Jo Cameron, a 71-year-old former teacher residing in Inverness, has had extraordinary experiences throughout her life. Despite enduring broken limbs, cuts, burns, childbirth, and numerous surgical procedures, she has rarely required pain relief. Astonishingly, she is not alerted to pain through physical sensations, but rather by the smell associated with it.

Cameron stands unique, but it’s not only because she can’t feel pain; she also never panics.

Six years ago, when a van driver forced her off the road, causing her car to overturn and land in a ditch, she emerged from the wreckage and provided comfort to the shaken young driver who caused the accident. It was only later that she noticed her own bruises. Her resilience is further evident in stress and depression assessments, where she scored zero.

A case report published in the British Journal of Anaesthesia details an in-depth investigation conducted by a team of researchers from University College London (UCL) into the genetic makeup of Cameron to unravel the reasons behind her unique condition. The study uncovered two noteworthy mutations that contribute to her remarkable attributes. These mutations not only diminish her ability to feel pain and experience anxiety but also enhance her overall sense of happiness, forgetfulness, and wound healing.

The first mutation identified by the scientists is relatively common in the general population. It reduces the activity of a gene called FAAH, which produces an enzyme responsible for breaking down anandamide—a chemical essential for pain perception, mood regulation, and memory. Anandamide functions similarly to the active compounds found in cannabis. When its breakdown is limited, its pain-relieving and other effects become more pronounced.

The second mutation involves a segment of missing DNA that initially puzzled the researchers. Subsequent analysis revealed that this “deletion” affects a nearby gene, previously unknown, which the scientists named FAAH-OUT. They speculate that this newly discovered gene acts as a regulator for the FAAH gene, akin to a volume control. With the mutation present in Cameron, FAAH-OUT becomes inactive, resulting in the silencing of FAAH. As a consequence, anandamide, a natural cannabinoid, accumulates in her system, with levels double that of the general population.

The recent research conducted by UCL, published in the journal Brain, builds upon their initial discovery of the FAAH-OUT gene and the rare mutations responsible for Cameron’s extraordinary pain insensitivity and lack of anxiety or fear.

The new findings shed light on how the FAAH-OUT mutation downregulates FAAH gene expression, as well as its cascading effects on other molecular pathways associated with wound healing and mood. The hope is that these findings will uncover new targets for drug development and inspire further exploration in these areas of research.

After an extensive six-year quest, researchers have successfully identified a novel gene referred to as FAAH-OUT. This gene harbors a rare genetic mutation that, when combined with a more common mutation in FAAH, has been determined to be the underlying cause of Jo’s distinctive characteristics.

Previously disregarded as “junk” DNA with no discernible function, the region of the genome containing FAAH-OUT was unexpectedly discovered to regulate the expression of FAAH—a well-known gene associated with the endocannabinoid system, recognized for its involvement in pain perception, mood regulation, and memory formation.

The primary objective of this study conducted by the UCL team was to gain insights into the molecular mechanisms of FAAH-OUT, thereby paving the way for potential applications such as drug discovery. To accomplish this, the researchers employed various methodologies, including CRISPR-Cas9 experiments on cell lines to simulate the mutation’s impact on other genes. Additionally, they analyzed gene expression patterns to identify the active molecular pathways associated with pain, mood, and tissue repair.

The research team made an interesting observation regarding FAAH-OUT’s role in regulating the expression of FAAH. In the case of Jo Cameron, who carries a specific mutation, the activity levels of the FAAH enzyme are significantly diminished due to a significant downregulation of FAAH-OUT.

“The FAAH-OUT gene is just one small corner of a vast continent, which this study has begun to map. As well as the molecular basis for painlessness, these explorations have identified molecular pathways affecting wound healing and mood, all influenced by the FAAH-OUT mutation. As scientists it is our duty to explore and I think these findings will have important implications for areas of research such as wound healing, depression and more,” explains senior author Dr. Andrei Okorokov.

The researchers examined fibroblasts extracted from patients in order to investigate the impact of the FAAH-OUT-FAAH axis on various molecular pathways. In addition to the FAAH downregulation caused by the mutations observed in Jo Cameron, the study identified 797 genes that were upregulated and 348 genes that were downregulated. Notably, these alterations included modifications to the WNT pathway, known for its involvement in wound healing. Specifically, there was an increase in the activity of the WNT16 gene, which has previously been associated with bone regeneration.

Furthermore, the study revealed two other significant genes that exhibited changes. One of them was BDNF, a gene that has been previously associated with mood regulation. The other gene, ACKR3, plays a role in regulating opioid levels. The observed alterations in these genes may contribute to Jo Cameron’s experience of low anxiety, fear, and pain.

“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,” comments senior author Professor James Cox.

“By understanding precisely what is happening at a molecular level,” add the professor, “we can start to understand the biology involved and that opens up possibilities for drug discovery that could one day have far-reaching positive impacts for patients.”

Source: 10.1093/brain/awad098

Image Credit: Stil from BBC clip