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Brewing Cannabinoids from Bacteria and Sugar: How (and Why) Creo Ferments

Lance Griffin
Written by Lance Griffin

An Interview with Roy Lipski

Insulin for diabetics was once extracted from animal pancreases. This proved cumbersome and costly. In a race to bioengineer the hormone and meet demand, company Genentech turned to recombinant DNA technology. They effectively modified the bacteria Escherichia coli (E.coli) to churn out huge quantities of insulin and meet global demand.

Today, this technology has found another purpose: mass producing rare cannabinoids.

Conversing with Roy Lipski, creator of Creo, I learned about his company’s biosynthesis of cannabinoids from bacteria and sugar. Lipski emphasized the cutting-edge nature of the technology and its sustainability. He explained that cannabinoid biosynthesis from bacteria can never replace traditional horticulture. Rather, manufacturing cannabinoids without growing any plants aims to expand the industry.

 

Can you tell me about your biosynthesis process and how you produce cannabinoids?

Biosynthesis is the process whereby you build up more complex molecules from simple building blocks like sugars.

Within a cell, life is chemistry. Hundreds of chemical reactions take place simultaneously to sustain life. A pathway is a collection of chemical steps, each catalyzed by proteins called enzymes. Let’s take this into context of cannabinoids.

Cannabinoids are complex organic compounds. They are produced naturally in the cannabis plant via a chemical pathway catalyzed by particular enzymes. You can transport that pathway into a microbe. Given the same starting materials and the same enzymes, you get the same outcome. It’s bioidentical to what’s made from the plant because it uses the same enzymes and pathways; you could put the two side by side and not be able to tell the difference. But what you’ve now done is put it into a much more efficient host.

The cannabis plant doesn’t exist to make cannabinoids. It exists to grow and to make stalks, leaves, buds, etc. A lot of its energy makes things that are not cannabinoids. In that way, when you’re harvesting plants just for cannabinoid content, there’s quite a lot of waste. That’s without going into intense agricultural practices or growing indoors.

On the other hand, microbes grow very fast. You can control what they do with their energy, and the yield is much higher than you get from the plant. The cycle times are much shorter.

The way you grow a bug [(i.e., E.coli)] is in a broth. It’s basically fermentation. You put it in liquid. You add sugar. You give it some air and mix it around. These vats look like what you’d see in a microbrewery. They are big fermentation vats. You feed them, and two days later you’re finished. With the cannabis plant, you’ve got maybe one harvest per year outdoors or 3-5 per year indoors. Here, you can have two harvests a week.

 

Do you see this technology as potentially disruptive?

Biosynthesis has been making steady inroads not only into the pharma space but increasingly flavors, fragrances, vitamins, and complex organic molecules. Probably the best-known biosynthesized ingredient today is the heme that makes Impossible Foods taste like meat.

I think about biosynthesis as the manufacturing embodiment of the biology revolution taking place today. We’re living in the century of biology, just like the last century was the century of physics. This has really been driven by the exponential fall in the cost of sequencing DNA—it’s falling faster than Moore’s Law (from the IT world). We can now read the blueprint of nature.

Biosynthesis is the last great domestication. We domesticated animals, we domesticated plants, and now we’re domesticating microbes. Microbes grow quickly. The doubling time for E. coli is a few hours. You can use them as cellular machinery to manufacture organic compounds. As a technology, it’s going to play a critical role in the way we combat climate change. It can replace petrochemically-derived ingredients and in select cases intensive agriculture (e.g., cutting down rainforests).

 

Is biosynthesis of cannabinoids energy intensive? How does it impact sustainability?

You have to feed the bugs sugar. The sugar can come from sustainable sugar, for example, sugarcane grown in Brazil that’s irrigated with rain. Sugarcane plants make a lot of sugar; this is much more efficient than cannabis plants making cannabinoids. It’s a renewable feedstock grown renewably. Your final product is also renewable.

Think of it as a brewery. What do you need to brew beer? You need a big container, you need to stir it, you need to make sure it stays warm, and you need to feed it. Generally speaking, you’re going to have less water, less land, and less electricity to produce cannabinoids. I’ve seen some data (shared with me confidentially) that suggests you can get seven times the cannabinoids out of an acre of land using biosynthesis compared to an acre of land growing hemp.

We’ve partnered with a company called Genomatica. Their entire mission is sustainability, having chosen to attack petrochemicals. They are increasingly replacing petrochemically-derived intermediates (e.g., plastics or spandex) with renewable equivalent materials. These are not substitutes; they are exactly the same but essentially made from sugarcane.

 

What are the advantages of cannabinoid biosynthesis?

You can make the rare cannabinoids just as easily as you can the common ones. We could make cannabichromene (CBC), tetrahydrocannabivarin (THCV), cannabigerol (CBG), etc. That’s where we’ve focused the business.

There are more than 100 identified cannabinoids. At the moment, we’re seeing the world in black or white: tetrahydrocannabinol (THC) or cannabidiol (CBD). Actually, there’s a whole spectrum of color. All these different cannabinoids do different things. We believe CBG is the skincare cannabinoid. Cannabinol (CBN) is good for sleep. THCV works for reducing appetite.

Because you’ve controlled everything that’s happening inside of that cell, you can produce cannabinoids with no THC. These are truly free of THC, which helps a lot from a legal point of view. The fact that there are no cannabis plants involved also simplifies legal aspects. That really fits in with our vision of business.

 

What is Creo’s “vision of business”?

