People who don't Feel Pain
Chris - Geoff recently published a paper on people who seem to congenitally, in other words have a genetic preponderance, not to be able to feel pain. So tell us about these people.
Geoff - We came across a bunch of children who were reported never to have felt pain. At first we didn't believe that this was the case, but we slowly saw a number of these children and they and their parents reported that they'd never felt pain of any type throughout their lives; whether they'd fractured bones, burnt their skin, scalded themselves drinking boiling water. It was a huge problem for the parents bringing these children up and later on for these people for when they became older children, teenagers and later adults. Furthermore, there was nothing that we could find wrong with their nervous system. They had normal intelligence, they had normal nerves, the nerves seemed to conduct signals normally, their brain seemed to be put together normally, and it didn't make any sense by the current theories of how pain is controlled. So we set about trying to find if there was a genetic disease that they had, because it wasn't all people in the family that were affected by this condition; it was just some members. So we used three families where the parents were first cousins, so-called consanguineous relationships. Using those three families we mapped the condition down to a gene called SCN9A, and in each of our three families we found a different fault in that gene that abolished its normal function.
Chris - Where is that gene turned on? What cells carry that gene and switch it on?
Geoff - It's not entirely clear at the moment. It's probably expressed in a number of parts of the brain and in a number of different types of nerves, but it's very highly expressed in the pain sensing nerves. It probably has a redundant function elsewhere, but in the pain sensing nerves it seems to be expressed only at the very tips of those nerves and it's at the tips that pain is sensed.
Chris - So what does it do? How does it work?
Geoff - All pain is tissue damage, so it's very important that a species knows it's being damaged and can stop itself from being damaged. It seems there are a whole series of proteins that detect various types of damage, be it hot, cold, pressure, etc. These seem to be integrated together by this SCN9A, which seems to be an amplifier that takes these small initial tissue damage signals and turns them into a much larger sodium impulse and a nerve can fire. The brain can then sense that there's tissue damage going on and avoid it.
Chris - So it's almost like an engine. You turn the key but the engine doesn't start, and what you've got in your nerves is lots of starter motor activity but there's no firing of the engine.
Geoff - Absolutely right.
Chris - So why should these families have this? What's happened? Where did this change come from?
Geoff - I guess it's just the random mutation that happens in the human genome. Unfortunately if the mutation happens in an essential gene, it's going to give rise to damage.
Chris - Why is it so uncommon?
Geoff - I don't know. Some diseases are desperately rare and some are common. We usually use the excuse that if the disease is common, there must be some benefit to carrying that disease, but it's very unclear. Probably this gene's very important and any mutation in it is not well tolerated and is usually got rid of as time goes by.
Chris - Now you mentioned that the people who you spotted that had this problem couldn't feel any pain. They had inbred within their families so that means one person was carrying one dodgy copy of the gene and they got together with someone with another dodgy copy. When you put the two together, you end up with two dodgy copies of the gene, which is why they can't feel pain.
Geoff - Yes, that's absolutely right. We all have two copies of most genes. Just having one faulty copy is fine because as long as you've got one good copy of the gene telling the body what to do, everything seems alright. The parents of these children have no problems at all with their pain sensation.
Chris - But what I'd like to ask Geoff is that if you normally have two copies of this gene and they're working and switched on, does this mean that if I married someone who has one copy working and had children with them, that you'll get kids that only have one copy of the gene working and therefore they'd be less sensitive to pain than I would be?
Geoff - No that doesn't seem to be the case. Most diseases like this are called recessives and carriers of recessives are very common in the general population. Carriers have no minor features of the disease they carry; they're just normal. So we don't think it matters if you carry a fault in this gene. We have extended our studies as we discussed prior to this programme, looking at changes in the gene that occur called SNIPs - variants that go in almost all genes.
Chris - So that's just natural variation people have in the population. It doesn't switch the gene off, it just means it maybe works slightly differently from one person to the next.
Geoff - Well we've asked that very question. Is there any link between the degree of pain people feel and changes in this gene which occur in the normal population. And it seems that this gene is one of about three or four genes where small changes in its function change our pain thresholds.
Chris - So if you've got a gene that only seems to make a difference to your nervous system when it's in a pain-conveying nerve fibre, does this gene explain why some people for instance have an incredibly high pain threshold, while other people seem to wince at a gnat flying past them?
Geoff - I think it does and it could be one of the explanations. There's a number of genes now that have been found to alter people's susceptibility to pain. Initially people were thought to lack moral fibre et cetera, but it seems that there's a strong genetic basis to feeling pain differently. It's always been the case that some children cry when blood's been taken and people say that they're not being brave. Some women need a lot of pain control when they're having babies while others need very little. It now actually seems that these people have different abilities to tolerate pain.
Chris - What were the consequences for the people in Pakistan in the families you studied?
Geoff - Much greater than being rather stoic.
Chris - Because it seems rather exciting because when I go running, it's actually the pain of being grossly unfit that holds me back. Could these people become super athletes for example because they can't feel that they've got this heart-wrenching stitch and their legs are about to collapse and feel as though they're gasping for oxygen?
Geoff - We thought along the same lines as you, that pain was holding us back from being able to do better things. But in fact no, pain is actually there for a very very good purpose. Pain is telling you that you're working too hard and starting to cause tissue damage, and if you carry on you'll either break bones, tear muscles or fall down exhausted. These children and some adults we've now met with this condition have none of those restraints on their body and so they continually damage themselves.
Chris - They do dangerous things.
Geoff - Not necessarily. They don't deliberately do dangerous things. When they're children they'll do stupid things because they don't know to stop running into walls and jumping off high areas.
Chris - One of them jumped off a roof and died, didn't he?
Geoff - Yes that's right and he did that on his birthday because he'd had none of the restraints the rest of us have to stop us doing dangerous things. He was just trying to give his friends a great show on his birthday. We've met some adults with this condition now and they'll tell terrible stories about the types of injuries they've put up with because they didn't want to not go on a school trip or appear unusual, and yet they'd have broken major bones and not be able to stand up. They'd have burnt their lips on boiling water.
Chris - They'll do things like walk on fire, and literally do it without any jiggery pokery or tricks. They can walk on hot coals and things.
Geoff - They will and they won't feel pain, but they'll do as much damage as if you did it.
Chris - So we've proved that it can be bad if you have all your pain turned off all the time, but it strikes me that you've found something incredibly interesting because there are lots of people who in their lives have to go through incredibly painful things. Anaesthetics are not brilliant, are they? They're very non-specific, they cause lots of side effects and if you take things like morphine or heroin for pain killers they can switch down your heart and breathing so that people die of heart and respiratory depression. If you've got something that has the power to inactivate just this part of your nervous system, can we exploit that to make an amazing drug?
Geoff - I certainly hope so.
Chris - You have a patent on it already I suppose!
Geoff - No we don't have a patent on it at all. We haven't exploited this result at all and are interested in it academically. Others hopefully will and I know that drug companies are already looking at this sodium channel and many other similar ones. The hope is that if people who have none of this protein feel no pain but don't have other side effects, then if you block this protein in a normal person, they'll have a pain killer without side effects. That's exactly the hope that drug companies are now working on.
Chris - Is that feasible?
Geoff - We think so. The problem is that there are about eleven of these sodium channels and they are very similar to each other. So the problem's going to be getting drugs that are totally specific to just one of these sodium channels and doesn't spill over and block other sodium channels.