The future of psychiatric medicine is upon us. Soon we may see the use of psilocybin and other psychedelics instead of the numerous psychiatric drugs on the market. The original paper, In vivo production of psilocybin in E. coli was recently published in Metabolic Engineering , Volume 56, December 2019, Pages 111-119. Following are a pair of news articles that elaborate on the findings of the study.
Scientists have transformed a common bacterial cell into a psychedelic "drug factory" capable of pumping out copious quantities of psilocybin, the chemical famously found in "magic mushrooms," according to a new study.
Psilocybin can be found in more than 100 'shroom species, most notably in one called Psilocybe cubensis, which has a domed cap and skinny stem. Although best known for inducing mind-bending hallucinations, psilocybin is currently being tested as a potential treatment for several psychiatric conditions, including addiction, major depressive disorder and post-traumatic stress disorder, according to ClinicalTrials.gov. If 'shroom-based drugs ever come to market, scientists will need a better method for harvesting psilocybin than farming tons of fungi, the authors said.
So, the researchers turned to bacteria, which can be engineered to churn out chemicals in high amounts. Some medications — including the hormone insulin — are already produced with the help of genetically engineered bacteria.
In the new study, the Miami University, researchers manipulated the metabolism of the bacteria Escherichia coli, so that its cells began producing psilocybin.Later, the research team scaled up production to brew the hallucinogen in huge batches, according to a statement from the university.
"We are taking the DNA from the mushroom that encodes its ability to make this product and putting it in E. coli," study co-author Andrew Jones, a professor of chemical and biological engineering, said in the statement. The team developed multiple strains of psychedelic E. coli and tested what environmental conditions — temperature, nutrients, culture medium — were required to consistently produce high concentrations of psilocybin with few unwanted side products. The team eventually selected the most efficient strain, dubbed pPsilo16, and cultivated it in a bioreactor for mass production, according to the study, published online Sept. 21 by the journal Metabolic Engineering.
"What's exciting is the speed at which we were able to achieve our high production," Jones said. Over the course of the 18-month-long study, the researchers were able to increase production by 500-fold.
According to the authors, their E. coli produced more psilocybin than any other organism retrofitted with "magic mushroom" DNA to date. The scientists assert that their results provide compelling evidence that psilocybin could be produced on an industrial scale for use in psychiatric medications.
Andrew Jones at Miami University and his team of students may have developed a research first.
Through metabolic engineering, they discovered a way to sustainably produce a promising drug candidate to help patients with treatment-resistant depression.
Their findings are published in the journal Metabolic Engineering titled, “In vivo production of psilocybin in E. coli.”
Psilocybin is now in clinical trials, and medical professionals see promising results for its use in treating addiction, depression and post-traumatic stress disorder in humans.
Jones, assistant professor in Miami’s department of chemical, paper, and biomedical engineering, believed he could come up with a process using genetically engineered bacteria to produce the drug candidate.
The chemical, psilocybin, is naturally found in a specific mushroom, Psilocybe cubensis. Jones said to mass produce psilocybin from its natural mushroom host, it would require extensive real estate and time. Currently, alternative synthetic chemical production methods are used but are very expensive. Jones, the principal investigator of this research, wanted a solution that maintains biological integrity and reduces production costs.
Andrew Jones' idea sparked a research path where he guided students as they conducted experiments.
Finding an optimal organic host
Through metabolic engineering, which finds ways to increase a cell’s ability to produce a compound of interest, his team of students developed a series of experiments to identify optimal psilocybin production conditions. The recently published article describes their work to optimize the production of psilocybin in the Escherichia coli bacteria. The team is using a well-known E. coli strain that is engineered for safe lab production.
“We are taking the DNA from the mushroom that encodes its ability to make this product and putting it in E. coli,” he said. “It’s similar to the way you make beer, through a fermentation process. We are effectively taking the technology that allows for scale and speed of production and applying it to our psilocybin producing E. coli.”
Their end result is a significant step toward demonstrating the feasibility of producing this drug economically from a biological source.
“What’s exciting is the speed at which we were able to achieve our high production. Over the course of this study we improved production from only a few milligrams per liter to over a gram per liter, a near 500-fold increase,” Jones said.
He gives much credit and praise to his students who designed many of the experiments performed during the 18-month-long study.
“A big part of my job is training undergraduates to do this work. The basic idea was mine, but much of the experimental design fell on the students. Early on, I would help guide them in the experimental design process. Toward the end, they were becoming more independent. That’s the type of student we want as they near graduation,” Jones said.
Undergraduate students help mentor other students on the basics of working in a scientific laboratory.
Learning to run laboratory experiments
Lead author Alexandra (Lexie) Adams, a junior chemical engineering major, became a member of the research team her freshman year, just as the Jones Lab was getting started. Patient and meticulous, Jones worked with the admittedly nervous Adams on the basics of laboratory research. It paid off.
The initial work was done in the summer of 2018 as Adams and another undergraduate student co-author, Nicholas Kaplan, took part in Miami’s Undergraduate Summer Scholars Program. The program provides funding to students for undergraduate research.
Both students, working on separate studies, learned the ins and outs of research, gaining confidence and learning lessons as the summer progressed.
Kaplan, a junior chemical engineering major, studied the feasibility of cyanobacteria as another potential metabolic engineering host. His findings showed mixed results, and it was decided that the lab team would focus on Adams’ psilocybin in E. coli project.
Celebrating a research breakthrough
Adams remembers when they saw the breakthrough in their research. Their goal was to transfer the DNA from the mushroom and see activity in the E. coli host.
“Once we transferred the DNA, we saw [a tiny] peak emerge in our data. We knew we had done something huge,” she said.
Other members of the team included: graduate Zhangyue ‘Tom’ Wei (Miami ’19), graduate John ‘Jack’ Brinton (BS Miami ’17, MS Miami ’19), junior Chantal Monnier, senior Alexis Enacopol, and staff member Theresa Ramelot, instrumentation specialist.
Both Adams and Kaplan continue to work with Jones. The students are leading projects that build on the recent success of the psilocybin work. Each of them is starting to pass down what they have learned in the lab by mentoring new undergraduate students that join the Jones Lab.
“It’s important for [the new students] to understand the big picture so they see the reasons for the different steps of the experiments,” Kaplan said.
Jones is pursuing the next phase of this research by studying ways to make the E. coli bacteria a better host — the next step toward enabling sustainable production at levels required by the pharmaceutical industry.