The Startup Turning Yeast Into Psychedelics
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Over recent years, scientific research into psychedelics have been pitched by some as "riding a new wave of positive momentum", a "resurrection" or "revival". This is quite an upturn in fortunes for a field that was virtually eradicated several decades ago by regulations that strictly controlled psychedelics’ use in research. Whilst these compounds remain illegal for recreational use in most parts of the world, a growing body of scientific research is exploring their potential application in psychopathologies.
The chemical synthesis of psychedelic compounds such as psilocybin is associated with a variety of limitations, including the potential to produce harmful emissions and the process’s high cost and low yield. As such, scientists are turning to bio-based methods as an alternative.
Octarine is a synthetic biology company based in Denmark that is using yeast fermentation to sustainably produce a range of cannabinoids, psychedelics and improved derivatives.
Technology Networks recently spoke with Nick Milne, co-founder and CSO at Octarine to learn more about what science says on the therapeutic benefits of psychedelic compounds, why a bio-based approach for manufacturing is advantageous and the challenges associated.
Molly Campbell (MC): For our readers that may be unfamiliar, please can you discuss why psychedelics are "riding a wave of positive momentum" in the drug development space?
Nick Milne (NM): The world is in the midst of a mental health crisis, driven by outdated theories on the causes of (and solutions for) mental illness. Current treatment options rely heavily on correcting “chemical imbalances” in the brain, the result of this simplified view on mental health is a series of drugs (namely SSRIs) which are barely more effective than a placebo, often come with intolerable side-effects and can produce intense withdrawal symptoms if you decide to stop taking them.
It's clear that to solve this crisis we need a radically new approach to how we treat mental illness. The use of psychedelics in modern psychotherapy actually began in the 1960s, where psilocybin and LSD were used successfully to treat psychological disorders ranging from alcoholism to mood disorders. Unfortunately, psychedelics got caught up in the “war on drugs” and, by the 1970s, the practice had been driven underground.
While this new wave of interest in using psychedelics in psychotherapy is driven in part by a growing body of high-quality scientific research demonstrating their incredible therapeutic potential, it’s also driven by the general public’s increasing acceptance of the use of “illicit drugs” in a therapeutic context. In my opinion, the clinical data on the effectiveness of psychedelic assisted psychotherapy (that is; a psychedelic experience followed up by talk therapy) should be enough to convince even the most conservative members of society that that these drugs should be approved for therapeutic use.
Psilocybin has remarkably low toxicity, isn’t addictive and has a harm potential significantly lower than alcohol, tobacco or prescription drugs such as benzodiazepines, amphetamines and opiates. Data coming out of clinical trials show that a single dose of psilocybin leads to a significant reduction in the symptoms of depression which persists for many months, with similar results observed for studies in alcoholism and smoking cessation.
The potential of psychedelic assisted psychotherapy has also been recognized by the FDA which has granted “breakthrough therapy designation” for the use of psilocybin to treat treatment resistant depression and major depressive disorder, as well as the use of MDMA to treat PTSD.
Ruairi MacKenzie (RM): How is yeast modified to induce the production of psilocybin?
NM: We work with a particular yeast species called Saccharomyces cerevisiae which is most commonly known as the micro-organism which turns water, malt and hops into beer. S. cerevisiae is arguably the first known example of domestication by humans where, through trial and error, humans converted this organism from a wild species living in trees and on fruits into a domesticated organism which thrives in a large-scale production environment (i.e. the brewers tank). This makes S. cerevisiae an ideal organism to produce molecules in large-scale fermentation; it tolerates a range of harsh conditions, grows quickly, has an extremely fast metabolism and doesn’t succumb to viral infection.
To modify yeast to produce psilocybin, we took the genes that Psilocybe cubensis uses to produce psilocybin, optimized them for expression in yeast, then, through genetic engineering, introduced these genes into the genome of our yeast. The production of psilocybin starts with the amino acid tryptophan, which yeast also naturally produces from simple sugars. To further boost psilocybin production, we increased the yeast’s ability to produce tryptophan by modifying a few of its genes to help channel the yeast’s metabolism towards this amino acid. This is actually a really important aspect of metabolic engineering; these days it’s usually relatively straight forward to engineer an organism to produce a foreign molecule, but getting the organism to produce enough of the molecule to be commercially relevant is a key challenge in the field.
MC: Why is a bio-based production of therapeutic compounds advantageous?
NM: Many valuable therapeutic compounds are produced by natural hosts, however in most cases these compounds are produced in very small amounts and often by organisms that are difficult to reproducibly cultivate on a large scale.
This problem is traditionally solved using chemical synthesis; however, this often requires non-renewable petrochemical starting substrates and generates harmful by-products and emissions. Using bio-based production to address this sustainability issue is a core focus of the Novo Nordisk Foundation Center for Biosustainability, where this research initially took place. Additionally, while chemical synthesis is good for producing some molecules, it’s not so good at producing molecules with complex stereochemistry. Psilocybin exemplifies these problems. Psilocybe mushrooms are difficult to reproducibly cultivate on a large-scale, they require a lot of infrastructure and maintenance and are prone to infection that can be very difficult to get rid of. The amount of psilocybin produced is typically below 1% of the total weight but this can vary a lot, making it extremely difficult to standardize production. You also need to extract the psilocybin from the mushroom which adds and additional layer of complexity.
