Pain Sensitivity in Twins
There’s a real need for these new type of drugs and epigenetics
Well, there are hundreds of examples, but pick a trait like pain sensitivity. All of us say we’ve got different pain thresholds, different people are super macho, others a bit wimpy. Ten years ago no one really knew whether this was maybe the way you’re brought up or cultural, you know, your mother sort of…if you complained, gave you a clip round the ear and said get on with it, or did they start blubbing and say, you know, that’s so terrible, go and lie down and have some sweeties; did that influence you more than any genes?
We did a study to look at this using our twins, where we did a mini form of torture really, putting little heat electrodes on them which heated the skin up at 40 degrees very slowly and asked them to say at what point it became either painful or unbearable. And it was very interesting because some twins, basically as soon as you put the electrode on they said, ooh, that hurts, the real wimpy ones and others, basically you could smell the skin frying and they wouldn’t worry about it. So you had this huge range and a bit of competition between the twins as well, which we’ve seen several times: we did the same test on TV with some twins and cold water and they were basically fainting before they’d admit the other one would win.
Basically we did this study that showed that your pain sensitivity had a moderately strong genetic component: it was around 40-50%. The rest of it was either culture or random effects or your individual life experiences. So we then said, let’s try and find out what the genes are that underlie this. So we did some experiments and basically got lots of non-identical twins together and looked at which segments were linked together – it’s called a linkage study – it didn’t help us much but we just said, well, these bits are linked, we don’t know how many genes, there’s too many genes in there. So we tried another approach with this latest technology which is these snips, where we basically add half a million snips per person and once we did that…did this in several thousand of the twins we could narrow the signal down where people with high sensitive versus low sensitive, we could tell a slight difference. So this gave us about ten genes or so that we knew were different.
So we said, OK this is really good, and some of those were very interesting to the drug companies because they could say “we’ve got some drugs that do actually influence these pathways” and that shows us really that that’s one of the power of genetics to link it to a biological system, so you find something a bit…what seems to be unusual or odd and you say, what does that gene do and they say oh, I don’t know, we’ve got a drug somewhere that links to that, so we can use that.
So that was a few years ago, so we found these but each one had a very small effect. So if you remember, they weren’t very good at predicting how you would respond. Basically, I could say you have a 20% more or 20% less chance depending on your genes. But we know that they’re useful in designing drugs, so that was good. Then we got the idea of actually looking at the epigenetics of the conditions, so we say, we’ve gone as far as we can do with finding these genes, but what if you can actually influence those genes, can you switch them on and off? Because if you could that would be a pretty good treatment because at the moment, we’ve hardly got any painkillers that work that don’t have horrible side effects and we haven’t really invented any new ones for about twenty years.
So there’s a real need for these new type of drugs and epigenetics, basically the idea by which you get chemical signals in the cell which can switch your genes on and off like a dimmer switch. So they work in lots of different ways, some by attaching another chemical group, others by changing the folding of the chromatin which holds all the DNA together, opening it and closing it a bit like a lock. Anyway we decided to do this study and the best design is to take identical twins where one has a high pain threshold and the other has a low pain threshold. So we did study thousands of twins and we got our, if you like, our top fifty pairs that were a bit unusual, they were different, so we said, if we look at this particular group, it’s a bit like finding a needle in a haystack, we can actually pick out what the differences are in those genes. And again, because we have this fantastic technology which arrived about three years ago we were able to start looking at 20 million sites on each person, looking to see whether these chemical switches were on or off at these places. And we found that where they were definitely more on than off in the high sensitive twins was often in the same pain genes that we’d seen in the other study. So it looks as if we’ve found that the same genes that give a susceptibility to pain, we can also influence them so we can change actually how much pain we feel, we can switch them on or off in a reversible manner that lasts perhaps anything from months, years, and some people believe can actually cross generations, and the fact that it’s reversible means that you can get drugs to do the same as well as just what’s happening to us in our normal lives. So that’s an example of where we are, having taken something from understanding is it worth studying in the first place, is it heritable, can we find some genes, let’s look at the genes and the next level, lets see how those genes behave even when it’s the same gene, it might work differently in different people and that’s exactly what we showed. So that’s a good example of taking something from beginning to end over the course of about ten years.