Sometimes in science, things don’t always go as planned. Often, this causes frustration, confusion, and funding woes. But other times, it leads you in a new, exciting direction. This is a story of the latter, a story that movies are based on. It details the pitfalls, the ingenuity, and the surprises common to scientific endeavors. On the surface, this article reads like a niche publication. But there is a thinly veiled story of surprise and seized opportunity underneath.
Understanding it requires some background, however. First and foremost, let’s break down the title: Altered cerebral protein synthesis in fragile X syndrome: studies in human subjects and knockout mice by Qin et al. from the Journal of Cerebral Blood Flow and Metabolism [paywall].
This tells us there will be two main topics intersecting to form this paper: cerebral protein synthesis and fragile X syndrome, along with the model organisms (humans and mice). Cerebral protein synthesis is the creation of proteins, the get’r’dun, action-inducing unit of a cell, in the more ‘thinky’ part of the brain called the cerebrum, or as an adjective, cerebral.
Fragile X syndrome is a genetic disorder in which the gene for a protein previously called Fragile X Mental Retardation Protein, but now simply FMRP, is not expressed, meaning that the DNA blueprint for this protein is inaccessible to the cellular construction crew. FMRP plays a large role in dampening the rush of neurons attempting to communicate with other neurons, like a traffic cop outside a Catholic church on a Sunday morning.
The study used a sparsely used but fascinating technique that measures, quantitatively, the real-time protein synthesis in the brain in living subjects. No decapitation required!
One of the biggest breakthroughs in neuroscience has been the advent of neuroimaging, which allows recording pictures of the brain without cutting it open. Even bigger is the use of functional neuroimaging, which lays a map of brain activity onto the anatomical picture, like live traffic information being displayed on your Google Maps.
A limit of this, however, is that this functional activity is depicted at a relative level, meaning that we know Brain Part A is more active than Brain Part B, which is less active than Brain Part C, etc. The end result gives an idea of what is engaged or disengaged at any given moment in the brain, which is further complicated by the fact that some brain parts act to engage or disengage other brain parts, creating a messy flow chart of what a certain brain part being engaged truly means.
The exciting part of the method used in this study is that it combines the functional neuroimaging maps and with information from a radiolabelled protein injected into the bloodstream, the end result of which is a live, quantitative map of protein activity.
Using this technique, researchers investigated the protein activity of people with Fragile X Syndrome. Without FMRP, it seemed a foregone conclusion that they would have unusually high levels of protein synthesis, compared to a group of healthy volunteers. Protein is what allows neurons to grow toward other neurons, facilitating communication. Without FMRP to act as a traffic cop, the neural roads get backed up with too many neurons all trying to go somewhere at the same time, the end result of which is mass confusion. Both groups of people were put through the brain scanner, injected with the radioactive protein label, and lo and behold, the group of individuals had lower levels of protein synthesis!
The researchers found the exact opposite of what they expected. This means that either they were working with a very wrong idea of what is happening with this genetic disorder or there was something in the experiment that screwed up the results. In the biz, that second option is a called a confound.
Because people who have Fragile X Syndrome develop with, at times, severe cognitive impairment, they needed to be put under the influence of a sedative to maintain the required stillness for the brain imaging (the device used to take pictures of the brain is a large future-looking machine with tight space that makes loud and intimidating noises). But the healthy volunteers were also scanned under the influence of the same drug, Propofol, so that any effect it had on one group would be the same on the other group.
But perhaps it didn’t. With these surprising results, the researchers questioned if there was a special interaction between the drug and the brain of a person with Fragile X Syndrome that didn’t occur in a healthy brain.
To answer this question, the researchers would need to see what happens in the brain of a person with Fragile X while they were on and while they were off the drug. Unfortunately, because of the severity of the disorder, they couldn’t study people with Fragile X without Propofol unless they sliced up their brains. In order to continue the investigation, they used the next best thing: mutant mice with analogously impaired brains.
These mice were genetically designed to have the same faulty gene that humans with Fragile X do, and many studies have demonstrated analogous impairments between the two mammals. With the mice, a similar protocol was followed, quantifying protein synthesis in healthy brains and Fragile X brains, both on and off the drug.
What the results show is that Propofol does have an effect on protein synthesis but only in Fragile X brains! While there was no difference between healthy brains on and off the drug, Fragile X brains that were on the drug had significantly decreased protein synthesis.
“but wait, didn’t you say earlier that too much, uncontrolled protein action was the problem in the first place?”
Why yes. Yes I did. And that is the exciting reveal of the study. Propofol decreases protein synthesis in Fragile X brains. That this study set out to confirm a well-reasoned suspicion, but ended up discovering an existing drug may be repurposed become a new treatment! An entire new vein of valuable, therapeutically-relevant research was stumbled upon!
Of course there is plenty to do before that happens, such as figuring out why it works (currently speculated to be via the endocannabinoid system…yes, cannabinoid like cannabis) and how to separate that from the sedative action of the drug. And so the research will continue. But the story of accidental discovery, with a huge breakthrough hidden right under researchers’ noses, remains.