While psilocybin can be chemically synthesized it requires petrochemical-derived substrates and overall, the cost of production is relatively high, as psilocybin has complex stereochemistry requirements. In contrast, production of psilocybin by yeast fermentation uses sugar as the starting substrate, is easy to scale, is significantly cheaper than either mushroom extraction or chemical synthesis, and since the yeast continuously excretes the psilocybin into the fermentation media, is much easier to purify.
An added bonus that we’re exploiting at Octarine is that the whole production system is highly modular. By simply adding or swapping one gene for another we can instead produce closely related molecules or completely novel derivatives. This was demonstrated in the recent publication where by making one small genetic tweak we could coax the yeast into producing the natural psilocybin derivative aeruginascin, and by adding a new gene from the melatonin biosynthesis pathway of cattle we could get the yeast to produce a completely novel derivative resembling both psilocybin and melatonin.
RM: Is it likely that similarly bio-based production techniques will be utilized for other restricted compounds?
NM: Yes absolutely! As well as working on producing psychedelics, Octarine is also developing yeast fermentation platforms to produce cannabinoids and improved derivatives by yeast fermentation. Cannabinoids have a huge therapeutic potential for difficult-to-treat conditions and are also very difficult to chemically synthesize. Cannabis is also a difficult plant to cultivate on large-scale, requiring a staggering amount of land, energy and water. Furthermore, cannabinoids are completely insoluble in water, rapidly degrade under ambient conditions and have a very low oral bioavailability which severely limits their therapeutic application.
Octarine is developing a cost-effective, stable and scalable production platform for these molecules, and further using enzymatic modification to produce improved derivatives that overcome the limitations of natural cannabinoids. Our expertise in this area made psychedelics a natural addition to our portfolio.
MC: In a press release you discuss an issue that still needs to be addressed in this research space - the phosphate group falling off. Can you please expand on this and how you are hoping to overcome it?1
NM: The psilocybin molecule has a phosphate group attached to the oxygen atom at the 4-carbon position. When psilocybin is ingested this phosphate group is cleaved off in the body to produce psilocin which is actually the psycho-active molecule. There are some theories on what role this phosphate group plays both in Psilocybe mushrooms and once ingested by humans, so it’s probably important from a physiological and therapeutic point of view, even if we don’t fully understand why.
This means we should focus (for now at least) on producing psilocybin not psilocin. Unfortunately, this phosphate group is quite weakly bound to the oxygen atom and tends to “fall off”, in our study we found that roughly half of the psilocybin produced by our yeast strain degraded to psilocin. From a production point of view, losing half of your product is a huge waste of money and resources. Before we solve this issue, it’s important to understand why this is happening in the first place.
Figuring this out is actually one of the really interesting parts about working in the cannabis and psychedelic fields. Since these molecules are (for the most part) illegal there’s a big gap in our scientific understanding of them, as it's been almost impossible for scientists to get approval to study them until very recently. But these molecules are regularly consumed by a significant portion of the population, many of whom are happy to share and discuss their experiences. It has been a really interesting experience for us to use anecdotal personal experience to generate hypotheses which we can then go test in the lab.
MC: You’ve mentioned investigating molecules similar to psilocybin that could have therapeutic effects, which are hard to purify. Are there any particular derivatives that you are prioritizing in these efforts?
NM: From a scientific point of view, it would be really interesting to scale up production of the various intermediates and natural derivatives of the psilocybin biosynthetic pathway such as baeocystin and aeruginascin. In our study we demonstrated the production of all (known) intermediates and derivatives of the psilocybin biosynthetic pathway and scaling up the production of these molecules will be an important follow-up step. Compared to psilocybin, we know almost nothing about the therapeutic potential of these molecules. The main reason for this is that while psilocybin can accumulate in Psilocybe mushrooms, up to 1% of the total dry weight, the concentration of these “minor” products is hundreds of times lower, making extraction of meaningful quantities practically impossible.
This yeast strain gives us the ability to produce enough of these molecules so that their therapeutic potential can be assessed. In our opinion this is something worth investigating. A key lesson from the cannabis industry is that while THC and CBD (the most abundant cannabinoids produced by plants in the genus Cannabis) have interesting therapeutic properties, a growing body of research is finding that some of the minor cannabinoids have additional or even more potent therapeutic properties not found in THC or CBD.
In terms of novel derivatives, there’s a few interesting modifications that we’re looking into, but I can’t say much more than that at this stage.
Nick Milne, Co-founder and CSO at Octarine was speaking to Molly Campbell and Ruairi MacKenzie, Science Writers, Technology Networks.
1. Milne et al. (2020). Metabolic engineering of Saccharomyces cerevisiae for the de novo production of psilocybin and related tryptamine derivatives. Metabolic Engineering. DOI:https://doi.org/10.1016/j.ymben.2019.12.007.