What is the importance of this study, and what potential is there for having an impact on the study of other diseases and possible cures?
Classic trigeminal neuralgia is a terrible enough condition in its own right. Although there are treatments, I think that the first group this could help is people who’ve got the condition, and either the treatments haven’t worked for them very well or the treatments that are available, the drug treatments in particular, make them foggy-headed and not able to perform. Side effects can be fairly severe sometimes. So there’s that group of people who need help. But I think it goes a lot beyond that, and this is what interests me the most.
Trigeminal neuralgia is one of a much larger class of pains that are called neuropathic pains. These pains are paradoxical from the beginning – the whole family of them. We don’t really understand what’s going on with them. And I believe there are many things in common in the underlying mechanisms of all these neuropathic pain conditions. Classic trigeminal neuralgia has certain features about it that make it an excellent place to search for mechanisms. That’s why I think the importance of this particular genetic study goes beyond just understanding classic trigeminal neuralgia, even though that’s a good enough reason. I think it has much more importance in understanding the underlying science, which can help not only trigeminal neuralgia patients, but maybe an awful lot of other facial pain patients, and patients with other kinds of pains as well.
How are you going about doing this research, with its focus on DNA?
We have good reasons to believe that there’s something special in the DNA in people who have trigeminal neuralgia pain compared to those who don’t. It turns out – and this is something we’ve actually known for a long time, but it’s become more and more clear as the years have gone by – that an awful lot of people have the pathology, the nerve injury, that is characteristic of trigeminal neuralgia. But of those people, a very small fraction actually have the pain. We don’t really know what the difference is, why a lot of people have the injury, but very few of the people with the injury have the pain. But we have good reason to believe that the difference might be genetic.
So the idea is to look at the genes of people who have the pain and make a comparison to people who don’t have the pain, in the hope that we detect some consistent difference – that is, a genetic difference that’s common to a lot of the people with the pain and isn’t present, or is rarely present, in people without the pain. That will point to the genes involved, and the genes involved will, we hope, point to the neural mechanism.
Why did you decide to focus on pain in your career?
I began in neuroscience not studying pain but studying pleasure centers in the brain. You may have heard that if you stimulate certain places in the brain a pleasurable sensation is created. We know that from animals, and it’s been tested in people as well. From there, I went on to motivated behavior, behavior that we do because it’s pleasurable – feeding, drinking, sexual behavior.
My doctorate was on the sense of smell, and pheromones in animals – smells that turn animals on sexually. At the end of my Ph.D. studies I decided that I very much wanted to continue working on something that had to do with juicy, emotional things that have an element of good and bad. But I didn’t want to continue with the sense of smell, despite its obvious importance for animals. There may be some hidden importance for humans, but I think it’s fairly minor.
I wanted to find something that involves "affect", that has an emotional texture to it, but that has more relevance to the human condition. I looked around and decided that pain is probably the best of those. There are some others – addiction is a condition that’s related. But I chose to go into pain because there’s such an urgent clinical need. And it struck me for a variety of reasons that we could make more progress on this one than on others.
Some research reviewers believe that people of your professional stature should be researching cures for diseases that cause death, like heart disease or cancer. How do you respond to such thinking?
First, I’ll take that as a compliment – “people of my stature.” Death is certainly something that we don’t want to happen. But it’s something that’s going to happen anyway, and the best we can do is sort of push it off. The major diseases that kill people – cardiovascular and cancer – have received an enormous [research] investment. The war on cancer’s been going on for many decades, extremely well-funded, and led by the best brains in the world.
It’s true that not a lot of people die of pain. Some do. Suicide happens, if not that infrequently. But an awful lot of people die in pain, including people with cardiovascular disease and almost everybody who eventually dies of cancer. And a much larger number of people live in pain. So I think it’s critical, as in every other part of our lives, to be thinking not only of how many years you can chalk up but the quality of your life while you’re living those years. And I think that’s where the urgency and the essential interest in pain lies. I personally would be willing to trade some number of years at the end for better quality of life earlier on, especially if I’m suffering pain. And my guess is that most people would be willing and happy to make that trade.
