Dr. Allan Basbaum is professor and chairman of the Department of Anatomy at the University of California San Francisco. A neurobiologist, he is recognized worldwide for his work in understanding the mechanisms that contribute to the development of chronic pain, particularly the neuropathic pains produced by nerve injury, a condition that he considers a disease of the nervous system.
He is an expert in the use of neural stem cells to alleviate neuropathic pain in animals and has been rewarded by long-term funding of his research by The National Institutes of Health. He believes that his research has demonstrated that it is possible to repair damaged neural circuits. His work will have major consequences for neuropathic pain, including trigeminal neuralgia and related conditions, phantom limb pain and the pains generated in the course of cancer chemotherapy.
Dr. Basbaum spoke by telephone from San Francisco with Mervyn Rothstein, who was an editor and writer at The New York Times for 29 years before retiring in 2010. Mr. Rothstein is now a columnist for Playbill Magazine, where he writes the “A Life in the Theatre” column. He has had trigeminal neuralgia since 2005.
MR: Why did you decide to focus on pain in your career?
That’s an easy one. It was the need for a summer job when I was a student at McGill University in Montreal. Now you’ll figure out how old I am, but I was trying to get a job at the [1967] world’s fair in Montreal. I was on the waiting list to get a job at the fair, which everybody wanted, and I couldn’t wait any longer. And I saw an advertisement for a summer research assistant, not at the fair but in the lab of Ronald Melzack. I had taken a course with him, and I got the job.
He’s one of the godfathers of pain research. He and Patrick Wall had published a major paper in 1965 called “Gate Control Theory of Pain,” which revolutionized the way people thought about what causes pain, why chronic pain develops. They argued that pain is not produced exclusively by the activation of “pain” specific nerve fibers, but rather by the balance of activity in different types of peripheral nerve fiber, small diameter nerve fibers that respond to painful stimulation and large diameter fibers that, in fact, respond to innocuous stimuli. The latter nerve fibers have the capacity to regulate pain produced by the small fibers. Gate Control Theory provided a new perspective not only on ways to regulate pain (i.e. by increasing the activity of the large diameter fibers) but also on a mechanism for the generation of neuropathic pain (i.e., dysfunction or frank damage to the large fibers). My summer job in the Melzack laboratory started my research in pain mechanisms, and I’ve been doing it ever since. If I had received a job at the world’s fair, I might be doing something different.
MR: What led you to believe that pain is a disease?
Well, I wouldn’t say that all pain is a disease. I refer more specifically to neuropathic pain, namely pain associated with nerve damage. There’s clearly persistent pain that results secondarily from a particular disease, for example, arthritis. You have inflammation in the course of severe arthritis, and the inflammation causes pain. We understand some of the mechanism by which arthritis causes it. If you weren’t able to treat the arthritis, the pain wouldn’t go away. So arthritis is the disease. Cancer that hits tissue causes inflammation and the tissue damage causes pain. If you could get rid of the tumor the pain would probably go away.
Neuropathic pain is different in that the damage is to the nervous system, and the only consequence is pain, so in a sense the disease is the damage to the nervous system and thus pain, in effect, is the disease that needs treatment. The nerve damage could occur after spinal cord injury, it could be peripheral nerve injury, or more specifically it could be trigeminal neuralgia. We’re not quite sure what the nature of the nervous system damage is with TN but there has to be some pathology in the nervous system. That is TN’s feature – its main feature is pain. That’s it. So you can try to treat the pain by suppressing it with drugs, sort of damping it down, but you’re not really treating the underlying pathology. It’s different if you use an anti-inflammatory drug in a patient with arthritis. You can help the arthritis and coincidentally the pain gets helped. But in the case of treating trigeminal neuralgia, when you give a drug you’re not treating the underlying condition at all. You’re suppressing its manifestation. Our approach is to say, all right, is it possible to actually treat the condition itself, namely the disease itself, whose only manifestation is pain? That’s our objective, to repair the damage.
Neurological associations will probably never accept this notion. They have very specific criteria for what is a disease. But I also think that it’s very important for the public to understand that there is a disease element to this type of chronic pain. The public generally thinks of disease as things that kill you, like cancer, like MS or Alzheimer’s, where you eventually die. And so their focus is understandably on the disease and not the aspect of the disease, which is often pain that ruins a person’s life. People don’t die of pain, but they often die in pain.
