The first year I could vote, in the early 2000’s, medical marijuana was on the Michigan ballot. I voted yes, even though I didn’t know nearly as much as I do now as a PhD-trained research scientist. I was aware even then that marijuana could have many more uses than just giving someone a good time. While many conservatives laughed at the word “medical” tacked to the front of it, viewing it as a ploy to legalize bad behavior, this conservative placed her bets on the future of medical marijuana in the clinic.Now there is no question about the potential benefits of the marijuana -- or Cannabis sativa L. -- plant. The two main plant components (cannabinoids) used in medicine -- tetrahydrocannabinol (THC) and cannabidiol (CBD) -- have been used to treat a variety of conditions, from pain to nausea and vomiting caused by chemotherapy. In 2018, the FDA approved the use of EPIDIOLEX®, an oral CBD formulation used to treat seizures in young children. Even “recreational” use is changing, with a considerable number of users self-medicating for anxiety, pain, or to sleep better -- they’re not using it simply to get high.Investors have taken notice, and the market is booming. Over $10 billion USD was poured into the North American cannabinoid market in 2018, and that number is expected to grow to over $16 billion this year. And, according to Arcview Market Research and its research partner BDS Analytics, spending on legal cannabis worldwide is expected to hit $57 billion by 2027. Many of these dollars certainly go toward recreational use, but it won’t be long until cannabinoid-based drugs represent a significant proportion of cannabis spending.

The problem with plants

One of the biggest challenges facing medicinal cannabinoids is the growth of the plant itself -- and extraction of pure cannabinoids from the plant in consistently high amounts. There are over 100 known cannabinoids, and we don’t know what most of them do. They can be present in the plant at such low amounts that extracting them in any useful amount is impossible.Plants also need space to grow, and cannabis farmers face dwindling arable land as any farmer in the U.S. -- or the world -- does. Many have turned to indoor cultivation, but even then, only 4-6 harvests per year are possible. And, purifying cannabinoids and resins from the plants is costly and unsustainable. The THC content can also vary across harvests -- not necessarily critical for recreational users, but a potentially significant problem for patients who rely on specific daily doses.So, how to solve these issues? The answer shouldn’t come as a surprise, for it’s solved similar challenges for other food ingredients, such as steviol glycosides from the Stevia plant.The answer is microbes.

Microbial cannabinoid factories

Leveraging fermentative microbes to produce cannabinoids from sugar could transform the medical marijuana market. Instead of 4-6 harvests per year, the number of “harvests” from cannabinoid-producing microbes could rise to over 20 -- and all with less intensive and expensive extraction of the desired product(s). And, the 100+ other cannabinoids that we know nothing about? Microbes can be used to produce those at high levels, too, potentially opening the doors to treatments for a range of conditions we haven’t even thought to target with cannabinoids yet. With synthetic biology techniques facilitating microbial production of novel cannabinoids, too, the potential uses grow even more.Several groups -- both academic and industrial -- are working to develop high-throughput, high-yield cannabinoid-producing fermentation processes. Many of them are leveraging one microbe we are already familiar with -- Saccharomyces cerevisiae, the yeast used to brew beer. In February, UC Berkeley synthetic biologist Jay Keasling and colleagues reported in the scientific journal Nature the first complete biosynthesis of cannabinoids in a yeast cell -- demonstrating that it’s not just a good idea, but that it’s possible. They produced 8mg of THC per liter of yeast culture (their yeast strain can also produce CBD and novel cannabinoids not produced naturally by the plant).While it’s a start, those levels are quite low, yielding some skepticism. At the current rate of production and development, it could take 18-24 months for the cost-effectiveness of cannabinoids produced via fermentation to reach marketable levels, predicts David Kideckel, a cannabis analyst with AltaCorp Capital in Toronto, Canada. But in the grand scheme of things, 18-24 months isn’t that long -- and Keasling is already ahead of the game. His company Demetrix, founded in 2015, has already boosted these yields by several orders of magnitude, according to a Nature News article.Other companies are also working to scale up production of synthetic cannabinoids with yeast, including Ginkgo Bioworks (together with Cronos Group), Hyasynth Bio, and Librede, which holds the first patent on a process making cannabinoids from sugar via yeast fermentation. With a shortage of medicinal cannabinoids leaving some patients desperate, such a competitive, healthy ecosystem is a welcome arrival.Yet not everyone is focused on yeast as a chassis organism. Farmako, based out of Frankfurt, Germany, is using a bacterial species called Zymomonas mobilis -- the same species used in tequila production -- to produce cannabinoids. The company is the first to produce synthetic cannabinoids in an organism other than yeast, and has filed a worldwide patent application with the European Patent Office for their organism.Farmako has also made large strides toward making the production of synthetic cannabinoids cost-effective: the cost of producing one kilogram of THC with their bacteria is one one-thousandth that of traditional plant cultivation. This is in part because Farmako’s fermentation process is continuous. The bacteria secrete the cannabinoids directly into the surrounding medium, from where they can subsequently be extracted. Yeast do not, and therefore their cells must be split open to release the cannabinoids -- stopping the fermentation process.“With one production run, we can produce cannabinoids for 900 hours without interruption …. 4.5 kilograms of THC are produced per gram of bacterial mass during this time,” said Patrick Schmitt, co-founder and Chief Science Officer (CSO) of the company. Farmako can produce 180 different cannabinoids through this process.

What about bioavailability?

But improving the production of cannabinoids, while a critical issue, is only one side of the problem. Both the administration and effectiveness of cannabinoids is also seriously hindered by the chemical nature of the molecule itself, which renders it insoluble. This characteristic critically lowers the bioavailability -- and thus the effectiveness -- of cannabinoids.Take, for example, cannabinoids for pain relief. Most application is via patches on the skin, but because the molecule is so poorly absorbed through the skin, it can take quite some time for the patient to experience any type of pain relief. Cannabinoids taken orally to relieve seizures also suffer from insolubility and low bioavailability. So, while microbial production of cannabinoids can solve the issues around production, higher quantities of purer cannabinoids doesn’t mean much to patients that need rapid relief from symptoms. Can microbes be used to solve the bioavailability problem, too?The answer is yes, as it turns out. Copenhagen-based Octarine is developing a yeast-based platform to produce cannabinoids with improved pharmacokinetics properties. The chemical diversity their platform can create within cannabinoid molecules could one day facilitate the production of several important cannabinoid-based pharmaceuticals for a range of conditions.“We look into the pharmacokinetics and pharmacodynamics of these molecules, and how we can improve them,” says Nethaji Gallage, co-founder and CEO of Octarine. “We are not creating new value by producing said molecules at high titers like other synthetic biology companies are planning to do, our value proposition is quite different than that. Our plan is to create a huge chemical diversity within these molecules. We will create the diversity and improved cannabinoids that are IP protected, allowing the pharmaceutical industry to go toward certain applications.”It may have taken over a decade for synthetic biology to begin propelling medical marijuana to promising new levels -- both in terms of sustainable, high throughput production and in terms of value to the patient. We have reached an inflection point, and new fermentation technologies and optimized organisms are about to spill over. I’m glad I voted for medical marijuana way back then.Learn more about synthetic cannabinoids and the cannabinoid market at SynBioBeta 2019, October 1-3 in San Francisco.