Some trigeminal neuralgia patients are fearful that we may never find a cure, and are fearful to try risky surgeries. What encouraging words do you have for those people?
As you know, there are treatments that are not surgical. They’re not as good, and they have side effects. With trigeminal neuralgia – although it’s considered one of the worst of the chronic pain states – unlike with a lot of other chronic pain states, at least there’s something that can be done. But even if this research does not come up with a cure within the life span of people who are now suffering from trigeminal neuralgia – which is possible, as we have no guarantees – I think there’s a way in which people with trigeminal neuralgia will benefit. There is something they can take home just by knowing that this research is being carried out, that can be valuable for them, and for their lives.
One of the things that often happens with chronic pains is that people are stigmatized, by their friends, by their employers and by society in general, “I don’t see anything wrong with you, why are you complaining so much that your face hurts? Your face looks OK to me.” There’s an implication – not just with trigeminal neuralgia, but also with many other chronic pains – that you’re lying, you’re exaggerating, you’re trying to cheat the system, you’re trying to get out of doing your work, you’re trying to get somebody else to do the dishes. There’s a stigma placed on people, which of course is extremely unfair.
There is comfort if somebody knows that this is not their fault. That it’s not because they have a weak personality. It’s not because they’re unable to face life the way other people are able to face life. It’s just the bad luck of the genetic draw. Just knowing this can help. We make a lot of choices in life but we don’t choose our parents and we don’t choose the combination of genes we’ve inherited. So the simple knowledge that it’s not your fault – I think that in itself can help.
How did the development of this research project come about, and what motivated you to take on the leadership role?
Well, I was invited to take on the leadership role, but I can tell you how I got into the subject. It happened very early in the game. When I first decided that I wanted to study pain, I came to the person who was probably the leader of the field at the time. He’s no longer with us, Patrick Wall, a brilliant, very creative guy. One of the first things I learned about pain – I knew very little about it up until then – is that pain is incredibly variable from person to person. Pain varies even when you’re talking about the same nerve injury – let’s say an amputation, where you know exactly where the level of the amputation is, and you know that the nerves were injured basically identically from one person to another. There’s incredible variety, where some people have severe chronic pain and others have no persistent pain at all for the same injury. Pat himself was very interested in that and had done a research project on amputees from the 1973 Israeli-Arab war.
So the subject of variability came up, and we talked about why that might be, and we decided it might be possible to ask the question, could this be genetic? So one of my first studies after leaving graduate school and coming to live in Israel was to compare animals that had a lot of pain behavior against those with little. In the same way that people have a lot of variety, animals do too. We chose rats that had a lot of pain and other rats that had very little pain. And then we just bred them together and looked at the offspring. And after three or four generations of selective breeding it turned out that all the babies from parents suffering from pain had pain. And all of the ones that were bred from parents that had no pain, they had no pain. This clearly showed that there is a genetic signal. We proceeded along that line to work out more and more about what genetics might be doing - what is the basis for the variability.
I think that in trigeminal neuralgia there probably is an important genetic basis, but I think that’s probably true of all the neuropathic pains. The trouble with most neuropathic pains is that if you have an amputation, for example, the chances of having severe pain are maybe 30 percent - a third of the people have it, a third of the people have less pain and a third of the people have no pain or very little pain. Finding genes in that situation is difficult.
It’s much easier to find genes [as with trigeminal neuralgia] when a very small percentage of the people with the injury have the pain, because there’s something that really stands out with them. And the hope is that we’ll be able to find it.