The public needs to understand that if you could address the chronic pain problem in individuals that have these other disease conditions you will dramatically improve their quality of life. In other words, rather than just focusing on the arthritis or the cancer, it is critical to also address the pain. What ruins people’s lives is the pain. People don’t realize that individuals with spinal cord injury who are in a wheelchair – if you look at them and you are empathetic because they’re paralyzed and you think that that’s the major problem they suffer, they will tell you it’s terrible that they’re paralyzed, but 70 percent of them have horrific pain that ruins their lives, perhaps more so than being in a wheelchair. If you can get rid of their pain they would be so much better off. But nobody sees pain so they don’t recognize it. I think if we explain to the public that chronic pain is a disease, an entity in itself, especially neuropathic pain, they will be a little more understanding and perhaps more committed to solving the problem.
MR: What is the importance of this trigeminal neuralgia research study, and what potential is there for having an impact on the study of other diseases and possible cures?
Trigeminal neuralgia, No. 1, is to many people considered the worst pain you can have – not that any pain is good, but trigeminal neuralgia is one of the most debilitating.
No. 2, we believe because it’s responsive, like other neuropathic pains – sometimes, not always – to anticonvulsive drugs, it is really a condition in which there’s loss of inhibition, so that the central nervous system is hyperactive, as it is in epilepsy. We use an anticonvulsant to reduce the hyperactivity. If that is the essence of the disease, it might be possible to repair, literally rebuild the nervous system and overcome the loss without using drugs, which even when they are effective often have horrible side effects. That’s the big problem – drugs can be good, but it’s very difficult to come up with a drug to treat these kinds of conditions without having side effects that make patients miserable.
So the idea here is to literally repair the nervous system. And that’s the approach we’re taking. We believe we can use transplants of precursor, so-called progenitor cells that have the capacity to develop into inhibitory nerve cells and reconstitute the inhibitory controls that are missing. In the course of our studies, I have not only been excited at our ability to treat animals that manifest hypersensitivity in models of neuropathic pain, but am also overwhelmed at how plastic the nervous system is. The adult nervous system will accept these transplants and the cells will integrate into circuits. The host nerve cells make synaptic connections with the transplanted cells, i.e. communicate with the cells, and the transplanted cells make connections with the host. As far as I can tell the new circuits are permanent. We’ve now gone at least six months and shown that these cells continue to make beautiful connections, so that it really is possible to take advantage of the plasticity and malleability of the nervous system. And in that sense we are really targeting a cure, not just some salve. We are not just trying to suppress the pain – we are actually trying to treat the condition that generates it. That’s why I’m so excited about it. And trigeminal neuralgia is one of many neuropathic pain conditions that I believe would be particularly amenable to this approach.
MR: Are you developing the cell-replacement therapies to be used clinically to treat neuropathic pain (including trigeminal neuralgia) or are you using them as a proof-of-principle preclinical research tool?
Well, at the moment it’s preclinical, but the success we’ve had is incredibly encouraging. We began in the mouse because we were using embryonic cortical cells as the source of the transplant. These are cells from the brain of an embryonic mouse that we know are the cells that normally make all the inhibitory neurons in the cerebral cortex. Although these are not normally destined to become the inhibitory neurons in the trigeminal nucleus or the spinal cord, they will survive and grow in these regions. And of course, they form connections and importantly can treat the mice in models of neuropathic pain. It’s a model that we believe mimics what is happening in the human with neuropathic pain.
So that is the first step. And that is a proof of principle, a very exciting proof of principle. Then the next step, which we’re doing, is using embryonic stem cells that have been modified to become inhibitory neurons. Here we’re talking about a human cell, human embryonic stem cells. And we transplanted them in the mouse, and they survive, grow and are functional. We have to use immunologically suppressed mice otherwise the mice would reject the human cells. So now we have proof of principle that human cells can be effective in an animal model of the human condition.
What’s the next step? To get the cells to a state where you can actually reach the quality where you can transplant them into a human. There’s no question that our objective is to take this into the clinic.
Somebody inevitably asks: when is this going to happen? I don’t answer questions like that because I honestly can’t predict. But is that our objective? Unquestionably. We’re working with the stem cell people at UCSF to get these cells to a condition where they can be used clinically, and I’m much more optimistic than I’ve ever been that we’ve got a handle on something that can work. It’s because of the remarkable ability of the nervous system, of its circuits, to be manipulated. I really didn’t think that the system was that plastic, but it is. The adult brain and spinal cord will accept those cells, I think in a therapeutic way.
MR: This question is something you just alluded to, but when do you envision (or hope) that cell-replacement treatments for neuropathic pain (including trigeminal neuralgia) will be ready for use in humans?
