as phytocannabinoids. Beyond the cannabis genus, they have been found in Echinacea spp., tea (Camellia sinensis), kava (Piper methysticum,) and many other plants. These compounds come in many shapes and sizes. What they have in common is that they interact in some way with your CB receptors.
The cannabis plant produces at least 113 different cannabinoids. However, biosynthesis can also produce cannabinoids not found in nature.
These new cannabinoids may have unique properties and therapeutic potential. Though little is known about them yet, they may prove to be more effective and potent than THC or CBD.
These compounds will also pose the opportunity for big profits since, unlike naturally occurring cannabinoids, they can be patented.
Other Drugs Produced by Yeast
Yeast has continued to make a popular test subject in the era of genetic modification, and there are untold numbers of genetically modified strains of yeast.
Researchers have created many of these simply to test the function of specific genes. This work has provided many important insights into genetic disorders and biochemistry.
Genetically modified yeast strains have also been used to produce other pharmaceuticals. Notably, these biosynthetic techniques have been used to produce opiates. Opiates are another class of chemicals that are difficult to synthesize in a lab. These compounds are still synthesized from opium poppies.
Pharmaceutical companies continue to make huge profits pushing these highly addictive pain medications, ignoring many safer options. Sadly, bioengineering may soon offer yet another way for pharmaceutical companies to profit off the opioid crisis.
Other Ways to Produce Cannabinoids
Though yeast has many benefits, it is far from the only option for biosynthesis. Genetic modification allows bioengineers to place the genes for cannabinoid production in many organisms. It also allows us to create purified versions of the enzymes needed for these reactions.
Finally, genetic modification can be applied to the cannabis plant itself. Directly editing the cannabis genome may allow the plant to produce cannabinoids more efficiently.
Bacteria
Another common organism in scientific research is bacteria. The simplicity of these cells and their rapid replication make them another popular candidate for biosynthesis.
A German company called Farmako has already filed a patent for this process. They are using genetically modified versions of bacteria used in tequila to produce cannabinoids. They claim to produce far larger quantities of cannabinoids than has been achieved with yeast.
Enzymes
Dr. Jim Bowie of UCLA has developed a way to synthesize complex biological molecules that doesn’t rely on microorganisms. Instead, enzymes (naturally occurring molecular machines) synthesize these compounds outside of a cell. This technology has applications for the synthesis of many complex drugs. Avoiding the use of microorganisms can simplify the process of biosynthesis while retaining the benefits.
Dr. Bowie has succeeded in using this process to efficiently synthesize precursors to THC and CBD. In describing the advantages of these techniques over yeast, he told CBD Hacker:
“We don’t have to worry about keeping the yeast happy. … The yeast don’t really want to make cannabinoids, so this has a tendency to annoy them and they fight back by finding ways to avoid making cannabinoids. … By freeing ourselves from biological limitations it can be easier to make what we want.”
The Cannabis Plant is Still King (for now)
The Cannabis Plant is Still King (for now)The obvious biological machine for making cannabinoids is, of course, the cannabis plant. Humans have cultivated cannabis for millennia, selectively breeding it for potency, medicinal value, and many other desirable traits.
Even without genetic engineering, humans have changed cannabis from a weed with mild medicinal properties into an extremely potent medicine and recreational drug. The flowers of the cannabis plant can contain nearly 30% cannabinoids by dry weight. Extracts made from cannabis often reach a purity of over 95%.
Genetically Engineering the Cannabis Plant
Today, some companies are beginning to apply genetic engineering to the cannabis plant itself. Ronan Levy is the chief strategic officer at Trait Biosciences. This company is using genetic engineering and biochemistry to create water soluble cannabinoids in the cannabis plant. He provided us with valuable insight into the advantages of the cannabis plant.
“The hemp/cannabis plant has evolved over hundreds of thousands, if not millions, of years to efficiently produce cannabinoids. Our philosophy is that when it comes to the major cannabinoids (THC and CBD) there is no more efficient organism to synthesize these.”
We asked Mr. Levy to tell us more about the advantage of using the cannabis plant rather than biosynthetic technologies.
“The plant can produce concentrations of cannabinoids 10,000 times greater than is currently being produced in these other organisms. … [O]ur focus [is] on optimizing the current machine (the plant) to produce cannabinoids more efficiently.”
Though biosynthetic techniques promise to offer trace and novel cannabinoids in their pure form, Trait Bio is unconcerned. Mr. Levy told us that Trait Bio’s modified cannabis plants can now produce these trace cannabinoids in large amounts.
“[O]ur team has actually developed a new technology to produce most of the minor cannabinoids at an industrial scale without the need for biosynthesis.”
The Future of Cannabinoids
Though today this is still in the research stages, that will change. Companies will likely begin using these technologies in consumer products very soon. Dr. Poulus says consumers should expect to see yeast-grown CBD products in the next 18-24 months. He believes these technologies are the future of cannabinoid production.
“[Expect] big changes, this type of production will replace the majority of agricultural production.”
Right now Dr. Poulus sees consumer bias against GMOs as the largest barrier in this industry. Biosynthetic pathways produce the same exact chemicals as “natural” pathways, so these products are indistinguishable from pure cannabinoids extracted from plants.
Patenting Weed Genes
Currently, Dr. Poulus’ company, Librede, is the only company with rights to the US patent for cannabinoid production in microorganisms. Dr. Poulus’ filed his patent in 2014, five years before Dr. Keasling published in Nature. However, research published in patents is not subject to peer review. It therefore does not hold the same weight in scientific communities.
Included in this patent are the 53 sequences of genetic code used to create their yeast. These include modified versions of the genes cannabis uses to produce cannabinoids.
The ethics of patenting genomes and organisms has been discussed for decades. Currently, genetic patents only apply to “useful” products that only exist due to human intervention. However, the legal definition is still being debated, and human-bred cannabis strains may present a gray area.
A company called BioTech Institute has been broadly patenting cannabis genes, with unclear intentions. Fear of lawsuits could hamper innovation and decrease research into the production and uses of cannabinoids.
Additionally, cannabis patents could also create a “Monsanto of cannabis” that dominates the industry.
Librede is creating a novel and valuable technology and is clearly entitled to profits from their innovation. However, these technologies might develop more quickly if all research was shared. The balance between healthy competition and incentives to innovate is difficult to strike.
As this nascent industry matures, encouraging healthy competition is essential — but far from simple.
A Changing Landscape
The future of cannabinoid production is still uncertain. One thing, however, is clear: technology will fundamentally change the way we produce cannabinoids.
Whether it involves yeast, bacteria or GMO cannabis plants, change is coming. These maturing technologies (and the evolving laws surrounding them) are sure to greatly affect the cannabis and CBD industries in years to come.
