Team:SDU-Denmark/Description
Project
Abstract
This page entails a description of our project, as well as an in depth description of the
problem that inspired us to choose this particular solution. You can read about the occurrence
of depression, the impact it has on society, as well as how COVID-19 has affected mental illness.
Project Description
The Problem
Following the COVID-19 pandemic, more people than ever are getting diagnosed with depression. The CDC conducted an investigation, which shows that in June 2020, there was a prevalence of depressive disorder approximately four times higher than was reported in the same period the previous year. [1] That is, before the pandemic break-out. But it is not only the pandemic that has caused the increased prevalence of the depressive disorder. In fact, before the pandemic, the number of diagnoses were already on the rise. There has been an increase in the incidence of depression by 49.8% worldwide from 1990 to 2017. [2] In 2017 the WHO determined that 322 million people worldwide are living and struggling with depression, just over 4% of the global population. [3][4]. This observed increase in the prevalence of depression shows the severity of the situation and why we need to produce better solutions today.
Possible Solutions
The primary treatment methods for depression today are counselling and anti-depressants. [3] However, studies show that only about 20% of patients on anti-depressants respond to the treatment.[5] This leaves a majority of patients without proper medication in the battle with depression.
During the past decades, researchers have begun exploring the possibility of treating depression with psychedelics. So far, 21 clinical trials have been conducted and published with promising results, and there are 40 ongoing clinical trials across the globe. [6][7] The most frequently used psychedelics in these studies are MDMA (45.7%) and psilocybin (41.4%). While MDMA is primarily used in studies investigating its effect on PTSD, psilocybin is used mainly in investigating its effect on depression. [6]
Our Project: PsiloAid
The promising aspects of treating depression with psilocybin spiked our interest. After further research, we discovered that the notable market price of psilocybin inhibits research in the field. [8] Psilocybin is a naturally occurring substance in various fungi, but use of the psychedelic as medication, requires knowledge of the exact amounts of active substance given to patients. We want to inspire future use of psilocybin’s absolute potential by reducing the costs of acquiring the substance for research projects.
Currently, it is challenging and expensive to either synthesize psilocybin chemically or purify it from the mushrooms. With recent improvements, the production of psilocybin in single cells organisms has brought costs down from 65 USD to 2 USD per milligram [9] [10] [13]. The methods, however, persist in being tedious and costly with a limited yield, thus calling for further improvement. This iGEM-project aims to construct an enhanced biosynthesis procedure to create psilocybin from the amino acid tryptophan: We will create a psilocybin producing Escherichia coli strain producing psilocybin using standard expression vectors (pSB1C3). This step requires cloning the four genes encoding the enzymes in the psilocybin biosynthesis pathway from the natural fungi. [11]
Since psilocybin is produced in a wide variety of fungi, you would think that yeast should be the most optimal single cell host organism for its production. Long generation time, the risk of the organism converting psilocybin to psilocin and limited knowledge about its pathways, however, makes it more complicated to work with.
That is why we chose to work with E. coli as our host organism instead of yeast cells. E. coli has a shorter generation time, it is well studied which makes it simpler to work with, and we will avoid the risk of psilocybin conversion. The key enzyme for facilitating de novo synthesis is PsiH, however N-terminal modifications are required for synthesis in E. coli, due to the lack of the organelle essential for PsiH. Furthermore, we will introduce other crucial enzymes to produce psilocybin; PsiD, PsiK and PsiM. For the optimization of the production and an easier purification of psilocybin in E. coli we will try to implement a transporter.
However, E. coli is not the sustainable cell factory. Therefore, a future solution will be to transfer the system to another bacterium like Rhodovulum sulfidophilum, which will be able to remove CO2 from the atmosphere and making a more sustainable and eco-friendly production system.
References
Proof Of Concept
