UCL researchers have discovered the biochemistry behind a genetic mutation that reduces pain, speeds recovery, and reduces anxiety and terror.

The study, published in Brain, follows the team’s 2019 discovery of the FAAH-OUT gene and its unusual mutations, which make Jo Cameron nearly pain-free and fearless.

The current study shows how this mutation decreases FAAH gene expression and affects mood and wound healing pathways. These discoveries may inspire new therapeutic targets and research in these fields.

After hip and hand operations, Jo, from Scotland, was referred to UCL pain geneticists in 2013. They found FAAH-OUT, a gene with an uncommon hereditary mutation, after six years. It caused Jo’s unusual traits together with a more common FAAH mutation.

FAAH-OUT, formerly thought to be “junk” DNA, regulates the expression of FAAH, a gene in the endocannabinoid system that affects pain, mood, and memory.

UCL researchers studied FAAH-OUT’s molecular mechanism to produce drugs.

This includes CRISPR-Cas9 tests on cell lines to imitate the mutation’s effect on other genes and gene expression analysis to identify those implicated in pain, mood, and healing molecular pathways.

FAAH-OUT modulates FAAH, the team found. Jo Cameron’s mutation drastically reduces FAAH enzyme activity.

“The FAAH-OUT gene is just one small corner of a vast continent, which this study has begun to map,” stated senior author Dr. Andrei Okorokov (UCL Medicine). These studies have shown FAAH-OUT-influenced molecular pathways for wound healing, mood, and painlessness. As scientists, we must investigate, and I think these discoveries will impact wound healing, depression, and more.

The FAAH-OUT-FAAH axis’ impacts on molecular pathways were examined in patient fibroblasts. Jo Cameron’s mutations down FAAH, but they discovered 797 genes up and 348 down. This includes changes to the wound-healing WNT pathway and enhanced activity in the bone-regenerating WNT16 gene.

The mood-regulating gene BDNF and the opioid-regulating gene ACKR3 were also changed. These DNA modifications may lower Jo Cameron’s anxiety, dread, and pain.

Professor James Cox (UCL Medicine), a senior author of the paper, said: “The initial discovery of the genetic root of Jo Cameron’s unique phenotype was a eureka moment and hugely exciting, but these current findings are where things really start to get interesting.

Understanding what is happening at the molecular level helps us comprehend biology, which offers up drug discovery options that might benefit patients.