We believe cannabinoids belong in every household—from homecare products, personal care products, over-the-counter medication, pharmaceutical drugs, etc. We also believe that the way to get there is through mainstream consumer packaged goods companies. Nestle, Unilever, Proctor and Gamble, etc., have the channels for global distribution of products. Our focus is to get cannabinoids to the point where those companies are willing to adopt them.

Two barriers stop them today. One is legal uncertainty. CBD, for example, is considered a drug by the U.S. Food & Drug Administration (FDA). There is also the “0.3% THC or less” rule for hemp plants. If Proctor and Gamble develops a product, they need to be able to sell it all over the world or it’s not worth the investment. While the US Farm Bill has carved out some space for hemp-derived cannabinoids, it’s not the same in other countries. Companies need a framework where they can create global products.

Secondly, they need a reliable supply chain. They need to know that they get the same product again and again with high purity for the same price (price stability). The current ecosystem of hemp and cannabis leads to a lot of inconsistency and price volatility.

 

What are some current product applications?  

At the moment, we’re bringing our first product to market—finished cannabigerolic acid (CBGA). It takes 15-20 steps to get to CBGA. We can then convert to CBG without any problems if required. CBG stands out for skin applications. It moisturizes the skin, stops flaking, and soothes inflammation. [1] It’s also anti-bacterial and has been shown to destroy the bacteria that produce acne. [1]

Next year, we plan to introduce two additional products: CBCA and (probably) cannabigerovarinic acid (CBGVA). CBGVA is the parent cannabinoid for the –varin group of cannabinoids.

 

Where is your production of CBGA in terms of cost and output?

We are aiming to be able to produce 100-300 kilograms per day of finished isolate. There are different cost curves depending on scale, but we can get it down to under $1000 per kilogram. That’s what you need to make this a mass product. You have to get it cheap enough that people can afford to put it into everything.

 

What are the challenges to bioengineering cannabinoids?

We’re pushing the envelope of science. We’ve been at this for 5 years and spent $40 million developing this technology. Those are the barriers to entry. This is not something that anyone can do in their garage.

The other challenge is scaling up. You start with a little test tube and a domesticated bug. You grow it in a small fermenter, or seed tank, just to get enough going. From the early days of working in a little shake flask all the way to where we are today required over a million-fold increase in scale. During that scale up, there are so many things that can go wrong.

Getting to 12,500 liters (commercial demo) took 4.5 years; getting from 12,500 liters to 28,000 liters (small commercial) — over 1-million-fold increase in scale from the lab — took six months. Now we are at commercial scale. There are different sizes of commercial scale and fermentation vats. We’re at 28,000 liters, which is 28 metric tons of liquid. If we were to go to the world’s largest fermenter, that would be 500,000 liters, only an 18-fold increase in scale from where we are today.

 

Where do you see the future of cannabinoids?

Cannabinoids will be in many everyday things. There will be CBG for some purposes, CBC for others, and many cannabinoids with different applications. Toothpaste, for example, is an area we’re interested in. A dentist in Belgium showed that cannabinoids were more effective at destroying and preventing bacteria and plaque than a leading toothpaste. [2] Colgate has filed a patent using cannabinoids in oral care products.

 

Do you anticipate this technology will compete with cannabis and hemp plants?

I’m at pains to point out that our work does not replace the plant. The analogy I use is this: think of a good bottle of wine. It’s a unique mixture of hundreds of different chemicals. It’s unique to that grape, to that region, and to that vintage. You can’t reproduce that. On the other hand, think of an alcoholic seltzer or alcohol-enhanced lemonade. No one cares where the alcohol came from. So, we’re in the latter world. We’re not going to produce anything like wine. But there’s a big market for seltzer.

The area where we interface is around the rare cannabinoids. If you’re producing a plant extract, typically you can get fairly consistent composition of CBD or THC. But the composition of the rarer cannabinoids jumps all over the place. When you have biosynthesized rarer cannabinoids identical to what comes from the plant, you can use them to create consistent extract compositions. Also, we can help create a profile that is hard or impossible to create from plant extract, like 50% CBC extract or 60% THCV.

The other area where we can collaborate is education. People still don’t know much about minor cannabinoids. It’s in the interest of both industries to educate the consumer about the rich experience of these other cannabinoids.

We’re not enemies. We’re allies in this mission of bringing the benefits of cannabinoids to every person around the world.

Furthermore, we’re not in the CBD business and have no plans to get into THC. This technology excels in bringing rarer cannabinoids to market. Frankly, there are so many of them to keep us busy that we have enough to do.

Roy Lipski has led growing technology companies based on cutting-edge science for more than 20 years. Prior to founding Creo, he successfully founded several other pioneering technology companies, led a company to IPO, another to a transformative acquisition, and ran a public company for close to 10 years (valued at some $500 million).

References

1- Oláh A, et al. Differential effectiveness of selected non-psychotropic phytocannabinoids on human sebocyte functions implicates their introduction in dry/seborrhoeic skin and acne treatment. Exp Dermatol. 2016;25(9):701-7. [Impact Factor: 3.960; Times Cited: 35 (Semantic Scholar)]

2- Stahl V, Vasudevan K. Comparison of efficacy of cannabinoids versus commercial oral care products in reducing bacterial content from dental plaque: A preliminary observation. Cureus. 2020;12(1):e6809. doi:10.7759/cureus.6809. [Impact Factor: n/a; Times Cited: 9 (Semantic Scholar)]

About the author

Lance Griffin

Lance Griffin

Lance

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