Imagine never getting hurt. You could break your arm without blinking and give birth without breaking a sweat. This is reality for the people who feel no pain and their secrets could help the rest of us switch off our suffering.
For centuries the problem of pain has eluded easy answers. It’s part of everyone’s daily life and causes constant agony for the millions suffering from chronic conditions that refuse to respond to treatment. Now, though, new answers about the nature of pain are emerging not from the everyday, ordinary experience of it but from the extraordinary: from the handful of people who don’t experience pain at all.
These ‘real-life X-Men’ are pain-free from birth because of genetic mutations. And studying them is revealing that, amid all the other complex contributors to the way we feel pain, the role of our genes may be crucial.
Burns, bleeds and bruises
Until she was in her 60s, Jo Cameron, 71, thought she was just like everybody else – a bit more accident-prone, carefree and happy-go-lucky maybe, but not in any ways that would set her apart.
Except that when she burned her arm on the cooker it was the smell of burning flesh, not the pain, that alerted her to the injury. And when she cut herself, she only noticed when she spotted blood dripping from the wound. And when her car was run into a ditch and overturned, she climbed out and went to help the driver of the other car involved in the crash while paying no heed to her lacerations and bruises. “My brain doesn’t stop me from doing things, which is stupid really,” she says.
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It was only when Jo had a notoriously painful hand operation that doctors picked up on her complete inability to experience pain. Before the procedure she had teased the anaesthetist that she wouldn’t need any painkillers after the surgery and he was dumbfounded when, visiting her hours later, he found that she had been as good as her word. Not a single paracetamol had passed her lips.
In the months afterwards, Jo worked with the consultant anaesthetist, Dr Devjit Srivastava from Raigmore Hospital, Inverness, and molecular biologist Dr James Cox from the Wolfson Institute for Biomedical Research at University College London to find out more about her remarkable blitheness to pain. Thanks to our increasing ability to analyse the human genome, they discovered that Jo was one of a growing, but still tiny, group of people in the world who have genes that render them impervious to pain.
In Jo’s case, they found that she had a mutation in a gene that controls the FAAH (fatty acid amide hydrolase) enzyme. This enzyme controls release of a brain lipid called anandamide, which binds to cannabinoid receptors on the surface of cells – part of the chemical system by which cells signal each other about pain, appetite, mood and memory. Anandamide effectively mimics the effects of cannabinoid drugs. Animal experiments have already shown that inactivity in the FAAH gene results in more circulating anandamide – resulting in them being mildly spaced out, with less pain, improved mood and poorer memory. It’s no surprise, then, that anandamide has become known as the ‘bliss molecule’.
Jo also displayed a deletion in part of an associated gene called FAAH-OUT, which seems to have a role in regulating FAAH. This genetic oddity has excited scientists because targeting FAAH-OUT provides a possible new route for developing pain-control drugs.
Jo’s son also has the FAAH-OUT microdeletion (and she suspects her father did too), but not the FAAH mutation, so Jo may be an extreme case. She has almost double the normal amount of circulating anandamide in her system, which may explain why she was violently sick when given morphine after her hip operation. “It was like having an overdose because I already have masses of painkiller in my brain. For the first time in my life I felt really ill.”
The anandamide may also explain Jo’s exceptionally positive and healthy disposition. Jo says she is constantly losing things and doesn’t worry about anything.
“I’m happy about most things, which I think can be quite annoying for my family,” she says. “My father was the same.” Even when her first husband died leaving her to look after a young child, Jo wasn’t overwhelmed with grief or anxiety. “I was very sad obviously, but I just coped. I missed him, but I just got on. If everything goes wrong I go into practical mode. I don’t go into the depths about anything.”
Her memory, she says, is hopeless. “The number of expensive new car keys my husband has had to buy because I lose everything – I put things down and I haven’t a clue where they are.”
All these characteristics can be explained by Jo’s elevated levels of anandamide. Studies looking a loss of FAAH function and raised anandamide have found it results in decreased pain sensitivity, erasure of fear memories, reduced anxiety and short-term memory problems. It also results in accelerated wound healing, which explains Jo’s remarkable powers of self-recovery.
“I cut myself all the time but you can barely see any of the scars. When I’m sunburned you can see some white marks, but I do heal really quickly, which is strange.”
No pain, no gain
The anandamide is what make’s Jo’s case so exceptional. Prof Chris Eccleston, director of the Centre for Pain Research at the University of Bath, says that it’s unusual for people without pain to stay healthy until later life.
“If you’ve never experienced pain and you don’t have fear of harm, your brain never develops that part of your cortex,” he says. “Pain is a coach: a way to teach you about potential harm in your environment; a way to drive your motivational system so that you can avoid danger.”