As I said, I can’t predict the future. There are so many steps hurdles that have to be crossed. The first thing is to get the cells to a state where the Food and Drug Administration would accept a transplant. That’s more a stem cell expert issue. We use the stem cells that our colleagues provide to us. They continue to address this need and of course the whole stem cell field is growing at a tremendous rate. So I don’t think it should take too long to get the cells to that stage. Stem cell therapy is being used very preliminarily in other conditions now, and I think it’ll grow exponentially within the next five to ten years. With respect to chronic neuropathic pain we believe that we understand how the cells can be used and where they should be transplanted. So in my mind the major barrier is to get the stem cell people to tell us that yes, these things are ready to be put into people. We believe that the therapeutic proof of principle is established and that the fundamental biology, between what we’ve seen preclinically and what we believe occurs in humans, is solid.
I am confident that the neurosurgeons are ready to take this to the clinic. They know about the work and are following it closely. I’m going to give a talk at the annual meeting of the Society of Neurological Surgeons. They recognize the need for a novel, exciting and feasible approach and want to learn more about what we are doing. But will it be next year? No. Five years? Possibly. I really don’t know.
MR: Perhaps you’re already answered this question, but what are the biggest obstacles you face in translating your preclinical findings to the clinic?
It has to do with the quality of the stem cells, to be sure that they meet all the standards to put into a human. One needs to demonstrate unequivocally that the cells don’t become tumors, because there’s certainly an ongoing concern that some stem cells might become tumors. Our data so far says that the stem cells we’ve worked with do not become tumors. They don’t have tumor markers and are not proliferative. So that’s very encouraging. This is one of the major issues that one has to be concerned about.
Always, with any therapy, there’s the potential for adverse side effects. So far, we haven’t seen these in the animal models, but there may always be some unexpected adverse side effects when you use a new therapy. One of the first things, especially when you’re dealing with pain studies in animals, is that you don’t have motor side effects. We haven’t seen these so far – that’s encouraging.
We’re talking about a therapy meant to rebuild parts of the nervous system, so it’s always possible there will be unexpected side effects. We don’t anticipate them, but those are the things we need to watch for. One of the first things you want to know is not so much does it work but is it safe. This is key. You’re dealing with a patient who has a long life span, so safety becomes incredibly important.
MR: The Facial Pain Research Foundation is moving forward with a sense of urgency to find cures for trigeminal neuralgia and related facial pain. Why have you linked your efforts to such a new organization in the field of pain research?
That’s an interesting question. Why? I usually don’t answer ‘why’ questions, but rather where, how and what. I recognize that these facial pains are among the worst pains that patients can experience. I believe that the neurosurgical approach to therapy is very feasible in these individuals. And the neurosurgeons agree. So the type of therapy we’re proposing, namely using transplants is rationale to the neurosurgeons, particularly as the target for transplantation is known and accessible. These are places the neurosurgeons have gone in previously, and it’s a very doable procedure. It’s a very discrete type of pain, and the area that’s involved is quite localized, to one side. That’s also advantageous.
Contrast that for example with a patient with chemotherapy-induced neuropathy, which can be associated with terrible pain. But here, for example, it can be in both hands and the feet. That’s a systemic, widespread disease, because the drug acts everywhere. For this reason it may be very difficult to pinpoint the particular area of the nervous system that you want to treat. But in the case of trigeminal neuralgia and facial pains, the target is restricted. It makes sense to target something that is so focused, because then the cells can really do their job. It’s a very tractable system.
And the other reason is that I was impressed with the Facial Pain Research Foundation, and its enthusiasm to get financial support. Our lab is well funded; that’s great, but these are expensive studies. And as I said previously, the study of pain is not something that the philanthropic world tends to support. Families tend to support the diseases that kill their loved ones, even though the pain clearly destroyed their quality of life.
MR: Every day many people in pain are contacting the Facial Pain Research Foundation asking if it is truly possible to find a cure for trigeminal neuralgia. How would you respond to their questions?
Until we started this type of work, I would have said, “A cure, probably not; the idea is to come up with something that can ameliorate the condition better than what exists now.” Now we have a better understanding of the nature if you will of the neurological problem, of the damage that has occurred. As a result our approach is truly reparative, i.e. disease modifying. We want to rebuild parts of the nervous system, and in that sense we are trying to develop a cure rather than just to ameliorate. This is an unusual opportunity to dream of a cure rather than just palliative pain management.