The woman who is neither afraid nor in pain illuminates the development of new drugs

Jo Cameron carries a double genetic mutation that allows her to live virtually pain-free, heal more quickly, and experience less anxiety and fear. Her case was revealed in 2019. Now, new research from the University College of London (UCL) reveals the unique molecular machinery that enables her not to feel pain, anxiety or fear.

The information, which is published in “The Brain”, opens the door to new treatments for pain and anxiety.

The study follows up on the team’s 2019 discovery of the FAAH-OUT gene and the rare mutations that cause it to Jo Cameron feel virtually no pain and never feel anxiety or fear. The new research describes how the mutation in FAAH-OUT it ‘turns off’ the expression of the FAAH gene, as well as knock-on effects on other molecular pathways linked to wound healing and mood. The results are expected to lead to new drug targets and open new avenues of research in these areas.

In addition to the molecular basis for painlessness, molecular pathways affecting wound healing and mood have been identified.

Jo, who lives in Scotland, was first referred to UCL pain geneticists in 2013, after her doctor realized she was pain-free after major surgeries on her hip and hand. After six years of searching, they identified a new gene which they named FAAH-OUT, which contained a rare genetic mutation. In combination with another, more common mutation in the FAAH, it was found to be the cause of Jo’s unique characteristics.

The area of ​​the genome containing FAAH-OUT was previously considered non-functional “junk” DNA, but it was found to mediate the expression of FAAH, a gene that is part of the system endocannabinoid and is well known for its involvement in pain, mood, and memory.

In the new research, the UCL team sought to understand how FAAH-OUT works at the molecular level, the first step in being able to harness this unique biological feature for applications such as drug discovery.

Various methods were used for this, such as experiments CRISPR-Cas9 in cell lines to mimic the effect of mutation on other genes, as well as gene expression analysis to see which ones were active in molecular pathways related to pain, mood and healing.

The team found that FAAH-OUT regulates the expression of FAAH. When it is greatly decreased as a result of the mutation carried by Jo Cameron, the activity levels of the FAAH enzyme are significantly reduced.

  • It is possible that Jo’s case is not unique and that there are other people with the same mutation who are insensitive to pain or fear and who have not reported it.

  • In Jo’s own family, her father, now deceased, she never took painkillers and probably had the same numbness, while her son is very good at handling pain, although not as well in her case as his mother. And this has a scientific explanation because he only has one of the two genetic mutations identified in his mother.

“The FAAH-OUT gene is just a small corner of a vast continent, which this study has begun to map. In addition to the molecular basis for painlessness, these scans have identified molecular pathways affecting wound healing and mood, all of which are influenced by the FAAH-OUT mutation. As scientists it is our duty to explore and I believe these findings will have important implications in areas of research such as wound healing, depression and other», says Andrei Okorokov, co-lead author of the study.

The authors analyzed fibroblasts taken from patients to study the effects of the FAAH-OUT-FAAH axis on other molecular pathways. Although Jo Cameron’s mutations reduce FAAH, they also found another 797 genes that increased it and 348 that decreased it. This included alterations in the WNT pathway, associated with wound healing, with increased activity of the WNT16 gene, previously linked to bone regeneration.

Two other key genes altered were BDNF, related to mood regulation, and ACKR3, which helps regulate opioid levels. These genetic alterations may contribute to Jo Cameron’s low anxiety, fear and pain.

“The initial discovery of the genetic root of Jo Cameron’s unique phenotype was a hugely exciting and eureka moment, but these current findings are where things really start to get interesting. By understanding precisely what is happening at the molecular level, we can begin to understand the biology involved, opening up possibilities for drug discovery that could one day have far-reaching positive impacts for patients,” adds James Cox (UCL Medicine). , co-lead author of the study.

By Editor

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