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In truth, most of us need pain to learn and survive. According to social psychologist and author Dr Brock Bastian, we need pain to feel happiness. “We need pain to provide a contrast for pleasure,” he writes. “Without it, life becomes dull, boring and downright undesirable.” But Jo’s personal chemistry seems to help her override this hard truth.
But she is by no means unique in being unable to feel pain. For decades scientists have studied pain-free people in the hope of understanding pain better. Many have had a group of diseases called HASANs (hereditary sensory and autonomic neuropathies), which means that their nociceptors – the nerve cells that send pain signals to the brain and spinal cord – do not function properly. These conditions have a genetic source and run in families.
But recently researchers using gene-sequencing technology have been able to trace other genetic characteristics that aren’t associated with disease or damaged pain-sensing cells but which seem to influence the signalling of pain in all of us.
Dr James Cox, senior lecturer at UCL, is among the leaders in this field and over the past 15 years has worked with families who have inherited pain insensitivity. In 2006, he was part of the team that found three families from northern Pakistan who were completely immune to pain because of a mutation to the gene called SCN9A, which regulates a nerve-signalling mechanism called sodium channel Nav1.7.
More recently he studied a pain-insensitive family in Italy and found that a mutation of a pain signal regulating gene called ZFHX2 was responsible.
Together, the research suggests that genes affect our pain in two ways: by regulating the amount of natural painkillers in our system, and by regulating the chemical and electrical channels along which pain signals are transmitted.
Each time such research has been publicised, more pain-free people have come forward. Since discovering the families in Pakistan with the SCN9A mutation, more families around the world have been found with the same characteristic. Since Jo’s case was publicised in the UK in March 2019, 80 families have contacted Cox saying that they have similar experiences and volunteering to be researched.
“We’re working through those now,” he says. “The common theme is they all have extreme pain insensitivity so I’m hopeful that when we get the DNA in for these guys we’ll find further families for research.”
The rush of new volunteers is important because it may indicate that being pain-free isn’t as rare as once thought. “There are potentially countless people who have similar experiences to Jo,” says Cox. “It may just be that genes or mutations haven’t been found.” But it’s also opening the door to finding other genes that are important in the pain system and could lead to new and better targets for pain relief. “There’s a massive need for new painkillers,” says Cox.
Prof Geoff Woods and a team from the Cambridge Institute for Medical Research studied a group of 196 women who didn’t request or require analgesia during their first labour, finding “a significant overrepresentation” of a rare, but by no means one-off, variation in the gene KCNG4. The genetic variation seems to affect pain channel signals from the sensory neurons in the uterus.
Many existing painkillers – opioids, for example – are essentially sophisticated versions of herbal medicines. They’re not carefully targeted on pain and so are tricky to dose, which can lead to addiction, overdose and unpleasant side effects. At the same time, around one in five people is living with chronic pain and for some, pain won’t fade whatever medications are used.
So the pharmaceutical industry, aware of this and the publicity surrounding an opioid addiction epidemic, is paying close attention. Drug companies have picked up on the significance of the SCN9A mutation and have been investigating specific blockers of sodium channel Nav1.7 as possible new targeted painkillers.
The multifaceted nature of pain
Eccleston says there’s no doubt that the genetics of pain has, until recently, been under-researched. “It’s still a very small part of what people are doing because, although we have new methods to examine the genetics, pain is a tremendously complex system, and it’s still difficult to know where to look for the right pain transduction mechanisms.”
What’s important, he says, is that in the search for cures for pain that won’t go away, genetics is not looked at in isolation from other contributors, such as stress, environment, psychology and age. The new field of epigenetics – the way that our environment changes the way our genes express themselves – is also crucial, he says.
“We need to know why some people develop refractory pain, whether there’s a genetic predisposition to that and what makes that predisposition express itself,” he says.
On a human level, perhaps what’s most intriguing about the hundreds of pain-free people turning up around the world is that they exist at all. On the face of it, there is no evolutionary advantage to feeling no pain. It increases the risk of injury from cuts, blows and knocks that cannot be felt. Life is likely to be short, because the brain is less likely to learn self-protection strategies.
Yet here is Jo, approaching old age, active, healthy, bubbling with enthusiasm for life and feeling just as she always has, that living without pain is normal. That’s all that millions of people in constant pain could ever want. And Jo feels her genes may be able to help them: she’s happy to keep stepping into the public eye to promote the research, to ensure it continues. “It’s unbelievable, all the interest,” she says. “I’m a very ordinary person.”
- This article was first published in the June 2019 issue of BBC Science Focus Magazine – subscribe here.