A Scottish mum who can't feel pain could hold the key to developing better analgesics, according to new research.
Mum-of-two Jo Cameron, 74, has experienced broken limbs, surgery and childbirth - with no need for drugs.
She is one of just two people on Earth known to carry a gene that allows her never to feel anxious, fear - or discomfort. Now scientists have unravelled mechanisms underpinning the rare mutation - offering hope of more effective painkillers.
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Senior author Professor James Cox 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. By understanding precisely what is happening at a molecular level, we can start to understand the biology involved.
"That opens up possibilities for drug discovery that could one day have far-reaching positive impacts for patients."
Jo, a former teacher, lives with her husband Jim in Whitebridge, near Inverness. She only realised she was almost unique a decade ago - after her doctor noticed she was in no pain after major surgery on her hip and hand.
She said: "I knew I was happy-go-lucky, but it didn't dawn on me that I was different. I thought it was just me. I didn't know anything strange was going on until I was 65."
Jo had been diagnosed with severe joint degeneration in her hip - despite experiencing no pain.
A year later, she then underwent surgery on her hand at Raigmore Hospital in Inverness and reported no pain afterwards - although the treatment is normally very painful.
Jo says: "Although people were saying 'do you need painkillers?' and I said 'no', the look from the nurses was 'you should need painkillers'.
"The anaesthetist said 'this is an extremely painful operation, you're bound to need painkillers' - and I didn't.
"My father was the same, he was a jolly man who never seemed to get stressed about anything.
"He just bounced back. I just thought I was like him - I'd got a kind of role model in my mind so I never felt different."
Dr Devjit Srivastava, an NHS consultant in anaesthesia and pain medicine, diagnosed her pain insensitivity and she was referred to pain geneticists.
In 2013 the University College London team identified the variant - which they named 'FAAH-OUT'.
It switches off the normal version as well as knock-on effects of other molecular pathways linked to wound healing and mood.
Senior author Dr Andrei Okorokov explained: "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."
Pain warns people something is not right - and can cause them to take certain actions. So Jo's condition - known medically as congenital analgesia - can be dangerous.
She only realises her skin is burning when she smells singed flesh. She often burns her arms on the oven, but feels no pain to warn her.
Jo says: "Pain is there for a reason, it warns you - you hear alarm bells.
"It would be nice to have warning when something's wrong - I didn't know my hip was gone until it was really gone, I physically couldn't walk with my arthritis."
Doctors believe she might also be able to heal more quickly than normal. This particular combination of genes also makes her forgetful and less anxious.
She said: "It's called the happy gene or forgetful gene. I have been annoying people by being happy and forgetful all my life - I've got an excuse now."
Jo said recently she had a "minor bump" in the car, but was unmoved by what many would have found an upsetting experience.
She added: "I don't have adrenalin. You should have that warning, it's part of being human, but I wouldn't change it."
The area of the genome containing FAAH-OUT had previously been assumed to be 'junk' DNA - portions appearing to have no specific purpose.
But it was found to control expression of FAAH, a gene that is part of the endocannabinoid system that regulates sensations of pain, stress and emotions.
Prof Cox and colleagues carried out a series of experiments on cell lines using gene editing techniques to mimic the effect of the mutation on other genes.
They also looked at fibroblast cells taken from actual patients that fuel chronic pain.
Observations showed FAAH-OUT regulates expression of FAAH. When it is significantly turned down as a result of the mutation, protein levels are significantly reduced.
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While Jo's gene switches off FAAH, they identified a further 797 genes that were turned up and 348 that were turned down.
This included alterations to the WNT pathway that is associated with wound healing, with increased activity in the WNT16 gene that has been previously linked to bone regeneration.
Two other key genes that were altered were BDNF, which has previously been linked to mood regulation and ACKR3, which helps to regulate opioid levels.
These gene changes may contribute to Jo's low anxiety, fear and pain. The study is published in the journal Brain.
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