PSP94, fungi and prostate cancer
The PSP94 Project started at the beginning of 2012, when it was discovered that a human protein called PSP94 is a potent fungicide (Edstrom et al 2012). The human body produces dozens of similar antimicrobial proteins, so this finding was not surprising. However, PSP94 is very interesting because:
The prostate produces a large amount of PSP94, and in doing so uses a lot of the body’s resources. This means protecting prostates from fungi must be very important.
Men whose prostates produce less PSP94 are at much higher risk of prostate cancer.
Men whose prostates produce a defective variant of PSP94 are at much higher risk of benign prostatic hyperplasia (BPH).
An infectious cause for prostate cancer?
Many researchers studying prostate cancer have suspected that men’s immune systems are attacking a persistent infection in the prostate. This never-ending battle causes long-lasting inflammation, which is known to greatly increase cancer risk. The main problem with this hypothesis is that no one can find the microbe or virus that the immune system is fighting in the prostate, despite a century of research! It’s as if the immune system is fighting a ghost… Nearly all research to find the causative infection focused on bacteria and viruses—few studies considered the possibility of a fungal infection.
PSP94 shows us the way forward
PSP94’s fungicidal activity showed that studies looking for a microbe in the prostate had a blindspot: they overlooked the kingdom most likely involved in these diseases, fungi. The PSP94 Project’s first goal was to figure out which fungi are commonly present in the prostate. A few weeks into the project, I made the following predictions about the causative microbe based on PSP94 and prostate disease studies (Sutcliffe et al 2014):
It has ergosterol in its plasma membrane (ergosterol is PSP94’s molecular target, and is only present in fungi and a few protists).
It is intracellular (in the prostate, PSP94 is only fungicidal within human cells).
It is ubiquitous (lifetime risk of latent prostate cancer and BPH are >70%).
It is sexually acquired to the prostate (prostate cancer has clear sexual risk factors).
From March 2013, this project took a special interest in spondyloarthropathies, in addition to diseases of the prostate. Spondyloarthropathies are a set of immune-mediated diseases very strongly associated with prostatic inflammation (Laurence et al 2018). Interestingly, spondyloarthropathy studies had already made the four predictions listed above based on observations completely unrelated to prostate cancer! What were the odds?! This gave much credence to the hypothesis of a fungal infection in the prostate as the root cause of inflammation and cancer.
Advanced microbe detection
From 2013 to 2018, I developed a microbe detection method which could identify all fungi, protists and bacteria in the prostate by looking for their DNA. The main advantage of this method over previous techniques is that it can detect microbes which do not grow in culture. The main disadvantages are that it is slow (it takes days or weeks to complete) and expensive (thousands of dollars per specimen).
I found no protists. The only fungi present were Malassezia globosa and Malassezia restricta. These fungi are known to colonize everyone’s skin from birth, but they are not known to colonize our internal organs. I dismissed them as contaminants, which meant the prostate was devoid of fungi and protists. There were no microbes in the prostate susceptible to PSP94! :-(
It’s Malassezia, stupid!
Between 2012 and 2018, many research groups reported that Malassezia are in fact present in our internal organs, including the mouth, nose, breasts, gut, joints, brain and lungs. These researchers were also surprised to find them inside the body! Importantly, several studies were reporting very strong and specific associations between Malassezia and spondyloarthropathies. Based on this, I concluded that Malassezia were not contaminants after all: they really were in the prostate! Given that they are the only fungi commonly present in the prostate, they are probably PSP94’s main target and are causing prostate cancer and BPH. This is how the six year old PSP94 Project graduated into The Malassezia Project!
NB: This post is based on Laurence et al 2018 (simplified for clarity).
Animated prostate cancer video: https://youtu.be/bNGvEU0TaHY