In addition to studying rats and mice, we have some data from humans – from women who underwent mastectomy, breast removal because of cancer, which also causes neuropathic pain in a fair fraction of the women. After finding a gene that is relevant to amputation, to nerve-injury pain in mice, we tested whether this gene might be relevant to women who have chest pain after mastectomy. And it turns out that it is. That’s work I did with Ze’ev Seltzer, who’s my friend and genetics partner on this project. He continues to be interested in post-mastectomy pain in women, and even more so in post-leg amputation phantom limb pain. He’s in addition agreed to take on a guidance role in the genetics part of the trigeminal neuralgia project.
The Facial Pain Research Foundation is relatively new and very different. Why have you gotten involved with this organization rather than a research organization that is more established?
The reason I got into it is there was a conference a year ago in Miami, funded by the International Association for the Study of Pain, the biggest international organization in the pain field. They funded the first-ever conference on pain genetics. I was asked to give one of the opening speeches. As part of my comments, I mentioned that trigeminal neuralgia is in my opinion an excellent venue for studying pain genetics, and that this has never been done. Joanna Zakrzewska [of the Facial Pain Research Foundation] was in the audience. She picked up on that, brought it to the foundation, got back to me and asked me specifically if I would be willing to organize, to put together a plan for a specific project on genes that predispose to trigeminal neuralgia. That’s how it all began.
After you find out about the "gene" or "genes," the DNA, what happens next? Do you visualize people taking a pill or a shot or do you visualize invasive surgery?
There’s a long way to go between identifying the gene or a couple of genes and an actual treatment. But how long is really something that’s impossible to predict. It depends completely on what the gene is and whether it fits into our notions of how pain works. If it’s something we know about, it could be that a new treatment proposal will come fairly quickly. But maybe it’s something that’s totally different. A gene that we never before realized had anything to do with pain. That might actually be the biggest advance, because it could open entirely new chapters in our understanding of pain. But it would probably put the treatment off a little bit longer.
I should add that from having a drug candidate to having a drug on the market that people can go into the drugstore and buy often takes an awfully long time in itself. So I think it’s unrealistic to be expecting a new treatment in the short term, unless there’s a drug that’s already available, and being used for something else, that could also be helpful for face pain. That’s of course how we got the best drugs we have now for trigeminal neuralgia. People still use Tegretol as the No. 1 treatment for trigeminal neuralgia, and Tegretol was not developed for treating trigeminal neuralgia. It was developed as an anti-epileptic drug and it just happened to be really good for trigeminal neuralgia. So maybe there’s some drug from psychiatry or from cardiovascular disease, from some other direction, that acts on the same receptor or the same biological mechanism as trigeminal neuralgia, and is just sitting there waiting for somebody to try. There are so few people in the world with trigeminal neuralgia that to find one who happened by chance to take a drug that was meant for some totally different disease, and hope he would have noticed that this also helped his trigeminal neuralgia, may be too much to ask.
So there is room for optimism, but I wouldn’t go overboard on that.
Supposing your theory and project is proven successful. What implications or lessons will this work provide for other researchers?
For one thing, it would encourage people to do more work on the genetics of diseases in general. For the very rare Mendelian conditions, conditions that are caused by a single DNA mutation that has a very powerful effect [Cystic Fibrosis, Tay-Sachs disease], it was quite easy to find what the gene is. In many cases, when the gene was discovered, people understood why that gene would cause that disease. When it comes to more common and more widespread diseases, like migraine, schizophrenia, Parkinson’s, things of this sort, it’s been harder going. It turns out that sometimes there are many genes that contribute, each one contributing only a little bit.
I wouldn’t say things are getting pessimistic, because progress is being made, but the projects that find genes that are really interesting turn out to be very large and very expensive. . I personally think that trigeminal neuralgia may be an exception, for the reasons I’ve already mentioned. So if we succeed it might encourage people to look for other exceptions of that sort, other opportunities. We’re not expecting a Mendelian gene, where if you’ve got it, your kids have it – but there may be other circumstance where one can make quicker and less expensive progress toward the cause of disease. Success would probably encourage the field of medical genetics in general. Certainly it would encourage pain genetics, which is still in its infancy. As I mentioned, it’s only a year ago that the very first conference on this subject was held.